Towards Better Management of Diabetic Foot Complications · Management, P.O. Box 490, East Islip,...

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Following this article, an answer sheet and full set of instructions are provided (p. 252).—Editor

The search for the commondenominator continues.

Towards BetterManagement ofDiabetic FootComplications

NOVEMBER/DECEMBER 2007 • PODIATRY MANAGEMENTwww.podiatrym.com 243

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Objectives1) To clarify the main mechanisms that un-

derlie all complications of diabetes mellitus.

2) To understand the role that hy-perglycemia plays in the developmentof diabetic complications.

3) To appreciate other mechanismsin the development of diabetic compli-cations besides hyperglycemia.

4) To delineate the role of microan-giopathy vs. macroangiopathy in complica-tions relating to diabetes mellitus.

5) To identify the relationship betweensystemic complications and those found inthe foot of the patient with diabetes.

6) To empower the podiatric physi-cian to evaluate the whole patientwhen treating a problem in the foot.

ment and most importantly, the pre-vention of these devastating sequellae.

Terms of ArtTerms such as “carbonyl stress”,

“oxidative stress”, “glycoxidation”,“lipoxidation”, “non-enzymatic glyco-sylation”, “glycation”, “Maillard reac-tion” and “cross-linking of collagen”are repetitively used in the literature todescribe the chemical reactions thatmay be at the root of the commonthread with which science is seeking to

Continued on page 244

Diabetes mellitus, a conditioncharacterized, for the mostpart, by a deficiency in insulin

secretion or a resistance to insulin ac-tion, is estimated to afflict approxi-mately 8% of the population.22

Complications of this systemic dis-ease, which are basically either macro-or microangiopathic in nature, encom-passing the neurologic, vascular, mus-culoskeletal, dermatologic and im-munologic systems, can be responsible

for devastating effects on the body.Pedal complications seen by DPM’sdemonstrate these areas of pathology,each of which plays a decisive role inthe disease’s occurrence, chronic na-ture, and eventual recovery, or loss oflimb, if left untreated.

The complexity of these diabeticfoot complications creates a huge clini-cal and financial challenge to theirmanagement; but the additionalknowledge gained as a result of oursearch for a common thread will facili-tate the diagnosis, treatment, manage-

By Kenneth Rehm, DPM

Towards BetterManagement ofDiabetic FootComplications

address the glycemic hypothesis (thatretinopathy, nephropathy and neu-ropathy are each related to hyper-glycemia).

The study demonstrated a 60% re-duction in risk involved in the develop-ment and/or progression of nephropa-thy, neuropathy and retinopathy be-tween a standard treatment group andan intensive treatment group that fo-cused on very strict control of hyper-glycemia. The outcome establishedthat reduction of the HgA1C from 9%to approximately 7% reduced the pro-gression and/or development of all mi-crovascular complications.

In fact, according to the Stock-

holm Diabetes Interven-tion Study, any improvedor lowering of blood glu-cose delayed the onset andslowed the progression ofall microvascular complica-tions in all categories of pa-tients who had Type-1 dia-betes. Although the DCCTwas not designed to evalu-ate the effects of glycemiccontrol on macrovasculardisease, some of its indica-tors were evaluated. Inten-sive insulin therapy was as-sociated with a significantrelative reduction (34%) (p< 0.02) in the developmentof hypercholesterolemia(serum low-density-lipoprotein [LDL] choles-terol concentrations of>160 mg/dL). Targeted LDL

cholesterol levels have been revised forall populations, including patientswith diabetes.

The National Cholesterol Educa-tion Program recommends that pa-tients with diabetes achieve LDLcholesterol concentrations of <100mg/dL. Intensive insulin therapy alsoreduced the relative risk of actualmacrovascular disease (peripheral andcardiovascular disease) by 41%.

UKPDSIn another landmark study, The

United Kingdom Prospective DiabetesStudy (UKPDS) compared intensiveglycemic control in Type II diabetic

subjects with conventionaltreatments to determinewhether intensive glycemiccontrol could reduce thefrequency of diabetes-relat-ed microvascular andmacrovascular complica-tions. These subjects werefollowed for an average often years.Researchers soon becameaware that high blood pres-sure may be an evenstronger risk factor thanhyperglycemia; and bloodpressure treatment wasadded to the study. Con-firming the DCCT data, theUKPDS showed that tightlycontrolling blood glucoseconcentration reduced therisk of complications in


244 www.podiatrym.comPODIATRY MANAGEMENT • NOVEMBER/DECEMBER 2007

CME 2...

tie in all diabeticcomplications. These

terms will be defined inthis article as part of ourdiscussion of the search forthese common links.

Hyperglycemia andDiabetic Complications

The evolution of thenumerous long-term com-plications of diabetes melli-tus has been shown to cor-relate well with the severityand duration of hyper-glycemia. For instance, ithas been consistentlydemonstrated22 that post-prandial glucose levelsabove 200 mg/dL have astrong association withrenal, retinal, and neurologic compli-cations that could show up five to tenyears after the onset of the disease.

It is important to note that manypatients demonstrate postprandialglucose at or above these critical lev-els when first diagnosed and alreadydemonstrate a degree of diabeticcomplications. In addition, recentepidemiologic studies23 revealed thatpoorly controlled diabetic patientshave a greater risk for cardiovasculardisease than those with well-con-trolled glucose levels.

