review blood glucose and atherosclerosis...

Review

Blood Glucose and Atherosclerosis

Robert W. Stout

The relationship of diabetes to cardiovasculardisease has been known for over half a cen-

tury and has been the subject of a number ofreviews. The topic was discussed by the authorand two colleagues in 1975,1 and the presentpaper concentrates on information publishedsince that time.

Although it is well known that diabetic patientscommonly die from cardiovascular disease andthat cardiovascular disease is particularlycommon in diabetes, a number of questionsremain unanswered. It is now clear that diabetesmellitus consists of at least two distinct disordersthat differ both genetically and in their metabolicabnormalities.2 The majority of diabetics haveType II, or noninsulin-dependent, diabetes melli-tus (NIDDM), characterized by mild to moderateglucose intolerance, a high frequency of obesity,absence of a tendency to ketoacidosis, and re-sponse to treatment with diet or oral antidiabeticdrugs. A minority (20%) of diabetics have Type I,or insulin-dependent, diabetes mellitus (IDDM),characterized by marked hyperglycemia, weightloss, and a requirement for insulin therapy toprevent the development of ketoacidosis. Theold terms of "juvenile diabetes" for IDDM and"maturity-onset diabetes" for NIDDM are nolonger used, as either type of diabetes can occurat any age. The possibility that the two majortypes of diabetes have different relationships toatherosclerosis remains to be explored. Thecriteria for the diagnosis of diabetes are clearlyarbitrary, although they correlate with clinicaland epidemiological data. Assessment of the se-verity of diabetes is even more arbitrary, whilethe duration of diabetes can only be measured asthe time since diagnosis.

From the Department of Geriatric Medicine, Queen's Uni-versity of Belfast, Belfast, Northern Ireland.

Address for reprints: Dr. Robert W. Stout, Department ofGeriatric Medicine, Queen's University of Belfast, WhitlaMedical Building, 97 Lisburn Road, Belfast, BT9 7BL, North-ern Ireland.

Received March 31,1981; revision accepted May 26,1981.

Atherosclerosis and Diabetes

Autopsy Evidence

Epidemiological Evidence—The FraminghamStudy

Blood Glucose and Arterial Disease

Risk Factors for Atherosclerosis in Diabetes

Nonatherosclerotic Heart Disease in Diabetes

Other Factors Associated with Atherosclerosisand Diabetes

Insulin and Atherosclerosis

Chlorpropamide-Alcohol Flushing and VascularDisease in Noninsulin-Dependent Diabetes

Conclusions

(Arteriosclerosis 1981; 1:227-234)

While classical myocardial infarction with char-acteristic clinical features accompanied by elec-trocardiographic (ECG) and other abnormalitiescan be ascribed to atherosclerosis with someconfidence, the pathological processes respon-sible for congestive cardiac failure, suddendeath, and cardiovascular death may not alwaysbe primarily atherosclerotic. Many clinical andepidemiological studies have used the latter end-points in investigating the relationship of dia-betes to atherosclerosis; the validity of theseassumptions must be questioned. Other ques-tions concern the relationship of atherosclerosisto the severity and duration of diabetes and to itsmode of treatment; the role of blood glucoseelevations in atherosclerosis in nondiabetics; therelationship of cardiac disease in diabetics toother risk factors for atherosclerosis; andwhether diabetics have a specific heart muscleabnormality independent of disorders of thecoronary arteries. Each of these topics will beconsidered in this review.

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228 ARTERIOSCLEROSIS VOL 1, No 4, JULY/AUGUST 1981

Atherosclerosis and Diabetes

Autopsy Evidence

Many of the autopsy studies of diabeticspublished in the past are unsatisfactory bymodern standards. In particular, the controlgroups were not always appropriate, and oftenthere were only limited examinations of the heartand coronary arteries. However, in the largeststudy in which arteries were examined by stan-dardized techniques, the coronary arteries andaortas of diabetics showed more atherosclerosisthan those of nondiabetics regardless of sex,age, race, or geographic location.3

