9

Endocrine system

Diabetes mellitus 582 • Management 604 • Physiological principles of glucose and • Monitoring 628 insulin metabolism 582 Thyroid disease 630 • Epidemiology and classification 587 • Physiological principles 630 • Aetiology and pathogenesis 589 • Hypothyroidism 633 • Natural history 591 • Hyperthyroidism 637 • Clinical features 593 • References and further reading 643 • Complications 593

Endocrine control of physiological functions represents broadly targeted, slow acting but funda- mental means of homeostatic control, as opposed to the rapidly reacting nervous system. In endocrine disease there is usually either an excess or a lack of a systemic hormonal mediator, but the cause may be at one of a number of stages in the endocrine pathway. Thyroid disease and diabetes mellitus represent contrasting extremes of endocrine disease and its management. Diabetes is one of the most serious and probably the most common of multisystem diseases. Optimal control of diabetes requires day-to-day monitoring, and small variations in medication dose or patient activity can destabilize the condition. Therapy requires regular review and possible modification. Furthermore, long-term complications of diabetes cause considerable morbidity and mortality. Thyroid disease is a disorder of thyroid hormone production that has, compared to diabetes, equally profound overall effects on metabolic and physiological function. However, it causes few acute problems and has far fewer chronic complications. Moreover, management is much easier, requiring less intensive monitoring and few dose changes. Furthermore, control is rarely disturbed by short-term variations in patient behaviour. 582 Chapter 9 • Endocrine system

Diabetes mellitus

Diabetes mellitus is primarily a disorder of • Rapid: in certain tissues (e.g. muscle), insulin carbohydrate metabolism yet the metabolic facilitates the active transport of glucose and problems in properly treated diabetes are not amino acids across cell membranes, usually troublesome and are relatively easy to enhancing uptake from the blood. control. It is the long-term complications of • Intermediate: within all cells, insulin diabetes that are the main causes of morbidity promotes the action of enzymes that convert and mortality. People with diabetes suffer far glucose, fatty acids and amino acids into more from cardiovascular and renal disease more complex, more stable storage forms. than other people, and diabetes is the principal • Long-term: because of increased protein cause of acquired blindness in the West. Most synthesis, growth is promoted. people with diabetes do not die from metabolic One important consequence is the prompt crises such as ketoacidosis but from stroke, MI (though not complete) clearance of glucose from or chronic renal failure. the blood after meals. Glucose would otherwise Diabetes is associated with obesity and lack of be lost in the urine because of the kidney’s exercise, and the steady increase in prevalence limited capacity for reabsorbing glucose filtered in the West is being reproduced in large parts of at the glomerulus. the developing world as they adopt that life- style. Diabetes is in danger of becoming almost pandemic. Particularly worrying is the rise in the Glucose transport incidence of diabetes of both types in ever Glucose uptake into cells across the cell younger patients. This threatens to put an intol- membrane is dependent on the concentration erable strain on health services, particularly in gradient between the extracellular medium (e.g. developing countries. blood plasma, gastrointestinal contents) and the cell interior. However, because glucose is such an important metabolite, there exist a Physiological principles of glucose and number of membrane transport pumps or facili- insulin metabolism tators in certain tissues. There are special insulin-

Insulin action DIET

Insulin is the body’s principal anabolic typical body cell absorption hormone. It expands energy stores during times into plasma PROTEIN of adequate nutrition against times of food Plasma shortage. Opposing this action are several cata- AMINO AMINO ACID bolic ‘counter-regulatory’ or ‘stress’ hormones ACID that mobilize glucose for use when increased GLYCOGEN energy expenditure is necessary. The most Plasma important of these are adrenaline (epinephrine), GLUCOSE GLUCOSE corticosteroids, glucagon, growth hormone and growth factors. These two opposing systems Energy FAT work in harmony to maintain glucose home- ostasis. Insulin also enhances amino acid utiliza- Figure 9.1 Simplified scheme showing the anabolic tion and protein synthesis, the latter action actions of insulin. Insulin aids the uptake of metabolites into being shared with growth hormone. body cells and enhances the action of enzymes that utilize Insulin action has three main components them as precursors to synthesize more complex molecules. (Figure 9.1): Note: not all actions shown occur in all body cells. Physiological principles of glucose and insulin metabolism 583 independent sodium-dependent transporters down is inhibited. Tissue growth and cell divi- (SGLT) for uptake from the GIT into intestinal sion are also promoted by enhanced nucleic acid cells and a variety of insulin-dependent and (DNA, RNA) synthesis, amino acid assimilation insulin-independent glucose transporters (GLUT) and protein synthesis. for most other tissues or organs (Table 9.1). In muscle and adipose tissue the transporter Overall effect depends on an insulin-requiring active pump for glucose uptake, so insulin deficiency deprives Only a general appreciation of how insulin and them of glucose. Other cells, particularly in the the catabolic hormones control everyday meta- liver, brain, kidney and GIT, do not absolutely bolic variations is given here (see also References require insulin for glucose uptake, but diffusion and further reading). is nevertheless facilitated by it. In the liver, enhanced phosphorylation of glucose drives Anabolic actions of insulin intracellular concentrations down, encouraging Following a meal, glucose is absorbed from the uptake. Insulin lack does not deprive tissues such GIT into the blood and rapidly transported into as these of glucose; on the contrary, the hyper- the cells, to be converted into forms suitable for glycaemia associated with diabetes can produce storage and later use. intracellular glucose overload, and this may be In the liver some glucose is converted into responsible for some diabetic complications (p. glycogen and stored but most is converted into 593). This is particularly relevant to tissues such lipid (free fatty acid, FFA [or non-esterified fatty as nerves, which are freely permeable to glucose. acid, NEFA], and triglyceride). Lipid is released Insulin also facilitates the uptake of amino into the blood as very-low-density lipoprotein acids into liver and muscle, and of potassium (VLDL), to be taken up and stored in adipose into most cells. This latter effect is exploited tissue. However, the release of glucose into the therapeutically for the rapid reduction of blood is inhibited. Hepatic regulation of glucose hyperkalaemia (see Chapter 14). output is an important mechanism for limit- ing the uptake of glucose into tissues where transport is independent of insulin. Metabolic effects In adipose tissue, fat breakdown is inhibited By facilitating certain enzymes and inhibiting and glucose uptake promoted. The glucose others, insulin has wide-ranging effects on inter- provides glycerol for esterification with FFAs, mediary metabolism in most tissues (Table 9.2; and the resulting fat is stored. Adipose tissue also Figure 9.1). The synthesis of the energy stores takes up the fat-containing chylomicrons (glycogen in liver and skeletal muscle, fat in liver obtained by digestion (see Chapter 3). In muscle, and adipose tissue) is facilitated, and their break- fat metabolism is inhibited and glycogen is

Table 9.1 Insulin requirement and transporters for glucose uptake into different tissues

Tissues not requiring insulin Transporter Tissues requiring insulin Transporter

Gastrointestinal – uptake SGLT Adipose Gastrointestinal – release to blood GLUT2 Muscle – skeletal, cardiac, smooth · GLUT4 Liver GLUT7 Other tissues Nerves, brain GLUT1,3 Kidney tubules GLUT2, SGLT Eye – retinal vessels, lens SGLT Leucocytes GLUT Blood vessel endothelium GLUT Pancreatic beta cells GLUT2

SGLT, sodium-dependent glucose transporter; GLUT, glucose transporter. 584 Chapter 9 • Endocrine system

Table 9.2 Metabolic effects of insulin

Metabolite Process Tissue Liver Muscle Adipose

Carbohydrate Increased • Glycogen synthesis (glycogenesis) ✓✓ ↔ • Glucose oxidation (glycolysis) ✓✓ ✓ Decreased • Glycogen breakdown (glycogenolysis) ✓✓ ↔ • Glucose synthesis (gluconeogenesis) ✓ ↔↔ Lipid Increased • Fat synthesis (lipogenesis) ✓ ↔ ✓ • Utilization of dietary fat ✓ ↔ ✓ Decreased • Fat breakdown (lipolysis) ↔↔ ✓ • Fatty acid oxidation (ketogenesis) ✓✓ ✓ Protein Increased • Protein synthesis ✓✓ ✓ Decreased • Protein breakdown (proteolysis) ✓✓ ↔ Nucleic acid Increased • DNA and RNA synthesis ↔ ✓ ↔ • Cell growth and division ↔ ✓ ↔

✓, insulin has important effect (increase or decrease) on process in this tissue; ↔, no effect. synthesized, which increases glucose availability It will be explained below that obese type 2 for immediate energy needs. Amino acid uptake patients may not at first have an absolute defi- is promoted so that growth can be continued. ciency of insulin; rather, there is a degree of insulin resistance. This may be described as a Catabolic actions of counter-regulatory relative lack because the result is the same; more- hormones over, eventually their insulin levels do fall. There During stresses such as ‘fight or flight’, infection are important differences between the physio- or any major trauma, catabolic hormones reverse logical effects of partial (or relative) deficiency these processes. Blood glucose is rapidly raised to and total insulin deficiency. supply energy for the muscles and if this is insuf- ficient fats can also be mobilized. Peripheral Partial deficiency (type 2) oxidation of FFAs produces large amounts of energy, but in the liver excess acetyl-CoA is Even small amounts of insulin will prevent produced. This is condensed to produce high- severe metabolic disruption, especially acceler- energy ketoacids such as acetoacetate, which ated fat metabolism, i.e. ketosis. Thus, although many tissues can utilize in small amounts. In fasting blood glucose levels may be raised, the insulin insufficiency these ‘ketone bodies’ may main problems only arise after meals; these arise accumulate in the plasma, causing ketoacidosis. from impaired glucose transport and cellular uptake resulting in impaired clearance from the blood. Adipose and muscle tissue cannot take up Insulin deficiency glucose efficiently, causing it to remain in the blood, and glucose deficiency in muscle may The consequences of insulin deficiency, and thus cause weakness. Becuse other tissues cannot many of the clinical features of diabetes, can be compensate sufficiently to assimilate the deduced from these considerations (Figure 9.2). entire postprandial glucose load, the blood Physiological principles of glucose and insulin metabolism 585

Subsequently fat is mobilized, mainly from DIET adipose tissue, so that plasma triglyceride and typical body cell FFA levels rise, as does lipoprotein. These supply absorption energy needs for a little longer while the into plasma negative PROTEIN nitrogen patient loses yet more weight. The brain cells Plasma balance switch to metabolizing the hepatically produced AMINO AMINO ACID keto-acids. Fat stores are not replenished, and ACID eventually may be exhausted. Finally, protein GLYCOGEN must be broken down into amino acids, which Plasma can be converted to glucose in the liver (gluco- GLUCOSE GLUCOSE FATS neogenesis), at the expense of lean muscle mass. Other than in uncontrolled diabetes, this process Energy Urinary normally occurs only in times of prolonged star- loss Ketones Lipoprotein vation; it is a desperate remedy that is akin to burning the house down to keep warm. Further, without insulin, any glucose so produced cannot Figure 9.2 Metabolic consequences of insulin lack. Cellular uptake of glucose is prevented so that after be utilized effectively anyway. This situation is exhausting their glycogen supplies, cells need to use fats inevitably fatal within months. and even protein for their energy needs. Compare with Thus many of the clinical problems in type Figure 9.1. Note: not all actions occur in all body cells. 2 diabetes are a direct consequence of hyperglycaemia, while in type 1 diabetes there is glucose level rises causing hyperglycaemia also disrupted intracellular metabolism. In (Ͼ11 mmol/L). addition, chronic complications occur in both When the blood glucose level increases so that types, related to both hyperglycaemia and the concentration in the glomerular filtrate dyslipidaemia. These are discussed below. exceeds the renal threshold (see Chapter 14, p. 876), glucose is lost in the urine (glycosuria). Urinary glucose acts as an osmotic diuretic Insulin physiology carrying with it large volumes of water (polyuria and urinary frequency), resulting in excessive Insulin (molecular weight about 5800 Da) is thirst and fluid intake (polydipsia). Because of composed of 51 amino acids in two chains of reduced fat uptake by adipose tissue, plasma 21 (A chain) and 30 (B chain) amino acids lipid levels rise, especially triglycerides (dyslipi- connected by two disulphide bridges. It is syn- daemia). LDL is relatively unaffected but HDL is thesized in the pancreatic islet beta-cells. Other reduced, increasing atherogenic risk (Chapter 4). cells in the islets are the alpha-cells (producing Protein synthesis may be reduced but patients glucagon) and the delta-cells (producing somato- are often still relatively obese. However, they statin). Islet cells altogether comprise less than usually do lose weight in the weeks before first 3% of the pancreatic mass. Insulin is stored in diagnosis, in part due to dehydration. granules in combination with C-peptide as proinsulin (molecular weight 9000 Da), which is split before release into the portal vein. Insulin Total deficiency (type 1) has a plasma half-life of only about 5 min. With no insulin at all there is severe hypergly- Approximately 50% of insulin is extracted by the caemia at most times. This may raise the blood liver, which is its main site of action, and after osmotic pressure sufficiently to cause neurolog- utilization it is subsequently degraded. Eventu- ical complications including coma; this is ally, kidney peptidase also metabolizes some discussed on pp. 594–596. Cellular metabolism is insulin. C-peptide is less rapidly cleared and is profoundly disturbed. No glucose is available for thus a useful index of beta-cell function. The energy metabolism, and the first result is a main control of insulin level is plasma glucose: a depletion of liver and muscle glycogen stores. rise stimulates both the release and the synthesis 586 Chapter 9 • Endocrine system of insulin. Amino acids and possibly fats also is a delayed second phase of secretion after promote insulin release (Figure 9.3). about 45 min. Appoximately 5–10 units are A wide variety of other neuronal, endocrine, secreted with each meal. pharmacological and local influences on insulin Thus the plasma insulin concentration curve release have been identified (Figure 9.3), but normally closely parallels the plasma glucose their physiological or pathological significance concentration curve throughout the day, reflect- is not established. Adrenergic beta-receptors ing every small change in nutrient supply or mediate release, so beta-blockers can theoreti- demand (Figure 9.4). Considering these subtle cally inhibit this, though stimulation of and sometimes rapid adaptations, it can be inhibitory adrenergic alpha-receptors, magnified appreciated how far current therapeutic methods during the hyperglycaemic stress response, fall short of mimicking the physiological ideal. usually predominates. In non-diabetics, the total daily secretion of Interestingly, glucose is a more powerful insulin is probably rather less than the average stimulant orally than parenterally, and various daily requirement in type 1 diabetes of 50 units gut hormones have been implicated in this. of exogenous insulin, mainly because of losses at Glucagon also promotes insulin release, possibly the injection site. to facilitate cellular uptake of the glucose that it causes to be released into the plasma. Amylin The 37-amino acid peptide amylin is co-secreted Pattern of secretion with insulin from beta-cells. It appears to It is important to note also that there is a contribute to glucose regulation by a local continuous basal level of insulin secretion (paracrine) action on islet cells, which moderates throughout the 24 h, independent of food intestinal glucose uptake, thereby reducing the intake, which contributes to the regulation of load presented to the pancreas, or by suppressing metabolism and promotes glucose uptake into glucagon secretion. In diabetes, amylin defi- cells. This amounts to about 1 unit/h. Following ciency parallels that of insulin and it is believed a meal there is an additional bolus secreted, that patients whose postprandial hypergly- which is biphasic. Within 1 min of blood caemia is not adequately controlled by conven- glucose levels rising, preformed insulin is tional therapy may benefit from amylin released from granules in beta-cells into the agonists, although none is yet in clinical use. blood. This release is stimulated by certain antidiabetic agents (insulin secretagogues) and Insulin receptors is the first component to be compromised in early diabetes. Should hyperglycaemia persist, These are present on the cell surfaces of all further insulin synthesis is stimulated and there insulin-sensitive tissues and are normally down-

Glucose Amino acids (some) Somatostatin Hormones (e.g. glucagon, incretin, CCK)

Parasympathetic nervous system/ BETA-ISLET Beta-blocking drugs cholinergic agents CELL Thiazides Sympathetic nervous system – beta-adrenergic agents Sympathetic nervous system – alpha-adrenergic agents Sulphonylureas/meglitinides

INSULIN Corticosteroids/oral contraceptives

Figure 9.3 Factors affecting the release or action of insulin. CCK, cholecystokinin. –––––● inhibition/antagonism; –––––● stimulation/potentiation. Epidemiology and classification 587

Mid- Mid- morning afternoon Evening 10 Breakfast snack Lunch snack meal 80 (mU/L) Fasting blood glucose level 5 40 Plasma insulin Blood glucose (mmol/L) Basal plasma insulin level 10 0 0 2400 0600 1200 1800 2400 Time (hours)

Figure 9.4 Schematic representation of normal diurnal variations in blood glucose and plasma insulin levels. As the blood glucose level rapidly rises after a meal, it is closely followed by an increase in insulin level to limit the rise. The insulin returns towards the basal level as blood glucose reaches the normal fasting level once more. Note how the two substances follow almost parallel curves, the insulin a little later than the glucose. The small but positive constant basal insulin level emphasizes that insulin has functions other than just dealing with dietary glucose. Note: this diagram does not differentiate the two phases of insulin release.

regulated by insulin, especially if it is present at 2 diabetes insulin is secreted but is either continuously high levels, e.g. the hyperinsuli- inadequate or insufficiently effective to meet naemia of over-eating, obesity or obesity-related metabolic needs. type 2 diabetes. This may account for the The current WHO definition of diabetes is reduced insulin sensitivity (insulin resistance) based on standardized measurements of plasma found in some patients and the beneficial effect glucose concentrations. It defines three classes, of weight reduction, especially of abdominal fat, diabetes, impaired glucose tolerance and on glucose tolerance: there is a vicious cycle impaired fasting blood glucose (Table 9.3). whereby hyperglycaemia and reduced insulin Patients in the second category are borderline action reinforce one another. Long-term insulin and about half will progress to frank diabetes treatment also often gradually reduces the eventually (up to 5% per year). However, they insulin requirement, perhaps owing to reduced need not be treated immediately, depending on glucose levels. However, there is still much to be age and the presence of other risk factors: older learned about the interactions between insulin, patients or those with no cardiovascular risk insulin receptors and carbohydrate metabolism. factors may just be monitored. More recently the category of impaired fasting glucose has been introduced in an attempt to identify at an even earlier stage those with latent or ‘pre-diabetes’ Epidemiology and classification who should be monitored. It is a less reliable predictor but has the advantge that it does not The hallmark of diabetes is hyperglycaemia, require a glucose tolerance test (see below). owing to abnormalities of insulin secretion or Often, a single random plasma glucose of action. There are two primary forms of diabetes Ͼ11.1 mmol/L (blood glucose 10 mmol/L) is and a variety of minor secondary ones. In type 1 sufficient for diagnosis in a patient with classic diabetes there is usually gross destruction of the symptoms, although this should be confirmed insulin-secreting pancreatic beta-cells. In type with a fasting plasma glucose Ͼ7 mmol/L. 588 Chapter 9 • Endocrine system

Table 9.3 WHO definitions of diabetes mellitus (based on plasma glucose levels, as measured in laboratory)

Class Plasma glucose (mmol/L)

Fasting OGTT at 2 h Diabetes mellitus Ͼ7 and/or Ͼ11.1 Impaired glucose tolerance (IGT) Ͻ7 and 7.8–11.1 Impaired fasting glucose (IFG) 6.1–7 Normal fasting glucose Ͻ6.1 and Ͻ7.8

If whole blood is used (as obtained by finger prick) all figures would be approx. 10% lower (e.g. 6.1 and 10 mmol/L for diabetes mellitus). The apparently non-uniform thresholds derive from conversion from old mg/100 mL units, as still used in North America. OGTT, oral glucose tolerance test.