DCCTThree large prospective random-

ized trials and one largeepidemiologic trial found acorrelation betweenglycemic control and re-duction in the progressionof chronic complicationsassociated with diabetes.Subsequent studies haveconfirmed these findings.The Diabetes Control andComplications Trial(DCCT) was designed todetermine if there was a re-lationship between hyper-glycemia and diabetic vas-cular complications. Thisstudy evaluated intensiveinsulin replacement andself-monitoring of bloodglucose in subjects whohad type-1 diabetes for aknown duration; and usedwell-established goals to

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Figure 2: Mechanisms By Which Hyperglycemia Creates Damage

Figure 1: Factors Promoting Diabetic Complications

HYPERGLYCEMIA


The Wisconsin EpidemiologicThe Wisconsin Epidemiologic

Study of Diabetes Retinopathy(WESDR) studied the relationship be-tween hyperglycemia and the fre-quency and progression of diabetes-related microvascular and macrovas-cular complications. The initial trialfocused on diabetic retinopathy, but afollow-up trial examined the frequen-cy and progression of microvascularand macrovascular complicationsover a ten-year period. A strong corre-lation was reported between higherHbA1c values and loss of vision,retinopathy, renal failure, lower-ex-tremity amputation, myocardial in-farction, and overall mortality.

The Mechanisms Which LinkHyperglycemia to DiabeticComplications

It is clear by the strong evidencepresented that there is a significant re-lationship between chronic hyper-glycemia and diabetic complications.How then does chronic hyperglycemiainduce the functional and morpholog-ic changes that define diabetic compli-cations (Figure 1)?

type-2 diabetes. Theoverall microvascularcomplications rate wasdecreased by 25% inthose receiving inten-sive therapy versus con-ventional therapy. Acontinuous relationshipbetween the risk of microvascularcomplications and glycemia wasshown to exist. In fact, for every per-centage point decrease in HbA1c, therewas a 35% reduction in the risk of mi-crovascular complications.

The UKPDS results confirm that itis glucose itself that is toxic in type-2diabetes and extend the previous evi-dence that hyperglycemia and its se-quelae are a major cause of microvas-cular complications of diabetes. Theaverage difference in HbA1c valuesbetween the conventional and inten-sive therapy groups was only 0.9%,but this small reduction reduced by12% (p = 0.029) the risk of any dia-betes-related endpoint, including anymacrovascular sequellae such as my-ocardial infarction, heart failure, angi-na, sudden death, stroke, amputation,retinal photocoagulation, renal fail-ure, and vitreous hemorrhage.

The authors reported a 16% re-duction in the risk of both fatal andnonfatal myocardial infarction (p =0.052). Also, interestingly, this studyshowed that tight blood pressurecontrol also reduced the risk of thesediabetic complications.

The Kumamoto StudyThe Kumamoto study ex-

amined the effects of strictglycemic control on the devel-opment and progression of di-abetes-related complications inpatients with type-1 and type-2 diabetes mellitus, respective-ly. This study demonstrated adirect relationship betweenglycemic control and a reduc-tion in microvascular compli-cations and neuropathic prob-lems in these patients. Thestudy found no worsening ofretinopathy or nephropathy inpatients with HbA1c concen-trations of <6.5%, fastingblood glucose concentrationsof <110 mg/dL, and two-hourpostmeal glucose concentra-tions of <80 mg/dL.

CME 2... Aconsensualframework hasnot been estab-lished which encom-passes all that isknown about the linkbetween hyper-glycemia and compli-cations, but over the

last 30 years, four seemingly indepen-dent major mechanisms of hyper-glycemia-induced damage have beendiscovered:

1) Polyol/sorbitol pathway activa-tion

2) Advanced glycation endproduct(AGE) formation

3) Protein kinase C (PKC) activa-tion

4) Hexosamine pathway activa-tion.

It is important to note that oxida-tive stress is generated in all thesepathways as well as in others that takeplace and helps fuel the intensity ofcomplications due to hyperglycemia.Briefly, to explain these four pathways,an increase in intracellular glucose willlead to an increase in the flux of glu-cose to sorbitol via the polyol/sorbitolpathway, an increase in glucosamine-6-phosphate via the hexosamine path-way, and the activation of PKC (pro-tein kinase C) via de novo synthesis ofDAG (diacylglycerol).

In addition, glucose and glucose-derived dicarbonyl compounds reactnonenzymatically with the basic

amino acids lysine and argininein proteins to form AGEs (ad-vanced glycosylation end-prod-ucts) both extra- and intra-cellu-larly. These different pathwaysare interrelated and potentiateeach other. Intracellularly, thesefour biochemical mechanismsmay all be the consequence ofhyperglyemia-induced overpro-duction of ROS in mitochondria(Figure 2).

The key biochemical mecha-nism for these pathologic pro-cesses is the direct deleterious ac-tion of glucose and other sugarson proteins, known as glycationor non-enzymatic glycosylation.Thus, glycosylation results from adirect chemical reaction betweenglucose and amino groups onproteins. Clinically, the measure-


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Figure 4: Complications in Diabetes Have a Microvascularor Macrovascular Component

Figure 3: Efforts of The Pharmaceutical Industry Geared Toward DecreasingEffects of AGEs.

formed.Incidental-

ly, a similar re-action, calledthe Maillard re-action, occursbetween sugarsand proteins infoods and is re-sponsible forthe brown col-oration of beer,cola and toast.These post-Amadori prod-ucts accumu-late in diabetic tissues over long peri-ods and thus may contribute to capil-lary closure in the retina and glomeru-lus, and to arterial narrowing in thecoronary, cerebral, and peripheral cir-culation. These AGE-products accumu-late in vivo as a function of both ageand levels of glycemia.

