Coronary Heart Disease Risk Factor Profiles in Black Patients with Non-Insulin-Dependent Diabetes Mellitus: Paradoxic Patterns

PURPOSE: Non-insulin-dependent diabetes mellitus (NIDDM) in black Americans consists of two variants: one with insulin resistance and one with normal insulin sensitivity. This study examined whether cardiovascular disease risk factors are significantly different between the two Vtib.

PATIENTSANDMETH0Dfk Twenty-twoblackpatients with NIDDM in near-normoglycemic remission who were receiving no pharmacologic therapy for NIDDM were evaluated for insulin sensitivity by the euglycemic iusulin clamp, plasma insulin levels, degree of obesity, glucose metabolism, serum total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol levels, and fasting plasma triglyceride levels. RESIJLTS: Fifty-nine percent of these patients had normal insulin sensitivity (glucose disposal rate in response to a 1 mu&g-%ninut.& insulin infusion greater than 6.0 n&g%ninut&). The insulin-sensitive patients were less obese (body mass index [BMI] 26.5 f 0.6 versus 30.8 f 0.9 kg/m2) and had lower fasting plasma insulin levels (56.9 f 7.8 versus 88.0 f 6.0 pmol/L), lower serum cholesterol (4.47 f 0.30 versus 6.39 f 0.26 mmol/L), lower serum LDL cholesterol (2.77 f 0.31 versus 4.51 f 0.27 mmol/L), and lower fasting plasma triglyceride levels (0.83 f 0.08 versus 1.45 f 0.16 mmol/L) than the insulin-resistant patients. Serum HDL cholesterol was not different between the two groups and was in the highnormal range (1.31 f 0.08 and 1.19 f 0.07 mmol/L). Univariate analysis demonstrated that serum total cholesterol, LDL cholesterol, and fasting plasma triglycerides were highly correlated with insulin-mediated glucose disposal and From the Department of Medicine, Division of Endocrinology, State University of New York, Health Science Center at Brooklyn, Brooklyn, New York. This work was supported by grants from the Division of Research Resources of the National Institutes of Health (RRO0318) and the Roerig Division of Pfizer Pharmaceuticals Company. Requests for reprints should be addressed to Mary Ann Banerji. M.D., State University of New York, Health Science Center at Brooklyn, 450 Clarkson Avenue, Box 1205, Brooklyn, New York 11203. Manuscript submitted September 4, 1990, and accepted in revised form March 15, 1991.

fasting plasma insulin. The differences in insulin sensitivity and lipid profiles were independent of obesity, as they were present in six insulin-resistant and six insulin-sensitive patients matched for BMI. CONCLUSIONS: Black patients with the insulinsensitive variant of NIDDM have a low risk factor profile for cardiovascular disease as compared with those with the insulin-resistant variant, who have a high risk factor profile. A high prevalence of the insulin-sensitive variant of NIDDM in the black population might explain the lower prevalence of angina and myocardial infarction in black patients with NIDDM as compared with white patients with NIDDM.

pidemiologic and clinical studies have led to E the hypothesisthat non-insulin-dependentdiabetesmellitus (NIDDM) is one component of a chronic diseasecomplex that is occurring in epidemic proportions around the world and is being precipitated in part by changinglifestyles [l]. This chronic diseasecomplex includes acceleratedmacrovasculardisease,hypertension, glucoseintolerance,and central obesity [l-4]. Metabolic components of the chronic diseasecomplex are insulin resistance, hyperinsulinemia, increased fasting plasma very-low-density lipoprotein (VLDL) triglyceride,and decreasedserum high-density lipoprotein (HDL) cholesterol.Reaven[4] hasproposed the following pathogeneticsequence:(1) Insulin resistanceis the underlying primary abnormality. (2) Insulin resistanceresults in compensatoryhyperinsulinemia, which maintains normal glucosetolerancebut causesincreasesin plasma VLDL triglyceridesand decreasesin serum HDL cholesterol.(3) Insulin resistanceand hyperinsulinemia result in hypertension. (4) Accelerated macrovascular diseaseoccursbecauseof the high macrovasculardiseaserisk profile created. (5) Glucose intolerance (NIDDM) developsonly if the p-cells can no longer maintain the compensatory hyperinsulinemia neededto overcomethe insulin resistance. Data to support this hypothesiscome from many diversesources[P161. A study of 247healthy, norJuly 1991