Laboratories may report plasma glucose levels, as Classification specified by the American Diabetic Association diagnostic criteria, whereas finger prick tests Primary diabetes – type 1 and type 2 measure blood levels; nevertheless, it is customary always to refer to blood glucose in In the vast majority of cases there is direct discussing diabetes. In borderline cases the oral damage to the pancreatic islet cells. Different glucose tolerance test (OGTT) can be attempts to classify diabetes comprehensively performed: the patient’s blood glucose is have been confounded by the use of criteria that measured before and at 2 h after a standardized are not mutually exclusive (e.g. age at onset, 75-g glucose load, given orally following an patient build or need for insulin). For example, overnight fast. some older (‘maturity onset’ or type 2) patients eventually require insulin, some older patients need it from the start (‘latent autoimmune diabetes in the adult’, LADA) and a few younger Epidemiology patients may not (‘maturity onset diabetes of the young’, MODY). Whether the patient needs Diabetes is known to affect more than 2% of the insulin may be the most practical distinction, UK population, and probably as many again are but does not correspond consistently with other likely to have impaired glucose tolerance or even important parameters. frank diabetes if screened. The prevalence varies A classification based on the pathogenesis of considerably between populations. For example, the pancreatic damage is now accepted as the Europeans are prone to type 1, especially in most meaningful. This distinguishes two broad northern Europe, whereas the incidence in Japan types (Table 9.4), which correspond roughly with is less than 10% of that in Finland. insulin dependency. The key criterion is the mode Type 2 seems to be related partly to the afflu- of pancreatic damage, but many other distinc- ence of a population, possibly through the tions follow from this classification, including prevalence of obesity, inactivity or both, which natural history, family history and patient type. are major risk factors. However, genetic factors These will be discussed in the following sections. are also important. In some ethnic groups the prevalence is very high, e.g. in some Pacific Secondary diabetes Islanders and the North American Pima Indians it reaches 50%. Among South Asian immigrants A minority of cases with identifiable primary to the UK it is five times that in the host popu- causes (e.g. severe pancreatitis, steroid-induced lation, suggesting a possible genetic suscepti- diabetes) do not fit readily into either of the bility to changed environmental factors, e.g. a conventional categories. They may or may not diet richer in fats and sugar. require insulin for treatment (p. 591). Aetiology and pathogenesis 589

Table 9.4 Comparison of the main types of primary diabetes mellitus

Type 1 Type 2

Endogenous insulin Absent Present Insulin deficiency Absolute Relative or partial Insulin receptor defect? Insulin resistance Usually absent May be present Pancreatic islet damage Severe (destruction) Slight/moderate Immunology Auto-immune; islet cell antibodies No antibodies demonstrated Usual age of onset Ͻ30 years Ͼ40 years Build of patient Thin Obese (usually) Therapeutic class Insulin-dependent (IDDM) Non-insulin-dependent (NIDDM; but may require insulin) Genetics Weak family history; HLA-linked Strong family history Ketoacidosis prone? Yes No

Aetiology and pathogenesis patients. However, interestingly, it is not these anti-islet antibodies that mediate cell destruction but T-cells; the islets are invaded by inflamma- Primary diabetes tory cells causing insulitis. Insulin autoanti- bodies may also be found but their significance Despite having similar clinical pictures and is uncertain. As is usual with autoimmune complications, types 1 and 2 primary diabetes disease, there is rarely a strong family history: have very different causes (Table 9.5). siblings or children of people with type 1 diabetes have about a 5% chance of developing the disease. However, there is a correlation with Type 1 diabetes the patient’s HLA tissue type (see Chapter 2) In type 1 diabetes the islet beta-cells are almost and in a minority of patients an association with completely destroyed by an autoimmune other autoimmune diseases, especially of process. Antibodies against all islet cells, and endocrine tissues (e.g. thyroiditis, pernicious beta-cells specifically, are found in 80% of anaemia).

Table 9.5 Aetiology and pathology of primary diabetes

Type 1 Type 2

Risk factors HLA antigens (DR3, DR4) Family history Over-eating; lack of exercise Toxin? Amyloid? Ethnic group

Trigger factors Viral infection Obesity Metabolic stress/excessive demand Metabolic stress/excessive demand Environmental toxin?

Pathogenesis Rapid autoimummune destruction of islet cells Gradual islet cell degeneration / depletion Peripheral insulin receptor defect? 590 Chapter 9 • Endocrine system

Overt diabetes may follow many years of • Absolute insulin deficiency, i.e. reduced subclinical pancreatic damage, and when it insulin secretion. occurs there is usually less than 10% of func- • Relative insulin deficiency: not enough tional islet cell mass remaining. Clinical onset is insulin is secreted for metabolic increased usually abrupt, over a few weeks, and often asso- needs (e.g. in obesity). ciated with, or precipitated by, a metabolic stress • Insulin resistance and hyperinsulinaemia: a such as an infection, which acutely increases peripheral insulin utilization defect. insulin demand beyond capacity. This might In most cases type 2 diabetes is associated with account for the winter seasonal peak in inci- obesity (particularly abdominal obesity) on dence and also the brief temporary remission first presentation, and in a quarter of all people that frequently follows, as the infection remits with diabetes simple weight reduction reverses and the marginal insulin levels once again just the hyperglycaemia. This is commonly associ- compensate. Subsequently, full-blown disease ated with peripheral insulin resistance owing irreversibly takes hold. As with other autoim- to receptor-binding or post-receptor defects. mune diseases, viral infection may be causing Obesity and reduced exercise also contribute the expression of a normally suppressed HLA to insulin resistance and are modifiable risk receptor, which subsequently activates lympho- factors for type 2 diabetes. The resultant hyper- cytes (see Chapter 2). Other environmental trig- glycaemia induces insulin hypersecretion, gers such as toxins or certain foods (including hyperinsulinaemia and insulin receptor down- milk protein) may also be involved. regulation, i.e. further insulin resistance. Hyper- Autoantibodies may be found in some glycaemia itself is known to damage beta-cells patients up to 15 years before the onset of acute owing to the direct toxic effect of excessive intra- disease. This could eventually provide a means cellular glucose metabolism, which produces an of early identification of prediabetes, so that excess of oxidative by-products; these cannot be they may be treated prophylactically, possibly destroyed by natural scavengers such as catalase by immunotherapy. However, such markers are and superoxide dismutase. The vicious cycle also often found in close relatives who never eventually depletes (‘exhausts’) the beta-cells, develop the disease, and the chance of the intrinsic insulin levels fall and some patients identical twin of a diabetic patient subsequently may eventually come to require exogenous developing diabetes is less than 50%. The insulin therapy. Thus, type 2 diabetes is usually a introduction of the category of ‘impaired progressive disease, although the late onset fasting glucose’ was another attempt at early usually means that some patients die before identification of potential sufferers. requiring insulin. Thus it seems that in type 1 diabetes there is a There is still debate as to the primary defect of genetically determined HLA-dependent suscepti- type 2 diabetes. It has also been proposed that bility that requires an environmental trigger for the amyloid deposits (insoluble protein) long full expression. Following contact with this known to be found in the pancreas of type 2 trigger, which may never be encountered, swift patients are related to abnormalities in amylin deterioration and complete insulin dependence secretion (p. 586) and contribute to the are inevitable. There is still considerable ignor- pancreatic defect. ance of the relative contributions of genes and There is an association between abdominal environment and of specific environmental obesity, hyperinsulinaemia, insulin resistance, factors. hyperlipidaemia, type 2 diabetes and hyperten- sion, and this combination of risk factors is Type 2 diabetes termed metabolic syndrome. However, despite These patients have one or more of the following much research, as yet it is not known which of fundamental abnormalities, and in established these factors (if any) is the prime cause, or if disease all three commonly coexist: there is another underlying reason. Natural history 591

Genetics Natural history The genetic component in type 2 diabetes is much greater than in type 1. A family history is Onset very common, often involving several relatives. Identical twins almost always both develop the About 80–90% of diabetic patients have type 2 disease, and offspring with both parents having diabetes, which tends to occur late in life, hence diabetes have a 50% chance of developing the the obsolete description ‘maturity onset’. Onset disease. The ‘thrifty gene’ hypothesis proposes is usually insidious and gradual, patients toler- that the ability to store fat efficiently – and ating mild polyuric symptoms perhaps for many hence develop obesity – conferred a survival years. advantage in more primitive societies where The other 10–20% have type 1 diabetes and famine was a regular phenomenon, hence its require insulin at the outset. Almost invariably persistence in the genome. This may explain they become ill at an early age: the peak onset why some pre-industrial groups (e.g. Pacific of type 1 is around puberty, starting most Islanders) readily develop diabetes when commonly in the winter months. Although the exposed to the industrialized lifestyle. disease may be present subclinically for some considerable time (months, or possibly years), clinical onset is invariably abrupt. Secondary diabetes

Most diabetes results from primary defects of Presentation the pancreatic islet cells. However, there are occasionally other causes of ineffective Type 2 diabetes is usually first diagnosed insulin action, impaired glucose tolerance and following one of three common presentations hyperglycaemia (Table 9.6). (Table 9.7):

Table 9.6 Some causes of secondary diabetes

General mechanism Aetiology Example

Hepatic glucose metabolism defect Liver failure Viral hepatitis, drugs Pancreatic destruction Cirrhosis Alcoholism Pancreatitis Anti-insulin hormones Corticosteroids Cushing’s disease Steroid therapy Pregnancy (‘gestational diabetes’) Major trauma/stress Growth hormone Acromegaly Adrenaline (epinephrine), etc. Phaeochromocytoma Glucagon Glucagonoma Thyroid hormones Hyperthyroidism Major trauma/stress Adrenergic drugs Hyperglycaemic/anti-insulin drugs Thiazide diuretics, diazoxide Oral contraceptives Insulin antibodies Autoimmune disease Abnormal insulin receptors Congenital lipodystrophy 592 Chapter 9 • Endocrine system

• About half of patients first complain of some time and then have undergone some major increasing polyuria and/or polydipsia. stress such as MI or serious infection. Another • In about a third it is a chance finding of glyco- possible trigger factor could be starting a drug suria or hyperglycaemia at a routine medical that impairs glucose tolerance, e.g. a thiazide examination. diuretic or an atypical antipsychotic. Such • In less than 20% of cases the patient stresses may also uncover latent disease in a less complains of symptoms subsequently found dramatic manner. to result from a complication secondary to Unfortunately, a severe acute presentation is diabetes. far more common at the onset of type 1 disease. This is usually associated with some metabolic Type 2 patients may be asymptomatic or may stress (e.g. infection), and presents with rapid have been only mildly symptomatic for several weight loss, weakness, extreme thirst, severe years. Commonly, they ignore these symptoms polyuria, urinary frequency and multiple or attribute them to ageing, and only present nocturia. Some may even go on to acute meta- when classical symptoms such as polyuria, thirst, bolic decompensation (ketoacidosis) and even tiredness or recent weight loss (even though the coma, being practically moribund on hospital patient may still be relatively obese) become admission. Following recovery with insulin unacceptable. In many other cases their diabetes therapy there may follow some months of is only detected when they undergo a medical apparent remission with a reduced or absent examination, e.g. for insurance purposes or a insulin requirement, the so-called ‘honeymoon new job. Alternatively, the complaint may be of period’, but these patients then deteriorate an infective complication not obviously linked rapidly. Before the isolation and therapeutic use to diabetes, at least not in the patient’s mind, of insulin in the 1920s they inevitably died such as recurrent candida infections or boils, a shortly thereafter. non-healing foot lesion or a persistent urinary- tract infection. Rarely, as the complications proceed insidiously even during this early period, the primary reason for consultation may Progression result from vascular disease, nephropathy, neuropathy, retinopathy or impotence. In some Insulin secretion in type 2 diabetes declines cases IHD, even MI, is the first presentation. relatively slowly, but up to one-third of patients A common manifestation of the complications may eventually need exogenous insulin, i.e. they is the ‘diabetic foot’. The patient presents with are ‘insulin-requiring’ as opposed to insulin- a possibly gangrenous foot lesion, probably dependent. following a recent injury and subsequent In most type 1 diabetes, pancreatic beta-cell infection. destruction is already almost complete at diag- Only very rarely will a type 2 patient first nosis, and routine insulin requirements do not present with metabolically decompensated generally increase. However, in both types the disease (ketoacidosis). These patients will prob- multisystem complications progress throughout ably have had impaired glucose tolerance for life at rates that vary considerably between patients and will very likely be the eventual Table 9.7 Different presentations of type 2 diabetes cause of death. People with diabetes have a reduced life expectancy, although the prognosis Typical diabetic symptoms (see text) 55%(a) has greatly improved with advances in treat- Chance finding 30% ment. Younger patients have mortality rates of Complication – infective 15% up to five times that of the general population, – other 2% while for older ones it is about twice normal. The precise prognosis for any given patient will (a) Approximate figures; after Watkins (2003) (See References and depend on many factors, but particularly the further reading). overall consistency of control of blood glucose. Complications 593

Clinical features Diabetic urine dries to leave a white glucose deposit, a clue that sometimes leads to diagnosis: there may be underwear stains or white specks Symptoms on the shoes of elderly males (from careless micturition). Severe plasma hyperosmolarity The symptoms of diabetes as summarized in may reduce the intraocular pressure, causing Table 9.8 are best understood in relation to their eyeball and lens deformity, and glucose pathogenesis. may alter lens refraction: both lead to blurred vision. This is sometimes a prodromal sign of hyperglycaemic crisis in type 1 diabetes. Symptoms due to hyperglycaemia The classic symptoms, which give diabetes Impaired metabolism and complications mellitus its name (‘sweet fountain’), are easily explained by the osmotic effect of the elevated The metabolic consequences of insulin lack were blood glucose levels that occur when glucose is discussed in detail above. The pathophysiology denied entry to cells. They are more pronounced of hyperglycaemia and ketoacidosis is now when the blood glucose level rises rapidly, e.g. considered. in decompensation or acute onset. The osmotic effect of chronic hyperglycaemia will to some extent be compensated by compensatory Complications hyponatraemia and an increased intracellular osmolarity (see Chapter 14). When the blood glucose level exceeds the Most complications of diabetes are due to either renal threshold (about 10 mmol/L), glucose acute metabolic disturbances or chronic tissue appears in the urine in large quantities. The damage. traditional method of distinguishing diabetes mellitus from diabetes insipidus – almost the only two idiopathic causes of chronic polyuria – Acute complications was simply to taste the urine: in the former case it is sweet, and in the latter literally insipid The most common acute complications are (tasteless). Glycosuria predisposes to urinary- disturbances in glycaemic control. Optimal tract infection, partly because of the favourable management of diabetes aims for a delicate growth medium presented to perineal organisms balance, preventing excessive glucose levels but and partly because diabetic patients are generally not forcing glucose levels too low. A variety of more susceptible to infection (see below). circumstances can drive the glucose level outside

Table 9.8 Clinical features of diabetes

Direct consequences of high blood glucose levels Polyuria, frequency, nocturia, polydipsia (osmotic diuresis) Visual disturbance (osmotic changes to intra-ocular pressure) Urethritis, pruritis vulvae, balanitis (urogenital infection) Metabolic consequences of impaired glucose utilization Lethargy, weakness, weight loss (intracellular glucose deficit) Ketoacidosis (increased fat metabolism) Long-term complications of hyperglycaemia and hyperlipidaemia Vascular disease, heart disease, renal disease, neuropathy, eye disease, infections, arthropathy 594 Chapter 9 • Endocrine system these narrow limits, and if treatment is not glucose level of approximately 15–20 mmol/L, adjusted accordingly, the result is either excess or both hyperosmolar and metabolic problems insufficient glucose in the blood (Table 9.9). develop (Figure 9.5; Table 9.10). Blood glucose levels can exceed 50 mmol/L and this high osmotic load (which is also in the Hyperglycaemia/ketoacidosis extracellular fluid) cannot be matched within Causes, pathogenesis and symptoms those cells from which glucose is excluded owing Hyperglycaemia in treated diabetes usually to the absence of insulin. Thus, water is drawn arises because normal medication is somehow from the intracellular compartment and this omitted or becomes insufficient to meet an causes tissue dehydration. This particularly increased insulin requirement. Drugs that raise affects the brain where the resultant reduced blood glucose levels can also interfere with intracranial pressure leads to CNS depression. control. When diabetic control is lost, blood The skin is also dehydrated, and loses its elas- glucose rises and the symptoms develop gradu- ticity; this reduced skin turgor can be detected by ally over a number of hours. Above a blood pinching a fold of skin and noting its delay in

Table 9.9 Causes of acute disturbances in diabetic control

Hypoglycaemia Hyperglycaemia/ketoacidosis

Excess (mis-measured?) dose Missed antidiabetic dose Potentiation of oral hypoglycaemic (drug interaction) Hyperglycaemic drugs, e.g. thiazides, steroids Missed meal; dieting Excess dietary intake Unexpected physical activity Metabolic stress, e.g. infection, surgery, pregnancy Excessively tight blood glucose control Alcohol

INSULIN DEFICIENCY

REDUCED increased glucose INTRACELLULAR HYPERGLYCAEMIA in glomerular GLUCOSE filtrate

increased plasma osmolarity osmotic diuresis switch to fat metabolism polyuria, tissue dehydration hypovolaemia glycosuria

ketoacidosis

thirst hyperkalaemia Na/K depletion polydipsia

CNS depression tachycardia hyperventilation confusion, coma hypotension

Figure 9.5 Pathogenesis and clinical features of acute hyperglycaemia and ketoacidosis. Complications 595

fatty acids, and the liver converts some of these Table 9.10 Clinical features of hyperglycaemia and to acid ketones that can be readily utilized as an ketoacidosis alternative energy source by many tissues. The resulting metabolic acidosis (diabetic ketoaci- Glycosuria, ketonuria dosis) is misinterpreted by the respiratory centre Polyuria, nocturia as carbon dioxide retention, resulting in an Thirst, polydipsia increased respiratory drive and hyperventilation. Hypotension Acidosis impairs oxygen dissociation from Hb, Rapid (bounding) pulse and respiration exacerbating the gasping (overbreathing, ‘air hunger’), and also causes peripheral vasodilata- Dry mouth, reduced skin turgor tion, exacerbating the hypotension. Both respi- Visual disturbance ratory rate and blood oxygen level fall as coma Hyperkalaemia, acidosis, ketonaemia supervenes. Ketoacidosis is more likely to Sweet smell of ketones on breath develop in type 1 patients, although fortunately Weakness, drowsiness, eventually coma it is uncommon. People with type 2 diabetes usually secrete sufficient insulin to prevent them developing springing back, but this is less conclusive in the ketoacidosis (except during severe stress), but elderly, in whom skin elasticity is already they may still suffer hyperosmolar non-ketotic reduced. hyperglycaemic states. This may result in coma In the kidney the high load of glucose in the and is associated with a higher mortality than glomerular filtrate, not all of which can be reab- ketoacidosis. sorbed, produces an osmotic diuresis. This results in a reduction in circulating fluid volume, leading to hypotension and reflex tachycardia. Management The high urine volumes also cause a loss of elec- Diabetic ketoacidosis is a medical emergency trolytes, especially sodium and potassium. with about a 15% mortality rate. Close moni- However, the plasma potassium level may be toring and very careful attention to the patient’s paradoxically high because acidosis inhibits the fluid and electrolyte balance and blood Na/K pump throughout the body, preventing biochemistry are essential (Table 9.11). Imme- intracellular potassium uptake (see below and diate attention is life-saving, but the patient may Chapter 14, p. 891). Osmoreceptors and baro- take several days to stabilize. receptors detect the electrolyte and fluid losses, IV soluble insulin is essential. An initial causing thirst, but as CNS depression and confu- bolus of about 6 units is followed by contin- sion develop the patient often cannot respond uous infusion (6 units/h). Fluid replacement by drinking. needs are estimated from measurements of the In the absence of glucose, many cells start to CVP and plasma sodium level. Hyponatraemia metabolize fat instead. Adipose tissue releases (‘appropriate hyponatraemia’, glucose having