AGE MoleculesAGE molecules are present as pep-

tides that are free or protein-bound.They are found in the plasma, cells,and tissues and are able to accumu-late in the arterial wall on vascularwall collagen, the kidneymesangium, and glomerular andother basement membranes.

The accumulation of AGEs inthese long-lived proteins con-tributes to the age-related increasein brown discoloration, florescence,poor solubility of lens crystallinscausing cataracts, and to the gradu-al protein cross-linking and decreasein elasticity of connective tissue col-lagens with age.These processes are amplified in

diabetic patients. It is a critical pointthat even modest increases in dia-betic blood glucose levels result inconsiderable increases in AGEsaccumulation. This is a result ofAGE formation increasing at amuch greater rate than the in-crease in blood glucose.

Excessive formation of thesetypes of non-enzymatic glycosyla-tion products appears to be thecommon biochemical link be-tween chronic hyperglycemia anda number of pathological processesthat be involved in the develop-ment of long-term diabetic compli-cations. The pathologic effects ofexcessive non-enzymatic glycosyla-tion include those processes which

promote thesepost-Amadoriproducts suchas

• Inactiva-tion of en-zymes;

• Inhibi-tion of regula-tory moleculebinding;

• Cross-linking of gly-cosylated pro-teins and trap-ping of soluble

proteins by glycosylated extracellularmatrix;

• Decreased susceptibility to prote-olysis;

• Abnormalities of nucleic acidfunction;

• Altered macromolecular recogni-tion and endocytosis;

• Increased immunogenicity.

Inhibiting the Formation andProtein Cross-linking of AGE’s

Although a macrophage receptorsystem may antagonize this glycosyla-tion-mediated accumulation of pro-teins by recognizing and ingestingthose proteins combined with the ad-vanced glycosylation end products,excessive formation of these may out-weigh the capacity of the macrophageremoval system.

Inherited differences in this sys-tem and others that detoxify AGE in-termediates might be a result of thegenetic factors responsible for thelarge clinical variability that the im-pact of a given level of glycemia hason diabetic complications.

It is believed that circulating AGE-peptides are probably the result of in-



Figure 7: XEROSIS IN PATIENTS WITH DIA-BETES MELLITUS By permission from Dr.Robert G. Smith DPM

CME 2...

ment of the glycated form ofhemoglobin, HbA1c, has revolu-

tionized monitoring and the study ofdiabetic patients. Measurement of gly-cated plasma proteins (usually called‘the fructosamine’ assay) is used as atool for monitoring glycemic controlover a three-week period.

Hemoglobin is not unique, inthat non-enzymatic glycosylation isa common action on many bodyproteins. This early glycation is onlythe beginning of a deleterious cas-cade of events. Excessive chemicalattachment of glucose to proteinswithout the involvement of enzymesleads to the formation of Amadoriproducts. The early Amadori prod-ucts resembling hemoglobin A1cslowly give rise to complex irre-versible glycosylation adducts.

Ketoamine AdductThe first stable product of the reac-

tion is termed the “ketoamine adductto protein”, Fructosamino-protein

adduct or “Fructosamine” and is usedto indicate any glycated plasma pro-tein in this first stage. These Amadoriproduct adducts form in proportion toglucose concentration. Equilibrium isreached after several weeks and furtheraccumulation of these early nonenzy-matic glycosylation products does notcontinue beyond that time.

Subsequent reactions of theAmadori products slowly give rise tononequilibrium advanced glycosylationend-products which continue to accu-mulate indefinitely on longer-livedmolecules. Through a complex series ofrearrangements and oxidative reactions,multiple, very reactive end products,collectively named advanced glycationend products or AGE-products, are

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Figure 5: Capillary in Striated Muscle. A singleRBC fills lumen. Arrows point to thickened base-ment membrane.

Red Blood

Thickened CapillaryBasement Membrane

Muscle Nucleus

Striated Muscle Cross

Figure 6: Basement Membrane ThickeningCaused By Age Modification of GlomerularProteins


with protein to form glycoxidationproducts or lipids to form lipoxidationproducts, termed ALEs.

Some authors2 have coined a moregeneral comprehensive term for all ofthese harmful reactions: carbonylstress. The formation of AGEs can re-sult from the action of various metabo-lites other than glucose, such as fruc-tose, trioses and dicarbonyl com-pounds, and promote intracellular gly-cation at a much faster rate than thatwhich occurs extracellularly. Interest-ingly, intracellular AGE formation oncell proteins may thus, in turn, affectDNA function, suggesting a possibleexplanation for the increased teratoge-ny associated with diabetes mellitus.

Vascular Disease:Microvascular andMacrovascular

Most of the complica-tions in diabetes have avascular component.Vascular disease in dia-betes is usually designat-ed as either microvascu-lar or macrovascular.

Macrovascular diseaseis basically cardiovasculardisease and refers to ill-nesses affecting the largerarteries supplying theheart (i.e., heart disease

including myocardial infarction andcongestive heart failure), brain (i.e.,stroke) and the legs (large vessel steno-sis leading to peripheral vascular dis-ease and gangrene). Cardiovascular ormacrovascular disease accounts for ap-proximately 70% of the deaths of peo-ple with diabetes.17

Diabetics also experience microvas-cular disease. The effects of microvas-cular disease or microangiopathy, thesmall vessel disease in diabetes, includeneuropathy, nephropathy, retinopa-thy and dermopathy. These complica-tions can occur in type-1 diabetes asearly as adolescence, particularly if in-sulin treatment has been inadequate.