Three recent studies have applied modern tech-niques to the study of atherosclerosis indiabetes. In a reexamination of the hearts of dia-betics in the Mayo Clinic, the degree of cross-sectional area narrowed by atheroscleroticplaques in each of the four major epicardialarteries was measured.4 The patients had allattended a diabetes clinic; in addition, diabeteswas defined by standard criteria and includedboth IDDM and NIDDM. The control group con-sisted of age- and sex-matched subjects whohad had fatal coronary events but not diabetes.The nondiabetic controls were patients who hadnot attended the diabetes clinic. There was nomention that blood glucose measurements hadbeen made on these patients. Overall, the studydisclosed similar degrees of severe narrowing ofthe main coronary arteries by atheroscleroticplaques in both diabetic patients with or withoutclinical evidence of coronary heart disease andin nondiabetics with fatal coronary heart disease.No significant differences were observed in thedegree of severe narrowing by atheroscleroticplaques between the proximal and distal halvesof the three coronary arteries in either thediabetic group or in the controls. The degree ofcoronary artery narrowing was not related to theage of onset and the duration of diabetes, nor tothe treatment or to the random blood sugarlevels. Acute myocardial infarction was the mostfrequent fatal coronary event in the diabeticsstudied, with "sudden coronary death" second,and chronic congestive cardiac failure third. Thefrequency of these three types of fatal coronaryevent was not altered by the patient's age atonset of diabetes or by the duration of thediabetes. However, a significantly higher fre-quency of severe narrowing of the left maincoronary artery occurred in the patients withdiabetes mellitus. Healed transmural ventricularscars were found at autopsy more frequently inthe diabetics than in the nondiabetic controls,but a similar frequency of cardiac rupture oc-curred in the patients with and without diabetes.The results of this study are somewhat difficult tointerpret, and it is unfortunate that the study didnot include a fourth control group made up of

nondiabetic patients who had died from causesother than coronary disease.

In an autopsy study from Baltimore publishedat the same time, the hearts of 185 patients whohad clinically established adult-onset diabetesmellitus of mixed type were examined by a stan-dardized coronary arteriography technique.5 Theclinical severity of diabetes was assessed by areview of the medical records. There was no sig-nificant association between the overall degreeof coronary artery atherosclerosis and either theduration or severity of diabetes. Similarly, therewas no significant correlation between the sever-ity of diabetes and systemic, pulmonary, orcerebral atherosclerosis. The type of treatmentof diabetes (by diet, oral hypoglycaemic drugs,or insulin) was not related to the degree ofcoronary atherosclerosis. However, when thediabetic group was compared with an age- andsex-matched control group, the diabetics hadsignificantly more coronary atherosclerosis. Thenumber of myocardial infarctions, the number ofdiseased coronary arteries, the diffuseness ofcoronary atherosclerosis, and the presence ofcoronary arterial collateral channels were all sig-nificantly greater in the diabetics than in the non-diabetics. These results suggest that diabeticshave more extensive atherosclerosis than non-diabetics. However, the findings also suggestthat the progress of coronary atherosclerosis indiabetes of adult onset is independent of theprogress of the diabetes itself.

In a rare autopsy study of young, juvenile-onset insulin-treated diabetics, nine patients(average age, 29 years; average age at onset, 9years) had significantly more extramural cor-onary narrowing by atherosclerotic plaques thandid nine age-matched control subjects.6 Both thedegree of narrowing and the extent of coronaryarterial involvement were greater in thediabetics. In the diabetics, 47% of the entirelength of the coronary arteries was narrowedmore than 50%, compared with only 1% in thenondiabetic controls. There was no evidence of asignificant abnormality in the small intramuralcoronary arteries. Although this study demon-strated accelerated coronary atherosclerosis indiabetics, the presence of early-onset diabeteswas not always accompanied by severe coronaryheart disease 20 or more years later. In twodiabetics, little coronary artery narrowing wasfound, and it has been suggested that this wasrelated to the infrequent occurrence of keto-acidosis in these subjects. A clinical, retrospec-tive case study of coronary angiograms in dia-betics and controls also found no evidence ofsignificant disease of the small coronaryvessels.7

These studies indicate that coronary athero-sclerosis is more severe at all ages and occurs ata younger age in insulin-dependent diabetics.