Table 9.11 Principles of the management of ketoacidosis

Problem Treatment

Underlying cause Discover and treat Hyperglycaemia and hyperosmolarity Insulin (soluble): small bolus plus continuous infusion Dehydration IV infusion: saline/dextran/plasma Acidosis Bicarbonate? Hyperkalaemia/potassium deficiency Careful potassium repletion, after correction of acidosis Hypoxaemia Oxygen, up to 60% initially 596 Chapter 9 • Endocrine system osmotically displaced sodium in the plasma) Pathogenesis and symptoms and/or sodium depletion require 0.9% saline Hypoglycaemic symptoms fall into two main administration. However, if the dehydration has groups (Table 9.12). At glucose levels below caused hypernatraemia, especially in the non- about 4 mmol/L insulin release is inhibited ketotic patient, hypotonic saline (e.g. 0.45%) and the counter-regulatory hormones such as may be indicated. Severe hypotension or shock glucagon and adrenaline are released in an effort require plasma replacement (see Chapter 14 to raise blood glucose. At a glucose level below p. 903). Potassium replacement is difficult to 3.5 mmol/L the body responds by activating manage because the initial hyperkalaemia the sympathetic nervous system and adrenal masks a total body potassium deficit. However, medulla (the ‘fight or flight’ response). The once insulin is started and potassium moves consequent sympathetic/adrenal symptoms intracellularly, closely monitored IV potassium (Table 9.12) should provide the patient with a replacement is required. Acidosis will often preliminary warning (but see below). resolve spontaneously with conservative therapy As the glucose level falls below about as ketone production falls and existing ketones 2.5 mmol/L, neurological signs develop owing to are metabolized. Many clinicians would not use the deficiency of glucose in the brain. These bicarbonate unless blood pH was below 7.00 for neuroglycopenic features may be noticed more fear of overcompensating. by others than by patients themselves, although many patients do report an awareness of subjec- tive prodromes. Sometimes the signs are subtle Hypoglycaemia changes in mood or visual disturbances, but eventually there is almost always erratic behav- Causes iour resembling drunkenness. This has some- In all forms of diabetes, hypoglycaemia (blood times led to police arrest and delayed treatment, glucose Ͻ3 mmol/L) is much more common occasionally with fatal results. Frequent hypo- than symptomatic hyperglycaemia, and it glycaemic attacks may have a cumulative delete- develops very rapidly, sometimes within rious effect on higher brain function (cognition), minutes. Usually, either an excessive insulin especially in the elderly. All people with diabetes dose is accidentally injected (many patients have should carry, in addition to a readily available eyesight problems) or else the normal dose of sugar source such as dextrose tablets, a card or insulin or antidiabetic agent is not matched by an adequate dietary intake (Table 9.9). Insulin- induced hypoglycaemia is usually associated Table 9.12 Clinical features of hypoglycaemia with injections of short-acting insulin. Deliberate overdosing is not unknown. Adrenergic (autonomic) – enhanced sympathetic Hypoglycaemia induced by sulphonylurea activity antidiabetic drugs is rarer but more prolonged, • tremor, sweating more severe and more difficult to treat than • shivering, palpitations insulin-induced hypoglycaemia. The elderly are • anxiety, pallor especially prone, partly because the drugs are Neuroglycopenic – reduced CNS glucose delivery cleared more slowly and partly because of • drowsiness, disorientation, confusion impaired homeostasis. Drug interactions that • apparent drunkenness; aggression, might potentiate oral antidiabetic drugs are inappropriate behaviour considered on p. 615. Alcohol not only causes • convulsions, coma, brain damage; death hypoglycaemia by inhibiting hepatic gluconeo- Other effects – multiple or indirect pathogenesis genesis but also impairs the patients’ perception • hunger, salivation, weakness, blurred vision of it, reducing their ability to respond. Complications 597 bracelet stating that they have diabetes and response is usually satisfyingly prompt, occur- should be given sugar if found acting strangely. ring within minutes. Glucagon injection can A patient’s ability to recognize ‘hypos’ (their usually be managed easily by patients’ relatives, hypoglycaemic awareness) should be checked who should be fully informed on how to regularly because it tends to diminish. Long- recognize and deal with hypoglycaemic term diabetes patients become less sensitive to episodes. Unless patients or their relatives are the warning signs and thus more vulnerable. taught to recognize the early signs, the patient This may result partly from autonomic may become comatose before being able to neuropathy and partly from reduced counter- correct it. regulatory hormone response. It is also possible Persistent hypoglycaemic attacks require that frequent attacks may reduce the patient’s reassessment of therapy. Dietary modification ability to recognize them. Awareness is pro- may be required (e.g. increased carbohydrate), gressively reduced by frequent hypogly- although this might compromise weight reduc- caemic episodes but may be at least partially tion efforts. Modern intensive insulin therapy restored by minimizing or eliminating episodes regimens aimed at producing ‘tight’ glycaemic through relaxing control slightly, more careful control have increased the likelihood of monitoring and patient education. hypoglycaemia, and a judgement of risk and Most of the adrenergic symptoms are medi- benefit has to be made when such regimens are ated by beta-receptors, and so may be antago- considered (p. 626). nized by concurrent beta-blocker therapy. Although this rarely presents a serious problem, such drugs should be avoided in people with Unstable diabetes diabetes if they already experience hypogly- A small proportion of people with type 1 caemic unawareness. Otherwise, there is no diabetes prove exceptionally difficult to control, contra-indication but a cardioselective beta- experiencing frequent episodes of hypogly- blocker is preferred. Theoretically, beta-blockers caemia, hyperglycaemia or both. They are vari- might help by preventing beta-mediated insulin ously termed brittle, unstable or labile. It is release (Figure 9.3), but this is swamped by the unlikely that this condition is inherent to their symptom-masking effect. disease, and specific causes are always sought. Poor compliance through error, ignorance or Management disability, e.g. visual problems measuring insulin Although both hypoglycaemia and hypergly- doses, unrecognized intercurrent illness and caemia can result in coma, there is rarely any drug interaction must first be eliminated. In problem distinguishing them, especially as rapid older patients with recurrent hypoglycaemia the blood glucose test stick methods are readily possibility of reduced hypoglycaemic awareness available. A test dose of glucose would clinch must be investigated. matters because hypoglycaemia will be very Recurrent hyperglycaemia/ketoacidosis is rapidly reversed, whereas glucose would have no more common in young patients and may significant effect, either helpful or harmful, in sometimes be associated with psychological or hyperglycaemia. In contrast, insulin given psychopathological factors such as teenage rebel- blindly would severely exacerbate hypogly- lion or illness denial, self-destructive impulses caemia and should never be given where there is or other emotional instability. A particular doubt. subgroup has been identified of slightly obese The conscious patient must take glucose females aged 15–25 years who may be covertly tablets, or sugar, chocolate, sweet tea, etc. Semi- manipulating their therapy adversely. Supervised conscious or comatose patients require IV IV therapy in some of these patients seems to glucose 20% or IM glucagon (1 mg). The resolve the problem temporarily. 598 Chapter 9 • Endocrine system

Chronic complications gies, supports the hyperglycaemia hypothesis. The extensive Diabetes Control and Complica- In many patients, even before diagnosis, wide- tions Trial (DCCT; 1992) confirmed that better spread damage occurs in the kidney, nerves, eyes control is associated with less severe complica- or vascular tree (Figure 9.6). These long-term tions in type 1 diabetes. The UK Prospective complications are to different degrees common Diabetes Study (UKPDS; 1998) supported the to both types of diabetes, and their prevention or same hypothesis in type 2 patients. treatment are the real challenges for diabetes Other hypotheses have been proposed. It management and research. could be that an as yet unidentified primary lesion in diabetes is responsible independently for both the hyperglycaemia and the complica- Pathogenesis tions. If so, correcting one would not neces- It is important to determine whether or not sarily improve the other. Some complications these chronic problems are a direct consequence could be secondary to the abnormal pattern or of hyperglycaemia. If so, then optimal control to amount of insulin secretion, which is not achieve normoglycaemia would be expected to completely rectified by conventional treatment. minimize them. Evidence has accumulated that For example, the hyperinsulinaemia seen in this is broadly true for the so-called microvas- many type 2 patients may contribute to blood cular complications (mainly kidney, eye, nerves). vessel disease (macrovascular complications) or The fact that similar complications arise in most hypertension. Alternatively, the abnormally types of diabetes, despite their different aetiolo- high levels of counter-regulatory hormones

Hypertension

NEPHROPATHY RETINOPATHY PROTEIN Small blood vessels Dermopathy GLYCATION MICROANGIOPATHY Arthropathy

HYPERGLYCAEMIA NEUROPATHY POLYOL ACCUMULATION Cataract

Stroke Ischaemic heart disease large blood vessels Peripheral vascular MACROANGIOPATHY disease (Atherosclerosis)

Dyslipidaemia Platelet/clotting defect

Infections

Figure 9.6 Possible pathogenetic mechanisms of chronic diabetic complications. The central box lists the clinical features. Also shown is possible interlinking of pathogenetic mechanisms. Complications 599 usually found in diabetes may be deleterious. result from a combination of this and direct The involvement of growth hormone and glycation of the sheaths of small nerve axons, insulin-like growth factor in angiopathy has e.g. sensory nerves. Similarly, glycation of the also been investigated but no clear pattern glomerular basement membrane probably causes detected. Finally, there seems to be a genetic the characteristic glomerular sclerosis of diabetic variation in the susceptibility to different nephropathy, although renal arterial disease complications, regardless of the degree of probably also contributes. Glycation of tendon glycaemic control. sheaths and joint capsules may be responsible Thus there is unlikely to be a simple answer, for the joint problems, particularly the stiffness but the general strategy of normalizing blood in hands and feet, that some patients suffer; glucose is well established as the best we glycation of collagen in skin sometimes gives it a currently have for minimizing complications. thickened, waxy appearance. The myocardium Three general mechanisms are proposed for the may also be affected, as may immune cells such pathological basis of the complications: protein as macrophages and leucocytes. glycation (glycosylation), abnormal polyol metabolism and accelerated atheromatous Polyol metabolism arterial changes. Some tissues do not require insulin for glucose transport into their cells (Table 9.1), relying Glycation instead simply on diffusion down a concentra- Normally, almost all body protein is to some tion gradient. Thus, while other tissues are extent glycated, i.e. glucose molecules from body glucose-depleted in diabetes, these will accumu- fluids are covalently bound to free amine groups late excess glucose in the presence of hypergly- on protein side chains. The degree of glycation is caemia. Being surplus to energy needs, some of directly proportional to the average blood the excess glucose is reduced to polyols such as glucose level. An accessible marker for this is sorbitol by the enzyme aldose reductase via an Hb glycation, particularly the HbA1c fraction. otherwise little used pathway (Figure 9.7). Other proteins, and also lipids and nucleopro- The resulting polyols are not readily elimi- tein, throughout the body are similarly affected. nated from the cells, possibly because they are In excess, one result is the formation of more polar than glucose and of greater molec- abnormal crosslinks between different regions of ular weight. Furthermore, low dehydrogenase protein chains. Protein configuration is thus activity, particularly in the eye lens and nerve changed, disrupting secondary and tertiary sheaths, means that they are not metabolized structure and hence function. Basement efficiently. The resultant accumulation of membrane proteins seem particularly susceptible osmotically active molecules draws water into to glycation, the result being thickening and the cells, causing them to expand, severely increased permeability (i.e. reduced selective disrupting their function and possibly killing barrier function). As basement membranes are them. Retinal blood vessels, the eye lens and present in most tissues, and especially in blood the glomeruli may be damaged in this way, vessels, this could account for the widespread, contributing to retinopathy, cataract and multisystem distribution of diabetic complica- nephropathy, respectively. It has long been tions. Chronic hyperglycaemia also results in known that an analogous intracellular accumu- oxidative stress through increases in mito- lation of galactitol in the lens is linked to the chondrial superoxide formation, producing high prevalence of cataracts in the inherited advanced glycation end-products (AGPs) that metabolic disorder galactosaemia. can cause a variety of damaging effects. A further abnormality may also contribute. Basement membrane damage in capillaries Myoinositol, an important intermediate in and smaller arterioles can cause microan- energy handling, may (although also a polyol) giopathy and subsequent ischaemia in almost instead of accumulating become deficient. By a any organ. Retinopathy is undoubtedly caused poorly understood series of steps this deficiency in part by this mechanism. Neuropathy may may impair nerve conduction (Figure 9.7). 600 Chapter 9 • Endocrine system

Normal pathway hexokinase GLUCOSE Glucose-6-phosphate GLYCOLYSIS

hyperglycaemia

excess glucose aldose reductase

OSMOTIC SORBITOL DAMAGE ? and other polyols ? reduced IMPAIRED NERVE MYOINOSITOL MYOINOSITOL reduced Na pump activity uptake depletion CONDUCTION

Figure 9.7 Polyol pathway and effects of polyol accumulation.

Macroangiopathy Diabetes and hypertension. There is an Almost all people with diabetes suffer from association between diabetes (especially type 2) increased obstructive vascular disease owing to a and hypertension, as part of the metabolic greatly increased predisposition to atheroscle- syndrome. The precise cause and effect rosis. Several factors contribute to this. Because of relationships have not yet been elucidated. their more active lipid metabolism, people with Many hypertensives have insulin resistance, diabetes have raised plasma levels of triglycerides hyperinsulinaemia and impaired glucose toler- and lowered HDL, producing an unfavourable, ance, and insulin may have several hypertensive atherogenic lipoprotein ratio (see Chapter 4, actions including promoting renal sodium reten- Figure 4.28). Furthermore, many type 2 patients tion, increasing sympathetic vasconstrictor are initially hyperinsulinaemic and insulin may activity and directly increasing vascular reac- itself be a growth factor for atheroma. Platelet tivity, via an effect on sodium handling. In aggregating ability is also usually raised, and some cases hypertension may be secondary to hypertension is common. Thus major risk factors diabetic kidney disease, although the converse for atherosclerosis are intensified and cerebro- may also be true (see Chapter 4, p. 213). vascular disease, stroke, IHD and peripheral vas- Alternatively, it may be that a third, as yet cular disease are common. Macroangiopathy also unknown, independent factor first causes insulin contributes to kidney disease. resistance, which then leads to both type 2 diabetes and hypertension. Hyperinsulinaemia could then be a common link in the Other mechanisms vascular complications of both diabetes and As illustrated in Figure 9.6, other complications of hypertension. diabetes occur, the pathogenesis of which remain The UKPDS (1998) found that rigorous control obscure. Moreover, different complications of blood pressure in diabetes reduced complica- may be inter-related or coexistent. Neuropathy tions. However, prolonged therapy with two may result partly from direct neuronal damage common antihypertensive agents, thiazide and partly from impaired blood supply to the diuretics and beta-blockers, while effectively nerve sheaths. Microangiopathy may result lowering blood pressure, can also lead to glucose partly from glycation, partly from polyol accu- intolerance or even overt diabetes. For this mulation and partly from hyperinsulinaemia. reason beta-blockers are not recommended as Once nephropathy is established, it promotes first-line treatment for hypertension in diabetes, hypertension and vascular disease. and extra care is needed with both. Complications 601

Clinical consequences Renal. Diabetic nephropathy is the cause of death in about 25% of type 1 diabetes. Predomi- Almost any system in the body may be affected nantly a form of sclerosis of the glomerular base- by diabetic complications, which is why diabetes ment membrane, it develops very slowly and so is regarded as a multisystem disease (Table 9.13). most commonly occurs in type 1 patients, up to 40% of whom may be affected. The increased Eyes. Diabetes is the most common cause of glomerular filtration rate (‘hyperfiltration’) in acquired blindness in developed countries. After early diabetes, which is due to hypertension and 30 years of diabetes, about 50% of patients have to the osmotic loading of hyperglycaemia, may some degree of retinopathy, and up to 10% overload renal capillaries. Nephropathy is become blind. The blindness is due to small- heralded by microalbuminuria, with increasing vessel damage in the retina, with dilatation, proteinuria frequently progressing to end-stage haemorrhage, infarction and ultimately exces- renal failure, associated with worsening hyper- sive proliferation of new vessels that project tension. Diabetic nephropathy is one of the most into the vitreous humour (neovascularization). common causes of chronic renal failure, with Retinopathy is frequently associated with people with diabetes comprising about 15% of nephropathy. People with diabetes also have an the caseload of UK renal replacement therapy increased incidence of glaucoma and cataract. units. Renal decline is hastened by inadequate or tardy treatment of associated hypertension. Nervous system. Diabetic neuropathy may affect any part of the peripheral nervous system, Cardiovascular. About half of diabetic deaths but most commonly starts with the peripheral are from the consequences of macroangiopathy. sensory nerves, causing tingling and numbness People with diabetes have a twofold greater risk of (paraesthesias), loss of vibration sense or the stroke and a fivefold greater risk of MI compared sense of balance and limb position. It may inter- with matched non-diabetic subjects. Peripheral fere with the ability of blind people with vascular disease is also common, with a 50-fold diabetes in reading Braille. Autonomic higher risk of peripheral gangrene. Some patients neuropathy is potentially devastating because undergo progressively extensive amputation; it can seriously disturb cardiovascular, gastro- usually the lower limbs (especially the feet; see intestinal or genitourinary function, causing below) are affected, but fingers are also at risk. numerous symptoms; postural hypotension and Hypertension is often associated with diabetes. impotence are common. Voluntary motor nerves Up to 50% of type 1 patients have it, and it is are less commonly affected. probably secondary to nephropathy. About a

Table 9.13 Clinical consequences of diabetic complications

System Clinical features

Eyes Retinopathy, glaucoma, cataract; blindness Nerves Sensory, autonomic and motor defects Renal Glomerulosclerosis; chronic renal failure Cardiovascular Ischaemic heart disease (angina, MI), peripheral vascular disease, stroke; cardiomyopathy; congestive heart failure Locomotor Slow-healing peripheral lesions; ‘the diabetic foot’; amputations; joint stiffness Immune Increased susceptibility to infection

MI, myocardial infarction. 602 Chapter 9 • Endocrine system fifth of type 2 patients are hypertensive; the aeti- their onset combines control of blood glucose, ology is uncertain but related to the metabolic risk factor reduction and regular monitoring. syndrome, with obesity and hyperinsulinaemia contributing. Optimal glycaemic control. Although the A rare complication is diffuse cardiac fibrosis aetiology and pathogenesis of the complications (cardiomyopathy), which may lead to heart are still uncertain and likely to be multiple, the failure. main clinical approach has been to aim for scrupulous control of blood glucose levels, Locomotor. The ‘diabetic foot’ is a common keeping them within the normal range, in an problem. In normal people minor foot injuries, attempt to mimic physiological normality. This such as a blister or a lesion from ill-fitting foot- is based on the assumption that complications ware, usually heal before being noticed. In people are due to hyperglycaemia. This seems to be with diabetes, however, these often develop into particularly likely for the microvascular, possibly non-healing painless ulcers that become infected polyol-related, complications in nerves, eyes and and irreversible damage sometimes occurs before kidney. Evidence derives from clinical trials, medical attention is sought. In some cases this including those using the more ‘physiological’ results in osteomyelitis or gangrene, both of treatments such as continuous SC insulin infu- which can lead to amputation. This results from sion (p. 624) or other methods of achieving a combination of poor peripheral sensation ‘tight’ glycaemic control. This means keeping (neuropathy, so that the wound is not felt), poor fasting blood glucose levels below 7 mmol/L and peripheral circulation (angiopathy, so that not exceeding 11 mmol/L after meals, and may healing is impaired) and reduced resistance to necessitate conversion to insulin therapy in infection. All people with diabetes should see a poorly controlled type 2 patients. chiropodist regularly. Correctly fitting footwear is Good control has been shown to reduce essential. No pharmacist should attempt to treat the incidence of complications. The most any foot problem in a diabetic, or sell them ‘corn convincing evidence in type 1 diabetes was the plasters’ or similar products. Any foot problem, DCCT trial, which reported significant slowing however minor, should be referred to their of deterioration in retinopathy, microalbumin- chiropodist or doctor urgently. uria and, to a lesser extent, neuropathy. The Diabetes can also cause soft tissue damage UKPDS trial found broadly similar benefits in resulting in limited joint mobility (stiffness), and type 2 patients and also strongly demonstrated a characteristic arthropathy, usually in the feet, the synergistic role of hypertension in exacer- where angiopathy and sensory neuropathy also bating complications and the importance of contribute (Charcot joints; see Chapter 12). achieving normotension as well as normogly- caemia. Unfortunately, this study failed to iden- Systemic. People with diabetes are very prone tify clearly the treatment mode that offered the to infections owing to an impaired immune best protection, although this had been one of response caused by defects in immune and its aims. inflammatory cells. Recurrent bladder infection An unwanted side-effect of tight control is that is common, which can ascend to cause by keeping the average blood glucose low the pyelonephritis: urinary retention and stasis due incidence of hypoglycaemia is increased, espe- to autonomic neuropathy exacerbate this. Skin cially among elderly and unstable diabetics. In infections are also frequent, and contribute to the DCCT trial there was a threefold increase in foot problems. the incidence of hypoglycaemia when under tight control. This means that in some circum- stances a compromise is necessary because of the Management of complications acute and the long-term complications of General strategy frequent hypoglycaemic attacks. Thus, older The overall approach to preventing diabetic patients in whom the diabetes onset occurred complications, minimizing them or delaying quite late, i.e. type 2, are usually allowed to run Complications 603 higher average levels. The long delay in onset of microalbuminuria. In treating hypertension, complications will mean that life expectancy ACEIs (and ARAs) seem to have an additional may be little reduced, whereas quality of life direct beneficial effect in diabetes, dilating would be markedly reduced by frequent intrarenal (efferent glomerular) vessels and thus hypoglycaemia. minimizing glomerular hypertension. ACEIs are For the macrovascular complications (cardio- increasingly used early unless contra-indicated vascular, cerebrovascular and peripheral athero- e.g. by bilateral renal artery stenosis, which is sclerosis) this approach is less successful, perhaps always a possibility in someone with diabetes. because insulin and related endocrine abnormal- ACEIs are indicated when there is hypertension ities and hypertension may contribute directly, with proteinuria or microalbuminuria; in type 1 independently of glycaemia. It is still unknown diabetes their use is recommended if there is whether the generally higher insulin levels asso- microalbuminuria, even with normotensive ciated with tight control regimens can actually patients. However, at present there is no exacerbate some macrovascular problems. evidence that ACEIs benefit normotensive diabetes with no evidence of nephropathy. Minimize risk factors. It is important to Other antihypertensives may not offer similar control any additional risk factors that could extra benefits but another antihypertensive exacerbate organ damage, especially via athero- should be used if ACEIs are contra-indicated or sclerosis. These include smoking, hypertension, inadequate at reducing pressure. obesity, hyperlipidaemia and hyperuricaemia. Once established, renal failure is managed as usual (see Chapter 14), although haemodialysis Monitoring. This essential component in is more difficult because of vascular and throm- minimizing complications is discussed below botic complications. Continuous ambulatory (see also Table 9.22). peritoneal dialysis is particularly suitable in diabetes because insulin may be administered Reduce polyol accumulation. According to intraperitoneally (thus directly entering the the polyol hypothesis for certain of the compli- portal circulation, which is more physiological). cations, it should be possible to impede However, there may be a problem with the this process by interfering with the metabolism glucose, which is usually added to dialysis fluid of polyols. Unfortunately, aldose reductase to promote water removal. People with diabetes inhibitors (e.g. sorbinil), although they do are nowadays unlikely to be given low priority minimize sorbitol accumulation and prevent for renal transplantation, as they tended to be in myoinositol depletion, have not proven clini- the past, and this is sometimes combined with cally successful in reversing or even retarding pancreatic transplantation (p. 605). There are neuropathy, cataract, nephropathy or retino- however some problems: the poor general health pathy. Dietary myoinositol supplementation has of these patients and multiple organ damage also been unsuccessful. increase the operative risk, and there is an increased likelihood of post-transplant infection Specific complications owing to the immunosuppression required. Nephropathy. There are currently four Nevertheless, graft survival is only about 10–15% methods that have been shown to slow the rate poorer than the average for renal transplants. of deterioration in renal function: Macroangiopathy. The usual dietary constraints • Careful glycaemic control. on saturated fat and cholesterol are important. • Control of hypertension. Monounsaturated fats, especialy olive oil, are • Use of ACEIs or ARAs. recommended. The HPS study supported the • Moderate protein restriction (in more use of statins for all people with diabetes of advanced nephropathy). either type at cardiovascular risk, whatever It is essential that people with diabetes are moni- their lipid level, and this is now accepted. The tored annually for the onset of hypertension and CARDS study extended the recommendation in 604 Chapter 9 • Endocrine system type 2 diabetes to those patients with even tion for impaired glucose tolerance (Table 9.1). normal or low lipids, regardless of CVS risk. Ideally, this would require a continuous basal However, such routine use is not yet officially level of insulin to maintain metabolism, supple- recommended. In the PROactive trial type 2 mented by rapid pulses following meals and a patients with pre-existing macrovascular disease reduced level during exercise. used pioglitazone in addition to their usual Optimal management should attain three treatment. A small but significant reduction in important interlinked aims: all-cause mortality, MI and stroke was achieved • Prevent symptoms. but at the expense of weight gain and an • Maintain biochemical stability. increase in heart failure. • Prevent long-term complications. Other conventional atheroma risk factors such as smoking and hypertension must also be At present, this ideal is not achievable. Even if scrupulously addressed (see Chapter 4). pancreatic transplantation were to be perfected, insulin receptor defects might still remain. Neuropathy and neuropathic pain. Little can Current therapy is limited to artificially manipu- be done for diffuse neuropathy, but neuropathic lating diet and insulin (endogenous or exoge- pain can be partially relieved and fortunately nous) in order to mimic normal patterns as severe attacks, although prolonged, tend to closely as is practicable. remit. Drug therapy may be of help in the some- The older directive, paternalistic medical times excruciating pain. Conventional analgesic model for such manipulation is no longer or anti-inflammatory drugs are generally ineffec- acceptable, clinics preferring to negotiate a ‘ther- tive. A variety of other drugs have been tried apeutic contract’ with the patient. The aim is to and the first-generation tricyclic antidepressants agree a desired level of control – optimal, (e.g. amitriptyline) are standard first-line therapy. prophylactic or perhaps merely symptomatic – Second-line agents include anticonvulsants such based on the severity of the disease and the as carbamazepine, gabapentin or topiramate (see patient’s age, understanding, likely compliance also Chapter 6). and normal way of life. Sometimes it is inadvisable to strive too zeal- Retinopathy. Retinal disease is conventionally ously to approach the ideal. For the elderly, treated by laser photocoagulation. where long-term complications are of less concern, keeping symptoms at a tolerable level without excessive disruptions to normal life patterns may be adequate. For this, the target Management need only be to achieve random blood glucose levels below 12 mmol/L. In some patients the Aims and strategy incidence of hypoglycaemic attacks is unaccept- ably high if control is too tight. The advent of Preventative methods for diabetes are as yet the insulin pen has enabled the flexibility to poorly developed. More progress has been made achieve these differing aims. with potentially curative surgery. However, at present the vast majority of people with diabetes Prevention require long-term management of established disease. Because type 1 disease involves immune destruc- The cardinal aim of management in diabetes is tion of the pancreas, immunotherapy has been to keep blood glucose levels within the normal attempted experimentally, as early as pos- range; this should produce patterns of glucose sible after initial diagnosis or even in the pre- and insulin levels in the blood similar to those symptomatic stage in at-risk individuals, e.g. that follow normal changes in diet and activity where there is a strong family history or impaired (see Figure 9.4). Blood glucose levels should glucose tolerance. In animal models anti-T remain below the maxima in the WHO defini- cell antibodies, bone marrow transplantation, Management 605 thymectomy, azathioprine and ciclosporin have is still limited by the risks of surgery and been tried. In the Diabetes Prevention Trial-1 the penalty of lifelong immunosuppression early introduction of insulin therapy, to ‘spare’ (Chapter 14). the beta cells and perhaps to reduce their expres- The implantation of donated beta-islet cells is sion of autoantigens, was unsuccessful. Another still experimental but looks promising. Stem trial using nicotinamide to inhibit macrophages cells may offer even more fundamental a solu- has also failed to reduce progression. tion for the future. A number of artificial However, considerable pancreatic damage has pancreas devices have been devised, although usually occurred by the time symptoms are none is yet available for routine use (p. 624). noticed. Only about 10% of functional islet cells then remain, so no great improvement can be Therapeutic strategy expected. Research is now concentrating on discovering reliable early prognostic markers, Using conventional methods, the only way for a such as islet cell antibodies. Patients at risk could diabetic to enjoy relatively normal eating and then be identified by screening. activity (i.e. unpredictable, unplanned and No specific aetiological agents have been iden- uncontrolled) would be to have frequent, tified for type 2 diabetes, but risk factors are well precisely calculated injections of soluble insulin known. These correspond with many of the well- (or appropriate doses of a rapidly acting oral established cardiovascular risk factors associated hypoglycaemic [insulin secretagogue] drug). The with the lifestyle of industrialized countries, i.e. dose would be based on blood glucose measure- diets high in sugar and fats and low in fibre and ment or guided by experience and recent diet slowly absorbable complex carbohydrates, lack and activity level: thus insulin is supplied on of exercise and obesity. Weight loss in particular demand in a manner emulating normal physi- has been shown to delay development of the ology (see Figure 9.4). With the introduction of disease in high-risk individuals and achieve insulin pens, such an ‘insulin demand-driven’ remission in severely overweight people with strategy is becoming practicable, although diabetes. In the Diabetes Prevention Programme dosage adjustment is still imprecise. The artificial both intensive lifestyle intervention and pancreas, if perfected, may prove a better option. metformin significantly reduced the risk of devel- oping diabetes in people with impaired glucose ‘Insulin supply drive’ tolerance. Another trial showed benefit with The alternative (and original) approach, still acarbose. In the Finnish Diabetes Prevention used for many older patients, is to turn physi- Study dietary modification and exercise was ology on its head and to accept a model driven similarly beneficial. More recently the DREAM by insulin supply. Instead of matching insulin trial with rosglitazone over 3 years showed signif- supply to instantaneous changes in demand, icant reduction in progression from impaired demand in the form of diet and activity is glucose tolerance/impaired fasting glycaemia to adjusted and controlled to conform to available overt type 2 diabetes. insulin (whether endogenous or administered exogenously). Because both drugs and insulin must be given prospectively this is in effect Cure: organ replacement ‘feeding the insulin’, as opposed to the normal Pancreatic transplants are now a realistic situation where insulin follows feeding. Meals option. Dual renal plus pancreatic transplanta- and activity must be regular and of predictable tion is especially considered for people with composition: explicit adjustments in drug or diabetes with advanced nephropathy, because insulin dose must be made to allow for such patients are going to have to undergo deviations (Figure 9.8). immunosuppression anyway. One-year patient This places considerable constraints on survival exceeds 90% and 5-year graft survival patients, particularly children. Education and exceeds 50%. Transplantation substantially counselling are extremely important and increases the quality of life, although of course Diabetes UK performs a valuable role here. 606 Chapter 9 • Endocrine system

