MedicalContinuing Education

Objectives 1) To clarify the main mechanisms that un- derlie all complications of mellitus. TTowardsowards BetterBetter 2) To understand the role that hy- perglycemia plays in the development of diabetic complications. ManagementManagement ofof 3) To appreciate other mechanisms in the development of diabetic compli- cations besides . DiabeticDiabetic FootFoot 4) To delineate the role of microan- giopathy vs. macroangiopathy in complica- tions relating to diabetes mellitus. ComplicationsComplications 5) To identify the relationship between systemic complications and those found in the foot of the patient with diabetes. The search for the common 6) To empower the podiatric physi- denominator continues. cian to evaluate the whole patient when treating a problem in the foot.

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By Kenneth Rehm, DPM for devastating effects on the body. ment and most importantly, the pre- Pedal complications seen by DPM’s vention of these devastating sequellae. iabetes mellitus, a condition demonstrate these areas of pathology, characterized, for the most each of which plays a decisive role in Terms of Art Dpart, by a deficiency in the disease’s occurrence, chronic na- Terms such as “carbonyl stress”, secretion or a resistance to insulin ac- ture, and eventual recovery, or loss of “oxidative stress”, “glycoxidation”, tion, is estimated to afflict approxi- limb, if left untreated. “lipoxidation”, “non-enzymatic glyco- mately 8% of the population.22 The complexity of these diabetic sylation”, “glycation”, “Maillard reac- Complications of this systemic dis- foot complications creates a huge clini- tion” and “cross-linking of collagen” ease, which are basically either macro- cal and financial challenge to their are repetitively used in the literature to or microangiopathic in nature, encom- management; but the additional describe the chemical reactions that passing the neurologic, vascular, mus- knowledge gained as a result of our may be at the root of the common culoskeletal, dermatologic and im- search for a common thread will facili- thread with which science is seeking to munologic systems, can be responsible tate the diagnosis, treatment, manage- Continued on page 244 www.podiatrym.com NOVEMBER/DECEMBER 2007 • PODIATRY MANAGEMENT 243 CME 2... holm Diabetes Interven- tion Study, any improved Continuingtie in all diabetic or lowering of blood glu- complications. These cose delayed the onset and Medical Education terms will be defined in slowed the progression of this article as part of our all microvascular complica- discussion of the search for tions in all categories of pa- these common links. tients who had Type-1 dia- betes. Although the DCCT Hyperglycemia and was not designed to evalu- Diabetic Complications ate the effects of glycemic The evolution of the control on macrovascular numerous long-term com- disease, some of its indica- plications of diabetes melli- tors were evaluated. Inten- tus has been shown to cor- sive insulin therapy was as- relate well with the severity sociated with a significant and duration of hyper- relative reduction (34%) (p glycemia. For instance, it < 0.02) in the development has been consistently of hypercholesterolemia demonstrated22 that post- (serum low-density- prandial glucose levels lipoprotein [LDL] choles- above 200 mg/dL have a Figure 1: Factors Promoting Diabetic Complications terol concentrations of strong association with >160 mg/dL). Targeted LDL renal, retinal, and neurologic compli- address the glycemic hypothesis (that cholesterol levels have been revised for cations that could show up five to ten retinopathy, nephropathy and neu- all populations, including patients years after the onset of the disease. ropathy are each related to hyper- with diabetes. It is important to note that many glycemia). The National Cholesterol Educa- patients demonstrate postprandial The study demonstrated a 60% re- tion Program recommends that pa- glucose at or above these critical lev- duction in risk involved in the develop- tients with diabetes achieve LDL els when first diagnosed and already ment and/or progression of nephropa- cholesterol concentrations of <100 demonstrate a degree of diabetic thy, neuropathy and retinopathy be- mg/dL. Intensive insulin therapy also complications. In addition, recent tween a standard treatment group and reduced the relative risk of actual epidemiologic studies23 revealed that an intensive treatment group that fo- macrovascular disease (peripheral and poorly controlled diabetic patients cused on very strict control of hyper- cardiovascular disease) by 41%. have a greater risk for cardiovascular glycemia. The outcome established disease than those with well-con- that reduction of the HgA1C from 9% UKPDS trolled glucose levels. to approximately 7% reduced the pro- In another landmark study, The gression and/or development of all mi- United Kingdom Prospective Diabetes DCCT crovascular complications. Study (UKPDS) compared intensive Three large prospective random- In fact, according to the Stock- glycemic control in Type II diabetic ized trials and one large subjects with conventional epidemiologic trial found a treatments to determine correlation between HYPERGLYCEMIA whether intensive glycemic glycemic control and re- control could reduce the duction in the progression frequency of diabetes-relat- of chronic complications ed microvascular and associated with diabetes. macrovascular complica- Subsequent studies have tions. These subjects were confirmed these findings. followed for an average of The Diabetes Control and ten years. Complications Trial Researchers soon became (DCCT) was designed to aware that high blood pres- determine if there was a re- sure may be an even lationship between hyper- stronger risk factor than glycemia and diabetic vas- hyperglycemia; and blood cular complications. This pressure treatment was study evaluated intensive added to the study. Con- insulin replacement and firming the DCCT data, the self-monitoring of blood UKPDS showed that tightly glucose in subjects who controlling blood glucose had type-1 diabetes for a concentration reduced the known duration; and used risk of complications in well-established goals to Figure 2: Mechanisms By Which Hyperglycemia Creates Damage Continued on page 245