Similar complications may occurlater in life in type-2 diabetic patientsand are frequently present at the timeof diagnosis. The precise mechanismswhich cause microangiopathy tooccur are not totally understood. Ge-netic influences seem to be the prima-ry factor in the development of smallvessel disease; and are secondarily af-fected by metabolic and hemody-namic arrangements.

complete catabolism of AGE-proteinsby macrophages and other cells whichare on the way to be excreted by thekidneys. In diabetes, AGE peptides areincreased because of an increase inproduction and with kidney failure,causing decreased excretion. The ef-forts of the pharmaceutical industryare geared at interfering with thepathological consequences of AGE For-mation and Cross-linking.

These compounds are being de-signed to inhibit or reverse the forma-tion or cross-linking of AGEs and mayprovide relief for many medical condi-tions where AGE cross-linking has con-tributed to a loss of normal function,elasticity, and/or flexibility (Figure 3).

AGEs are produced not onlythrough the direct action of sugars onproteins but also by way of distinct ox-idative reactions. Glucose may be in-volved directly in further advancedglycation reactions involving free radi-cal oxidation. It has recently beenfound that glucose can probably auto-oxidize to form reactive carbonyl prod-ucts (glyoxal) and methylglyoxal (reac-tive oxygen species) which may react

CME 2–Diabetic Foot... The pathological hall-mark of diabetic microan-giopathy is the thickening of thecapillary basement membrane,which ultimately causes occlusive pe-ripheral arterial disease, tissue hypoxia,and permanent tissue damage and tis-sue death (Figure 5).

In diabetes mellitus, this pathologi-cal process is usually initiated throughthe damaging effects of the AGEs.

Microvascular ComplicationsAGEs affect the microvessels in

two basic ways:1) Through the direct effect of

AGEs on proteins, and2) Through the receptor-mediated

effects.

Direct Effect of AGEs on ProteinsAGE affects proteins by modifying

the functional properties of the extra-cellular matrix molecules. In collagen,the most abundant protein in thebody, AGEs form covalent, intermolec-ular bonds. Luminal narrowing, amajor feature of diabetic vascularpathology, results, in part, from the ac-cumulation of plasma proteins, such asalbumin, low density lipoprotein(LDL) and immunoglobulin G (IgG) inthe subendothelium.

These plasma proteins then mayget trapped in the basement mem-branes by covalently cross-linking toAGEs on collagen. This changes thescaffolding of the basement membraneand results in clinical pathology. For in-stance, in the kidney, the AGE modifi-cation of glomerular basement mem-brane proteins could prompt proteinleaking and stimulate a compensatoryoverproduction of other matrix com-ponents in the vessel wall, creating asituation that could lead to diabeticKimmelstiel-Wilson nephropathy (Fig-ure 6). Similarly, these AGE-induced ab-normalities alter the structure andfunction of microvessels other than therenal mircrocirculation, as well as themacrocirculation (Figure 5).

Receptor-Mediated Effects onProteins

Many cells have receptors forAGEs. AGEs then react with these spe-cific receptors and regulate the uptakeand clearance of AGEs. These receptorsare activated in three cell types:mononuclear cells, such as monocytesand macrophages, endothelial cells,


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Figure 9: With Proper Blood Sugar Control and WoundCare, These Diabetic Ulcerations Can Heal.

Figure 8: Diabetic Dermopathy and Ve-nous Stasis Dermatitis That Became Ul-cerated

down the key enzyme that high glu-cose levels shut off.

Hyperglycemia enhances the fluxthrough the polyol/sorbitol pathway, re-sulting in glucose being converted toharmful amounts of fructose and sor-bital. Diabetic neuropathy is promotedthrough this pathway.

Recent studies4 have identified thatthe activation of protein kinase C(PKC), an enzyme that catalyzes thephosphorylation of tyrosine residues incertain proteins, and increased diacyl-glycerol (DAG) levels initiated by hy-perglycemia, are associated with manyvascular abnormalities in retinal, renal,and cardiovascular tissues.

Activation of the hexosaminepathway causes insulin resistance andleads to deterioration of the beta-cellfunction through the induction of ox-idative stress rather than glycosylation.

Thus, the hexosamine pathway maycontribute to the deterioration of thebeta-cell function found in diabetes(Figure 2).

Increased enzymatic cross-linkingof collagen may be involved in the col-lagen-related changes seen in diabetes,since the enzyme lysyl oxidase, whichcatalyzes the formation of naturalcross-links in collagen, may be in-creased in some tissues in diabetes.

Macrovascular Complications:Atherosclerosis andHyperglycemia

Although the role of hyper-glycemia in macrovascular complica-tions is fraught with numerous ques-tions, the data certainly suggests a pos-sible role for hyperglycemia in acceler-ating the atherosclerotic process in pa-tients with Type-1 diabetes; and there

are strong asso-ciations, asshown by theUKPDS data,between bloodglucose controlin Type-2 dia-betes and therisk of cardio-vascular dis-ease, suddendeath and all-cause mortali-ty. Nonethe-less, these stud-ies do notprove as yetthat highblood glucosecauses thesecomplications

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CME 2–Diabetic...

and mesangial cells. Bindingwith these mononuclear cell recep-

tors, AGE proteins stimulatemacrophage production, synthesis ofcollagen in the glomerular structureand proliferation of arterial smoothmuscle cells.