Mid- morning Evening Breakfast snack Lunch meal

10 80

Blood glucose level (mU/L)

5 40 Plasma insulin Blood glucose (mmol/L)

Basal plasma insulin level 10

0 0 2400 0600 1200 1800 2400 Time (hours)

Figure 9.8 Matching food intake to available insulin – schematic representation. In the insulin supply-driven model, insulin levels are maintained artificially either by direct injection or by augmentation using oral hypoglycaemic agents. To prevent hypoglycaemia, sufficient glucose must be provided by the diet at regular intervals. Note what would be the effect of missing the mid-afternoon snack: blood glucose would start to fall dangerously low just before the evening meal. Unusual activity, by causing increased glucose demand, would complicate this picture.

People with type 1 diabetes are inevitably present unambiguously with type 1 insulin- reasonable compliers in the strictest sense, in dependent diabetes, although a variable insulin- that the severe metabolic upset precipitated by independent (‘honeymoon’) period may occur drug defaulting is a powerful motivator. Never- following diagnosis. theless, excellent compliance with diet, and the Older patients, who are often obese, will very tight control of blood glucose demanded almost always be type 2 and must be tried first for avoidance of long-term complications, is less on diet alone. Should this fail, drug therapy common, especially in type 2. will be added. All drugs used in diabetes are classed in the BNF as antidiabetic, and this term will be used generically here (although Treatment modes NICE refers to these drugs as ‘glucose-lowering Dietary management is the bedrock of treat- drugs’). The older term ‘oral hypoglycaemic’ is ment. All people with diabetes, irrespective of obsolescent, owing to the development of other treatments, require some control of their classes of drugs that do not directly lower eating and exercise patterns, both in terms of blood glucose. Those that do, i.e. sulphony- total calorific intake, types of nutrients and lureas and meglitinides, are more accurately eating schedule. Indeed, about half of patients described as insulin secretagogues. will need no more than this, especially those Type 2 patients are usually to some extent who lose weight. A further 25% will need to overweight on presentation, and a biguanide is augment their natural insulin with drugs. The the first choice. Otherwise a sulphonylurea is remainder will need insulin. selected. Sometimes a synergistic combination of The initial choice is usually related to how the the two types will be required. For those for patient first presents (Figure 9.9). Younger whom these measures are ineffective a glitazone patients, who are frequently non-obese, usually may be added. For some patients even this is Management 607

DIET ؉ YOUNG/LEAN insulin (Ketoacidosis; recent weight loss)

DIET ؉ insulin ؉ Non-obese insulin sensitizer(a) uncommon) DIET ؉) sulphonylurea

DIET ؉ DIET ؉ biguanide ؉ DIET ONLY biguanide ؉ OLDER/OBESE sulphonylurea ؉ sulphonylurea (Asymptomatic; glitazone polyuric; complication) DIET ؉ Obese biguanide (common)

Figure 9.9 Treatment strategy for diabetes related to presenting symptoms. Meglitinides may be substituted for sulpho- nylureas. A glitazone or glucosidase inhibitor can be added or substituted at any stage to attempt to improve control before moving to next stage (but avoid meglitinide + sulphonylurea). See text. (a)Insulin sensitizer = metformin or glitazone. unsatisfactory and, especially if ketoacidosis include specialist diabetic nurse practitioners. occurs, insulin treatment is needed, as it will be However, regular diabetic clinic visits are eventually in those whose disease progresses desirable if they have developed complications faster. Type 2 patients may also need insulin or management becomes difficult. Some type 1 temporarily during periods of increased require- and most type 2 patients without acute compli- ment such as major infection, surgery or preg- cations may be treated by their GP from the nancy. Combining antidiabetic drugs with outset. insulin therapy is being used increasingly (see below). At any point in this sequence, an adjunctive Diet drug that reduces intestinal glucose absorption or reduces insulin resistance may be added. Most type 2 patients must first be encouraged to try to control their disease on diet alone, and no patient taking antidiabetic drugs or insulin Initiation of treatment should believe that these obviate the necessity to On first diagnosis, all patients will be fully exam- control their diet. Recommendations about diet ined and investigated to establish baseline have evolved in several important ways. Fats are measures for monitoring development and now discouraged, while complex carbohydrate progression of any complications. This will and fibre are encouraged, and the overall include ophthalmological, renal, cardiovascular, approach is now far less restrictive. The recom- neurological, lipid and foot assessment. mended diabetic diet, save in a few respects, now Some patients will need to be treated first in closely resembles the normal healthy diet that hospital, especially type 1 patients first everyone should eat: regular meals low in fats, presenting with ketoacidosis. Blood glucose simple sugars and sodium and high in complex levels will be measured 3-hourly during this carbohydrate (starch) and fibre. period, to establish the diet and possibly the Formerly, inflexible, unrealistic or impractical drug or insulin dosage necessary to achieve the prescriptions and restrictions (diet sheets, agreed level of control. After discharge some will ‘exchanges’) took little or no account of the continue to attend as outpatients. Others will be psychological importance of individual dietary managed by general practice clinics, which often habits, dietary preferences and ethnic variations. 608 Chapter 9 • Endocrine system

The result was poor compliance complicated by • Timing. guilt and anxiety. The modern approach recog- • Variation. nizes that: • Dietary records or recall are an imprecise basis Energy intake for future modification. All patients need to adjust their calorific intake • Nutrient uptake varies even from precisely to achieve and maintain the desired bodyweight regulated and measured portions, owing to for their size, aiming for a body mass index of the interactions between foodstuffs, varia- about 22 kg/m2. For most people with type 2 tions in temperature, physical form and diabetes, who are frequently obese, this implies a degree of chewing, etc. weight-reducing diet. Reliable tables are now • Compromise is needed to devise a regimen available to predict the required energy intake with which the patient can be concordant. according to age, gender, activity level and Thus a perfect diabetic diet is difficult to achieve lifestyle. in practice, and although the pursuit of it is worthwhile, this could be counter-productive in Constituents some patients. Rather, efforts are made to ensure that patients understand, in their own fashion, Macronutrients what the aims are. Counselling and education The unselective restriction on carbohydrate that are then used to maximize motivation. Advice used to characterize diabetic diets is now consid- from a dietician with experience in modifying ered misconceived. Carbohydrate is not harmful diabetic diets to suit individual lifestyles can if taken mainly as slowly absorbed complex help achieve good compliance. polysaccharides, e.g. starch. Such carbohydrates Four aspects of diet need to be considered allow people with type 2 diabetes to make best (Figure 9.10): use of their limited endogenous insulin secretory capacity by not raising postprandial blood • Total energy intake. glucose too rapidly. Foods can be classified • Constituents.

ALL PATIENTS

Main nutrients: energy proportions Carbohydrate, fat, protein

Other nutrients: amount, type Fibre

Other nutrients: maxima Sugar, alcohol

Timing Small frequent regular meals

Variability (1) Varied content (2) Vary amounts for variations in exercise/stress

IF OBESE

Reduced total energy content

Figure 9.10 Dietary considerations in diabetes (see also Table 9.14). Management 609 according to their glycaemic index, which somewhat inconsistent; however, the distinc- represents the ratio of the total glucose absorp- tions are relevant (Figure 9.11). Starch, in staple tion they produce compared with that from a foods like bread, potatoes and rice, is the main standard test meal of wholemeal bread and digestible carbohydrate energy source. Older cottage cheese. The lower the index the better, classifications grouped all other indigestible and representative values are rice 80%, potatoes matter together as ‘dietary fibre’, but there are 77%, pasta 60% and lentils 45%. Foods important and distinct components. The non- acceptable to various ethnic minorities, such as starch polysaccharides (NSP) are now known chappatis, kidney beans, chickpeas, etc. are also to be particularly important in diabetes. They now encouraged where appropriate. provide no energy but further delay absorption The relatively high fat content of early dia- of glucose from starch digestion (see above), and betic diets, which was needed in a carbohydrate- by forming intestinal bulk promote a feeling of reduced diet to provide calories more cheaply satiety that may reduce appetite and therefore than with protein, is now seen to be danger- help weight control. ously atherogenic. A reduced fat intake, low in The (semi)soluble or viscous fibres and gums saturated fats and comprising about one-third found in fruit, vegetables and pulses (Figure polyunsaturated and one-third monounsatu- 9.11) produce in addition a modest reduction in rated fat (e.g. nuts, fish, olive oil) is now blood cholesterol, possibly by binding bile salts encouraged. Cholesterol itself is usually reduced and thereby preventing their enterohepatic recir- inherently along with saturated fats. There are culation. The insoluble NSP fibres, as in bran and no particular constraints on protein except for unmilled cereals and grains, have little effect on patients with suspected nephropathy, when cholesterol, but contribute to stool bulk along restriction is indicated. with other fibrous residues, e.g. lignin. Although undigested in the ileum, some of this material is Other nutrients hydrolysed by colonic flora to release absorbable A small amount of simple sugar (sucrose) is now and metabolizable carboxylic acids. considered acceptable, if the calorific content is accounted for. This is usually consumed as a Proportions constituent, e.g. of baked products. Artificial The recommended proportions of macronu- non-nutritive sweeteners are still preferred and trient energy intake are approximately 60:30:10 patients must be advised to monitor their intake (carbohydrate:fat:protein; Table 9.14); tradi- of ‘hidden’ sugar in processed foods. So-called tional diabetic diets used to be nearer 25:65:10. ‘diabetic foods’ often contain sorbitol or fructose Within the fats, only a third should be saturated and, while they may not raise blood glucose as fats. How the patient implements this has also much as sucrose, have a high energy content and changed. Clinics no longer issue rigid menus, cause diarrhoea in excess. They are also expen- kitchen scales and detailed tables of what can be sive, offer nothing that a well-balanced diabetic exchanged for what. More generalized recom- diet cannot offer, and are not recommended by mendations with much wider variability are Diabetes UK. found to be more successful. Alcohol is not prohibited if its high calorific One such approach simply visualizes a meal content is accounted for and its hypoglycaemic plate divided into segments (Figure 9.12). About effect is appreciated, i.e. it should be taken with two-thirds contains polysaccharide: equal parts some carbohydrate. Recent evidence of its protec- staple carbohydrate sources such as rice, pasta or tive effect against heart disease suggests that potatoes starch and fibre such as fruit or vegeta- once again similar recommendations should bles. The remainder is mostly composed of fats apply to the diabetic population as to the popu- and protein sources such as meat, fish and dairy lation as a whole. There should be little added products. A small amount of sugar is allowed. salt, to minimize rises in blood pressure. The patient is advised to construct each meal in Fibre is extremely important. Although fibre these proportions. This roughly conforms to the is primarily carbohydrate, the terminology is recommended proportions, allowing for some 610 Chapter 9 • Endocrine system

CARBOHYDRATE

Simple sugars(a) COMPLEX POLYSACCHARIDE Sucrose, dextrins

Starch Non-starch polysaccharide

Digestible polysaccharide ‘NSP’, ‘dietary fibre’ Undigestible or unavailable Provides energy Delays glucose absorption, Breads: white, brown, chapati induces satiety and weight reduction Cereals: rice, pasta Vegetables: potato, cassava

Soluble (viscous) Insoluble

Pectin, gum, alginate (Hemi)celluloses Galactomannan Bran, wheat, rice Pulses, oats, barley (unmilled) Guar gum Vegetables Reduced cholesterol Bulk-forming

Figure 9.11 Different forms of dietary carbohydrate, including fibre; with functions and examples of foodstuffs. (a)Avoid as far as possible. fat and protein being included along with Variation the carbohydrate. People with diabetes need to understand that these constraints do not prevent them having a Timing varied, appetizing and nutritious diet. They Small, regular, frequent meals are important. should also understand how to augment their This means similar calorific intake at all main diet to match any unplanned or unusual exercise meals and regular snacks in between. For type 2 or stress so as to avoid hypoglycaemia. Tempo- patients this minimizes the load put on the rary changes in a patient’s metabolic require- pancreas at any one time. For both types it ments (as in serious illness) or oral absorptive helps to keep blood glucose levels within closer capacity (e.g. gastroenteritis) require appropriate limits, minimizing the risk of hypoglycaemia adjustment, which may involve temporary between drug or insulin doses and the risk of insulin therapy in a type 2 patient, and regular postprandial hyperglycaemia. There is some blood glucose monitoring is then essential. evidence that this too is a pattern that might Type 1 patients using the ‘insulin pen’ will benefit the general population. Nibbling or generally be even more flexible (see below). In ‘grazing’ appears to produce lower average mildly diabetic elderly patients the diet will also plasma lipid and blood glucose levels and less be far less rigid, for reasons already discussed. On obesity compared with a similar calorific intake the other hand, the diets of growing children obtained from intermittent, larger meals. need constant reassessment. The availability of Management 611

Table 9.14 Nutrients in diets recommended for diabetic and general population(a)

Nutrition Subcommittee of the National recommendations Diabetes Care Advisory Committee for optimal UK diet(c) of Diabetes UK (b)

Carbohydrate 50–60% 50–60% Total fat 30–35% [saturated fat 10%] 30–35% Protein 1 g/kg body weight 10% Simple sugars Յ10% 60 g Cholesterol(d) Not specified Not specified Soluble fibre(e) Not specified 18 g Alcohol 2 units (female) 2 units (female) 3 units (male) 3 units (male)

(a) Percentages are rounded and given as maximum proportion of total energy intake. Amounts are per day. (b) Diabetes UK, Diabetic Medicine 2003; 20: 786–807. (c) Based on reports from National Advisory Committee on Nutrition Education (NACNE, UK DoH) and Committee on Medical Aspects Of Food Policy (COMA, UK DoH). (d) Cholesterol intake usually automatically reduced sufficiently if saturated fat intake less than 10%. (e) 15 g soluble fibre equivalent to 18 g non-starch polysaccharides (NSP) or 30 g total dietary fibre.