244 PODIATRY MANAGEMENT • NOVEMBER/DECEMBER 2007 www.podiatrym.com MedicalContinuing Education CME 2... A consensual type-2 diabetes. The framework has overall microvascular not been estab- complications rate was lished which encom- decreased by 25% in passes all that is those receiving inten- known about the link sive therapy versus con- between hyper- ventional therapy. A Figure 3: Efforts of The Pharmaceutical Industry Geared Toward Decreasing glycemia and compli- Effects of AGEs. continuous relationship cations, but over the between the risk of microvascular The Wisconsin Epidemiologic last 30 years, four seemingly indepen- complications and glycemia was The Wisconsin Epidemiologic dent major mechanisms of hyper- shown to exist. In fact, for every per- Study of Diabetes Retinopathy glycemia-induced damage have been centage point decrease in HbA1c, there (WESDR) studied the relationship be- discovered: was a 35% reduction in the risk of mi- tween hyperglycemia and the fre- 1) Polyol/sorbitol pathway activa- crovascular complications. quency and progression of diabetes- tion The UKPDS results confirm that it related microvascular and macrovas- 2) Advanced glycation endproduct is glucose itself that is toxic in type-2 cular complications. The initial trial (AGE) formation diabetes and extend the previous evi- focused on , but a 3) Protein kinase C (PKC) activa- dence that hyperglycemia and its se- follow-up trial examined the frequen- tion quelae are a major cause of microvas- cy and progression of microvascular 4) Hexosamine pathway activa- cular complications of diabetes. The and macrovascular complications tion. average difference in HbA1c values over a ten-year period. A strong corre- between the conventional and inten- lation was reported between higher It is important to note that oxida- sive therapy groups was only 0.9%, HbA1c values and loss of vision, tive stress is generated in all these but this small reduction reduced by retinopathy, renal failure, lower-ex- pathways as well as in others that take 12% (p = 0.029) the risk of any dia- tremity amputation, myocardial in- place and helps fuel the intensity of betes-related endpoint, including any farction, and overall mortality. complications due to hyperglycemia. macrovascular sequellae such as my- Briefly, to explain these four pathways, ocardial infarction, heart failure, angi- The Mechanisms Which Link an increase in intracellular glucose will na, sudden death, stroke, amputation, Hyperglycemia to Diabetic lead to an increase in the flux of glu- retinal photocoagulation, renal fail- Complications cose to sorbitol via the polyol/sorbitol ure, and vitreous hemorrhage. It is clear by the strong evidence pathway, an increase in glucosamine- The authors reported a 16% re- presented that there is a significant re- 6-phosphate via the hexosamine path- duction in the risk of both fatal and lationship between chronic hyper- way, and the activation of PKC (pro- nonfatal myocardial infarction (p = glycemia and diabetic complications. tein kinase C) via de novo synthesis of 0.052). Also, interestingly, this study How then does chronic hyperglycemia DAG (diacylglycerol). showed that tight blood pressure induce the functional and morpholog- In addition, glucose and glucose- control also reduced the risk of these ic changes that define diabetic compli- derived dicarbonyl compounds react diabetic complications. cations (Figure 1)? nonenzymatically with the basic amino acids lysine and arginine The Kumamoto Study in proteins to form AGEs (ad- The Kumamoto study ex- vanced glycosylation end-prod- amined the effects of strict ucts) both extra- and intra-cellu- glycemic control on the devel- larly. These different pathways opment and progression of di- are interrelated and potentiate abetes-related complications in each other. Intracellularly, these patients with type-1 and type- four biochemical mechanisms 2 diabetes mellitus, respective- may all be the consequence of ly. This study demonstrated a hyperglyemia-induced overpro- direct relationship between duction of ROS in mitochondria glycemic control and a reduc- (Figure 2). tion in microvascular compli- The key biochemical mecha- cations and neuropathic prob- nism for these pathologic pro- lems in these patients. The cesses is the direct deleterious ac- study found no worsening of tion of glucose and other sugars retinopathy or nephropathy in on proteins, known as glycation patients with HbA1c concen- or non-enzymatic glycosylation. trations of <6.5%, fasting Thus, glycosylation results from a blood glucose concentrations direct chemical reaction between of <110 mg/dL, and two-hour glucose and amino groups on postmeal glucose concentra- Figure 4: Complications in Diabetes Have a Microvascular proteins. Clinically, the measure- tions of <80 mg/dL. or Macrovascular Component Continued on page 246 www.podiatrym.com NOVEMBER/DECEMBER 2007 • PODIATRY MANAGEMENT 245 CME 2... formed. promote these Incidental- post-Amadori Continuingment of the glycated form of ly, a similar re- Red Blood products such hemoglobin, HbA1c, has revolu- action, called as Medical Education tionized monitoring and the study of the Maillard re- Thickened Capillary • Inactiva- diabetic patients. Measurement of gly- action, occurs Basement Membrane tion of en- cated plasma proteins (usually called between sugars zymes; ‘the ’ assay) is used as a and proteins in • Inhibi- tool for monitoring glycemic control foods and is re- Muscle Nucleus tion of regula- over a three-week period. sponsible for Striated tory molecule Hemoglobin is not unique, in the brown col- Muscle Cross binding; that non-enzymatic glycosylation is oration of beer, • Cross- a common action on many body cola and toast. Figure 5: Capillary in Striated Muscle. A single linking of gly- proteins. This early glycation is only These post- RBC fills lumen. Arrows point to thickened base- cosylated pro- the beginning of a deleterious cas- Amadori prod- ment membrane. teins and trap- cade of events. Excessive chemical ucts accumu- ping of soluble attachment of glucose to proteins late in diabetic tissues over long peri- proteins by glycosylated extracellular without the involvement of enzymes ods and thus may contribute to capil- matrix; leads to the formation of Amadori lary closure in the retina and glomeru- • Decreased susceptibility to prote- products. The early Amadori prod- lus, and to arterial narrowing in the olysis; ucts resembling hemoglobin A1c coronary, cerebral, and peripheral cir- • Abnormalities of nucleic acid slowly give rise to complex irre- culation. These AGE-products accumu- function; versible glycosylation adducts. late in vivo as a