AGEs binding to endothelial cellsstimulate methylglyoxal (reactive oxy-gen species) where pro-coagulantchanges are stimulated in the endothe-lial membrane. Concurrently, theseAGE-induced alterations in endothelialcell function promote thrombus for-mation at sites of extracellular AGE ac-cumulation. AGE receptors have alsobeen described on glomerular mesan-gial cells. AGE protein binding to thesereceptors leads to focal glomeruloscle-rosis, mesangial expansion, and pro-teinuria, the hallmarks of diabetic mi-croangiopathy.

Glycation and the other threepathways linked to hyperglycemia-induced damage—namely 1)thepolyol/sorbitol pathway activation,2) protein kinase C (PKC) activationand 3) the hexosamine pathway acti-vation—are thought to arise from asingle hyperglycemia-induced pro-cess, the overproduction of toxic freeradicals. Normalizing the levels ofthese excess free radicals inhibits thepathways through which cell damageoccurs. It is interesting to note thatall of these damaging pathways canbe activated, even in the presence ofnormoglycemia, simply by usingmolecular genetic techniques to shut

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Figure 10: Early and Late Complications of Diabetes Mellitus

Complications of Type 2 DMEarly Late

• Hyperalbuminuria • Renal failure

• Background • Proliferativeretinopathy retinopathy

• Neuropathy • Gangrene & amputation

• Medical arterial calcification • Coronary heart disease

• Hypertension • Diabetes-related death

Figure 11: Skin Manifestations Associated with Diabetes Mellitus (By permission from Dr. Robert G. Smith DPM)

Skin Condition Suggested Pathogenesis Treatment

Diabetic thick skin Microangiopathy None

Yellow skin Increased carotene; Noneincreased glycosylated collagen

Diabetic bulae Reduced threshold to Noneblister formation

Necrobiosis lipoidica Microangiopathy; neuropathy None; intralesional injections’diabeticorum steroids to peripheral lesions

Perforating dermatosis Polymorphonuclear leukocytes’ Keratolytics, address renal failureenzymatic degradation of collagenand elastin

This table has been adapted from Perez Mt. and Kohn SR, Cutaneous Manifestations of Diabetes Mellitus. J Am Acad Drmatoi 1994;30(4) 519-5331.


On the other hand, the vast major-ity of research corroborates the role ofglycation of lipoproteins in atherogen-esis. This enhanced glycation in dia-betes not only has direct adverse ef-fects but also amplifies the effects ofoxidative stress on lipoproteins. Gly-cated and oxidized lipoproteins pro-mote the process of atherogenesis aswell as platelet and endothelial celldysfunction.

It is too early to conclude that re-duction of hyperglycemia would haveas great an impact on loweringmacrovascular disease risk as it has onmicrovascular disease risk (thoughsome authors strongly suspect that itsimportance should not be minimized).Other factors such as dyslipidemia, ho-mocysteinemia or hypertension maypredispose patients with diabetes mel-litus to cardiovascular complications.

It must be added, however, thateven though a ma-jority of diabeticpatients will devel-op micro- andmacro-vascularcomplications, asubstantial frac-tion will never de-velop these severevascular complica-tions in spite ofhyperglycemia.Thus, within thegroup of diabeticpatients, a sub-group exists with arelatively normalrisk of these com-plications. In everycase, however, pa-tients with ad-vanced nephropa-thy and associatedmacro-albumin-uria have veryhigh risk of devel-oping severe vas-cular complica-tions.5

The pattern ofincreased risk forvascular complica-tions can be ob-served even inearly nephropa-thy, i.e. microalbu-minuria, in Type-2diabetes8 and alsoin non-diabeticsubjects,9 which

and that intensive treatment to lowerhyperglycemia would reduce the risksof these events.

Many of the pathways, however,described in the formation of microan-giopathy also apply here. Collagen inthe arterial wall bearing AGEs can trapLDL and IgG particles, which in turnaccumulate in the intima. They are,therefore, prone to local oxidation anduptake by monocyte-macrophages.Low density liproproteins cause en-dothelial cell activation and this en-courages the deposition of atheroma.Also, activation monocyte receptors byAGEs on vascular wall proteins, such ascollagen and elastin, can trigger cy-tokine-mediated inflammatory reac-tions. Therefore all vascular complica-tions in the diabetic may in fact be due,in part, to these reactions.

CME 2–Diabetic... has raised the question ofwhat common mechanismsmay be at work. An obvious pos-sibility is that common risk factorssuch as hypertension, obesity, dyslipi-demia and smoking are involved inboth nephropathy and vasculopathy,and play a dominant role in all diabet-ic complications independent ofglycemic control and may stem fromendothelial dysfunction13 and chroniclow-grade inflammation.14

The Foot Is Attached to the Restof the Body

The pedal pathology present in di-abetes usually presents with the effectsof microangiopathy, which includethe peripheral neuropathies, and paral-lels the corresponding microangio-pathic effects, such as nephropathyand retinopathy. There are also directeffects of non-enzymatic glycosylation,glycoxylation and lipoxidation on thenerves, facilitating the onset and for-matting the degree of the peripheralneuropathies. Both macro-and mi-croangiopathy, as well as the direct ac-tion of non-enzymatic glycosylation,affect the condition of the skin andnails in the diabetic foot.