Fruit and veg Bread, cereal, potatoes (non-starch polysaccharide) (starch) 33% 33%

Foods with fat and sugar 6% Meat, fish (protein) Milk, dairy (fat) 16% 12%

Figure 9.12 The ‘plate model’ of meal planning recommended by Diabetes UK. Each meal should be constructed roughly of the types of foods and in the proportions shown, visualizing them as making up the complete plate of food. (Adapted from www.diabetes.org.uk/eatwell/food_diabetes/index.html). nutrients and the habits and constraints of Oral antidiabetic drugs different ethnic groups also need to be taken into account. Dieticians are an essential part of Aim and role the diabetic team. Diet as sole management may fail in up to Oral antidiabetic drugs (OADs) are used as the two-thirds of type 2 patients. Primary failure is next step for type 2 patients in whom diet has usually due to poor compliance, poor motiva- failed to control their condition adequately. The tion or inadequate counselling. Secondary majority may then be controlled by a combina- failure usually results from disease progression, tion of diet and oral drugs for a number of years, with falling insulin production. The next stage is but some type 2 patients may eventually require to introduce oral antidiabetic drugs. insulin treatment. 612 Chapter 9 • Endocrine system

There are four main therapeutic targets for Action OADs (Table 9.15). Doubts over the safety of some of these drugs have now been resolved. These drugs have different, albeit comple- The results of the University Group Diabetes mentary and sometimes overlapping, actions Programme (UGDP) trial in the 1970s, which on the underlying abnormalities in type 2 suggested significant toxicity in the sulphonyl- diabetes, so combination therapy is indicated if ureas, are now discredited. Phenformin, an early monotherapy fails. biguanide, caused numerous deaths from lactic Alpha-glucosidase inhibitors (acarbose) acidosis and was withdrawn. Newer biguanides inhibit the final stage of the digestion of starch are much safer: only metformin is currently within the intestine by blocking the enzyme available in the UK; elsewhere buformin is used. disaccharidase. This reduces the rate of glucose Novel incretin analogues are undergoing trials. absorption and thus the postprandial glucose Incretin is a newly discovered peptide hormone, load presented to the islet cells. Thus, a pancreas secreted in the small intestines following food with a limited insulin secretory rate might be intake, which enhances insulin secretion and better able to handle this load with less suppresses glucagon, slows gastric emptying hyperglycaemia. It can be regarded as anti- and reduces food intake. It was isolated from a hyperglycaemic rather than a hypoglycaemic lizard that eats only four times a year. Exenatide agent. It has a relatively small effect on has been shown to lower glycated Hb levels and glycaemia and is used only as an adjunct to other weight. Sitagliptin inhibits incretin inactivation. therapy, but may be added at any stage to All OAD strategies depend on endogenous improve control. insulin secretion and are therefore effective only Sulphonylureas enhance the release of in patients with type 2 disease who retain appre- preformed insulin in response to circulating ciable beta-cell function. Ketosis-prone patients, glucose, partly by increasing beta-cell sensi- patients with brittle disease or those whose tivity to blood glucose. This mimics the acute fasting blood glucose exceeds 15–20 mmol/L, phase of the normal response to hyperglycaemia. almost invariably need exogenous insulin, in However, sulphonylureas do not directly stim- both type 1 and type 2 patients. ulate subsequent insulin synthesis. Inhibition of

Table 9.15 Oral antidiabetic drugs

Therapeutic target Site of action Group Examples

Reduce or retard Intestine Alpha-glycosidase Acarbose glucose uptake inhibitors

Enhance insulin Tolbutamide, glibenclamide, Pancreas Sulphonylureas secretion(a) Ά glipizide, glimepiride, gliquidone Meglitinides Repaglinide, nateglinide

Peripheral Enhance insulin action Biguanides Metformin, buformin(b) receptors · Reduce gluconeogenesis Liver

Reduce insulin resistance Peripheral receptors Thiazolidinediones Rosiglitazone, pioglitazone (esp. adipose tissue) (Glitazones)

(a) Insulin secretagogues. (b) Buformin not licensed in UK. Management 613 glucagon has also been suggested. Pharmacody- Glitazones (thiazolidinediones: rosiglitazone namically, they differ only in relative potency but and pioglitazone) are also insulin sensitizers. there are important pharmacokinetic differences They activate a nuclear transcription regulator between them. Sulphonylureas can be combined for an insulin-responsive gene (peroxisome with most other OADs except the meglitinides. proliferators-activated receptor-gamma, PPAR), Althoughsomedoubtwascastoverthesafetyofthe which has numerous complex effects on lipid long-established combination with metformin by and glucose metabolism. An important compo- the UKPDS, this has not been confirmed and the nent is to promote triglyceride uptake and combination is still widely used. peripheral adipose growth. The effect of this is to Meglitinides (prandial glucose regulators) also reduce triglyceride availability, increase glucose stimulate insulin release but not at the sulpho- utilization, reduce insulin resistance and thus nylurea receptor. They are claimed to do so more reduce insulin levels. They also shift fat from specifically in response to the blood glucose level visceral, muscle and hepatic sites to peripheral and thus to mealtime glucose load, making them adipose tissue, which although resulting in an more glucose-sensitive. They have two main increase in weight, produces a more favour- advantages over sulphonylureas. A more rapid able cardiovascular risk. This is partly because onset means they can be given 15 min or less they alter blood lipids favourably, lowering before a meal, giving patients more flexibility triglyceride and raising HDL levels. and control; and their shorter duration of action The PROactive study suggested this group may reduces the likelihood of postprandial hyper- reduce complications, both macrovascular (by insulinaemia and between-meals hypoglycaemia. reducing insulin and lipid levels) and microvas- In addition, if a meal is missed they can easily cular (by reducing hyperglycaemia) complica- be omitted. Nateglinide has a prompter and tions, but this has not yet been confirmed. The shorter action than repaglinide. Currently prototype, troglitazone, was withdrawn soon after nateglinide is only licensed for use with release owing to liver toxicity but rosiglitazone metformin, whereas repaglinide can be substituted and pioglitazone are safe and effective either for sulphonylureas at any stage. The combina- alone or in combination if other OADs fail to tion of a meglitinide with a sulphonylurea is achieve control, although their precise role has irrational. not yet been determined. Currently NICE Biguanides do not stimulate or mimic insulin recommends that they should not be added as but are insulin sensitizers. They have two main second-line drugs to either metformin or a actions: they increase peripheral glucose uptake sulphonylurea, except when these latter two and utilization and they inhibit hepatic gluco- drugs cannot be used in combination owing to neogenesis and release of glucose from the liver contra-indications or intolerance. into the blood. The underlying effect is probably via a general inhibitory action on membrane Biopharmacy and pharmacokinetics transport. Intracellularly, this would prevent glucose entering mitochondria, thus promoting Sulphonylureas are generally well absorbed anaerobic glycolysis in the cytosol. Because this although potential bioavailability differences is less efficient than aerobic glycolysis, cellular mean that patients should avoid changing glucose uptake and utilization are increased. This formulation or brand. Most sulphonylureas are may also account for a tendency to cause lactic more than 90% protein-bound (except tolaza- acidosis. In the intestine, reduced membrane mide, 75%), and so are liable to competitive transport may be useful in slowing and reducing displacement interactions. glucose absorption. There may also be intestinal There are important differences in clearance, lactate production. They may also have an half-life and duration of action, which deter- anti-obesity action. Only metformin is licensed in mine frequency of administration, precautions the UK. and contra-indications. Clearance is usually Biguanides can be combined with most other hepatic with subsequent excretion of inactive or OADs. less active metabolites (Table 9.16; Figure 9.13), 614 Chapter 9 • Endocrine system usually renally. The older chlorpropamide is second-generation drugs avoid these problems, partially cleared renally and also has active but there are wide interpatient variations in the metabolite, which accounts for its long half-life. handling of all sulphonylureas and dose regi- Those with inactive metabolites (e.g. tolbu- mens must be individualized. Glibenclamide is a tamide) generally have the shortest half-lives. special case because it is concentrated within Some sulphonylureas have metabolites that are beta-cells so its biological half-life is considerably chiefly excreted in the bile, which makes them longer than its plasma half-life. For this reason, more reliant on hepatic function. it too is avoided in the elderly. The duration of action, or biological half-life, Biguanides differ substantially from the is related to the plasma half-life but is often sulphonylureas, being poorly absorbed, little longer, owing partly to the activity of metabo- protein-bound and cleared predominantly by lites. Chlorpropamide has too long a duration of renal excretion (with about 30% cleared by action and frequently produces between-meals hepatic metabolism). Metformin has a short half- hypoglycaemia; it has little if any role now and life and may require thrice daily dosing at higher is contra-indicated in the elderly. The other doses. However, modified-release preparations popular first-generation sulphonylurea, tolbu- are available for dosages up to 1 g twice daily; tamide, fell from favour because its action was higher doses need standard-release therapy. felt to be too short, requiring frequent dosing. Buformin is longer-acting. However, for this reason it may be useful in the Renal clearance of biguanides may exceed elderly, to minimize hypoglycaemia. Most newer glomerular filtration rate, implying some tubular

Table 9.16 Relative duration of action of sulphonylureas

Relative duration of action(a) Very short Short Medium Long Very long

Daily dose frequency 2–3 2–3 1(–2) 1 1 Examples Gliquidone Tolbutamide Glimepride, Glibenclamide Chlorpropamide(b) glipizide, gliclazide

(a) Approximate descriptive indication of relative durations: precise time will vary from patient to patient. (b) No longer recommended.

CLEARANCE

mainly partially HEPATIC RENAL Excretion

BILIARY RENAL (metabolites) inactive or less active metabolites active metabolites or partly unchanged

glibenclamide (50%), tolbutamide chlorpropamide (80%) chlorpropamide (20%) glimepiride (50%) tolazamide gliquidone glipizide glimepride (50%) gliclazide

Figure 9.13 Clearance and excretion of the sulphonylureas. Management 615 secretion. Thus minor renal impairment, un- Meglitinides do not present such risks of hypo- noticed because of a normal serum creatinine glycaemia and weight gain as the sulphonyl- level, might still permit significant accumula- ureas. No serious class effects have become tion, and renal function monitoring is essential apparent so far. with their use. Biguanides (with the exception of phenformin) Meglitinides are rapidly absorbed, reaching a cause minor adverse effects, being somewhat less peak within 1 h and have a very short half-life, well tolerated than sulphonylureas. The nausea, being cleared and eliminated hepatically. This diarrhoea, muscle discomfort and occasional means they may be useful in controlling blood malabsorption experienced may be due to the glucose in close association with meals. membrane effects inherent in their mode of

Glitazones (thiazolidinediones) are rapidly action. Malabsorption of vitamin B12 can occur. absorbed and hepatically metabolized. Biguanides are best taken with food, the dose Although the half-life is less than 24 h, and being increased gradually to improve tolerance. once or twice daily dosing is adequate, full Iatrogenic lactic acidosis, which has a high effect takes at least a week, owing to the slow mortality, occurs rarely with metformin and the speed of fat redistribution. risk can be further reduced by careful monitoring Alpha-glucosidase inhibitors are not of renal and hepatic function and ensuring absorbed, acting slowly within the gut. that it is avoided in patients with renal impairment and hypoxic/hypoxaemic condi- tions such as cardiopulmonary insufficiency. Adverse reactions Because biguanides do not release insulin, they Sulphonylureas are well tolerated and free from cannot cause hypoglycaemia and they do not serious long-term adverse effects. The principal cause weight gain. problem is hypoglycaemia, which may be Alpha-glucosidase inhibitors frequently protracted and even fatal. A related drawback is cause uncomfortable and sometimes unaccept- the tendency to produce or maintain obesity. able or intolerable gastrointestinal problems Both effects can be linked to increased insulin owing to the increased carbohydrate load deliv- levels, which also are giving concern over a ered to the large bowel. Subsequent bacterial possible exacerbation of macrovascular compli- fermentation causes distension, pain, flatulence cations, insulin being a possible growth factor in and diarrhoea. arterial walls. Glitazones can cause a number of problems. Hypoglycaemia may be caused by an overdose, Fluid retention results in oedema, and heart an interaction, a missed meal or unexpected failure in up to 3% of patients: this is potentiated activity and occurs more commonly with the in combination with insulin. There may also be longer-acting drugs (glibenclamide and chlor- a mild dilutional anaemia. Hypoglycaemia is rare propamide), especially in the elderly, who must but weight gain is common. In view of the avoid them. (The possible compliance advantage hepatotoxicity of the withdrawn troglitazone, is far outweighed by the likelihood that a meal monitoring of hepatic function and avoidance will be forgotten while plasma drug levels are in hepatic impairment is needed, but they are still significant.) With the newer, shorter-acting safe in renal impairment if allowance is made for drugs any hypoglycaemia that does occur is brief the fluid retention. and more easily rectified. Chlorpropamide can occasionally cause a mild Interactions disulfiram-like flush with alcohol (due to acetaldehyde dehydrogenase inhibition), and Interactions with OADs are potentially serious occasionally hyponatraemia and a syndrome because the patient’s delicate biochemical of inappropriate secretion of ADH. These balance is maintained by a specific dose. Potenti- effects, as well as minor idiosyncratic reac- ation can rapidly cause hypoglycaemia, whereas tions, are uncommon with second-generation antagonism could lead, more slowly, to a loss sulphonylureas. of glycaemic control and a return of polyuric 616 Chapter 9 • Endocrine system symptoms. Pharmacokinetic interference with Pharmacokinetic potentiation absorption, binding or clearance occurs almost Drugs that increase gastric pH may enhance exclusively with the sulphonylureas, when the absorption of sulphonylureas. Highly plasma temporary introduction of an interacting drug protein-bound drugs can theoretically displace can alter the free OAD plasma level, with poten- sulphonylureas. However, following redistribu- tially dangerous consequences. A number of tion and alterations in clearance there may be drugs cause a pharmacodynamic interaction by a little overall change in free drug levels. More- direct effect on glucose tolerance (Table 9.17). over, the newer sulphonylureas bind to different Fortunately, clinically significant problems are plasma protein sites and are less prone to this relatively rare, and certainly far fewer than the effect. The hepatic clearance of sulphonylureas theoretical possibilities. Moreover, different can be reduced by severe liver disease and drugs, especially among the sulphonylureas, have by enzyme-inhibiting drugs and enhanced by different tendencies to show a given interaction. enzyme inducers; similar considerations apply to

Table 9.17 Important interactions and precautions with antidiabetic therapy

Potentiation → hypoglycaemia Antagonism → hyperglycaemia

Interference with antidiabetic therapy generally(a) Beta-blockers – mask/may cause hypoglycaemia (Beta-blockers, calcium-channel blockers)(b) ACEIs – increase glucose uptake Corticosteroids Alcohol – potentiates hypoglycaemia Thiazide (and loop) diuretics Fibrates (Antipsychotics) MAOIs

Interactions with sulphonylureas(c)(d) Absorption

(Antacids, H2-RAs) Binding displacement Salicylates (high doses)

Hepatic clearance Sulphonamides Chloramphenicol enzyme inhibition enzyme induction Warfarin · Rifampicin · Antifungals: imidazoles Anticonvulsants Liver failure Excess alcohol

Renal clearance NSAIDs Sulfinpyrazone Renal impairment

Interactions with biguanides Renal/hepatic impairment Alcohol (potentiates lactic acidosis)

(a) Problems possible with either oral or insulin therapy. (b) Entries in parentheses are known to be rare or minor. (c) There are wide variations in the significance of specific interactions with individual oral antidiabetic drugs, and not all possible interactions are indicated. This table is merely to show possible effects and mechanisms. A detailed text is recommended to ascertain clinical significance of an interaction. (d) Meglitinides have similar pharmacokinetic properties to the sulphonylureas.

ACEIs, angiotensin-converting enzyme inhibitors; H2-RAs, H2-receptor antagonists; MAOI, monoamine oxidase inhibitor; NSAIDs, non-steroidal anti- inflammatory drugs. Management 617 the meglitinides. The glitazones have not been these patients may be forgetful about meals, reported to cause any hepatic enzyme interac- less able to recognize hypoglycaemia, and tions. The renal clearance of unchanged drug or less tolerant of it homeostatically and active metabolites of any of these drugs can be neurologically. reduced by renal impairment and by certain • Alcohol use must be carefully controlled: drugs that cause fluid retention (e.g. NSAIDs). although initially it may cause hypergly- caemia (owing to its caloric content), it Pharmacodynamic potentiation enhances hypoglycaemia and may impair the Alcohol is directly hypoglycaemic in fasting ability to respond to it. conditions, and it may also potentiate • Alcohol also dangerously enhances the biguanide-induced lactic acidosis. Both MOAIs possibility of lactic acidosis with biguanides and beta-blockers tend to cause hypoglycaemia; and it causes unwelcome flushing with the former may inhibit glucagon secretion sulphonylureas, particularly chlorpropamide. and the latter inhibit hepatic glycogenolysis. • Some clinicians manage all patients with Beta-blockers can ‘mask’ the effects of hypo- significant renal impairment (common in glycaemia as perceived by the patient. Beta- people with diabetes) or hepatic impairment blocker interactions are seen mainly with (less common) with insulin. non-cardioselective agents if at all, but aside from those with propranolol they are rare and Selection usually insignificant. ACEIs enhance glucose uptake and utilization by cells, although the Combinations effect may diminish with continued therapy and Most type 2 patients are overweight and a is of uncertain significance. biguanide is the preferred first choice. It is also satisfactory for others but a sulphonylurea might Antagonism be started in the non-obese. Patients who fail to Drugs that induce liver enzymes can increase the achieve blood glucose control on either regimen clearance of hepatically metabolized sulphonyl- use a biguanide in combination with a sulpho- ureas. Various drugs tend to raise blood glucose, nylurea. Meglitinides, with their faster, shorter either directly or via the suppression of insulin action may be substituted for the sulphonylurea release. Paradoxically, given the masking effect at any stage if the patient prefers it, especially if referred to above, beta-blockers can block insulin they are tending to suffer hypoglycaemia or release. weight gain. A glitazone can be added as a third As a consequence of the inhibited disaccharide agent when dual therapy fails, especially if the digestion, oral treatment of hypoglycaemia in patient has persistent postprandial or between- patients taking glucosidase inhibitors should meals hyperglycaemia, both of which imply preferably be with glucose/dextrose rather than insulin resistance. However, if metformin plus a sucrose preparations. sulphonylurea combined fail to control the patient, it is likely that they have very little beta- cell capacity left and the introduction of insulin Contra-indications and cautions should be considered rather than adding a third drug (see below). The main precautions may be summarized thus: Acarbose could be added at any of these stages • People with diabetes need to take particular to improve control but has a limited benefit and care when changing dose, brand or type of is often poorly tolerated. Sitagliptin and exenatide antidiabetic medication. (p. 612) are available as third-line agents. • Medication records should be monitored to identify the introduction of potentially Constraints interacting drugs. In addition to these pharmacodynamic consider- • The elderly are particularly prone to hypo- ations, the choice of any OAD must take account glycaemia with the longer-acting OADs; of: 618 Chapter 9 • Endocrine system

• duration of action; Patients using insulin require much finer • mode of clearance; control of all aspects of management, • age; including diet, activity and dose measurement, • renal and hepatic function; than other people with diabetes. There is less • tolerance of adverse effects; margin for error because patients rely totally • patient preference for number of daily doses. on the injected dose. In contrast to type 2 patients, they lack the small basal insulin secre- The elderly must avoid the longer-acting drugs, tion that, although insufficient to prevent while other patients may have particular reasons hyperglycaemia, keeps the type 2 patient free for preferring more or less frequent dosing. By from metabolic complications like weight loss analogy with insulin regimens, a combination of and ketosis. a single daily dose of a long-acting drug, combined with regular top-up doses of a short- acting one, has been recommended, but is little Aims and constraints used. In general there is little to choose between In theory, it should be possible to attain the sulphonylureas, but patients with renal glycaemic control with insulin that closely impairment might do better with gliquidone mimics the natural physiological variations in (Figure 9.13). response to food intake, exercise and metabolic Some patients cannot be controlled on requirement. However, until recently it was not maximal tolerated doses of combined OADs. possible even to approach that. This may occur after many years of therapy as Recall that natural insulin secretion from the the beta-cell function inexorably declines (i.e. pancreas into the portal vein is finely and secondary failure), occurring in up to one-third continuously tuned to variations in blood of type 2 patients within 5 years of diagnosis. glucose level (p. 586; see Figure 9.3): this is very Alternatively some patients present late, when different from the usual exogenous insulin there has already been considerable degenera- therapy. An approximation might be attained tion (primary failure). In either case the situation with a continuous basal injection plus regular IV signifies that there remains insufficient residual boluses of a rapidly acting insulin preparation to beta-cell function, and exogenous insulin coincide with meals and, ideally, continuously supplement becomes mandatory. titrated against the blood glucose level. This At that stage small doses of insulin may be would resemble the natural pattern except for added to OAD therapy to provide a basal level. the portal delivery to the liver. However, such a This may delay the onset of full insulin therapy, regimen is impractical for most patients. and may be preferred by patients anxious about Absorption from the usual SC injection sites, full insulin dependence. When type 2 patients whether as depot injections or by continuous eventually need to be controlled with insulin delivery, can vary in any one patient from time they do not of course become type 1, and they to time and from site to site, particularly with may more accurately be referred to as having the otherwise more convenient longer-acting insulin-requiring type 2 diabetes. Insulin- preparations. Moreover, whereas exercise augmented OAD therapy will be considered inhibits normal insulin secretion, it tends to below after insulin has been discussed (see speed absorption from an injection site by p. 627). promoting peripheral circulation; thus when less insulin is required, more is delivered exoge- nously. It is also likely that SC injections admin- Insulin istered by some patients are effectively IM now that perpendicular injection is recommended, About two-thirds of people with diabetes are changing absorption characteristics. Alterna- treated with insulin, about half of whom are tively, some patients retard absorption by truly insulin-dependent type 1 and others injecting into fat, which is less painful. Further- are type 2 in secondary failure of OAD therapy. more, the clearance of most forms of injected Management 619 insulin is generally slower than endogenous acteristics can be manipulated. Other chemical insulin, the half-life of soluble insulin after SC manipulation produces ultra-long-acting (basal) injection being about 1 h. formulations. A number of premixed formula- Until recently the most common compromise tions provide combinations of these properties. was to give a mixture of a fast-acting and a moderately long-acting preparation before Ultra-short (rapid) action. By substituting breakfast (e.g. soluble plus lente), perhaps with a different amino acids at key positions, insulin booster dose of soluble in the evening. With analogues have been produced that exist in appropriate ‘feeding the insulin’ throughout the monomeric form with little tendency to asso- day (p. 605) acceptable control can be achieved. ciate but retain full activity at insulin receptors. However, it results in relative hyperinsulinaemia, In insulin lispro lysine and proline are placed at a tendency to hypoglycaemia during the day and positions B28 and B29 near the end of the B after midnight (especially if a meal or snack is chain; insulin aspart has aspartic acid at B28. missed or there is unanticipated exertion), and These agents have an onset of less than 15 min, hyperglycaemia before breakfast (Figure 9.8). reach a higher peak within about half the time of Three recent advances have brought treat- conventional soluble insulin (1 h as opposed to ment closer to the ideal for many patients. 1.5–2.5 h) and a duration of action little greater Ultra-short-acting analogues such as lispro allow than 5 h (as opposed to 6–10 h). Thus, they can closer matching to meals; long-acting analogues be injected less than 15 min before a planned such as glargine provide more consistent basal meal, or even just after one has been started; the levels; and ‘insulin pen’ systems permit easier optimal time will need to be determined for each and more accurate injection. patient. The advantages include: • Less imposed delay between injection and Insulin types food intake (especially breakfast), and/or reduction of postprandial hyperglycaemia if Developments in insulin technology have delay not observed. produced a range of chemically pure, immuno- • Convenient pre-meal bolus doses, as part of logically neutral preparations of standard basal-bolus regimen (below). strength (100 units/mL in the UK and North • Easier adjustment for unexpected food intake America) with a wide range of pharmacokinetic or missed meal. parameters. • Reduction of between-meals hypoglycaemia, caused in some patients by excessive duration Pharmacokinetic differences of action on regular short-acting preparations. Formulations of insulin can be divided into four • Less reliance on foods with a low glycaemic broad groups depending on their duration of index. action; their times of onset and periods of peak activity also vary considerably (Table 9.18). The However, there is no advantage in using these fastest action is provided by solutions of insulin. intravenously instead of soluble insulin in emer- In solution, insulin molecules normally associate gencies or as part of a ‘sliding scale’ regimen (see non-covalently into hexamers, which are below). Patients who switch need careful re- progressively dissociated by dilution in body education about the relative timing of injection fluids to the active monomer. This process, and food intake. which delays onset and prolongs duration, can Short action. Clear solutions of soluble be accelerated by small rearrangements of (neutral) insulin act less rapidly than ultra-short molecular structure that affect association char- analogues and are cleared within 6–10 h. They acteristics but not pharmacodynamic activity. are useful: Increased duration may also be provided by forming stable suspensions of carefully • when IV use is required, e.g. for ketoacidosis; controlled particle size that gradually dissolve in • when titrating a newly diagnosed patient’s a uniform manner. Alternatively, solubility char- requirement; Table 9.18 Approximate pharmacokinetic parameters of insulin preparations(a)