function of both age • Altered macromolecular recogni- and levels of glycemia. tion and endocytosis; Ketoamine Adduct • Increased immunogenicity. The first stable product of the reac- AGE Molecules tion is termed the “ketoamine adduct AGE molecules are present as pep- Inhibiting the Formation and to protein”, Fructosamino-protein tides that are free or protein-bound. Protein Cross-linking of AGE’s They are found in the plasma, cells, Although a macrophage receptor and tissues and are able to accumu- system may antagonize this glycosyla- late in the arterial wall on vascular tion-mediated accumulation of pro- wall collagen, the kidney teins by recognizing and ingesting mesangium, and glomerular and those proteins combined with the ad- other basement membranes. vanced glycosylation end products, The accumulation of AGEs in excessive formation of these may out- these long-lived proteins con- weigh the capacity of the macrophage tributes to the age-related increase removal system. in brown discoloration, florescence, Inherited differences in this sys- poor solubility of lens crystallins tem and others that detoxify AGE in- causing cataracts, and to the gradu- termediates might be a result of the al protein cross-linking and decrease genetic factors responsible for the Figure 6: Basement Membrane Thickening in elasticity of connective tissue col- large clinical variability that the im- Caused By Age Modification of Glomerular lagens with age. pact of a given level of glycemia has Proteins These processes are amplified in on diabetic complications. adduct or “Fructosamine” and is used diabetic patients. It is a critical point It is believed that circulating AGE- to indicate any glycated plasma pro- that even modest increases in dia- peptides are probably the result of in- tein in this first stage. These Amadori betic blood glucose levels result in Continued on page 247 product adducts form in proportion to considerable increases in AGEs glucose concentration. Equilibrium is accumulation. This is a result of reached after several weeks and further AGE formation increasing at a accumulation of these early nonenzy- much greater rate than the in- matic glycosylation products does not crease in blood glucose. continue beyond that time. Excessive formation of these Subsequent reactions of the types of non-enzymatic glycosyla- Amadori products slowly give rise to tion products appears to be the nonequilibrium advanced glycosylation common biochemical link be- end-products which continue to accu- tween chronic hyperglycemia and mulate indefinitely on longer-lived a number of pathological processes molecules. Through a complex series of that be involved in the develop- rearrangements and oxidative reactions, ment of long-term diabetic compli- multiple, very reactive end products, cations. The pathologic effects of Figure 7: XEROSIS IN PATIENTS WITH DIA- collectively named advanced glycation excessive non-enzymatic glycosyla- BETES MELLITUS By permission from Dr. end products or AGE-products, are tion include those processes which Robert G. Smith DPM

246 PODIATRY MANAGEMENT • NOVEMBER/DECEMBER 2007 www.podiatrym.com MedicalContinuing Education CME 2–Diabetic Foot... with protein to form glycoxidation The pathological hall- products or lipids to form lipoxidation mark of diabetic microan- products, termed ALEs. giopathy is the thickening of the Some authors2 have coined a more capillary basement membrane, general comprehensive term for all of which ultimately causes occlusive pe- these harmful reactions: carbonyl ripheral arterial disease, tissue hypoxia, stress. The formation of AGEs can re- and permanent tissue damage and tis- sult from the action of various metabo- sue death (Figure 5). lites other than glucose, such as fruc- In diabetes mellitus, this pathologi- tose, trioses and dicarbonyl com- cal process is usually initiated through pounds, and promote intracellular gly- the damaging effects of the AGEs. cation at a much faster rate than that which occurs extracellularly. Interest- Microvascular Complications ingly, intracellular AGE formation on AGEs affect the microvessels in cell proteins may thus, in turn, affect two basic ways: DNA function, suggesting a possible 1) Through the direct effect of explanation for the increased teratoge- AGEs on proteins, and ny associated with diabetes mellitus. 2) Through the receptor-mediated Figure 8: Diabetic Dermopathy and Ve- nous Stasis Dermatitis That Became Ul- effects. cerated Vascular Disease: Microvascular and Direct Effect of AGEs on Proteins Macrovascular AGE affects proteins by modifying Most of the complica- the functional properties of the extra- tions in diabetes have a cellular matrix molecules. In collagen, vascular component. the most abundant protein in the Vascular disease in dia- body, AGEs form covalent, intermolec- betes is usually designat- ular bonds. Luminal narrowing, a ed as either microvascu- major feature of diabetic vascular lar or macrovascular. pathology, results, in part, from the ac- Macrovascular disease cumulation of plasma proteins, such as is basically cardiovascular albumin, low density lipoprotein disease and refers to ill- (LDL) and immunoglobulin G (IgG) in Figure 9: With Proper Blood Sugar Control and Wound nesses affecting the larger the subendothelium. Care, These Diabetic Ulcerations Can Heal. arteries supplying the These plasma proteins then may complete catabolism of AGE-proteins heart (i.e., heart disease get trapped in the basement mem- by macrophages and other cells which including myocardial infarction and branes by covalently cross-linking to are on the way to be excreted by the congestive heart failure), brain (i.e., AGEs on collagen. This changes the kidneys. In diabetes, AGE peptides are stroke) and the legs (large vessel steno- scaffolding of the basement membrane increased because of an increase in sis leading to peripheral vascular dis- and results in clinical pathology. For in- production and with kidney failure, ease and gangrene). Cardiovascular or stance, in the kidney, the AGE modifi- causing decreased excretion. The ef- macrovascular disease accounts for ap- cation of glomerular basement mem- forts of the pharmaceutical industry proximately 70% of the deaths of peo- brane proteins could prompt protein are geared at interfering with the ple with diabetes.17 leaking and stimulate a compensatory pathological consequences of AGE For- Diabetics also experience microvas- overproduction of other matrix com- mation and