Dr. Robert G. Smith, a podiatricphysician and pharmacist who hasworked extensively with the skin ofthe diabetic patient, states that xerosisis one of the most common skin con-ditions one will see among podiatricpatients who have type-2 diabetes. It isparticularly prevalent among elderlypatients (Figure 7). He states that thereason for the dryness is the redistribu-tion of blood flow in the soles by per-sistent and inappropriate dilatation ofarteriovenous shunts.

This activity diverts blood awayfrom the skin surface. When this oc-curs in combination with alterationsin the elasticity of the skin (due tonon-enzymatic glycosylation of struc-tural proteins and glycoproteins), theskin splits and portals for bacteria arecreated. This happens in combinationwith venous stasis dermatitis and dia-betic dermopathy. (Figures 8-9) In sev-eral studies, diabetic dermopathy (shinspots) has been found to be related tomicroangiopathy and neuropathy.1,2 Ina more recent study of 173 patientswith diabetes,3 diabetic dermopathywas present in 66%, 62%, and 63% ofthose patients with retinopathy, neu-ropathy, and nephropathy, respective-


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Figure 12: Optimal Prevention and Treatment

• Diabetes complications are common and almost triple the annual cost of managing diabetes.

• Microvascular complications are the major risk in type 1 diabetes, while macrovascular complica-tions are the major cause of morbidity and mor-tality in type 2 diabetes.

• Control of hyperglycemia (target HbA1c level < 7%) and hypertension (target blood pressure < 30/80 mmHg) prevents microvascular compli-cations in both types of diabetes; a multifactorial approach, comprising behavior modification and pharmacological therapy for all risk factors, re-duces the development of micro- and macrovas-cular complications in type 2 diabetes.

• The benefit of treating dyslipidaemia is at least as great in the diabetic population as in the non-diabetic population.

• Angiotensin-converting enzyme inhibitors and low-dose aspirin are indicated in people with diabetes and other cardiovascular risk factors.

• Regular annual medical, dental and foot screen-ing for diabetes complications allows treatable disease to be identified.21

Aggressive interdisciplinarymanagement of diabetes risk

factors can prevent manycomplications

studies, to coordinate care with theother members of the patient’s “medicalteam” that ultimately results in optimalprevention and treatment for the com-plicating sequellae of this devastatingdisease (Figure 12). The science gets verycomplicated, but the role of the podia-tric and diabetic foot specialist is simple.Every practitioner who treats diabeticfoot problems must communicate andempower the patient, as well as all theother members of their team, in an ef-fort to promote a healthful lifestyle thatincludes exercise, diet, and control ofthe unhealthy markers for amputationand death, i.e., hypertension, hyperlipi-demia, and hyperglycemia. ■

Bibliography and SuggestedReadings

1 Danowski TS, Sabeth G, Sarver ME, etal. Shin spots and diabetes mellitus. Am JMed Sci. 1966;251:570-5.

2 Murphy RA. Skin lesions in diabetic pa-tients: the “spotted leg”syndrome. Lahey ClinBull. 1965;14:10-14.

3 Shemer A, Bergman R, Linn S, et al. Di-abetic dermopathy and internal complica-tions in diabetes mellitus. Int J Dermatol.1998;37(2):113-5.

4 Experimental Diabesity Research. 2003Apr-Jun;4(2):125-32. Hyperglycemia-inducedprotein kinase C activation inhibits phagocy-tosis of C3b- and immunoglobulin g-op-sonized yeast particles in normal human neu-trophils. Saiepour D, Sehlin J, Oldenborg PA.Department of Integrative Medical Biology,Section for Histology and Cell Biology, UmeåUniversity, Umeå, Sweden.

5 Molitch, M. E., DeFronzo, R. A., Franz,M. J., et al. (2004) Nephropathy in diabetes.Diabetes Care 27 (Suppl. 1), S79–S83.

6 Parving, H. H., Chaturvedi, N., Viberti,G. and Mogensen, C. E. (2002) Does microal-buminuria predict diabetic nephropathy? Di-abetes Care 25, 406–407.

7 Mogensen, C. E. and Cooper, M. E.(2004) Diabetic renal disease: from recentstudies to improved clinical practice. DiabeticMed. 21, 4–17.

8 Jager, A., Kostense, P. J., Ruhe, H. G., etal. (1999) Microalbuminuria and peripheralarterial disease are independent predictors ofcardiovascular and all-cause mortality, espe-cially among hypertensive subjects: five-yearfollow-up of the Hoorn Study. Arterioscler.,Thromb., Vasc. Biol. 19, 617–624.

9 Yudkin, J. S., Forrest, R. D. and Jackson,C. A. (1988) Microalbuminuria as predictor ofvascular disease in non-diabetic subjects. Is-lington Diabetes Survey. Lancet ii, 530–533

10 Karalliedde, J. and Viberti, G. (2004)Microalbuminuria and cardiovascular risk.Am. J. Hypertens. 17, 986–993.

11 Gerstein, H. C. (2002) Epidemiologicanalyses of risk factors, risk indicators, riskmarkers, and causal factors. The example ofalbuminuria and the risk of cardiovasculardisease in diabetes. Endocrinol. Metab. Clin.

North Am. 31, 537–551.12 Gerstein, H. C., Mann, J. F., Yi, Q., et

al. (2001) Albuminuria and risk of cardiovas-cular events, death, and heart failure in dia-betic and nondiabetic individuals. JAMA, J.Am. Med. Assoc. 286, 421–426.