Insulin preparation Duration of activity (h)(b) Retarding agent 123456781012141618202224 ...... 36

Ultra-short Lispro/aspart

Short Neutral/soluble 1(c) Neutral/soluble 2

Intermediate/ IZS amorphous Zinc prolonged Biphasic isophane 1(c) Protamine Biphasic isophane 2 Biphasic isophane 3

Isophane (NPH) Protamine

IZS mixed Zinc

IZS crystalline Zinc

Protamine zinc suspension Protamine ϩ zinc

Basal Insulin glargine/detemir

(a) Data given are only approximate comparative indications. Activity in patients varies with manufacturer, dose, site and technique of injection, etc. (see Table 9.20). (b) Duration of biological activity Peak activity (c) Numbers indicate representative different preparations available in UK. IZS, insulin zinc suspension; NPH, neutral protamine Hagedorn; Biphasic, generic name for range of mixtures of short- and medium-acting preparations. Management 621

• in a continuous SC infusion system; tions available. If an excessive dose of this type • for the temporary insulin therapy of type 2 is injected, the hypoglycaemic effect is corre- patients during pregnancy, surgery or severe spondingly prolonged and glucose or glucagon illness. injection may be needed to reverse it. Because the variability in response between different Soluble insulin is being replaced by ultra-short- preparations increases with the duration of acting preparations when a booster dose is action (even in the same patient), these very needed rapidly, or when frequent injections are long-acting forms are little used unless patients needed for patients with brittle diabetes. of long standing are stabilized on them. Soluble insulin to cover a particular meal A variety of premixed biphasic preparations should be injected 15–30 min, or occasionally (compatible combinations, usually of soluble 45 min, beforehand. When newly diagnosed and isophane forms) are available to provide type 1 patients are being assessed they are further flexibility. Some patients mix specific usually put on an insulin sliding scale regimen, combinations immediately before injection. with 4-hourly soluble insulin doses adjusted according to the current blood glucose level. Basal. A more physiological approach to insulin provision has recently evolved. The Intermediate and prolonged action. Many basal-bolus regimen is designed to provide a patients still receive part of their daily insulin continuous backgound level of insulin supple- dose as a depot injection. This is intended to mented by bolus doses at mealtimes. Existing provide a continuous basal level of insulin for prolonged action formulations, while lasting metabolic activity, with little effect on postpran- 24 h or more, did not provide the required dial glucose disposal. The particular regimen is consistency of release: they all tended to give a dictated partly by life pattern and patient prefer- peak at 6–12 h (Table 9.18). Two different strate- ence, but ultimately by trial and error. Depot gies have been devised to solve this problem. In preparations are formulated by complexing insulin glargine, amino acid substitutions have insulin with either zinc or protamine, a non- changed the isoelectric point of the molecule allergenic fish protein. This produces a fine from below pH 7 to neutral. As a result it is suspension that is assimilated at a rate that is soluble when administered in a slightly acid dependent on particle size and injection site solution but precipitates out as microcrystals at perfusion. Being a suspension, it cannot be given body pH after injection. Subsequent dissolution intravenously. Available products span a wide and absorption from the depot provides a spectrum of times of onset, peak activity and predictable, consistently sustained action with duration, allowing flexibility in tailoring an essentially flat activity profile for up to 24 h regimens (Table 9.18). (Table 9.18). In insulin detemir, attaching a C14 The insulin zinc suspension (IZS) range contains fatty acid chain to the insulin molecule substan- an insulin–zinc complex in either crystalline or tially increases reversible binding to albumin in amorphous form, the latter being more readily body tissue, with a similar result. absorbed. Insulin zinc suspension mixed is 30% crystalline and 70% amorphous, and insulin zinc Purity and antigenicity suspension crystalline is 100% crystalline, with There are two significant factors here: chemical, proportionate increases in duration of activity. and therefore immunological, similarity to (Insulin zinc suspension amorphous, which is no human insulin; and contamination with extra- longer available, was purely amorphous and neous antigenic material. Originally, all insulin combined prompt onset with quite prolonged, was extracted from ox or pig pancreases supplied but rather variable, action). Isophane insulin by slaughterhouses. (Approval for insulin treat- containing protamine as the retarding agent also ment from these sources has been obtained from has an intermediate activity. most major religions, but strict vegans may Protamine zinc insulin and insulin zinc suspen- present a problem.) Beef insulin differs from the sion crystalline are the longest-acting prepara- human insulin polypeptide sequence by three 622 Chapter 9 • Endocrine system amino acids, and porcine by just one. These phenomena and resistance. These may be differences affect antigenicity but not hypogly- partially inter-related. caemic potency. As may be expected, porcine is the better tolerated, but neither causes great Hypoglycaemia problems. This is the most common complication of Contaminants derived from the extraction insulin therapy and potentially the most process (e.g. pro-insulin), insulin breakdown harmful; the clinical aspects were discussed on products and other unrelated proteins, can stim- pp. 596–598. Insulin can cause hypoglycaemia ulate the production of insulin antibodies, and either through an excessive (e.g. mis-measured) allergic reactions used to be quite common. dose or through an unexpectedly reduced Consequently, chromatographic purification is insulin requirement (most commonly, a missed now used giving highly purified or mono- meal). component animal insulins that cause far fewer Human insulin has been associated with an problems. apparent increase in the incidence of hypogly- Human insulin is made either semi- caemic attacks, including some deaths. This was synthetically, by chemically modifying the initially attributed to a reduced hypoglycaemic single variant amino acid in purified porcine awareness, i.e. hypoglycaemia is not more insulin (emp, enzyme-modified porcine), or common but is permitted to progress more biosynthetically (crb, chain recombinant-DNA frequently. The autonomic warning symptoms bacterial; prb, proinsulin recombinant-DNA of hypoglycaemia (see Table 9.12) seemed to be bacterial; pyr, precursor yeast recombinant). experienced less intensely or at a later stage Biosynthesis is becoming the preferred process when using human insulin, perhaps owing to and human insulin now costs less than animal autonomic (sympathetic) neuropathy. forms. There is no pharmacodynamic rationale for Unfortunately, the expectation that human this phenomenon and it has been suggested that insulin would be vastly superior has not been it is only incidentally related to human insulin realized. Anti-insulin antibodies are not signifi- use. The change to human insulin came at a time cantly less common with human insulin than when the need for tighter control became with the highly purified porcine form, and apparent and aids to this, e.g. injector pens and allergic phenomena still occur, probably due to home blood glucose monitoring, were devel- breakdown products occurring during manufac- oped. Improved control produces lower mean ture, storage, etc. Nevertheless, almost all new glucose levels and therefore an increased risk of patients are started on human insulin, and use of hypoglycaemia. Thus it is not now regarded as a animal-derived insulin is now rare. serious problem of human insulin, although it is Human insulin is slightly more hydrophilic stressed that great care is necessary in transfer- than animal forms. Thus, although it has an ring a patient to human insulin. Close moni- identical biological action to pork insulin when toring is essential and the daily dose may need to given intravenously, it is assimilated more be reduced, particularly when changing from rapidly from SC sites and acts more quickly in beef insulin or for patients with a higher than otherwise identical formulations. It is also average daily insulin requirement. cleared more rapidly, possibly by binding more avidly to those hepatic and renal enzymes that Injection site lipodystrophy destroy it. These differences are slight and only Some patients develop unsightly lumps (lipo- relevant to patients transferring from one form hypertrophy) or hollows (lipoatrophy) at to the other. frequently used injection sites if they fail to rotate the sites regularly. These are not due to scar tissue but are caused by local disturbances of Adverse reactions lipid metabolism. Lipoatrophy seems to be an The chief adverse effects of insulin are hypogly- immunological phenomenon; immune complex caemia, injection site problems, immunological deposition may possibly stimulate lipolysis in SC Management 623 adipose tissue. It responds to changing to a purer progressively higher concentrations to induce form of insulin, initially injected around the tolerance. Very occasionally, local steroid depression. Lipohypertrophy is more common injections need to be given with the insulin. with the newer insulins and may result from The term insulin resistance tends to be used in enhanced local lipogenesis, a known insulin an ambiguous manner (Table 9.19). In patho- action. It is reversed when the site is no longer genetic terms, it refers to one of the common used. Although patients may prefer to inject at underlying problems of type 2 diabetes, namely these easily penetrated, relatively painless sites, reduced receptor sensitivity. As an adverse effect such an approach results in delayed and erratic of insulin treatment, it refers to the requirement absorption. in some insulin-dependent diabetes for doses of insulin far above the physiological norm. Insulin antibodies and insulin resistance In the latter sense, insulin resistance occurs Insulin antibodies (insulin-binding globulins) only rarely and may be defined as an insulin occur in up to 50% of insulin-treated patients. It requirement Ͼ1.5 units/kg/day (about 100 units might be expected that they would speed the daily in an average patient). There are many clearance of insulin by forming immune possible causes; probably the most common is complexes that would be eliminated in the usual simply obesity, but poor injection technique way by the monocyte–macrophage system. may be an unsuspected problem. Insulin resis- However, on the contrary, insulin antibodies tance is less common now with the use of delay assimilation and prolong the action and so the monocomponent and human formula- are potentially beneficial. They are otherwise tions. Treatment involves eliminating any usually harmless, although they may sometimes obvious cause and then gradually switching to be responsible for insulin resistance (see below). highly purified or human insulin. As a final Insulin allergy ranges from minor local irrita- resort, systemic steroids, which are themselves tion to, very rarely, full-blown anaphylaxis. The diabetogenic, may be needed. less serious reactions commonly remit on prolonged use and are minimized by using the Administration highly purified modern insulin formulations as first choice. The size of the insulin molecule is Delivery systems borderline for antigenicity. Hyposensitization Pen injectors. Multidose insulin reservoir has been used to treat insulin allergy, by injector pens are now the most popular delivery injecting extremely dilute insulin solutions at system. Each pen has a replaceable cartridge

Table 9.19 Possible causes of insulin resistance

Metabolic Obesity Increased catabolic hormones Interacting diabetogenic drugs (e.g. steroids)

Immunological Anti-insulin antibodies Anti-insulin-receptor antibodies

Pharmacokinetic or biopharmaceutic Poor injection technique Increased insulinase activity Reduced assimilation from injection site • local enzymic degradation • scar tissue • lipohypertrophy Genetic Receptor defect 624 Chapter 9 • Endocrine system loaded with up to 300 units (3 mL), representing loop’ option, without the automatic dosage up to 1 week’s supply for some patients. There control. An external reservoir/pump strapped to are various forms of metered-dose injectors. One the body delivers a continuous basal level of automatically delivers a 2-unit dose for each insulin via an indwelling catheter, with meal- depression of a trigger, i.e. 2 units per ‘click’, a time boosts being activated manually. Modifica- situation that is particularly beneficial to visually tions include an implanted pump, contolled by impaired people with diabetes; another form radio, and the use of an intraperitoneal catheter, permits full doses to be preset visually on a which has the theoretical advantage of more digital scale, which may be palpable or audible. closely mimicking the natural insulin secretion. Most have a maximum deliverable single dose to Clearly this method would only suit patients minimize the risk of overdose. Each type of pen who are able to manage the technology and should only be used with the appropriate understand the relationship between blood cartridge. The main advantages are correct dose glucose, diet, activity and insulin dose. However, measurement, and hence less error, and the current prototypes are as yet too bulky, expen- facilitation of multiple daily dosing as part of a sive and demanding of patients’ motivation for basal-bolus regimen. general use.

Standard syringe. The use of disposable plastic Other forms. Simple oral administration of syringes with fixed needles is no longer the norm insulin is impossible owing to intragastric in the UK. If stored in a fridge, these syringes may enzymic destruction. Systems are being devel- be re-used for up to 1 week, without significant oped that avoid this but do not require the contamination of the vial contents (which complications of injection. One approach is to contain a bacteriostat) and no increase in skin incorporate insulin into liposomes that would be reactions. Patients change the syringe when the taken orally. The lipid coat would act as an needle is blunted or the barrel graduations enteric coating and the liposomes would be become unclear. Injection through clothing, long absorbed unchanged from the gut, as are practised by some people with diabetes, has also chylomicrons. Percutaneous jet injection has been reported to not cause significant problems. also been tried. Intranasal administration is Patients must use a safe method of contaminated being explored, using a liposomal or polymer waste and ‘sharps’ disposal. vehicle. People with diabetes with advanced nephropathy on peritoneal dialysis find it Artificial pancreas. The ideal replacement convenient to add insulin to their dialysis fluid. pancreas has not yet been constructed. One A metered dose inhaler (inhaled human insulin, experimental approach involves a feedback- Exubera) for pulmonary absorption is now avail- controlled, blood-glucose driven ‘closed loop’ able in the UK. It seems to offer an activity system. A sensor in an IV catheter monitors profile similar to injection with the rapidly blood glucose continuously and the results are acting insulin analogues but may be more fed to a microprocessor that calculates the acceptable to some patients in combination with instantaneous insulin requirement. This drives a a single basal insulin dose by injection. Concerns portable pump, strapped to or implanted in the remain over cost and possible lung damage, patient, delivering the appropriate dose. The especially in smokers, who should not use it. main problem is in designing a suitably sensitive Moreover, bioequivalence is an issue for patients indwelling blood glucose sensor. In another switching to inhaler, not least because the dose is experimental system, an implanted insulin expressed in milligrams, 1 mg being equivalent reservoir enclosed in a glucose-sensitive gel to 3 units. membrane permits insulin diffusion in propor- tion to external glucose concentration. The Storage reservoir is replenished percutaneously. Insulin should always be kept cool, but is Continuous SC insulin infusion is a more stable at room temperatures for up to 28 practicable but still relatively expensive ‘open days. Formulations incorporating polyethylene- Management 625 polypropylene glycol, specially developed for universally recommended. Most patients cope prolonged reservoir use, are stable for even well, but instruction and counselling when treat- longer. Thus, insulin may safely be used in ment is started are clearly important, especially pens and continuous SC infusion, etc. and with children. Diabetes UK and a number of while travelling. Pharmacy stocks and patients’ interested manufacturers produce helpful reserve supplies are refrigerated (but not literature on this and all other aspects of diabetes frozen). Before withdrawing a dose, the vial care. should be warmed to body temperature and Equally important is the need to rotate the site gently mixed by inversion or rotation (but not of injection regularly so that any one site is only shaken). used once in 10–20 injections. Seven general areas are recommended by Diabetes UK (upper Mixing arms, thighs, buttocks, abdomen), but within If a combination of two preparations of different these areas the precise injection site used on one durations is required, specially formulated occasion can be avoided on the next; they proprietary mixtures should be used whenever provide a template to assist such variation. This possible, and extemporaneous mixing avoided. minimizes skin reactions, especially lipohyper- The insulin zinc suspension formulations are trophy. Patients can also use the slower assimila- intended to be stable after intermixing but tion sites, e.g. thighs, for the overnight dose. others are not, and mixtures of these must be Sites usually covered by clothing are preferred. injected within 5 min. One problem is the Factors that may alter absorption from the adsorption of the soluble form onto the retar- injection site, possibly upsetting control, are dant from the longer-acting one, which may summarized in Table 9.20. seriously interfere with the expected rapid action of the former. The order of mixing is important: Dosage regimens the soluble form is drawn up first, then the depot form. This avoids contamination of the whole An initial dose titration period on first starting vial of soluble insulin with zinc or protamine. insulin will indicate the total daily dose required, but decisions on how this is to be Injection distributed throughout the day require discus- Now shorter needles have become available, sion with the patient. With fewer, medium- deep SC injection perpendicular to the skin is acting injections overall control is poorer and

Table 9.20 Factors affecting insulin absorption from injection site

Factor Example Effect on absorption Slower/reduced Faster/increased

Pharmaceutical Incorrect mixing of delayed and rapid forms ϩ (especially if injection delayed) Depth of injection ϩϩ

Local inactivation Proteolytic enzymes ϩ Insulin antibodies ϩ

Local perfusion Regional differences (abdomen Ͼ arm Ͼ thigh) ϩϩ Exercise (in limb sites); massage ϩ Skin temperature ϩϩ Angiopathy ϩ Scar tissue ϩ

Lipohypertrophy ϩ 626 Chapter 9 • Endocrine system there is the added risk of hypoglycaemia, with The choice ranges from multiple daily injec- the threat of coma if a meal is missed. However, tions of short-acting insulin closely co-ordinated when multiple injections are linked with close with eating and activity pattern, to a convenient blood glucose monitoring, aimed at achieving but very unphysiological single daily dose of a lower glucose levels (so-called ‘tight glycaemic longer-acting preparation (Table 9.21). control’) there is the risk of more frequent Whatever the regimen, the total daily dose episodes of hypoglycaemia. On the other hand, required is usually 0.5–1.0 unit/kg (about 2 use of multiple short-acting regimens can lead to 50 units). This is usually divided as ⁄3 during the 1 hyperglycaemia between injections and poorer day and ⁄3 at night for minimum frequency control. For each patient a balance must be regimens and 50/50 for basal-bolus regimens. struck that imposes no more restriction on their life than they are prepared to tolerate, which as Minimum dose frequency regimen closely as possible meets their treatment objec- Because of the potential compliance benefits of tives. Achieving this is not easy. Factors to fewer daily injections, this method used to be consider are: favoured. However it is no longer preferred because it imposes inflexibility on activity • the patient’s pattern of glycaemia (e.g. patterns and mealtimes, and risks both poor nocturnal hypoglycaemia, morning hyper- control and episodes of hypoglycaemia. The glycaemia); regimen usually consists of morning and • age; evening doses of a combination of short- and • severity of complications; medium-acting preparations, the relative doses • occupation, social habits and routine; being determined by trial and error. • compliance; There are numerous possible variations. For • physical disabilities; example, the morning dose could be a mix of • comprehension of disease, prescribed regimen about one-third soluble and two-thirds interme- and associated equipment; diate-acting forms, which covers breakfast and • patient preference; provides a sustained level throughout the day. • ethnic and religious constraints. This may be repeated in the evening, or later in The blood glucose targets are usually: those patients who get serious pre-breakfast hyperglycaemia. Alternatively there may simply • never below 4 mmol/L; be a booster dose of soluble before the evening • fasting (preprandial) 4–7 mmol/L; meal. If one of the commercially available • postprandial and bedtime Ͻ9 mmol/L. premixed combinations can be used it is Specialized units can organize test periods of certainly convenient, especially with a pen. 24-h blood glucose monitoring via temporary More flexibility is provided by individually indwelling sensors to plot the patient’s pattern determined combinations, but a pen cannot of glycaemia. However, the interpretation of then be used. these data is complex and it is an uncommon Some patients can be controlled satisfactorily technique. Somewhat easier is for the patient to with just a single dose of a long-acting form. This perform a short period of self-monitoring and includes type 2 patients with significant residual recording, the results of which can be discussed endogenous insulin production in whom OADs with their diabetologist. have failed, and some elderly patients requiring There are also more general considerations, only symptomatic relief and for whom the threat especially when first starting insulin. Many of long-term complications is less critical. people have a distaste for injections or fear them, and the psychological stress of accepting reliance Multiple injections on injections for life can be substantial. This is These are now preferred for all patients who can more of an issue with type 2 patients as they manage to self-inject frequent doses of short- approach secondary failure on OADs, which is acting insulin throughout the day, before each considered below. food intake. In addition, an evening dose of Management 627

