VI DIABETES MELLITUS Saul Genuth, m.d. Classification The classification of diabetes mellitus has recently been re- vised by a task force of the American Diabetes Association that Definition and Overview included representation from Europe.1 Major etiologic classes of Diabetes mellitus is a metabolic disease characterized by hy- the disease, along with more esoteric examples, have been cate- perglycemia that results from defects in insulin secretion, in- gorized [see Table 1]. The vast majority of cases of diabetes melli- sulin action, or both. Important abnormalities in fat and protein tus are either type 1 (insulin-dependent) or type 2 ( non–insulin- metabolism are also present. Nonetheless, the diagnosis still dependent) in an approximate ratio of 1:9. rests upon demonstrating elevated plasma glucose levels. The chronic hyperglycemia of diabetes mellitus is specifically asso- type 1 and type 2 diabetes mellitus ciated with long-term damage, dysfunction, and failure of var- Type 1 and type 2 diabetes were formerly known as insulin- ious organs, especially the retina and lens of the eye, the kid- dependent diabetes mellitus (IDDM) and non–insulin-dependent neys, and both somatic and autonomic nervous systems. The diabetes mellitus (NIDDM), respectively. This classification was heart, arterial system, and microcirculation are also adversely abandoned largely because it was difficult to distinguish patients affected. with IDDM from those patients with NIDDM who eventually re- A variety of pathogenic processes are involved in the devel- quired insulin treatment to mitigate hyperglycemia. Physicians, opment of different forms of diabetes. These processes range nurses, hospital-record-room personnel, health insurers, and from autoimmune destruction of the beta cells of the pancreatic even sometimes researchers were hard put to distinguish be- islets with consequent insulin deficiency to mutations in the in- tween these two forms of diabetes using the old terminology. The sulin receptor gene with consequent resistance to insulin action. new classification, dependent on etiology rather than mode of The basis for the metabolic abnormalities of diabetes mellitus is treatment, puts a greater emphasis on the history and characteris- deficient action of insulin on its major target tissues, including tics of the patients to determine the probable etiology and type. skeletal muscle, cardiac muscle, adipose tissue, and liver. Loss of Two categories of blood glucose elevation, impaired glucose tol- proper insulin regulation of metabolism results from inadequate erance (IGT) and impaired fasting glucose (IFG), that lie between secretion of insulin, from diminished tissue responses to insulin normal glucose levels and overt diabetes have also been estab- at one or more points in the complex pathways of insulin action, lished [see Impaired Glucose Tolerance, below].2 or from both processes. Impairment of insulin secretion and de- fects in insulin action coexist in many patients, and in these pa- gestational diabetes mellitus tients, it is often unclear which abnormality is the primary cause Gestational diabetes mellitus (GDM) constitutes a separate cat- of the hyperglycemia. egory for cases of diabetes first detected during pregnancy.3 When Acute life-threatening consequences of diabetes mellitus are diabetes is detected early in pregnancy, it is likely to be type 1 or ketoacidosis and nonketotic hyperglycemic hyperosmolar coma. type 2 diabetes mellitus that is presenting symptomatically and Overtreatment of hyperglycemia can lead to hypoglycemia, was probably precipitated or worsened by the pregnant state. Di- which may be severe enough to cause seizures and loss of con- abetes is commonly detected in the second and third trimester sciousness. Symptoms of poorly controlled hyperglycemia in- (i.e., in 4% of pregnant women) and is likely to be specific for the clude polyuria, polydipsia, blurred vision, weight loss, polypha- pregnant state, to be transient, and to reverse to normal glucose gia, stunting of growth, and vulnerability to infections or suscep- tolerance or to IGT on follow-up oral glucose tolerance testing 6 tibility to a more virulent or chronic course when infected. weeks after delivery. However, GDM is associated with a high Specific long-term complications of diabetes include (l) risk of future diabetes, especially in women who have IGT post retinopathy with potential loss of vision, (2) nephropathy lead- partum or who remain obese.3 Permanent diabetes will develop in ing to end stage renal disease (ESRD), and (3) neuropathy with approximately 50% of patients within 10 years of GDM. The great- risk of foot ulcers, amputation, Charcot joints, sexual dysfunc- est importance of any single episode of GDM lies in the