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motensive non-obesesubjectswith glucoseintolerance showed that those with the highest plasma insulin levels (beyond mean f 2 SD) had higher plasma glucoselevelsafter an oral glucosechallenge and, additionally, had higher fasting plasma triglyceridelevels,lower plasma HDL cholesterollevels, and higher blood pressuresthan those with “normal” plasma insulin levels [7]. Hyperinsulinemia occurs frequently in non-diabetic relatives of NIDDM patients and in populations with high prevalencerates for NIDDM [S-lo]. Normoglycemic relatives of patients with NIDDM have been shownto haveinsulin resistance[ll]. Insulin resistancehas beensaid to be a necessarycomponentof NIDDM [12,13]. Increasedfasting plasma VLDL triglyceride and decreasedserum HDL cholesterol have beendescribedin numerousNIDDM populations [14-161. During the last several years, we have studied insulin secretionand insulin action in a population of black individuals with NIDDM who have been able to maintain nearnormoglycemiaafter all medications have been discontinued. Our studies suggestthat NIDDM in black personsconsistsof two separatedisorders:one with primary insulin resistance and one with normal insulin action [17]. The presentstudy was done to determine if the cardiovascular diseaserisk factor profiles in these two separateforms of NIDDM differed and, if so, why? Our data indicate that patients with NIDDM with normal insulin sensitivity have low cardiovascular diseaserisk factor profiles as comparedwith those with primary insulin resistance,who havehigh risk factor profiles. Thesefindings predict that there is a population of black NIDDM patients with normal insulin sensitivity who may not be at increasedrisk for coronary heart disease. PATIENTS AND METHODS Population

Twenty-two black patients with NIDDM in nearnormoglycemicremission asdescribedrecently [18] made up the available study population. The patients had all presentedinitially with plasma glucoselevels between211and 1,665mg/dL and were unequivocally diagnosedas having NIDDM by the National Diabetes Data Group criteria [19]. At the time of study, the patients had beenin stablecondition for at least 3 months, were not receiving any pharmacologicagents,and were on their ordinary diabetic diets. The mean f SD fasting plasma glucose level for the 22 patients was 5.83 f 0.56 mmol/L (range4.56to 7.11mmol/L). Glycosylated hemoglobinvalueswerewithin the normal rangefor all the patients. The degreeof obesity for eachpatient was estimated by calculating the body mass index (BMI) (weight in kilograms divided by the 52

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squareof the height in meters). A BMI of 25 for a womanand 27for a man is comparablewith a desirable body weight of 120%[19]. The control population for glucosedisposalconsistedof six volunteers,three men andthree women whosemeanagewas45years(range31 to 59 years). Their BMI was 25.0 f 2.0 kg/m2 (mean f SD). All subjectshad ingestedat least 150g of carbohydrate for the 3 daysprecedingthe study. None of the patients had significant renal, hepatic, or cardiovascular disease.None were using any agent known to affect carbohydrateor lipid metabolism. All studiesweredoneat 8 AM to 9 AM following a 12hour overnight fast. The studies were approved by the institutional review board of the State University of New York, Health Science Center at Brooklyn. The studies were explained to each individual and informed written consentwasobtained.All studieswereperformed at the GeneralClinical ResearchCenter. Insulin Sensitivity