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BLOOD GLUCOSE AND ATHEROSCLEROSIS Stout 229

However, coronary atherosclerosis is not aninevitable accompaniment of diabetes, and allcoronary arteries are not equally involved.Atherosclerosis in diabetes is not related to theduration of diabetes, age of onset of the disease,blood glucose levels or type of treatment. No evi-dence of disease of the small intramural arterieswas found.

Epldemlologlcal Evidence—The FramlnghamStudy

The Framingham study, a large prospectivestudy of 5209 men and women, has addressedthe question of the relationship of diabetes toatherosclerosis. Diabetes was diagnosed whenthe subject was having treatment for diabetes,had a positive oral glucose tolerance test, or hadtwo or more blood glucose levels higher than 160mg/dl. By the 16th year of the study,8 diabeticmen and women had developed more cerebralvascular accidents, coronary heart disease, andperipheral arterial disease than age- and sex-matched nondiabetics. The mortality rate fromcardiovascular disease in the diabetics wasalmost three times that of the general population.However, there seemed to be a greater impact onwomen than on men, since the risk of cardiovas-cular mortality in diabetic women was 4Vfe timesgreater than in nondiabetic women, while therisk ratio in men was 2:1. However, this high riskwas confined to women treated with insulin. Al-though coronary disease was the commonestcause of death in diabetics, the impact ofdiabetes seemed to be greatest on intermittentclaudication. Although the diabetics had higherbeta lipoproteins, higher blood pressures, andgreater relative weight than the nondiabetics, thedifferences did not appear to be of sufficientmagnitude to account entirely for the excess ofcoronary heart disease (CHD) incidence indiabetics. Multivariate analysis of the various riskfactors suggested some unique effect ofdiabetes, especially in women, which could notbe explained by associated risk factors. Theresults of later examinations of the Framinghamcohort have confirmed the findings of the 16thyear examination.9 In particular, the increasedrisk of cardiovascular disease in women hasbeen emphasized. Nevertheless, diabetes is not ahighly prevalent condition and, thus, in thewhole spectrum of atherosclerosis, diabetescarries a relatively low risk.10 Factors such aselevated blood pressure and serum cholesterolhave the same relationship to cardiovasculardisease in diabetics as in nondiabetics, and therewas no evidence that diabetics cope less wellwith risk factors than nondiabetics.11 Even whenthe protective effect of high density lipoproteincholesterol (HDL) and the lower HDL values indiabetics were taken into consideration, the

impact of diabetes on cardiovascular diseasecould not be entirely explained by the associatedrisk factors.12

Blood Glucose and Arterial DiseaseThe relationship of mild abnormalities in blood

glucose to cardiovascular disease has been thesubject of recent studies. The largest investiga-tion has been the Whitehall study, a prospectivestudy of 18,403 London civil servants.13 Capillaryblood glucose was measured 2 hours afteradministration of a 50 g oral dose of glucose fol-lowing an overnight fast. The measurement wasrelated to the age-adjusted coronary heartdisease (CHD) mortality after 7V4 years. Subjectswith 2-hour blood glucose levels of 200 mg/dl(11.2 mmoles/liter) or more were designated newdiabetics and had the highest mortality. Previ-ously diagnosed diabetics also had high mor-tality rates as well as the highest age-adjustedECG measurements. The rates were the same indiabetics treated with insulin and in thosereceiving other treatment. In nondiabetics with2-hour blood glucose levels of less than 200mg/dl, the 2-hour blood glucose level was notlinearly related to the age-adjusted CHD mortal-ity, nor was there a linear correlation in theincrease in ECG abnormalities with increasingblood glucose. However, there was a sharpdoubling of CHD mortality at the 95th percentile(2-hour blood glucose, 96 mg/dl; 5.4 mmoles/liter) with no variation of mortality rate withblood glucose below that point. It was notablethat the increased risk of CHD mortality andECG abnormalities was found at blood glucoselevels considerably lower than those recentlysuggested as indicative of impaired glucose tol-erance.2 These findings contrast with thosereported for microvascular disease in diabetes asmanifested by retinopathy and proteinuria. In agroup of Pima Indians of Arizona, a communitywith the highest recorded incidence of diabetes,the development of retinopathy in a 3-yearperiod was very rare in those with a fasting bloodglucose level of less than 140 mg/dl (7.8 mmoles/liter) and did not occur if the 2-hour bloodglucose level was less than 200 mg/dl (11.2mmoles/liter). Proteinuria was less frequent thanretinopathy, but had a similar relation to bloodglucose levels.14