Table 9.21 Examples of insulin regimens

Regimen Before Before Before Bedtime Examples of patient groups suited breakfast lunch evening meal to the regimen 1a Long(a) ϮϪϪ Ϫ · short Insulin-requiring type 2 (with metformin) 1b ϪϪϪIntermediate Some elderly patients

2 Intermediate Ϫ Intermediate Ϫ Some type 1 ϩ short ϩ short

3 Intermediate Ϫ Short Intermediate Some type 1 ϩ short

4 Short Short Short Intermediate Well-motivated type 1 Unstable Morning hyperglycaemia and/or nocturnal hypoglycaemia

5 Ultra-short-acting Ultra-short Ultra-short Long-acting Well-motivated type 1 (Basal-bolus) analogue(b) analogue(c) Many newly diagnosed type 1

(a) Duration of action. (b) E.g. Insulin aspart or lispro. (c) E.g. Insulin glargine or detemir.

long-acting insulin is given for basal needs. The Insulin for type 2 patients most recent variation of this basal-bolus regimen Most type 2 patients will eventually need insulin utilizes ultra-short-acting and long-acting as their beta-cell capacity become exhausted analogues, e.g. Table 9.21, regimen 5. (secondary failure). Owing to the insulin resis- A multiple injection regimen is especially tance common in type 2, their insulin require- useful for brittle patients requiring close control, ment when they become completely insulin or for temporary transfer of patients to insulin, dependent will often exceed that of a type 1 e.g. type 2 patients during pregnancy or with patient. However, it may be preferable not to serious infections. However, many clinics are wait until insulin is absolutely necessary to starting most new patients on such a regimen, initiate treatment. It may be psychologically for which injector pens are ideal. Existing preferable to start patients on a combination of patients are also being converted. Many patients oral agents and small insulin doses. They will can, with experience, finely judge the dose invariably note an improvement in their well- required according to their food intake and exer- being and can adjust to insulin injections before cise. Others, more committed, will measure their becoming completely reliant on them. The blood glucose level immediately before the next combination can also be helpful in difficult to scheduled dose and adjust the insulin dose control type 2 patients with high insulin resis- accordingly. tance, or those with persistent morning hyper- The improved, more physiological control glycaemia. Another situation where the provided by this type of regimen reduces the combination is useful is with patients who are development or progression of complications; in already using insulin but are showing resistance: some trials they have even remitted. Such regi- adding metformin may reduce their insuin mens can also, if used properly, minimize the requirement. risk of hypoglycaemia between meals and of The most logical combination is insulin plus overnight hyperglycaemia. an insulin sensitizer. Metformin is the usual 628 Chapter 9 • Endocrine system choice. Combining insulin with a secretagogue Urine glucose estimations can never provide such as a sulphonylurea or a meglitinide is irra- precise information about current blood glucose tional. One regimen is to add a small dose of levels, particularly low, potentially hypogly- about 15 units of medium-acting insulin each caemic ones. Urinary concentrations will vary evening. When switching to this regimen, OAD according to urine volume independently of doses are reduced. blood glucose. Furthermore, aglycosuria does not necessarily guarantee normoglycaemia, Summary owing to differences in renal threshold between Diabetes therapy must be individualized patients and in the same patient at different following regular close consultation between times. patients and their clinicians. To a certain extent Nevertheless, urine testing remains useful as a the optimal result is found by trial and error, but simple initial screen and for type 2 patients not this must be supported by diligent monitoring of prone to hypoglycaemia when tight control is blood glucose and reporting of all hypogly- not essential, e.g. the elderly and patients averse caemic episodes and other disturbances of to repeated skin puncturing. A few patients may control. be monitored adequately by regular urinalysis and occasional blood glucose measurements, once the relationship between the two has been established. Monitoring Urinary glucose measurement also has the advantage that timing is less important than People with diabetes require self-monitoring of with blood testing because urine concentration their biochemical control, and regular assess- reflects control over the previous several hours. ment by a clinician of the development or Thus, newer glucose oxidase-based urine progress of long-term complications. The former dipsticks have been developed that are more has recently been much simplified and specific for glucose and far more convenient improved. Type 1 patients need much closer because they can simply be passed through the monitoring than type 2. urine stream.

Blood glucose Biochemical control There are three main uses for blood glucose monitoring: to detect hyperglycaemia or incip- While even moderate control relieves symp- ient hyoglycaemia; to monitor closely in times toms and prevents serious biochemical abnor- of changing glucose/insulin need (e.g. intercur- malities, tight control is believed to be essential rent illness); and to determine a new patient’s if complications are to be minimized. In general, diurnal glucose profile so as to construct an diligent monitoring is more important for type 1 appropriate insulin regimen. diabetes, but all patients should record all test Most patients, especially with type 1 disease, results. measure their blood glucose directly using a drop of blood from a finger prick on a glucose oxidase stick. This provides an immediate measure of Glucose glycaemia that is reasonably accurate and reli- Urine glucose able, not overly prone to error from poor tech- This has been the traditional way of assessing nique, and easy to read. Sticks for unaided visual control. A few elderly patients still use the colour reading are being replaced by ones to be inserted reaction based on Benedict’s test for reducing into automated meters that display the result substances. It is imprecise, non-specific and digitally and may give audible warnings. Some cumbersome, even with the ingeniously meters can store the most recent results, for formulated Clinitest reagent tablets. reporting at clinics. Monitoring 629

Various spring-operated skin puncture devices measured at diabetic clinics and is useful in may be used to help obtain the blood drop easily tracing any problems with control that might and safely, and percutaneous techniques of not be revealed by patients’ tendency to be extra measurement are being developed. meticulous on the few days before each clinic A few type 1 patients regularly test four times visit. daily, including at the lowest points, before meals Care must be taken to ensure adequate time and in the morning, and at the high point after between successive measurements, especially meals. This is necessary only in the more erratic, after a treatment change. This allows the level to brittle patients, in intensive multiple-dose regi- restabilize, bearing in mind the normal 120-day mens in younger patients, or when previously red cell lifespan. A reading taken too soon will well-controlled patients start to experience prob- give a falsely high reading because the glycosy- lems. Others, once stabilized, will test randomly a lated red cells originally measured will not have few times weekly and some may perhaps use died. One the other hand, when there is a urine dipsticks daily. The main guideline is to reduced red cell number or increased cell identify a patient’s risk times (e.g. between-meal turnover, e.g. in haemolysis or blood loss, a hypoglycaemia or postprandial hyperglycaemia) falsely low reading may be given. and subject those to special scrutiny. The glycated Hb level gives the best index of Once type 2 patients have become stabilized, the control needed to minimize complications weekly or even monthly fasting blood glucose and is now regarded as the ‘gold standard’. Non- measurement is usually sufficient. diabetics have about 5% of glycated Hb (HbA1c) Dose modification falls into two basic strate- and the target level for optimal diabetes control gies. Well-motivated patients on the basal-bolus is currently Ͻ7.5%, or Ͻ6.5% in patients at regimen who are suitably trained by the diabetic increased arterial risk, e.g with hypertension. team will be able to modify their next insulin dose, based on the results of their preprandial Ketones glucose level and the glycaemic content of their next meal. This is termed ‘dosage adjustment for Regular ketonuria monitoring is unnecessary for normal eating (DAFNE)’. type 2 and most type 1 patients, but is essential For patients who prefer regular dosing, in brittle ketosis-prone people with diabetes, and frequent changes following this apparently in all patients during periods of metabolic stress logical DAFNE strategy is both inconvenient and such as infection, surgery or pregnancy. Great inappropriate. More systematic is to note pre- accuracy is not required and urine dipsticks are meal blood glucose over several days. If it is adequate because any ketonuria at all in the pres- consistently unsatisfactory, they must alter the ence of glycosuria indicates a dangerous loss of previous scheduled dose on future days, because control. Combined glucose/ketone sticks are the current pre-meal level is a reflection of the preferred, especially as heavy ketonuria may previous dose. interfere with some standard glucose sticks.

Glycated (glycosylated) haemoglobin Clinical monitoring The abnormal, quantitative glycation of systemic protein as a consequence of excess In addition to biochemical monitoring, regular blood glucose (p. 599) applies also to blood medical examination is important in the long- proteins, including Hb and albumin, as well as to term care of people with diabetes. This will iden- plasma fructosamine. Because these substances tify as early as possible the development of any remain in the blood for long periods (120 days of the many possible systemic complications. for Hb, 7–14 days for the others), their glycation Table 9.22 lists the factors that need to be gives a long-term, integrated picture of blood monitored at intervals that will vary from glucose levels over those periods. This can be patient to patient. 630 Chapter 9 • Endocrine system

Table 9.22 Regular assessment in diabetic clinic

System Test or examination

Biochemical Glycated haemoglobin Blood lipids, body weight Feet Chiropody; pulses Eye Fundoscopy, acuity, cataract Renal Proteinuria, creatinine (clearance) Neurological Detailed sensory, motor and autonomic neurological examination Cardiovascular Blood pressure, ECG, peripheral perfusion (pulses, etc.) Symptoms of ischaemia

Thyroid disease

Thyroxine is a simple catechol-based hormone the organification of iodine. Ionic iodide in the but it has multiple crucial subcellular actions blood is taken up by the thyroid gland by an essential to life. It is involved with oxygen active sodium/iodide symporter (Figure 9.14) utilization within all cells, and thyroid abnor- then, catalysed by thyroid peroxidase, oxidized malities have profound effects on most organ to give I2, which is then bound to the aromatic systems in the body. Thyroid disease is one of ring of the tyrosine residues. the most common endocrine disorders, yet Mono- and di-iodotyrosine are covalently fortunately it is relatively straightforward to treat attached to thyroglobulin within the colloid- and to monitor. This is partly because the filled thyroid follicles, dimerized with another thyroid axis is largely independent of other tyrosine ring, then further iodinated to either endocrine systems and partly because the long tri-iodothyronine (T3) or thyroid hormone half-life of thyroid hormone means that dosing (T4). T3 is five times more potent than T4, but is not as critical as for insulin replacement. Thus 75% of thyroid hormone is synthesized and frequent variations in thyroid hormone levels do transported as T4. This is largely converted in not normally occur and the acute disturbances target tissues to T3. Several weeks’ supply is of control seen with abnormal insulin and stored in the gland in the bound form, but it is glucose levels are rare. Furthermore, long-term released into the blood as free hormone. complications are few and uncommon. In this chapter the term thyroid hormone(s) will be used when referring to the natural physi-

ological hormone. Thyroxine (T4) when used as a drug is officially termed levothyroxine, and Physiological principles tri-iodothyronine (T3) when used as a drug as liothyronine. Synthesis

Thyroid hormone is synthesized from the Control and release aromatic amino acid tyrosine (closely related to phenylalanine and cathecholamine) in the Control of thyroid function is an example of a thyroid gland, which sits across the trachea in classic endocrine negative feedback loop, which the front of the neck. Iodine is an essential ingre- enables fine control of many body systems dient, and the conversion from dietary inorganic according to need. A relatively simple peripher- iodide to iodinated thyroid hormone is termed ally active hormone (thyroid hormone) is Physiological principles 631

Thyroid gland

Na/l symporter Thyroid peroxidase Thyroid peroxidase ؊ ؊ I I I2 MIT DIT T4 T3 blood Tyrosine

Thyroglobulin Thyroglobulin

Free T4, T3

T4 T3 Serum

Free T4, T3 Thyroxine-binding globulin (0.02%)

Figure 9.14 Thyroxine synthesis. I, iodine; MIT, mono-iodotyrosine; DIT, di-iodotyrosine; T3 tri-iodothyronine; T4, thyroxine; Na/I symporter, see text. released from an endocrine gland that is its site Distribution and metabolism of synthesis, stimulated by a peptide trophic hormone (thyroid-stimulating hormone, Approximately 80 lg of thyroid hormones are thyrotropin, TSH) from the pituitary and also released daily, peaking overnight when TSH under CNS influence via a releasing hormone levels are highest. It has a biological half-life of (thyrotropin-releasing hormone, TRH) from about 7 days, being cleared by de-iodination in the hypothalamus (Figure 9.15). Both the the liver and kidneys. It is carried in the blood synthesis and the release of trophic and releasing almost entirely bound, mostly to thyroid- hormones are inhibited by the active hormone. binding globulin; only 0.02% is carried as free TSH is a 221-amino acid glycoprotein with T3 and free T4 (FT3, FT4). However, only the free receptors on the thyroid that mediate both the hormones are biologically active. synthesis and the release of thyroid hormones. It is the main physiological control on thyroid function, an important clinical indicator of Actions of thyroid hormone thyroid malfunction and a component in the aetiology of some thyroid diseases. Hypo- Thyroid hormone enters target cells and after thalamic control via the tripeptide TRH is less conversion to T3 interacts with nuclear receptors important because low thyroid hormone levels to influence the expression of genes coding for can stimulate TSH release directly, but it enables proteins invoved in energy metabolim, oxygen the CNS to exert an influence on thyroid consumption and general tissue growth; thus it function; it is particularly concerned with has far-reaching effects on metabolism, growth temperature control. Disease of this arm of the and development (Table 9.23). In some ways the thyroid axis is rare. action resembles that of catecholamines (e.g 632 Chapter 9 • Endocrine system

T3 (T4) Hypothalmus

TRH

Negative feedback T (T ) Anterior 3 4 loop pituitary

TSH

Thyroid

Clearance via serum hepatic and thyroxine renal [T4, T3] metabolism

Metabolic action

● ● Figure 9.15 Control and release of thyroxine (hypothalamic-pituitary-thyroid axis). ––––– inhibit; ––––– stimulate; T3, tri-iodothyronine; T4, thyroxine TSH, thyroid-stimulating hormone; TRH, thyrotropin-releasing hormone.

adrenaline), to which it bears a structural resem- fluid retention to maintain cardiac output and blance, but the effect is far more prolonged and blood pressure. more fundamental, whereas the catecholamines have a very brief action. CNS. The action on the CNS is known mostly through the consequences of thyroid Metabolism and growth. Thyroid hormone malfunction, considered below. There are has a generally catabolic effect, stimulating important effects on mentation and CNS devel- metabolism and increasing oxygen consump- opment. However, little is known of the precise tion, basal metabolic rate and body temperature. mechanisms. However, in children there are anabolic effects leading to protein synthesis and growth. Carbo- hydrate absorption is increased and plasma lipid Investigation levels fall. The three key parameters of thyroid function are

Cardiovascular and renal. There are inotropic serum levels of FT3, FT4 and TSH. Older tests and chronotropic effects mediated via up- measured protein-bound iodine and total regulation of numerous systems, including thyroid hormone, but now the precise radio- beta-receptors. In addition the calorigenesis pro- immunoassay of free hormones and TSH gives a motes peripheral vasodilatation and secondary far better correlation with physiological and Hypothyroidism 633

Table 9.23 Actions of thyroid hormone

System Effect

Metabolism

Calorigenesis↓ oxygen consumption and oxygen dissociation

basal metabolic rate, ↓↓ temperature

Lipid ↓ total cholesterol (↓ hepatic LDL receptors)

Carbohydrate↓ absorption from GIT Cardiovascular Inotropic: beta-receptors up-regulated

heart rate, ↓↓ cardiac output Peripheral vasodilatation Renal Fluid retention Neurological Essential for nervous system development (No calorigenic effect in brain) Growth Essential for normal growth, including bone clinical status. It is possible to measure the most prevalent endocrine abnormalities. Usually binding proteins, and several factors can the cause is idiopathic, often involving autoim- change binding, but the feedback control is muity, although iatrogenic causes occur. Detec- sensitive and precise, so FT4 levels tend to be tion and diagnosis are usually straightforward, very stable. It is not usually necessary to and management of hypothyroidism is also measure TRH. The measurement of FT4,FT3 simple. Hyperthyroidism is more complex to and TSH together is know as a thyroid func- manage and may develop complications. tion test (TFT). It has become clear that TSH There are several potentially confusing aspects levels are the most important index of thyroid to thyroid disease. Firstly, certain aetiological status, and management now stresses normal factors, such as autoantibodies, amiodarone and TSH levels. iodine, are common to both hypo- and hyper- In the initial investigation of thyroid disease thyroidism; similarly, an enlarged thyroid gland an autoantibody screen should be done for anti- (goitre) can occur in both. The action of thyroid antibodies, and also for anti-intrinsic iodine/iodide can seem paradoxical, causing factor and anti-gastric parietal cell antibodies, either stimulation or inhibition in different because there is an association with other circumstances. Long-term hyperthyroidism can autoimmune diseases including pernicious eventually evolve into hypothyroidism, and anaemia. Liver function, lipid profile, blood some forms of hypothyroidism can have a glucose and full blood count are also necessary. hyperthyroid phase. The possibility of primary hypothalamic or pituitary disease should always be borne in mind when thyroid dysfunction is detected, particu- Hypothyroidism larly hypothyroidism. In this case both thyroid hormone and TSH levels will be low. Aetiology and epidemiology

Thyroid disease Hypothyroidism is far more common in women than in men (prevalence 1.5% vs 0.1%) and Normal thyroid function is described as euthy- more common in the elderly, although it can roidism. Hypothyroidism (underactivity) and affect the very young and is then far more hyperthyroidism (overactivity) are about serious. It is usually due to intrinsic thyroid equally common and together constitute the gland disease although rarely it may occur 634 Chapter 9 • Endocrine system secondary to hypothalamic or pituitary disease, ature, and slowing of physical and mental or to drugs (Table 9.24). processes. More detail is given on p. 635. Simple atrophy is the commonest cause, mainly affecting elderly women. There may be an autoimmune component as it is sometimes Investigation and diagnosis associated with other autoimmune disease, but no antibodies are found. Autoimmune destruc- The standard thyroid function test is definitive. tion is the main cause of Hashimoto’s When thyroid hormone levels fall there is thyroiditis, which can affect the middle-aged almost invariably a compensatory rise in TSH. and elderly. Also common is hypothyroidism However, a small rise in TSH may precede both secondary to the treatment of hyperthyroidism clinical signs and a fall in thyroid hormone level (see below). by many months; this is known as subclinical In the developed world dietary iodine defi- hypothyroidism (see below). ciency is now almost unknown, partly owing to In rare hypothalamic-pituitary causes the iodination of salt, but it is far more common in combination of low FT4 and low TSH levels is developing countries. Congenital hypothy- diagnostic. roidism secondary to maternal iodine deficiency Screening for autoantibodies to thyroid perox- affects the developing nervous system of the idase or thyroglobulin is not necessary for diag- fetus to produce cretinism. nosis but can indicate a possible cause, and can The term myxoedema is sometimes used as a act as an alert for possible autoimmune compli- synonym for hypothyroidism but more precisely cations in Hashimoto’s thyroiditis. Occasionally describes one characteristic dermatological sign. there may be anti-TSH receptor antibodies with a blocking effect, although such antibodies are usually stimulant, causing hyperthyroidism Pathology (Graves’ disease, see p. 637). Hypothyroidism is often diagnosed following Low levels of thyroid hormone compromise vague generalized complaints of tiredness and many crucial metabolic processes, as can be lack of energy. However, these common symp- inferred from Table 9.23. There is a general toms can of course have many other causes, slowing of basal metabolic rate, a fall in temper- which sometimes makes diagnosis of mild

Table 9.24 Causes of hypothyroidism

Aetiology Example

Common (90% of cases in developed countries) Atrophy (idiopathic) Commonest form; no goitre Autoimmune destruction Hashimoto’s thyroiditis Iatrogenic Secondary to treatment of hyperthyroidism (antithyroid drugs, surgery, radiotherapy)

Less common Dietary Iodine deficiency where natural level low; goitre present Congenital Cause of cretinism (1/4000 in UK) Iatrogenic Lithium, amiodarone Secondary Hypothalamic or pituitary disease Hypothyroidism 635 disease problematic. Thyroid disease should dullnes of intellect combined with an unprepos- always be borne in mind as a differential sessing appearance. Therefore a history from a diagnosis of depression in the elderly. relative might be helpful, to identify recent or specific changes, which may be less apparent to the patient because onset is usually insidious. Clinical features The two most common erroneous diagnoses in mild disease would be simple ageing, owing to Most of the features of hypothyroidism can be the slowness, stiffness and general aches and understood from a knowledge of the physiolog- pains, or depression. ical action of thyroid hormone (Table 9.25). The The most characteristic symptoms are the overall clinical impression is of slowness and general physical and mental sluggishness,

Table 9.25 Principal clinical features of hypothyroidism

Common feature Less common

Systemic/metabolic Tiredness Weight gain Cold intolerance Hypothermia, cold periphery Goitre Hyperlipidaemia

Haematological Anaemia – iron deficiency – pernicious/macrocytic – normochromic normocytic

Cardiovascular Bradycardia Pericardial/pleural effusion Hypertension Heart failure

Dermatological Dry, thick skin Dry, thin hair; alopecia Myxoedema (non-pitting oedema) Periorbital oedema Vitiligo

Musculoskeletal Delayed relaxing reflexes Peripheral myopathy Slow movement Carpal tunnel syndrome Myalgia, arthralgia, stiffness Ataxia (unsteadiness) Deafness Hoarseness