risks it tion, and potentially disabling dysfunction of the stomach, bow- poses to the fetus. These risks include intrauterine mortality, el, and bladder. Numerous mechanisms have been discovered neonatal mortality, respiratory distress syndrome, hypoglycemia, that may mediate the specific tissue damage caused by hyper- hypocalcemia, jaundice, and macrosomia, which can cause trauma glycemia. Diabetic patients are also at increased risk for athero- such as shoulder dystocia during passage through the birth canal. sclerotic cardiovascular, peripheral vascular, and cerebrovascu- lar disease. These conditions may be related to hyperglycemia as secondary forms of diabetes mellitus well as to hypertension and abnormal lipoprotein profiles that Of the categories of secondary diabetes [see Table 1], endo- are often found in diabetic patients. crinopathies and drug- or chemical-induced diabetes are notewor- Sufficient hyperglycemia to cause pathologic and functional thy because they represent instances of diabetes that are poten- changes in target tissues may be present for some time before tially reversible if they are recognized and the physician can cure clinical symptoms lead to a diagnosis of diabetes in many pa- the endocrinopathy or discontinue the offending drug. The cate- tients. At an even earlier stage, an incipient abnormality in glu- gory of genetic defects in beta cell function illustrates how the cose metabolism can be identified on plasma glucose testing, classification will grow ever more detailed as knowledge increas- which indicates that the patient is at considerably increased risk es. For example, the single diabetes mellitus phenotype formerly for the full clinical disorder. called maturity-onset diabetes of the young (MODY) can now be © 2004 WebMD, Inc. All rights reserved. ACP Medicine May 2004 Update METABOLISM:VI Diabetes Mellitus–1 more precisely classified into at least four genetic varieties, each corticoids is an especially important continuing problem. Up to of which arises from mutation of a different gene. 25% of renal transplant patients develop so-called steroid dia- Diabetes caused by chronic pancreatitis, pancreatectomy, or betes.5 In a case-control study, use of glucocorticoids for up to 45 occasionally carcinoma of the pancreas is usually type 1 in char- days was a risk factor for diabetes that required pharmacologic acter. Because patients with this disease have glucagon as well as treatment.6 The odds ratio rose from 1.77 at a prednisone equiva- insulin deficiency, they are somewhat less likely to go into ke- lent of 10 mg/day to an odds ratio of 10.3 at 30 mg/day. Obesity toacidosis4 but are quite vulnerable to hypoglycemia. Because and family history of diabetes increased the risk of steroid dia- they are deficient in pancreatic enzymes, their digestion and sub- betes. Although insulin resistance in the liver and muscle is a sequent absorption of nutrients is somewhat erratic, even though well-recognized effect of glucocorticoids, an action on the beta replacement enzymes are ingested with meals. If alcoholism, of- cells to limit the compensatory response to hyperglycemia7 adds ten the cause of chronic pancreatitis, is irremediable, it also con- to the diabetogenic effect at higher steroid doses. Patients treated tributes to blood glucose instability, as does the often accompany- with glucocorticoids for more than a few days need to be warned ing irregular lifestyle. Small frequent doses of lispro insulin to watch for and report clinical symptoms of hyperglycemia should be helpful, but safety may require less stringent blood glu- promptly. Ketoacidosis is rare, but hyperglycemic hyperosmolar cose goals in such patients. nonketotic coma can occur. Insulin treatment is usually necessary Although many individual drugs have been incriminated as a for symptomatic patients and for those with a fasting plasma glu- cause of hyperglycemia, the continued use of pharmacologic anti- cose (FPG) level greater than 200 mg/dl, but sulfonylurea drugs inflammatory or immunosuppressive doses of synthetic gluco- are sometimes effective. There is little systematic information on the efficacy of the other oral agents. In most instances, steroid dia- betes is transient, but in a minority of cases, diabetes persists even after withdrawal of the glucocorticoids. Table 1 Etiologic Classification of Diabetes Type 1 diabetes mellitus* (β cell destruction, usually leading to absolute insulin deficiency) Screening for Diabetes Immune mediated Screening for type 1 diabetes mellitus by office glucose testing Idiopathic is currently indicated in high-risk patients. Current American Di- Type 2 diabetes mellitus* (may range from predominantly insulin abetes Association criteria for office screening of asymptomatic