The Whitehall findings must be judged in thecontext of the International CollaborativeProject, a combined report of 11 different studiesof blood glucose levels and coronary heartdisease.15 This project was not planned in ad-vance, and standardized methods of measuringblood glucose levels or assessing cardiac mor-tality were not used. In addition to the Whitehallstudy, four other investigations found highercardiovascular mortality in subjects with the



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highest blood glucose levels, although in all ofthese studies multivariate analysis did not con-firm an independent relationship of bloodglucose with cardiovascular mortality.16"19 Theother studies showed no relationship betweenthe blood glucose level and the subsequent mor-tality from coronary heart disease. The relation-ship between blood glucose and the prevalenceof ECG abnormalities was variable. The group ofauthors found no evidence for an association be-tween blood glucose levels and coronary heartdisease in nondiabetics. They did not find suffi-cient evidence for a threshold relationship, thatis to say, a consistently positive relation betweenthe highest levels of blood glucose and the inci-dence of CHD. It was suggested that hyper-glycemia should not be designated an independ-ent risk factor for CHD on present evidence.

There are a number of problems with the Inter-national Collaborative Project.20 Studies wereincluded in the project that differed in a numberof respects, including methods of measuringblood glucose, times at which samples weretaken for the measurement of glucose, certainexclusion criteria for patients with preexistingdiabetes, and differences among populations.The studies that did show an excessive CHD mor-tality in subjects with the highest blood glucoselevels were the only studies in which a significantnumber of coronary deaths occurred in subjectswith the highest blood glucose levels. Indeed,only four of the studies had more than one CHDdeath in the upper blood glucose quintile, and ofthese, three showed at least a doubling ofmortality in this blood glucose range. The resultsof the Whitehall study cannot be ignored, since itis by far the largest study and one of only twostudies in which glucose was measured incapillary blood. If this study is correct, it wouldsuggest a threshold of impaired glucose tol-erance above which the risk of CHD is increased.It is not surprising that multivariate analysis didnot reveal glucose as an independent risk factorwith a linear relationship to CHD mortality. Fur-thermore, the small number of people with thehighest blood glucose levels suggest that onlythe largest studies would be likely to identifysuch a threshold effect.

A new analysis of the Tecumseh study hasemphasized the complex relationship betweenblood glucose and atherosclerosis.21 Althoughpersons in the upper quartile of blood glucosedistribution had twice the risk of CHD comparedto those in the lowest quartile, even when thosewith diagnosed diabetes had been excluded,there was no significant independent linear rela-tionship between blood glucose and the risk ofCHD in nondiabetics. These results areconsistent with the threshold effect of bloodglucose on atherosclerosis found in the White-hall study. An important, but unanswered, ques-

tion is whether such a threshold effect resultsfrom the metabolic consequences of a criticallevel of blood glucose, or whether it identifies agroup of people who are genetically predisposedto both diabetes and atherosclerosis.

Risk Factors for Atherosclerosis In Diabetes

The question of whether atherosclerosis indiabetes is due to an increased frequency ofmajor risk factors for atherosclerosis in thegeneral population has been studied in a numberof ways. Restudy of the Tecumseh cohort21

showed that age, systolic blood pressure, bloodglucose, blood cholesterol, and cigarettesmoking were all significantly higher in thesubjects with CHD than in the rest of the subjectgroup. However, when all the variables wereincluded in a multiple logistic functions analysis,blood glucose was a lesser factor and not sig-nificant after exclusion of diagnosed diabetics. Ithas been suggested that the interaction of riskfactors may be more important than any singlefactor in predicting CHD. In the Whitehall study,the association of age, systolic blood pressure,and ECG abnormalities with CHD mortality wasstronger in the group with impaired glucose tol-erance than in the subjects with normal bloodglucose levels.