Cross-linking. cular disease. The effects of microvas- ponents in the vessel wall, creating a These compounds are being de- cular disease or microangiopathy, the situation that could lead to diabetic signed to inhibit or reverse the forma- small vessel disease in diabetes, include Kimmelstiel-Wilson nephropathy (Fig- tion or cross-linking of AGEs and may neuropathy, nephropathy, retinopa- ure 6). Similarly, these AGE-induced ab- provide relief for many medical condi- thy and dermopathy. These complica- normalities alter the structure and tions where AGE cross-linking has con- tions can occur in type-1 diabetes as function of microvessels other than the tributed to a loss of normal function, early as adolescence, particularly if in- renal mircrocirculation, as well as the elasticity, and/or flexibility (Figure 3). sulin treatment has been inadequate. macrocirculation (Figure 5). AGEs are produced not only Similar complications may occur through the direct action of sugars on later in life in type-2 diabetic patients Receptor-Mediated Effects on proteins but also by way of distinct ox- and are frequently present at the time Proteins idative reactions. Glucose may be in- of diagnosis. The precise mechanisms Many cells have receptors for volved directly in further advanced which cause microangiopathy to AGEs. AGEs then react with these spe- glycation reactions involving free radi- occur are not totally understood. Ge- cific receptors and regulate the uptake cal oxidation. It has recently been netic influences seem to be the prima- and clearance of AGEs. These receptors found that glucose can probably auto- ry factor in the development of small are activated in three cell types: oxidize to form reactive carbonyl prod- vessel disease; and are secondarily af- mononuclear cells, such as monocytes ucts (glyoxal) and methylglyoxal (reac- fected by metabolic and hemody- and macrophages, endothelial cells, tive oxygen species) which may react namic arrangements. Continued on page 248 www.podiatrym.com NOVEMBER/DECEMBER 2007 • PODIATRY MANAGEMENT 247 CME 2–Diabetic... Continuingand mesangial cells. Binding Complications of Type 2 DM with these mononuclear cell recep- Medical Education tors, AGE proteins stimulate Early Late macrophage production, synthesis of collagen in the glomerular structure • Hyperalbuminuria • Renal failure and proliferation of arterial smooth muscle cells. • Background • Proliferative AGEs binding to endothelial cells retinopathy retinopathy stimulate methylglyoxal (reactive oxy- gen species) where pro-coagulant • Neuropathy • Gangrene & amputation changes are stimulated in the endothe- • Medical arterial calcification • Coronary heart disease lial membrane. Concurrently, these AGE-induced alterations in endothelial • Hypertension • Diabetes-related death cell function promote thrombus for- mation at sites of extracellular AGE ac- cumulation. AGE receptors have also Figure 10: Early and Late Complications of Diabetes Mellitus been described on glomerular mesan- gial cells. AGE protein binding to these down the key enzyme that high glu- Thus, the hexosamine pathway may receptors leads to focal glomeruloscle- cose levels shut off. contribute to the deterioration of the rosis, mesangial expansion, and pro- Hyperglycemia enhances the flux beta-cell function found in diabetes teinuria, the hallmarks of diabetic mi- through the polyol/sorbitol pathway, re- (Figure 2). croangiopathy. sulting in glucose being converted to Increased enzymatic cross-linking Glycation and the other three harmful amounts of fructose and sor- of collagen may be involved in the col- pathways linked to hyperglycemia- bital. is promoted lagen-related changes seen in diabetes, induced damage—namely 1)the through this pathway. since the enzyme lysyl oxidase, which polyol/sorbitol pathway activation, Recent studies4 have identified that catalyzes the formation of natural 2) protein kinase C (PKC) activation the activation of protein kinase C cross-links in collagen, may be in- and 3) the hexosamine pathway acti- (PKC), an enzyme that catalyzes the creased in some tissues in diabetes. vation—are thought to arise from a phosphorylation of tyrosine residues in single hyperglycemia-induced pro- certain proteins, and increased diacyl- Macrovascular Complications: cess, the overproduction of toxic free glycerol (DAG) levels initiated by hy- Atherosclerosis and radicals. Normalizing the levels of perglycemia, are associated with many Hyperglycemia these excess free radicals inhibits the vascular abnormalities in retinal, renal, Although the role of hyper- pathways through which cell damage and cardiovascular tissues. glycemia in macrovascular complica- occurs. It is interesting to note that Activation of the hexosamine tions is fraught with numerous ques- all of these damaging pathways can pathway causes and tions, the data certainly suggests a pos- be activated, even in the presence of leads to deterioration of the beta-cell sible role for hyperglycemia in acceler- normoglycemia, simply by using function through the induction of ox- ating the atherosclerotic process in pa- molecular genetic techniques to shut idative stress rather than glycosylation. tients with Type-1 diabetes; and there are strong asso- ciations, as Skin Condition Suggested Pathogenesis Treatment shown by the UKPDS data, Diabetic thick skin Microangiopathy None between blood glucose control Yellow skin Increased carotene; None in Type-2 dia- increased glycosylated collagen betes and the risk of cardio- Diabetic bulae Reduced threshold to None vascular dis- blister formation ease, sudden Necrobiosis lipoidica Microangiopathy; neuropathy None; intralesional injections’ death and all- diabeticorum steroids to peripheral lesions cause mortali- ty. Nonethe- Perforating dermatosis Polymorphonuclear leukocytes’ Keratolytics, address renal failure less, these stud- enzymatic degradation of collagen ies do not and elastin prove as yet that high This table has been adapted from Perez Mt. and Kohn SR, Cutaneous Manifestations of Diabetes Mellitus. J Am blood glucose Acad Drmatoi 1994;30(4) 519-5331. causes these complications Figure 11: Skin Manifestations Associated with Diabetes Mellitus (By permission from Dr. Robert G. Smith DPM) Cont. page 249