Insulin sensitivity wasmeasuredutilizing the euglycemic hyperinsulinemic clamp and a D-[3-3H] glucoseinfusion [20] as previously described [17]. An antecubital vein was cannulatedretrogradeand kept in a warming box at 68Oto provide arterialized venousblood for sampling. D-[3-3H] glucosewas infused for 150minutes beforethe insulin infusion was started. Insulin infusion was begun with a priming insulin dosefor the initial 10 minutes in a logarithmically decreasingmanner to acutely raise the serum insulin to the desiredlevel, where it was maintained for 120minutes by a continuousinsulin infusion. The serum glucosewas measuredevery 5 minutes andwasmaintained at the patient’s fasting euglycemiclevel with a coefficientof varianceof 5%. The overall glucosedisposalrate was assessedwith plasma D-[3-3H] glucose-specificactivity (seebelow) for each of three 20-minute intervals during the second hour of the insulin infusion when steady-statelevels had been achieved.This mean value wasusedasthe data point for the study. Urinary glucoselosswasnot presentbecausethe measurementswere made while the patients were euglycemic. The patients were studied in the fasting state and at an insulin infusion rate of 1.0 mu-kg-l.minute-l for 120 minutes. Tpe rates of glucoseappearanceand overall glucosedisappearancewere measuredduring the fasting and insulin-infused state by infusing D-[3-3H] glucosein a primed continuousmanner.A priming dose(236nCi/kg/minute) was given as a bolus and wasfollowed by a continuousinfusion (2.36nCi/kg/ minute). After a 150-minute equilibration period (which resulted in a stable plasma glucose-specific activity), blood samplesweredrawn every 15 min-

CHD RISK FACTORS IN BLACKS WITH NIDDM / BANERJI AND LEBOVllZ

utes throughout the study for additional glucosespecific activity measurements.Steele’s[21] equations for non-steady-state kinetics were used to determine rates of appearanceand disappearance. The glucosedisposalis the sum of exogenouslyadministered glucoseand hepatic glucoseproduction. As noted previously by many investigators [22-251, a one- or two-compartment model for non-steadystate glucosekinetics is known to produceoccasional negative estimates of endogenousglucoseproduction when the insulin concentrationand glucose disposalare high. Negative numberswereobtained during the secondhour of the 1 mu-kg-l-minute-l insulin infusion in an occasionalpatient in both the insulin-sensitive and insulin-resistant groups. In such instances, it was assumedthat endogenous glucose production was completely suppressed. Since the number of negativevalues obtained was similar in both groups and when present was assigneda value of zero,the calculated mean hepatic glucoseproduction during the 1 mu-kg-l-minute-l euglycemic insulin clamp for the insulin-resistant and insulin-sensitive patients was not significantly different (0.10 f 0.08 and -0.33 f 0.21 mgkg-l-minute-l, respectively). Analytic Methods

Serum lipids were measuredafter a 12-hourfast. Total cholesterol and triglycerides were measured enzymatically using the Kodak Ektachem 400 system (Rochester,New York) [26,27].HDL cholesterol was similarly measuredenzymatically following the removal of low-density lipoprotein (LDL) and VLDL using a dextran magnesium precipitation [28].The interassaycoefficient of variation for total cholesterol and triglyceride was 2.6% and 3.0%, while that for HDL cholesterolwas 4.8%.Control serawere provided by the Collegeof American Pathology. All lipid assaysmet Centers for Disease Control and College of American Pathology Standardization Programs. LDL cholesterol was estimated accordingto Friedewald et al [29],i.e., LDL cholesterol= total cholesterol- (HDL cholesterol + 0.2 X triglyceride). Plasma glucosewas measuredby a glucoseoxidasemethod utilizing a Beckman glucoseanalyzer (Fullerton, California). Plasma insulin was measured with a double-antibody radioimmunoassay technique with a lower limit of detection of 15 pmol/L [30]. Specific activity of D-[3-3H] glucose was determined on plasma samples deproteinized with barium hydroxide and zinc sulfate.

Figure

1. Frequency distribution of glucose disposal rate during a 1.0 m&kg-l-minute-1 euglycemic insulin clamp in 22 near-normoglycemic black patients with NIDDM. The distribution is bimodal (p