In a group of 485 diabetics, the prevalence ofarteriosclerosis obliterans (ASO) was deter-mined by noninvasive methods.22 Overall,lipoprotein levels in the diabetics were higherthan in an age- and sex-matched nondiabeticgroup. However, the patterns differed in the dif-ferent types of diabetes. In noninsulin-depend-ent diabetics (NIDDM), the prevalence of ASOwas most dependent on age, and no independenteffect of duration of diabetes was found. Incontrast, in the diabetics treated with insulin,there was a significant correlation with both ageand duration of diabetes. This difference may bedue to the fact that the onset of diabetes isdifficult to identify in NIDDM. In diabetics treatedwith diet alone, low HDL cholesterol was themost significant risk indicator, while in thosetreated with sulphonylureas, age was the onlysignificant risk indicator. In the NIDDM subjectstreated with insulin, all lipoproteins were signif-icantly associated with ASO, but only VLDL tri-glyceride had a highly significant association. Inthe IDDM group all indicators except HDL choles-terol were highly significantly related to theprevalence of atherosclerosis. The study did nottake into account body weight, blood pressure,or cigarette smoking. The overall prevalence ofASO was 24% in the IDDM subjects and 38% inthe NIDDM subjects; the ASO prevalence was38% in men and 29% in women. However, the sex



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difference was very much less in those who weretreated with insulin than in those treated bydrugs or oral agents. The study shows that theassociation of risk factors with diabetes andatherosclerosis varies with the type of diabetesand with its treatment. Since the relation of riskfactors to atherosclerosis differed significantly inthe various groups of diabetics, it is difficult toassign to any single risk factor an essential rolein the pathogenesis of atherosclerosis in dia-betes. The data from the Framingham studysuggest that, while risk factors for atherosclero-sis are common in diabetes, diabetics are notmore sensitive to these risk factors, nor can theincreased incidence of atherosclerosis indiabetes be entirely related to the risk factors.

Nonatherosclerotic Heart Diseasein Diabetes

There is accumulating clinical and experimen-tal evidence that disorders of heart muscle, in-dependent of atherosclerosis of the coronaryarteries, may occur in diabetes. These findingsmay explain the high incidence of congestivecardiac failure that occurs in diabetics23 and alsothe fact that diabetics have a higher mortalityrate from acute myocardial infarction thannondiabetics.24

The Framingham study found that diabeticmen aged 45-74 years have more than twice theexpected frequency of congestive cardiacfailure, and that diabetic women have a fivefoldincrease in risk.23 The excess risks were still pres-ent when the history of CHD, rheumatic heartdisease, blood pressure, weight, and cholesterolwere taken into consideration. It appeared thatfactors other than atherosclerosis and CHD wereinvolved in the development of the cardiacfailure.

It is difficult or impossible to distinguish thecause of congestive cardiac failure without carry-ing out special and often invasive investigations.One study has used these methods. Coronaryangiography and left ventricular function studieswere performed in a group of 17 adult-onsetdiabetics who had a family history of diabetesbut no hypertension or obesity.25 Twelve of thegroup had no significant occlusive coronarydisease and no evidence of ischemic heart dis-ease on the basis of coronary sinus lactate levelsafter pacing-induced tachycardia. However,eight of these who had no cardiac failure didhave abnormalities in left ventricular function.Four persons with a history of cardiac failure hadsimilar but more extensive abnormalities. Leftventricular biopsy in two diabetics showed inter-stitial collagen deposition with relatively normalmuscle cells. Postmortem studies in 11 persons