248 PODIATRY MANAGEMENT • NOVEMBER/DECEMBER 2007 www.podiatrym.com MedicalContinuing Education CME 2–Diabetic... On the other hand, the vast major- has raised the question of ity of research corroborates the role of what common mechanisms and that intensive treatment to lower glycation of lipoproteins in atherogen- may be at work. An obvious pos- hyperglycemia would reduce the risks esis. This enhanced glycation in dia- sibility is that common risk factors of these events. betes not only has direct adverse ef- such as hypertension, obesity, dyslipi- Many of the pathways, however, fects but also amplifies the effects of demia and smoking are involved in described in the formation of microan- oxidative stress on lipoproteins. Gly- both nephropathy and vasculopathy, giopathy also apply here. Collagen in cated and oxidized lipoproteins pro- and play a dominant role in all diabet- the arterial wall bearing AGEs can trap mote the process of atherogenesis as ic complications independent of LDL and IgG particles, which in turn well as platelet and endothelial cell glycemic control and may stem from accumulate in the intima. They are, dysfunction. endothelial dysfunction13 and chronic therefore, prone to local oxidation and It is too early to conclude that re- low-grade inflammation.14 uptake by monocyte-macrophages. duction of hyperglycemia would have Low density liproproteins cause en- as great an impact on lowering The Foot Is Attached to the Rest dothelial cell activation and this en- macrovascular disease risk as it has on of the Body courages the deposition of atheroma. microvascular disease risk (though The pedal pathology present in di- Also, activation monocyte receptors by some authors strongly suspect that its abetes usually presents with the effects AGEs on vascular wall proteins, such as importance should not be minimized). of microangiopathy, which include collagen and elastin, can trigger cy- Other factors such as dyslipidemia, ho- the peripheral neuropathies, and paral- tokine-mediated inflammatory reac- mocysteinemia or hypertension may lels the corresponding microangio- tions. Therefore all vascular complica- predispose patients with diabetes mel- pathic effects, such as nephropathy tions in the diabetic may in fact be due, litus to cardiovascular complications. and retinopathy. There are also direct in part, to these reactions. It must be added, however, that effects of non-enzymatic glycosylation, even though a ma- glycoxylation and lipoxidation on the jority of diabetic nerves, facilitating the onset and for- patients will devel- matting the degree of the peripheral Aggressive interdisciplinary op micro- and neuropathies. Both macro-and mi- management of diabetes risk macro-vascular croangiopathy, as well as the direct ac- complications, a tion of non-enzymatic glycosylation, factors can prevent many substantial frac- affect the condition of the skin and complications tion will never de- nails in the . velop these severe Dr. Robert G. Smith, a podiatric • Diabetes complications are common and almost vascular complica- physician and pharmacist who has triple the annual cost of managing diabetes. tions in spite of worked extensively with the skin of hyperglycemia. the diabetic patient, states that xerosis • Microvascular complications are the major risk in Thus, within the is one of the most common skin con- , while macrovascular complica- group of diabetic ditions one will see among podiatric tions are the major cause of morbidity and mor- patients, a sub- patients who have type-2 diabetes. It is tality in . group exists with a particularly prevalent among elderly relatively normal patients (Figure 7). He states that the • Control of hyperglycemia (target HbA1c level risk of these com- reason for the dryness is the redistribu- < 7%) and hypertension (target blood pressure plications. In every tion of blood flow in the soles by per- < 30/80 mmHg) prevents microvascular compli- case, however, pa- sistent and inappropriate dilatation of cations in both types of diabetes; a multifactorial tients with ad- arteriovenous shunts. approach, comprising behavior modification and vanced nephropa- This activity diverts blood away pharmacological therapy for all risk factors, re- thy and associated from the skin surface. When this oc- duces the development of micro- and macrovas- macro-albumin- curs in combination with alterations cular complications in type 2 diabetes. uria have very in the elasticity of the skin (due to high risk of devel- non-enzymatic glycosylation of struc- • The benefit of treating dyslipidaemia is at least as oping severe vas- tural proteins and glycoproteins), the great in the diabetic population as in the non- cular complica- skin splits and portals for bacteria are diabetic population. tions.5 created. This happens in combination The pattern of with venous stasis dermatitis and dia- • Angiotensin-converting enzyme inhibitors and increased risk for betic dermopathy. (Figures 8-9) In sev- low-dose aspirin are indicated in people with vascular complica- eral studies, diabetic dermopathy (shin diabetes and other cardiovascular risk factors. tions can be ob- spots) has been found to be related to served even in microangiopathy and neuropathy.1,2 In • Regular annual medical, dental and foot screen- early nephropa- a more recent study of 173 patients ing for diabetes complications allows treatable thy, i.e. microalbu- with diabetes,3 diabetic dermopathy disease to be identified.21 minuria, in Type-2 was present in 66%, 62%, and 63% of diabetes8 and also those patients with retinopathy, neu- in non-diabetic ropathy, and nephropathy, respective- Figure 12: Optimal Prevention and Treatment subjects,9 which Continued on page 250 www.podiatrym.com NOVEMBER/DECEMBER 2007 • PODIATRY MANAGEMENT 249 CME 2–Diabetic... studies, to coordinate care with the North Am. 31, 537–551. other members of the patient’s “medical 12 Gerstein, H. C., Mann, J. F., Yi, Q., et Continuingly. Accumulation of glycoxida- team” that ultimately results in optimal al. (2001) Albuminuria and risk of cardiovas- cular events, death, and heart failure in dia- tion and lipoxidation products in prevention and treatment for the com- Medical Education betic and nondiabetic individuals. JAMA, J. skin collagen is associated with failure plicating sequellae of this devastating Am. Med. Assoc. 