13 Stehouwer, C. D., Henry, R. M.,Dekker, J. M., Nijpels, G., Heine, R. J. andBouter, L. M. (2004) Microalbuminuria is as-sociated with impaired brachial artery, flow-mediated vasodilation in elderly individualswithout and with diabetes: further evidencefor a link between microalbuminuria and en-dothelial dysfunction: the Hoorn Study. Kid-ney Int. 66 (Suppl. 92), S42–S44.

14 Nakamura, M., Onoda, T., Itai, K., et al.(2004) Association between serum C-reactiveprotein levels and microalbuminuria: a popu-lation-based cross-sectional study in northernIwate, Japan. Intern. Med. 43, 919–925.

15 Verrotti, A., Greco, R., Basciani, F.,Morgese, G. and Chiarelli, F. (2003) vonWillebrand factor and its propeptide in chil-dren with diabetes. Relation between en-dothelial dysfunction and microalbuminuria.Pediatr. Res. 53, 382–386.

16 Clinical Science (2005) 109, (143–159)(Printed in Great Britain) Review article Vas-cular complications in diabetes mellitus: therole of endothelial dysfunction Casper G.Schalkwijk and Coen D. A. Stehouwer.

17 Diabetologia (1984) 26: 93-98 Dia-betologia Springer-Verlag 1984 Review arti-cles Non-enzymatic glycosylation and thechronic complications of diabetes: anoverview L. Kennedy and J. W. Baynes.

18 Muller SA, Winkleman RK. Necrobio-sis lipoidica. Br J Dermatol. 1955;67:365-84.

19 Perez MI, Kohn SR. Cutaneous mani-festations of diabetes mellitus. J Am Acad Der-matol. 1994;30(4):519-31.

20 Jude E., Boulton A. (1998) ‘Foot prob-lems in diabetes mellitus’. Br J Podiatry, 1; 4:117-120.

21 MJA Practice Essentials—Endocrinolo-gy3: Preventing complications of diabetesKatherine L Bate and George Jerums SeriesEditors: Donald J Chisholm and Jeffrey DZajac MJA 2003; 179 (9): 498-503.

22 Textbook: Levin and O’Neal’s The Dia-betic Foot sixth ed. Pages 1-92 Edited by:John H. Bowker, MD and Michael A. Feiffer,MD, Mosby Publishing.

23 Diabetes Services in Wales 2003-12-04,2003 The Audit Commission.


CME 2–Diabetic...

ly. Accumulation of glycoxida-tion and lipoxidation products in

skin collagen is associated with failureof the kidney to thrive. Yellow toenailand skin syndrome from diabetes mel-litus is a result of non-enzymatic glyco-sylation and crosslinking of the pro-teins in the toenails.

Necrobiosis lipoidica diabeticorum,diabetic blisters, and eruptive xan-thomatosis are among the conditionscaused by large and small vessel dis-ease, as well as by the glycosylation ofcollagen in the skin. Limited joint mo-bility17 appears to be correlated withthe presence of thickened waxy skinand thickening, and contracture andloss of elasticity of the tendons in thefeet of diabetic patients, which hastremendous effects on gait and createssignificant biomechanical abnormali-ties. Non-enzymatic glycosylation isthought to be the main culprit here.

Many more diabetic foot complica-tions can be discussed, but whether itbe vasculopathy, neuropathy, im-munopathy or musculoskeletal prob-lems, it is clear that all pedal and sys-temic complications of diabetes melli-tus are interrelated; and the main cul-prits are the processes of non-enzymat-ic glycosylation, glycoxylation, andlipoxidation (Figure 11).

Cardiovascular and kidney diseaseare usually present in diabetes mellitusbut the main causes appear to be relatedto harmful fats and hypertension. Bymonitoring all complications, it’s rea-sonable to assume that one would be ina better position to evaluate or possiblyprevent some of the complications ofdiabetic foot disease (Figure 10).

The importance of understandingthe mechanisms of these complica-tions is essential to identifying, pre-venting, treating and managing thoseseen in the foot of a diabetic patient.Dealing with the diabetic complica-tions that all foot health practitionersare faced with starts with viewing thepatient as a whole; and understandingthat the patient is being treated forcomplications involving the foot, notjust for the foot exclusively, therebylooking at the pedal complications aspart of a generalized pathology.

It is incumbent upon the podiatricphysician to evaluate a patient in thisway, and to use information obtainedfrom the medical history, other treatingphysicians, blood tests and imaging

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Dr. Rehm, boardcertified in dia-betic woundcare, practices inSan Diego, CA.He lectures na-tionally and of-fers seminars forpodiatrists andother profession-als. Dr. Rehm is

Director of the Diabetic Foot andWound Treatment Centers in San Diegoand is a member of both the AAPPMand the APWCA.


with the following:A) Small vessel diseaseB) Large vessel diseaseC) HyperglycemiaD) All of the above

6) The measurement of theglycated form of hemoglobinwhich is a reflection of the last3 months of blood glucose iscommonly referred to as

A) HgA1cB) ZnD1CC) Glycosylated GlobulinD) NaCl-A1D

7) The following was a land-mark study involving the rela-tionship between high bloodsugar and diabetic vascularcomplications:

A) The Stanford GrowthFactor StudyB) The International Diabetic Foot StudyC) The Harvard GrowthHormone StudyD) The Diabetes Controland Complications Trial

8) The Diabetes Control andComplications Trial (DCCT)was designed to determine thefollowing:

A) The relationship be-tween high cholesterol andsmall vessel diseaseB) The relationship be-tween hyperglycemia and diabetic vascular complicationsC) The relationship between neuropathy,retinopathy and nephropathyD) The effectiveness of theStockholm Diabetes Inter-vention Study