with uncomplicated diabetes, many of whom hadno coronary occlusive disease, showed accu-mulation of collagen in the interstitial spaces,fibrosis, and triglyceride and cholesterol in themyocardium. Noninvasive methods such as echo-cardiography,26 vectorcardiography,27 andmeasurement of systolic time intervals28"30 haveshown abnormal left ventricular function inyoung diabetics with no evidence of ischemicheart disease. In one study, young diabetics hadno significant abnormality of left ventricularfunction at rest, but myocardial performance wasdepressed by doses of alcohol too small to affectcardiac function in normal subjects.31 Thus, thediabetic heart may respond abnormally to stress.There is only one report of the effect of treatmentof diabetes on myocardial function.32 A group ofnewly diagnosed diabetics with abnormalities inmyocardial function were divided into threegroups. In one group, myocardial functionreturned to normal after treatment of diabetes,suggesting a reversible metabolic abnormality inthe heart muscle. In the other two groups, myo-cardial function did not return to normal aftertreatment. In one group, there were abnormali-ties similar to those found in nondiabetics withischemic heart disease; in the other group, micro-vascular disease may have been present.

The effect of diabetes on cardiac performancehas also been studied by a number of differentexperimental techniques. The hearts of streptozo-tocin diabetic rats were shown to have abnormali-ties in left ventricular contraction and relaxa-tion,33 in relaxation of isolated papillary muscle,34

and in the contraction and response to catechola-mines of isolated atria.35 Alloxan diabetic dogswere shown to have impaired cardiac functionand an accumulation of cholesterol and triglycer-ide in the myocardium.36 Evidence for decreasedresponse to stress in the diabetic heart has comefrom studies of the effect of increasing ischemiaon the development of cardiac failure in alloxandiabetic rats.37 In all the experimental studies,causes of depressed myocardial function otherthan diabetes have been excluded.

The clinical and experimental evidence sug-gests the existence of a disorder of heart musclein diabetes. This appears to be related to thediabetic state itself and, at least in experimentalanimals, is not caused by small vessel disease.The existence of a diabetic cardiomyopathy, withits possibly fatal complication of congestivecardiac failure, must cause a reappraisal of someof the clinical and epidemiologic studies of heartdisease in diabetes. It is clearly no longerjustifiable to ascribe cardiac death or cardiacfailure in diabetics to the effects of atherosclero-sis. It is possible that low associations of cardiacdeath with risk factors for atherosclerosis may beexplained by the fact that a mixture of cardiacdiseases has been studied.



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Other Factors Associated withAtherosclerosis and Diabetes

Insulin and Atherosclerosis

A number of clinical studies have reported ele-vated insulin responses to oral glucose in sub-jects with atherosclerosis of the coronary, cere-bral, or peripheral arteries.3839 Now, threeprospective studies have identified a predictiverole of circulating insulin levels in the develop-ment of cardiovascular disease (table 1). Theinvestigations differed in the populationsstudied, the glucose load administered, and thecardiovascular endpoints. The Busselton,Australia study40 was the only one of the threethat included women in its population, and wasalso the only one in which insulin was not meas-ured in the fasting state. It was found that in menaged 60 years and over, insulin levels 1 hour after50 g of oral glucose were significantly related tothe 6-year incidence and 12-year mortality fromcardiovascular disease. No relationship wasfound in other age groups or in women. In theHelsinki policemen study of men aged 30-59years, the insulin levels taken in the fasting state1 and 2 hours after oral glucose (75 or 90 g,according to size) as well as the sum of theinsulin levels were all significantly related to thedevelopment of myocardial infarction and CHDdeath 5 years later.41 In the Paris civil servantstudy of men aged 43-54 years, insulin levelstaken in the fasting state and 2 hours after 75 goral glucose were related to the development ofmyocardial infarction and death from CHDapproximately 5 years later.42 However, theclosest association was found between theserum insulin:glucose ratio and cardiovasculardisease. In all three studies, the other cardiovas-

cular risk factors measured included plasmalipids, blood pressure, and blood sugar, whilebody mass index was also measured in theHelsinki and Paris studies. Multivariate analysisrevealed that the relationship of insulin to cardio-vascular disease was independent of thesemeasurements.