286, 421–426. of the kidney to thrive. Yellow toenail disease (Figure 12). The science gets very 13 Stehouwer, C. D., Henry, R. M., and skin syndrome from diabetes mel- complicated, but the role of the podia- Dekker, J. M., Nijpels, G., Heine, R. J. and litus is a result of non-enzymatic glyco- tric and diabetic foot specialist is simple. Bouter, L. M. (2004) Microalbuminuria is as- sylation and crosslinking of the pro- Every practitioner who treats diabetic sociated with impaired brachial artery, flow- teins in the toenails. foot problems must communicate and mediated vasodilation in elderly individuals without and with diabetes: further evidence Necrobiosis lipoidica diabeticorum, empower the patient, as well as all the for a link between microalbuminuria and en- diabetic blisters, and eruptive xan- other members of their team, in an ef- dothelial dysfunction: the Hoorn Study. Kid- thomatosis are among the conditions fort to promote a healthful lifestyle that ney Int. 66 (Suppl. 92), S42–S44. caused by large and small vessel dis- includes exercise, diet, and control of 14 Nakamura, M., Onoda, T., Itai, K., et al. ease, as well as by the glycosylation of the unhealthy markers for amputation (2004) Association between serum C-reactive collagen in the skin. Limited joint mo- and death, i.e., hypertension, hyperlipi- protein levels and microalbuminuria: a popu- bility17 appears to be correlated with demia, and hyperglycemia. ■ lation-based cross-sectional study in northern Iwate, Japan. Intern. Med. 43, 919–925. the presence of thickened waxy skin 15 Verrotti, A., Greco, R., Basciani, F., and thickening, and contracture and Bibliography and Suggested Morgese, G. and Chiarelli, F. (2003) von loss of elasticity of the tendons in the Readings Willebrand factor and its propeptide in chil- feet of diabetic patients, which has 1 Danowski TS, Sabeth G, Sarver ME, et dren with diabetes. Relation between en- tremendous effects on gait and creates al. Shin spots and diabetes mellitus. Am J dothelial dysfunction and microalbuminuria. significant biomechanical abnormali- Med Sci. 1966;251:570-5. Pediatr. Res. 53, 382–386. 2 Murphy RA. Skin lesions in diabetic pa- 16 ties. Non-enzymatic glycosylation is Clinical Science (2005) 109, (143–159) tients: the “spotted leg”syndrome. Lahey Clin (Printed in Great Britain) Review article Vas- thought to be the main culprit here. Bull. 1965;14:10-14. cular complications in diabetes mellitus: the Many more diabetic foot complica- 3 Shemer A, Bergman R, Linn S, et al. Di- role of endothelial dysfunction Casper G. tions can be discussed, but whether it abetic dermopathy and internal complica- Schalkwijk and Coen D. A. Stehouwer. be vasculopathy, neuropathy, im- tions in diabetes mellitus. Int J Dermatol. 17 Diabetologia (1984) 26: 93-98 Dia- munopathy or musculoskeletal prob- 1998;37(2):113-5. betologia Springer-Verlag 1984 Review arti- 4 lems, it is clear that all pedal and sys- Experimental Diabesity Research. 2003 cles Non-enzymatic glycosylation and the Apr-Jun;4(2):125-32. Hyperglycemia-induced temic complications of diabetes melli- chronic complications of diabetes: an protein kinase C activation inhibits phagocy- overview L. Kennedy and J. W. Baynes. tus are interrelated; and the main cul- tosis of C3b- and immunoglobulin g-op- 18 Muller SA, Winkleman RK. Necrobio- prits are the processes of non-enzymat- sonized yeast particles in normal human neu- sis lipoidica. Br J Dermatol. 1955;67:365-84. ic glycosylation, glycoxylation, and trophils. Saiepour D, Sehlin J, Oldenborg PA. 19 Perez MI, Kohn SR. Cutaneous mani- lipoxidation (Figure 11). Department of Integrative Medical Biology, festations of diabetes mellitus. J Am Acad Der- Cardiovascular and kidney disease Section for Histology and Cell Biology, Umeå matol. 1994;30(4):519-31. 20 are usually present in diabetes mellitus University, Umeå, Sweden. Jude E., Boulton A. (1998) ‘Foot prob- 5 Molitch, M. E., DeFronzo, R. A., Franz, but the main causes appear to be related lems in diabetes mellitus’. Br J Podiatry, 1; 4: M. J., et al. (2004) Nephropathy in diabetes. 117-120. to harmful fats and hypertension. By Diabetes Care 27 (Suppl. 1), S79–S83. 21 MJA Practice Essentials—Endocrinolo- monitoring all complications, it’s rea- 6 Parving, H. H., Chaturvedi, N., Viberti, gy3: Preventing complications of diabetes sonable to assume that one would be in G. and Mogensen, C. E. (2002) Does microal- Katherine L Bate and George Jerums Series a better position to evaluate or possibly buminuria predict ? Di- Editors: Donald J Chisholm and Jeffrey D prevent some of the complications of abetes Care 25, 406–407. Zajac MJA 2003; 179 (9): 498-503. 7 Mogensen, C. E. and Cooper, M. E. 22 diabetic foot disease (Figure 10). Textbook: Levin and O’Neal’s The Dia- (2004) Diabetic renal disease: from recent The importance of understanding betic Foot sixth ed. Pages 1-92 Edited by: studies to improved clinical practice. Diabetic John H. Bowker, MD and Michael A. Feiffer, the mechanisms of these complica- Med. 21, 4–17. MD, Mosby Publishing. tions is essential to identifying, pre- 8 Jager, A., Kostense, P. J., Ruhe, H. G., et 23 Diabetes Services in Wales 2003-12-04, venting, treating and managing those al. (1999) Microalbuminuria and peripheral 2003 The Audit Commission. seen in the foot of a diabetic patient. arterial disease are independent predictors of Dealing with the diabetic complica- cardiovascular and all-cause mortality, espe- cially among hypertensive subjects: five-year Dr. Rehm, board tions that all foot health practitioners follow-up of the Hoorn Study. Arterioscler., certified in dia- are faced with starts with viewing the Thromb., Vasc. Biol. 19, 617–624. betic wound patient as a whole; and understanding 9 Yudkin, J. S., Forrest, R. D. and Jackson, care, practices in that the patient is being treated for C. A. (1988) Microalbuminuria as predictor of San Diego, CA. complications involving the foot, not vascular disease in non-diabetic subjects. Is- He lectures na- just for the foot exclusively, thereby lington Diabetes Survey. Lancet ii, 530–533 tionally and of- 10 looking at the pedal complications as Karalliedde, J. and Viberti, G. (2004) fers seminars for Microalbuminuria and cardiovascular risk. part of a generalized pathology. podiatrists and Am. J. Hypertens. 17, 986–993. other profession- It is incumbent upon the podiatric 11 Gerstein, H. C. (2002) Epidemiologic als. Dr. Rehm is physician to evaluate a patient in this analyses of risk factors, risk indicators, risk Director of the Diabetic Foot and way, and to use information obtained markers, and causal factors. The example of Wound Treatment Centers in San Diego from the medical history, other treating albuminuria and the risk of cardiovascular and is a member of both the AAPPM physicians, blood tests and imaging disease in diabetes. Endocrinol. Metab. Clin. and the APWCA.