1) Diabetes mellitus is a condi-tion characterized by the fol-lowing:

A) Deficiency of thyroidfunctionB) Overproduction ofadrenal hormonesC) A deficiency in insulin se-cretion or resistance to in-sulin actionD) Hypermobile flatfoot

2) The complexity of diabeticfoot complications creates thefollowing:

A) Lack of time for appropri-ate treatment and diagnosisB) Clinical and financialchallenges to their manage-mentC) An opportunity to useadditional CPT codesD) Friction within the medi-cal community

3) The common thread of all di-abetic complications lies in thefollowing:

A) Electrical reactionsB) Financial problemsC) Chemical reactions with-in the bodyD) Non-compliance

4) High Glucose in the blood isharmful because

A) It produces a psychologi-cal dependenceB) It alters the transit timein the colonC) Of the combination ofglucose with proteins in thebodyD) It creates an unhealthydemand for sweet desserts

5) Complications of diabetesseen in the feet are associated

9) There is strong evidence of asignificant relationship between

A) Hyperglycemia and diabet-ic complicationsB) Myocardial infarction andabnormal HgA1cC) Loss of vision and largevessel cardiovascular diseaseD) Kidney disease and enzy-matic glycosylation

10) How many independentmechanisms are thought to con-tribute to the complications re-lated to high blood sugar?

A) 6B) 5C) 7D) 4

11) In diabetes mellitus, thepathological process is usuallyinitiated through the damagingeffects of

A) AGEB) LDLC) HDLD) IgG

12) A majority of diabetic pa-tients will develop the following:

A) Sudden death syndromeB) Vascular complicationsC) HypoglycemiaD) Hypothyroidism

13) The risk factors that are inde-pendent of blood sugar controlinclude:

A) Vascular complicationsB) HypertensionC) NephropathyD) Neuropathy

14) The condition of the skin and nails in the foot of a diabeticpatient are affected by all of

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252 PODIATRY MANAGEMENT

the following except:A) MacroangiopathyB) MicroangiopathyC) Enzymatic GlycosylationD) Non-Enzymatic Glycosylation

15) One of the most common skin conditions seenin diabetic patients is:

A) Erythromatosquamous dermatitisB) ErisypelasC) Psoriatic plaquesD) Xerosis

16) The reason for dryness of the skin in diabeticmellitus is usually associated with

A) Inappropriate dilatation of arteriovenousshuntsB) Venous hypotensionC) Arterial vasospasmD) Telangiectasias of the skin

17) “Shin Spots” in a diabetic patient is also called:A) Epidermolysis bullosaB) Venous stasis dermatitisC) Diabetic dermopathyD) Yellow skin syndrome

18) Loss of elasticity in the skin of the diabetic pa-tient is usually due to:

A) Non-enzymatic glycosylation of structuralproteinsB) Redistribution of blood flow in the skinC) Injury from the ultraviolet raysD) Peripheral neuropathy

19) Limited joint mobility is commonly correlated with:A) The presence of thickened waxy skinB) Cardiovascular diseaseC) Kidney diseaseD) Hypertension

20) All of the following are complications in thelower extremity due to diabetes mellitus except:

A) ParonychiaB) Yellow toenail syndromeC) Necrobiosis lipoidica diabeticorumD) Eruptive xanthomatosis

E X A M I N A T I O N

(cont’d)

See answer sheet on page 253.

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E N R O L L M E N T F O R M & A N S W E R S H E E T (cont’d)Con

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LESSON EVALUATION

Please indicate the date you completed this exam

_____________________________

How much time did it take you to complete the lesson?

______ hours ______minutes

How well did this lesson achieve its educational objectives?

_______Very well _________Well

________Somewhat __________Not at all

What overall grade would you assign this lesson?

A B C D

Degree____________________________

Additional comments and suggestions for future exams:

__________________________________________________

__________________________________________________

__________________________________________________

__________________________________________________

__________________________________________________

__________________________________________________

EXAM #9/07The Use of Epidermal/Dermal

Replacement Therapies and CombinedReplacement Matrices

(Rabjohn)

1. A B C D

2. A B C D

3. A B C D

4. A B C D

5. A B C D

6. A B C D

7. A B C D

8. A B C D

9. A B C D

10. A B C D

11. A B C D

12. A B C D

13. A B C D

14. A B C D

15. A B C D

16. A B C D

17. A B C D

18. A B C D

19. A B C D

20. A B C D

Circle:

LESSON EVALUATION

Please indicate the date you completed this exam

_____________________________

How much time did it take you to complete the lesson?

______ hours ______minutes

How well did this lesson achieve its educational objectives?

_______Very well _________Well

________Somewhat __________Not at all

What overall grade would you assign this lesson?

A B C D

Degree____________________________

Additional comments and suggestions for future exams:

__________________________________________________

__________________________________________________

__________________________________________________

__________________________________________________

__________________________________________________

__________________________________________________

EXAM #10/07Towards Better Management

of Diabetic Foot Complications(Rehm)

1. A B C D

2. A B C D

3. A B C D

4. A B C D

5. A B C D

6. A B C D

7. A B C D

8. A B C D

9. A B C D

10. A B C D

11. A B C D

12. A B C D

13. A B C D

14. A B C D

15. A B C D

16. A B C D

17. A B C D

18. A B C D

19. A B C D

20. A B C D

Circle:

Towards Better Management of Diabetic Foot Complications · Management, P.O. Box 490, East Islip,...

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