These investigations have shown that raisedserum insulin levels have a predictive role in thedevelopment of cardiovascular disease, at leastin men. The Busselton results differ from theother two in that the insulin-heart disease rela-tionship was found only in men who were olderthan those studied in Helsinki and Paris.Busselton was also the only study to includewomen. The results are of interest in view ofinsulin's effect on the arterial wall, stimulatingsmooth muscle cell proliferation43"46 and lipid syn-thesis.46 Similar studies need to be performed inother populations, including all ages and bothsexes. In particular, prospective studies ofinsulin levels in relation to cardiovascular dis-ease in the main types of diabetes are required.

Chlorpropamlde-Alcohol Flushing and VascularDisease In Nonlnsulln-Dependent Diabetes

Some patients with noninsulin-dependent dia-betes (NIDDM) treated with chlorpropamideshow facial flushing after taking a small amountof alcohol.47 This phenomenon has a dominantinheritance and is particularly common indiabetic patients who also have a first degreefamily history of diabetes ("Mason"-type dia-betes). A frequency of chlorpropamide-alcoholflushing (CPAF) of about 90% in Mason-typediabetes and about 65% in unselected noninsulindependent diabetics has been reported.47 It has

Table 1. Prospective Studies of Insulin and Cardiovascular Disease

Study

Busselton,Australia40

Helsinki,Finland41

Paris,France42

Sex

M,F

M

M

Age(yrs)

21-70+

30-59

43-54

Oralglucoseload (g)

50

75 or 90

75

Hours betweenglucose dose

and bloodsample

1

fasting,1 and 2

fasting,2

Durationof study

(yrs)

612

5

5V*

Cardiovascularendpoint

CHD incidenceCHD death

MlCHD deathOther CHD

MlCHD death

Otherrisk factorsmeasured

Blood pressure,blood glucose,cholesterol,uric acid

Blood pressure,blood glucose,body mass index,cholesterol,smoking,triglyceride

Blood pressure,blood glucose,body mass index,cholesterol,smoking,triglyceride

CHD = coronary heart disease; Ml = myocardial infarction.



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been suggested that CPAF may be due to sensi-tivity to enkephalin and that enkephalin mighthave a role in the pathogenesis of this type ofdiabetes.

In a study of large vessel disease in noninsulin-dependent diabetics, 41% of CPAF-negative dia-betics had evidence of macrovascular disease,compared with 24% of a matched CPAF-positivegroup.48 The main differences were found inpatients whose duration of diabetes was lessthan 15 years; the differences remained when thepresence of severe diabetic retinopathy was ex-cluded. A similar negative relationship betweenCPAF and diabetic retinopathy has been found.49

The authors suggest that flushing is related tothe pathogenesis not only of large vessel diseasebut also of small vessel disease. These resultsare rather unusual in that large vessel disease isoften considered to be quite different from smallvessel disease in diabetics. CPAF can be blockedby prior administration of indomethacin; thosewhose CPAF can be blocked with indomethacinare free of both small vessel and large vesseldisease.50 It was suggested that, since indo-methacin is a prostaglandin synthesis inhibitor,prostaglandins might be involved in the patho-genesis of the vascular complications of dia-betes. Studies in twins suggest that indo-methacin blocking of CPAF may, like CPAFitself, be an inherited phenomenon. These find-ings are difficult to reconcile with the previousreports by the same authors of an association ofCPAF negativity with the vascular complicationsof diabetes.

The frequency of CPAF in noninsulin-depend-ent diabetics has been challenged by the reportof a prevalence of only 4% true CPAF in a groupof 50 diet-treated diabetics.51 In a group of 21nondiabetics, two also showed the CPAF phe-nomenon. Thus, CPAF may not be nearly ascommon in noninsulin-dependent diabetics aswas previously suggested and may be onlyclosely related with the small subgroup ofdominantly inherited Mason-type diabetes.

It is impossible at present to assign a definitiveplace to CPAF in the pathogenesis of vasculardiseases in diabetes. However, the findingssuggest that genetic factors may be involved indiabetic vascular disease.