250 PODIATRY MANAGEMENT • NOVEMBER/DECEMBER 2007 www.podiatrym.com MedicalContinuing Education EXAMINATION

See answer sheet on page 253.

1) Diabetes mellitus is a condi- with the following: 9) There is strong evidence of a tion characterized by the fol- A) Small vessel disease significant relationship between lowing: B) Large vessel disease A) Hyperglycemia and diabet- A) Deficiency of thyroid C) Hyperglycemia ic complications function D) All of the above B) Myocardial infarction and B) Overproduction of abnormal HgA1c adrenal hormones 6) The measurement of the C) Loss of vision and large C) A deficiency in insulin se- glycated form of hemoglobin vessel cardiovascular disease cretion or resistance to in- which is a reflection of the last D) Kidney disease and enzy- sulin action 3 months of blood glucose is matic glycosylation D) Hypermobile flatfoot commonly referred to as A) HgA1c 10) How many independent 2) The complexity of diabetic B) ZnD1C mechanisms are thought to con- foot complications creates the C) Glycosylated Globulin tribute to the complications re- following: D) NaCl-A1D lated to high blood sugar? A) Lack of time for appropri- A) 6 ate treatment and diagnosis 7) The following was a land- B) 5 B) Clinical and financial mark study involving the rela- C) 7 challenges to their manage- tionship between high blood D) 4 ment sugar and diabetic vascular C) An opportunity to use complications: 11) In diabetes mellitus, the additional CPT codes A) The Stanford Growth pathological process is usually D) Friction within the medi- Factor Study initiated through the damaging cal community B) The International effects of Diabetic Foot Study A) AGE 3) The common thread of all di- C) The Harvard Growth B) LDL abetic complications lies in the Hormone Study C) HDL following: D) The Diabetes Control D) IgG A) Electrical reactions and Complications Trial B) Financial problems 12) A majority of diabetic pa- C) Chemical reactions with- 8) The Diabetes Control and tients will develop the following: in the body Complications Trial (DCCT) A) Sudden death syndrome D) Non-compliance was designed to determine the B) Vascular complications following: C) 4) High Glucose in the blood is A) The relationship be- D) Hypothyroidism harmful because tween high cholesterol and A) It produces a psychologi- small vessel disease 13) The risk factors that are inde- cal dependence B) The relationship be- pendent of blood sugar control B) It alters the transit time tween hyperglycemia include: in the colon and diabetic vascular A) Vascular complications C) Of the combination of complications B) Hypertension glucose with proteins in the C) The relationship C) Nephropathy body between neuropathy, D) Neuropathy D) It creates an unhealthy retinopathy and demand for sweet desserts nephropathy 14) The condition of the skin D) The effectiveness of the and nails in the foot of a diabetic 5) Complications of diabetes Stockholm Diabetes Inter- patient are affected by all of seen in the feet are associated vention Study Continued on page 252 www.podiatrym.com NOVEMBER/DECEMBER 2007 • PODIATRY MANAGEMENT 251 EXAMINATION PM’s Continuing (cont’d) Medical Education CPME Program the following except: Welcome to the innovative Continuing Education A) Macroangiopathy Program brought to you by Podiatry Management B) Microangiopathy Magazine. Our journal has been approved as a C) Enzymatic Glycosylation sponsor of Continuing Medical Education by the D) Non-Enzymatic Glycosylation Council on Podiatric Medical Education.