Neuropsychiatric Depression Dementia Slow thought Psychosis Poor memory

Gastrointestinal Constipation Anorexia

Reproductive Menorrhagia/oligomenorrhoea Infertility Delayed puberty

Developmental Growth retardation Mental retardation; cretinism 636 Chapter 9 • Endocrine system lethargy, intolerance of cold, weight gain and Complications coarsening of the skin. The voice is hoarse and hair is dry, brittle and falling. There may be a If thyroid hormone levels are corrected there is characteristic swollen thyroid, visible in the neck no reduction in life expectancy and there are no as a goitre. long-term problems. The classic dermatological feature is Heart failure or ‘myxoedemic’ coma can be myxoedema, which is an accumulation of precipitated by severe metabolic stress, such as mucopolysaccharide in the dermis that causes trauma, infection or hypothermia, which may widespread skin thickening and puffiness. This acutely increase thyroid hormone require- form of oedema is non-pitting because it is not ment. Psychosis can also occur (‘myxoedemic caused by excess fluid accumulation (contrast madness’). If the fetus is exposed to inadequate with the pitting oedema of heart failure; see thyroid hormone in utero, irreversible neurolog- Chapter 4, p. 184). ical damage leads to cretinism. Hypothyroidism The heart rate is slowed and this may cause in children results in retardation of mental and heart failure. The periphery is cold. physical development that is partially reversible Thought processes and memory are impaired on thyroid hormone treatment. Newborn are and mild depression is common. There is usually routinely screened. weight gain and constipation, despite anorexia. Biochemically, in addition to abnormal thyroid functions tests (low FT3 and FT4, raised Management TSH), there is usually hyperlipidaemia and possibly abnormal liver enzymes. Haematology The management of hypothyroidism is relatively (see Chapter 11) may show a mixed picture of straightforward, simply requiring oral thyroxine iron deficiency (hypochromic, microcytic for life. The general aim is to restore T4, T3 and anaemia), folate and/or B12 deficiency (macro- TSH levels to within the normal ranges. TSH cytic anaemia) or simply a normochromic, should not be suppressed too much in an normocytic pattern. attempt to maintain T4/T3 at high–normal levels: this represents overtreatment and can lead to long-term cardiovascular complications. Thus a mid-range TSH level is usually regarded as the

Subclinical hypothyroidism primary objective, ensuring of course that T4/T3 are also within range. However, low-end TSH In some patients there are few if any symptoms levels are regarded by some as preferable. and FT4/FT3 levels are within normal limits but TSH is elevated; this might be identified as a Levothyroxine chance finding. The pathogenesis is probably an This is the synthetic replacement drug used for early stage of thyroid insufficiency being compen- maintenance therapy, which is identical to sated by slightly elevated TSH level, initally natural thyroxine (T ). (This has completely keeping thyroid hormone levels adequate. Even- 4 replaced the original dried thyroid gland, a tually the slowly progressive nature of idiopathic natural product derived from animal sources, hypothyroidism will lead to frank insufficiency with all the quality control risks these entail.) that does not respond to increasing levels of TSH: Levothyroxine is well absorbed on an empty thyroid hormone levels then fall and symptoms stomach, but absorption is delayed and possibly develop. Regular monitoring is all that is required reduced by food. Dosing is not nearly as critical during the asymptomatic phase. for levothyroxine in hypothyroidism as it is for Hyperthyroidism 637 insulin in diabetes, because levothyroxine has a Liothyronine half-life of about 7 days and a gentle Liothyronine (tri-iodothyronine, T ) has a swifter dose–response curve. Moreover, day-to-day 3 onset and shorter half-life than levothyroxine and requirements do not change even with intercur- it is about five times more potent. It is mainly rent illness, nor do they tend to alter over the used for emergency treatment of severely long term. Owing to the natural diurnal varia- hypothyroid states such as coma, or for initi- tion of TSH secretion, which peaks overnight, a ating treatment in those with CVD. It is available single dose is usually taken each morning before in injectable and oral forms. breakfast. Levothyroxine is initialized at 50 lg daily and increased by 50 lg daily every 2–4 weeks depend- ing on response. Clinical improvement is usually Hyperthyroidism evident within the first month of therapy. Thyroid function testing is required 6 weeks after each dose change. Most patients are stabilized on For several reasons, hyperthyroidism is not 100–200 lg daily; subsequently only annual TFTs simply the opposite of hypothyroidism. The will be needed. causes are more diverse, there are more potential More care is needed when initializing treat- complications and there are more treatment ment in the elderly or those with known IHD, options with worse side-effects. Note that the using a lower starting dose, e.g. 25 lg on alternate term thyrotoxicosis is used to describe the days, and smaller increments, because the cardiac syndrome resulting from excess thyroid over-stimulation could precipitate ischaemic hormone levels, but hyperthyroidism refers symptoms or even an MI. Sometimes liothyronine specifically to when the syndrome is due to excessive secretion from the thyroid gland. (T3) is used for its shorter half-life, permitting a more rapid correction of overdosing. Regular ECGs are advisable and beta-blocker cover may be needed to limit the heart rate. Aetiology and epidemiology

Side-effects Hyperthyroidism is about 10 times more The adverse effects of excess levothyroxine (thyro- common in women, in whom the point preva- toxicosis) are exactly what would be predicted lence is about 1%. However, the lifetime inci- from the physiological action of excess dence in women is over 2%, some forms being thyroxine and are described below (p. 640). With acute or reversible. overdosage, as with untreated hyperthyroidism, Graves’ disease, caused by IgG auto- there is the possibility of osteopenia or osteo- antibodies that stimulate the TSH receptor, is the porosis in women, which should be monitored. commonest form, representing some 75% of all cases (Table 9.27). It typically follows a fluctating Cautions and interactions but progressive course, eventually leading to The dose may require increasing in pregnancy. hypothyroidism, either naturally or as a result ot Hepatic enzyme inducers (e.g. rifampicin, pheny- treatment. toin) increase clearance. Some drugs reduce Autonomous growth of multiple, hyper- absorption, so levothyroxine should be taken at a secreting ‘toxic’ nodules in the thryoid gland is different time from sucralfate, aluminium the second most common form and this is more hydroxide and iron salts (Table 9.26). Other often seen in elderly females, but isolated ‘toxic’ factors that affect the control of hypothyroidism adenomas (benign tumours) can also occur. These are also shown in this table. are usually associated with goitre. Occasionally Table 9.26 Cautions and interactions of levothyroxine therapy

(a) Factors affecting thyroid function Increased thyroid hormone action or Reduced thyroid hormone action or thyroid function or levothyroxine treatment thyroid function

Interfere with thyroid – Enzyme inducers (e.g. rifampicin) hormone action ↓ absorption (e.g. aluminium hydroxide, iron, etc.) ↓ TSH secretion (corticosteroids, dopamine)

Interfere with thyroid status Amiodarone (inhibit peroxidase) Amiodarone (excess iodine) Lithium (unknown effect) Lithium (blocks iodine uptake and thyroid hormone release) Iodide/iodine excess, e.g. older ‘expectorants’ Iodine deficiency Ϫ Ϫ Monovalent anions e.g. pertechnetate (TcO4 ), perchlorate (ClO4 ), thiocyanate (SCNϪ): compete for iodine uptake.

Pregnancy (↓ thyroid hormone requirement)

(b) Drugs affected by Drugs with action enhanced Drugs with action diminished levothyroxine treatment

Drug interaction Sympathomimetic (mimic action) Propranolol, digoxin (↓ serum level)

Warfarin (potentially ↓ action – monitor) Insulin/oral hypoglycaemic (↓ glucose tolerance) Hyperthyroidism 639

Table 9.27 Causes of hyperthyroidism

Aetiology Examples

Most common (75%) Autoimmune stimulation Graves’ disease (stimulatory anti-TSH receptor antibody)

Less common Multinodal goitre Adenoma Thyroiditis Post partum, viral, autoimmune Iatrogenic Amiodarone, excessive levothyroxine dose Dietary Excess iodine

Rare Secondary Pituitary – excessive TSH secretion Other endocrine abnormalities

general thyroid inflammation (thyroiditis) usually show raised FT4 and FT3 and barely occurs following radiation, childbirth or viral detectable TSH. illness; there may be an underlying auto- Further investigation will depend upon the immune aetiology to this. It usually remits degree of suspicion of different aetiologies, but without recurrence. Thyroid cancer is one of could include: the most common radiation-induced tumours, • Autoantibody scan; thyroid peroxidase and via ingestion of radioiodine (131I), e.g. after thyroglobulin antibodies are usually found, radiological accidents such as at Chernobyl. but there is a 10–20% false-negative rate Amiodarone, which has a high iodine con- because they may also occur in unaffected tent, frequently causes mild hyperthyroidism, individuals. TSH-stimulating receptor anti- possibly leading to thyrotoxicosis on prolonged bodies are difficult to assay and are not therapy. It can also cause hypothyroidism (Table routinely sought. 9.24). Very rarely hyperthyroidism can be • Imaging is best done with radiolabelled secondary to pituitary hyperactivity (Table 9.27). sodium pertechnetate (99mTc), which is prefer- entially taken up into the thyroid by the symporter but not organified. This will show Pathology the overall size of the organ, with concentra- tion in any nodules, showing their number High levels of thyroid hormone cause a general and size. It is a prerequisite if ablation therapy acceleration of metabolic processes with is planned. Ultrasound is less invasive. MRI or increased metabolic rate and energy utilization, CT scanning is used if ophthalmopathy (see hyperthermia and increased cardiovascular below) is suspected. activity (see below). There is a compensatory fall • Biopsy: if a tumour is suspected. in TSH, often to undetectable levels.

Clinical features Investigation and diagnosis The clinical features of hyperthyroidism (Table Owing to the several possible aetiologies, more 9.28) should be contrasted with those of extensive investigation is required than for hypothyroidism (Table 9.25): the picture is hypothyroidism. Typical clinical features will strikingly different. The range of features varies invariably be borne out by a TFT, which will slightly according to aetiology but is broadly 640 Chapter 9 • Endocrine system consistent. Typically the patient is thin, pretibial myxoedema, where the deposition of nervous, agitated, hyperactive, hot, thirsty and fibrous material causes painless dermal nodules sweaty. on the shin. Examination will show a raised heart rate, possibly even atrial fibrillation; in severe cases there may be signs of heart failure. The neck will Course usually be swollen and auscultation of the goitre will reveal bruits (the sound of rapid, excessive Graves’ disease may follow a relapsing and remit- blood flow). There are also usually diarrhoea and ting course, with remissions facilitated by anxiety. therapy. However, remissions become decreas- In Graves’ disease the common complication ingly likely following each successive relapse. of ophthalmopathy (see below) will cause Paradoxically, the end-stage for some patients bulging eyes and an unblinking stare, known as may be autoimmume hypothyroidism. There is exophthalmos – the classic sign of thyrotoxi- an increased risk of osteoporosis and heart cosis. Another characteristic Graves’ feature is disease in untreated disease.

Table 9.28 Principal clinical features of hyperthyroidism

Common feature Less common

Systemic/metabolic Fatigue, weakness Hyperactivity, restlessness Weight loss Heat intolerance, sweating Hyperthermia, warm periphery Polydipsia Polyuria Goitre Bruit over gland (excess perfusion)

Cardiovascular Tachycardia, atrial fibrillation Heart failure (high output) Palpitations Hypertension

Musculoskeletal Hyper-reflexia Myopathy Tremor Lid retraction, lid lag

Neuropsychiatric Irritability, anxiety, dysphoria Depression Insomnia Psychosis

Gastrointestinal Increased appetite Diarrhoea

Reproductive Oligomenorrhoea Loss of libido

Dermatological Pruritis Pretibial myxoedema(a)

Ophthalmopathy(a) Grittiness Diplopia Periorbital, conjunctival oedema Impaired acuity Scleral injection (‘red eye’) Proptosis (exophthalmos)

Family history Autoimmune disease e.g. Graves’ disease, pernicious anaemia, vitiligo, type 1 diabetes mellitus

(a) Only in Graves’ disease. Hyperthyroidism 641

Complications • Pharmacological suppression. • Radio-isotopic thyroid gland reduction/ Ophthalmopathy (thyroid eye disease) ablation. • Surgical thyroid gland reduction/ablation. A characteristic eye disease affects about half of Graves’ disease patients. It is potentially serious Beta-blockers are used for symptom control and for unkown reasons it is associated with while other therapy is initialized. This is effective smoking. The cause is autoimmune inflamma- because many of the effects of thyroid hormone tion of the oculomotor muscles, with fibrous are sympathomimetic and resemble those of overgrowth. This pushes the eyes forward and adrenaline (epinephrine), including cardiac impairs eye movement. The overexposed corneas stimulation, tremor and anxiety (Table 9.23). can become dry and painful, and there may be Propranolol is preferred, probably because it is diplopia (double vision). In the most severe form non-selective and crosses the blood–brain (Ͻ10% cases) the retro-orbital swelling can barrier, helping the anxiety. Agents with compress the optic nerve and threaten sight. intrinsic sympathomimetic activity (e.g. pindolol; It can be detected by examination of eye see Chapter 4) should not be used. movement and testing for double vision at the Patients may use different modes at different extremes of lateral eye rotation, but MRI scan- stages in their illness. Typical paths are shown in ning is needed for precise assessment. Its severity Figure 9.16. After initial stabilization with is not related to thyroid hormone levels nor is it antithyroid drugs patients may go into remission relieved if euthyroidism is achieved by medical after a year or so and drugs may be withdrawn. or surgical means, probably because it is due to However, relapse is common and remission is antithyroid antibodies rather than excessive then less likely. Thyroid gland reduction aims at thyroid hormone itself. For most patients it is an a graded reduction in thyroid mass, hoping to unsightly inconvenience rather than a threat to leave enough remaining to produce normal sight. amounts of thyroid hormone. However, judging this is difficult and it is always preferable to err on the side of greater destruction, obviating the Thyroid crisis (‘storm’) need for further invasive therapy at a later date. This rare condition, which occurs when there are Consequently, eventual iatrogenic hypothy- very high levels of thyroid hormone, is poten- roidism is common. Alternatively, a full ablation tially fatal. There is excessive cardiovascular may be decided on at the outset, removing doubt stimulation, high fever and extreme agitation. It and easing management by starting the patient can be triggered in hyperthyroid patients by on thyroxine replacement immediately. Thus extra metabolic stress, such as infection, by the choice of options depends on the cause, mental stress, or by radioiodine therapy. severity, patient age and patient preference.

Autoimmune disorder Pharmacotherapy Other autoimune diseases including pernicious Antithyroid drugs are usually first-line treat- anaemia, myasthenia gravis, type 1 diabetes and ment. They block thyroid peroxidase rapidly, but vitiligo are more common among Graves’ symptom control takes 2–4 weeks owing to disease sufferers. stores of thyroid hormone and its long half-life. The most common agents are the thionamides. Carbimazole is preferred in the UK but propylth- Management iouracil is used in the USA. The latter also blocks

T4–T3 conversion but this may not be clinically The aims of management are symptom control significant. Most antithyroid drugs also have and reduction of thyroid hormone output. For immunosuppressant activity, reducing TSH- the latter, three modes are available: receptor antibodies, which may account for the 642 Chapter 9 • Endocrine system

Antithyroid drugs

remission monitor Antithyroid Surgery or Hyperthyroidism Euthyroid Stop therapy Relapse Euthyroid Hypothyroidism Levothyroxine drugs radiotherapy

Figure 9.16 Treatment pathways for hyperthyroidism. sustained remission seen in about half of which can affect 0.1% of patients. This is usually patients after withdrawal of drug therapy It may rapid in onset, occurring during the first also be related to the most serious side-effect, 3 months of treatment, so not easily detected agranulocytosis. from blood counts. All patients must be warned A high initial dose (e.g. 40–60 mg carbimazole, to watch for swollen glands, throat infections depending on initial TFTs) is tapered after and bruising. If these occur they should stop 4–6 weeks, with advice to the patient to be alert their drug and consult their GP urgently. The for overtreatment (sluggishness, constipation, problem is reversed on withdrawal but antimi- slow pulse, etc). Repeated T3/T4 level estimations crobial cover (for neutropenia) and filgastrim (to guide dose reduction at 4- to 8-week intervals. stimulate leucocyte recovery) may initially be TSH takes longer to rise than thyroid hormone required. A change of drug may subsequently be levels do to fall. A maintenance dose of 5–10 mg tried: the effect may not recur. daily is continued for 18 months, after which a Iodide/iodine have an antithyroid effect and trial withdrawal can be attempted. About half of are sometimes used as an adjuvant in thyroid patients remain in remission and are monitored storm or before thryoidectomy, to reduce gland annually. Some eventually relapse; others size, but they are no longer first-line therapy. develop autoimmune hypothyroidism. Those who relapse have less chance of a further remis- sion and either long-term pharmacotherapy or Radiotherapy an alternative mode of therapy is then indicated. Selective thyroid reduction using sodium Block and replace radioiodide (131I) exploits the concentration of An alternative strategy is to continue antithyroid iodide in the thyroid, which minimizes exposure drugs at a high dose for the same period of of other organs and allows a low total body dose. 2 years, effectively producing a chemical abla- In the USA it it often the first line treatment for tion. Standard replacement doses of levothyroxine those over 50, owing to the potential cardiovas- are given, eventually withdrawing all drugs if cular risks of hyperthyroidism. In Europe it is euthyroidism is achieved. This strategy is preferred to surgery for medical failure to control simpler, requiring less monitoring and titration, hyperthyroidism or following relapse. Although and it allows for a more sustained immunosup- the aim is to spare enough gland to permit pressant action from higher doses of antithyroid normal thyroid hormone output, there is a drug. However, there is little evidence that it is 10–20% chance of hypothyroidism in the first more effective, and there is an increased risk of year following treatment and subsequently up to side-effects. a 5% annual incidence. Sodium radioiodide is Side-effects include minor dermatological taken as an oral solution. Little special contact problems, avoided by changing to another avoidance is necessary afterwards, except for antithyroid agent, and other minor non-specific avoiding public transport and sustained close drug side-effects. Most important, however, is contact with children for about 4 weeks. It is bone marrow suppression and agranulocytosis, contra-indicated in pregnancy. References and further reading 643

Complications Bloomgarten Z T (2004). Diabetes complications. The effect takes several months to develop, Diabetes Care 27: 1504–1512. during which thyroid hormone levels may rise Davies M, Srinivasan B (2005). Glycaemic management temporarily, and antithyroid drug or beta- of type 2 diabetes. Medicine 34(2): 69–75. blocker cover may be needed. Ophthalmopathy Devendra D, Liu E, Eisenbarth G S (2004). Type 1 diabetes: recent developments. BMJ 328: 750–754. is a relative contraindication because it may be Diabetes Control and Complications Trial Research exacerbated. There is a small increase in the risk Group (1993). The effect of intensive treatment of ot thyroid cancer. diabetes on the development and progression of long-term complications in insulin dependent Thyroidectomy diabetes mellitus. N Engl J Med 329: 977–986. Dinneen S F (2006). Management of type 1 diabetes. Surgery has a similar aim to radiotherapy, i.e. Medicine 34(2): 63–7. subtotal thyroid gland reduction, but has the Franklyn J A (2005). Hypothyroidism. Medicine 33(11): same imprecision and is more invasive. It is 27–29. particularly indicated if there is a large goitre. It Marshall S M, Flyvbjerg A. Prevention and detection of is important that patients are rendered euthyroid vascular complications of diabetes. BMJ 333: 475–480. before surgery, to avoid thyroid storm. Some are Nathan D M (1998). Some answers, more controversy, given oral iodine (Lugol’s iodine) or potassium from UKPDS. Lancet 352: 832–833. iodide for a few weeks before surgery, to inhibit NICE (September 2002). Type 2 diabetes – blood thyroid hormone synthesis and reduce gland glucose: Management of type 2 diabetes – vascularity. As with radioiodine, many patients Managing blood glucose levels (Clinical Guideline). eventually become hypothyroid. Potential Available from http://guidance.nice.org.uk/CGG/ surgical complications include laryngeal or ?cϭ91523 (accessed 16 August 2007). parathyroid damage. NICE (July 2004). Type 1 diabetes: Diagnosis and management of type 1 diabetes in children, young people and adults (CG15). Available from http:// Ophthalmopathy guidance.nice.org.uk/CG15/?cϭ91523 (accessed 16 Milder cases need symptomatic treatment, August 2007). including artificial tears and eye protection. If Nutrition Subcommittee of Diabetes UK (2003). The implementation of nutritional advice for people sight is threatened, high-dose corticosteroids, with diabetes. Diabetic Med 20: 786–807. surgery or radiation therapy may be indcated. Phillips P (2002). Insulins in 2002. Aust Prescr 25: 29–31. Thyroid storm Shepphard C S (2005). Goitre and thyroid cancer. Medicine 33(11): 35–37. Urgent antithyroid therapy with thionamides Stumvoll M, Goldstein B J, van Haeften T W (2005). and iodine are required to reduce thyroid Type 2 diabetes: principles of pathogenesis and hormone output. Symptomatic cover with beta- therapy. Lancet 365: 1333–1346. blockers, corticosteroids and possibly IV fluids Watkins P J (2003). ABC of Diabetes, 5th edn. London: will usually be necessary. The precipitating cause BMJ Publishing Group. must be discovered and treated. Weetman A P (2005). Thyrotoxicosis. Medicine 33(11): 30–34.

References and further reading Internet resources Alberti K G M M, Defronzo R A, Zimmet P, eds (1997). International Textbook of Diabetes Mellitus, 2nd edn. http://www.diabetes.org.uk (website of Diabetes UK, Chichester: John Wiley. the charity for people with diabetes).