Conclusions

Recent autopsy and clinical evidence confirmsthat atherosclerosis is both more common andmore extensive in diabetics than nondiabetics.However, the frequency and extent of athero-sclerosis is related neither to the severity nor theduration of the diabetes. Although cardiovascu-lar disease has an increased frequency in per-sons with elevated blood glucose levels, it doesnot show a linear relationship to blood glucose,but possibly there is a threshold effect. Risk

factors for atherosclerosis, including hyper-tension and abnormal plasma lipoprotein levels,are common in diabetics and have the same rela-tionship to the development of atherosclerosis asin nondiabetics. However, the increasedfrequency of atherosclerosis in diabetics cannotbe entirely explained by an increased prevalenceof, or an increased sensitivity to, the effects ofrisk factors. Diabetes is also associated withabnormalities of cardiac function that are notcaused by myocardial ischemia secondary tocoronary atherosclerosis, and are probably notentirely due to small vessel disease in the myo-cardium. These abnormalities contribute to thehigh mortality from congestive cardiac failureand acute myocardial infarction that occurs indiabetics. Two new associations with heartdisease and blood glucose regulation have re-cently emerged: 1) a relationship of cardiovascu-lar disease with elevated fasting and postglucoseserum insulin levels in general populations; and2) a negative association with chlorpropamide-alcohol flushing in noninsulin-dependentdiabetics.

The available information suggests thatdiabetes has a trigger mechanism in the patho-genesis of atherosclerosis, initiating a processthat then progresses under the influence of otherfactors. The trigger may be related to the bloodglucose itself, or to some underlying cellular ab-normality, perhaps genetically determined. Theother factors involved in the pathogenesis ofatherosclerosis in diabetes include well-estab-lished risk factors for atherosclerosis such ashypertension and hyperlipidemia, and perhapsalso abnormal serum insulin levels. It is likely,although still hypothetical, that attention to thesefactors will reduce, although not eliminate, thehigh incidence of atherosclerosis in diabetes.

References

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2. WHO Expert Committee on Diabetes Mellitus. Secondreport. World Health Organization Technical ReportSeries 646, Geneva, Switzerland, 1980

3. Robertson WB, Strong JP. Atherosclerosis in personswith hypertension and diabetes mellitus. Lab Invest 1980;18:538-551

4. Waller BF, Palumbo PJ, Lie JT, Robert* WC. Status of thecoronary arteries at necropsy in diabetes mellitus withonset after age 30 years. Am J Med 1980:69:498-507

5. Vigorlta VJ, Moore GW, Hutchlns GM. Absence of correla-t ion between coronary arterial atherosclerosis andseverity or duration of diabetes mellitus of adult onset.Am J Cardiol 1980;46:535-542

6. Crall FV, Roberts WC. The extramural and intramuralcoronary arteries in juvenile diabetes mellitus. Analysisof nine necropsy patients aged 19-38 years with onset ofdiabetes before age 15 years. Am J Med 1978;64:221-230

7. Dortlmer AC, Shenoy PN, Shlroff RA, et al. Diffusecoronary artery disease in diabetic patients. Fact orfiction? Circulation 1978;57:133-136



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8. Garcia MJ, McNamara PM, Gordon T, Kannel WB. Mor-bidity and mortality in diabetics in the Framingham Pop-ulation. Sixteen year follow-up study Diabetes 1974;23:105-111

9. Gordon T, Castelll WP, HJortland MC, Kannel WB,Oawber TR. Diabetes, blood lipids, and the role ofobesity in coronary heart disease risk for women. TheFramingham study. Ann Intern Med 1977;87:393-397

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13. Fuller JH, Shipley MJ, Rote G, Jarrett RJ, Keen H. Cor-onary-heart-disease risk and impaired glucose toler-ance. Lancet 1980;1:1373-1376

14. Pettlt DJ, Knowler WC, Llsse JR, Bennett PH. Develop-ment of retinopathy and proteinuria in relation toplasma-glucose concentrations in Pima Indians. Lancet1980;2:1050-1052

15. International Collaborative Group. Joint discussion. JChronic Dis 1979:32:829-639

16. Pyorala K, Savolalnen E, Lehtovlrta E, Punsar S, SlltanenP. Glucose tolerance and coronary heart disease: Hel-sinki Policemen Study. J Chronic Dis 1979:32:729-745

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Index Terms: blood glucose • atherosclerosis • insulin • diabetes mellitus



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