15) One of the most common skin conditions seen Now it’s even easier and more convenient in diabetic patients is: to enroll in PM’s CE program! A) Erythromatosquamous dermatitis You can now enroll at any time during the year B) Erisypelas C) Psoriatic plaques and submit eligible exams at any time during your D) Xerosis enrollment period. PM enrollees are entitled to submit ten exams 16) The reason for dryness of the skin in diabetic published during their consecutive, twelve–month mellitus is usually associated with enrollment period. Your enrollment period begins A) Inappropriate dilatation of arteriovenous with the month payment is received. For example, shunts if your payment is received on September 1, 2006, B) Venous hypotension your enrollment is valid through August 31, 2007. C) Arterial vasospasm If you’re not enrolled, you may also submit any D) Telangiectasias of the skin exam(s) published in PM magazine within the past twelve months. CME articles and examination 17) “Shin Spots” in a diabetic patient is also called: questions from past issues of Podiatry Man- A) Epidermolysis bullosa agement can be found on the Internet at B) Venous stasis dermatitis C) Diabetic dermopathy http://www.podiatrym.com/cme. Each lesson D) Yellow skin syndrome is approved for 1.5 hours continuing education con- tact hours. Please read the testing, grading and pay- 18) Loss of elasticity in the skin of the diabetic pa- ment instructions to decide which method of partici- tient is usually due to: pation is best for you. A) Non-enzymatic glycosylation of structural Please call (631) 563-1604 if you have any ques- proteins tions. A personal operator will be happy to assist you. B) Redistribution of blood flow in the skin Each of the 10 lessons will count as 1.5 credits; C) Injury from the ultraviolet rays thus a maximum of 15 CME credits may be D) Peripheral neuropathy earned during any 12-month period. You may se- lect any 10 in a 24-month period. 19) Limited joint mobility is commonly correlated with: A) The presence of thickened waxy skin The Podiatry Management Magazine CME B) Cardiovascular disease C) Kidney disease program is approved by the Council on Podiatric D) Hypertension Education in all states where credits in instruction- al media are accepted. This article is approved for 20) All of the following are complications in the 1.5 Continuing Education Contact Hours (or 0.15 lower extremity due to diabetes mellitus except: CEU’s) for each examination successfully completed. A) Paronychia B) Yellow toenail syndrome C) Necrobiosis lipoidica diabeticorum D) Eruptive xanthomatosis Home Study CME credits now See answer sheet on page 253. accepted in Pennsylvania

252 PODIATRY MANAGEMENT www.podiatrym.com ✄ MedicalContinuing Education Enrollment/Testing Information and Answer Sheet Note: If you are mailing your answer sheet, you must complete exam during your current enrollment period. If you are not en- all info. on the front and back of this page and mail with your rolled, please send $20.00 per exam, or $139 to cover all 10 exams credit card information to: Podiatry Management, P.O. Box (thus saving $61* over the cost of 10 individual exam fees). 490, East Islip, NY 11730. Facsimile Grading To receive your CPME certificate, complete all information and TESTING, GRADING AND PAYMENT INSTRUCTIONS fax 24 hours a day to 1-631-563-1907. Your CPME certificate will (1) Each participant achieving a passing grade of 70% or be dated and mailed within 48 hours. This service is available for higher on any examination will receive an official computer form $2.50 per exam if you are currently enrolled in the annual 10-exam stating the number of CE credits earned. This form should be safe- CPME program (and this exam falls within your enrollment period), guarded and may be used as documentation of credits earned. and can be charged to your Visa, MasterCard, or American Express. (2) Participants receiving a failing grade on any exam will be If you are not enrolled in the annual 10-exam CPME pro- notified and permitted to take one re-examination at no extra cost. gram, the fee is $20 per exam. (3) All answers should be recorded on the answer form below. For each question, decide which choice is the best an- Phone-In Grading swer, and circle the letter representing your choice. You may also complete your exam by using the toll-free ser- (4) Complete all other information on the front and back of vice. Call 1-800-232-4422 from 10 a.m. to 5 p.m. EST, Monday this page. through Friday. Your CPME certificate will be dated the same day (5) Choose one out of the 3 options for testgrading: mail-in, you call and mailed within 48 hours. There is a $2.50 charge for fax, or phone. To select the type of service that best suits your this service if you are currently enrolled in the annual 10-exam needs, please read the following section, “Test Grading Options”. CPME program (and this exam falls within your enrollment peri- od), and this fee can be charged to your Visa, Mastercard, Ameri- TEST GRADING OPTIONS can Express, or Discover. If you are not currently enrolled, the fee Mail-In Grading is $20 per exam. When you call, please have ready: To receive your CME certificate, complete all information 1. Program number (Month and Year) and mail with your credit card information to: 2. The answers to the test Podiatry Management 3. Your social security number P.O. Box 490, East Islip, NY 11730 4. Credit card information There is no charge for the mail-in service if you have already In the event you require additional CPME information, enrolled in the annual exam CPME program, and we receive this please contact PMS, Inc., at 1-631-563-1604.

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Check one: ______I am currently enrolled. (If faxing or phoning in your answer form please note that $2.50 will be charged to your credit card.) ______I am not enrolled. Enclosed is my credit card information. Please charge my credit card $20.00 for each exam submitted. (plus $2.50 for each exam if submitting by fax or phone). ______I am not enrolled and I wish to enroll for 10 courses at $139.00 (thus saving me $61 over the cost of 10 individual exam fees). I understand there will be an additional fee of $2.50 for any exam I wish to submit via fax or phone. Over, please 253 ✄ (cont’d) www.podiatrym.com 11. A12. B A13. C B A14. D C B A15. D C B A16. D C B A17. D C B A18. D C B A19. D C B A20. D C B A D C B D C D (Rehm) EXAM #10/07 owards Better Management Better Management owards T of Diabetic Foot Complications of Diabetic Foot 1. A2. B A3. C B A4. D C B A5. D C B A6. D C B A7. D C B A8. D C B A9. D C B A D C B D C D 10. A B C D LESSON EVALUATION exam Please indicate the date you completed this ______the lesson? How much time did it take you to complete ______hours ______minutes How well did this lesson achieve its educational objectives? ______Very well ______Well all ______Somewhat ______Not at lesson? What overall grade would you assign this A B C D Degree______Additional comments and suggestions for future exams: ______Circle: 11. A12. B A13. C B A14. D C B A15. D C B A16. D C B A17. D C B A18. D C B A19. D C B A20. D C B A D C B D C D (Rabjohn) EXAM #9/07 ENROLLMENT FORM & ANSWER SHEET & ANSWER FORM ENROLLMENT Replacement Matrices The Use of Epidermal/Dermal The Use PODIATRY MANAGEMENT • NOVEMBER/DECEMBER 2007 1. A2. B A3. C B A4. D C B A5. D C B A6. D C B A7. D C B A8. D C B A9. D C B A D C B D C D 10. A B C D Replacement Therapies and Combined Replacement Therapies ______Additional comments and suggestions for future exams: What overall grade would you assign this lesson? What overall grade would you assign this A B C D Degree______Somewhat ______Not at all ______Somewhat ______Not at How well did this lesson achieve its educational How well did this lesson achieve its educational objectives? ______Very well ______Well ______hours ______minutes How much time did it take you to complete the lesson? How much time did it take you to complete ______Please indicate the date you completed this exam Please indicate the date you completed this LESSON EVALUATION Circle:

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