Elizabeth J. Mayer

The Insulin Resistance Atherosclerosis Study (IRAS). Objectives, design, and recruitment results

The Insulin Resistance Atherosclerosis Study (IRAS) is the first epidemiologic study designed to assess the relationships between insulin resistance, insulinemia, glycemia, other components of the insulin resistance syndrome, and prevalent cardiovascular disease (CVD) in a large multiethnic cohort. Over 1600 men and women were recruited from four geographic areas to represent a range of glucose tolerance (normal, impaired, and diabetic) and ethnicity (hispanic, non-Hispanic white, and African-American). Insulin resistance was assessed directly using the frequently sampled intravenous glucose tolerance test with minimal model analysis. Intimal-medial carotid artery wall thickness, an indicator of atherosclerosis, was measured using B-mode ultrasonography. Prevalent CVD was assessed by questionnaire and resting electrocardiography. This report describes the design of the study and provides the recruitment results. Forthcoming cross-sectional analyses will help to disentangle the association between insulin resistance and CVD, apart from the concomitant hyperinsulinemia and related CVD risk factors.

Insulin Sensitivity and Acute Insulin Response in African-Americans, Non-Hispanic Whites, and Hispanics With NIDDM: The Insulin Resistance Atherosclerosis Study

NIDDM is usually characterized by β-cell failure decreased and insulin sensitivity. It has been reported that a high proportion of African-American NIDDM subjects are insulin sensitive. To examine this issue, we determined insulin sensitivity (SI) in 479 NIDDM subjects by minimal model analyses of frequently sampled intravenous glucose tolerance (FSIGT) from the Insulin Resistance Atherosclerosis Study (IRAS), a large multicenter study of insulin sensitivity and cardiovascular risk in African-Americans, Hispanics, and non-Hispanic whites. The African-Americans and non-Hispanic whites were sampled in Los Angeles and Oakland, California. The non-Hispanic whites and Hispanics were sampled in San Antonio, Texas, and San Luis Valley, Colorado. We defined the proportion of insulin-sensitive (SI) subjects as ≥1.61 min−1 · μU−1 · ml−1, which is above the median for nondiabetic subjects of all ethnic groups in the IRAS. Using this definition, the proportion of insulin-sensitive diabetic subjects was very low in all ethnic groups (non-Hispanic whites [14.3%] vs. African- Americans [6.5%], P = 0.039 in Los Angeles and Oakland; non-Hispanic whites [6.8%] vs. Hispanics [4.9%], P = 0.737 in San Luis Valley and San Antonio). These results were also similar in newly diagnosed mildly hyperglycemic diabetic subjects. In addition, these results were not affected by the adjustment for differences in obesity, body fat distribution, and severity of hyperglycemia. Even in nonobese subjects (with BMI <30 kg/m2), the proportion of insulin-sensitive subjects (S1 ≥1.61 min−1 · μU−1 · ml−1) was low (3.6–9.7%). The acute insulin response (AIR) was significantly higher in African-Americans than in non-Hispanic whites; there were no ethnic differences in AIR between Hispanics and non–Hispanic whites. There were no significant ethnic differences for non-insulin-mediated glucose disposal (SG). We conclude that the number of insulinsensitive NIDDM subjects is low and similar among non-Hispanic whites, Hispanics, and African-Americans in the U.S.

Alcohol consumption and insulin concentrations. Role of insulin in associations of alcohol intake with high-density lipoprotein cholesterol and triglycerides.

BackgroundThe relation between alcohol intake and insulin levels may explain, in part, the reported associations of alcohol with cardiovascular disease risk factors, including high-density lipoprotein (HDL) cholesterol, triglycerides, blood pressure, and glucose levels, each of which has been recognized as a component of the insulin resistance syndrome. Methods and ResultsSubjects included nondiabetic participants of the Kaiser Permanente Women Twins Study (1989 through 1990). Usual alcohol intake was assessed as part of a food frequency questionnaire. For women from twin pairs in which both twins drank (n=338), an increment of 12 g of alcohol per day (about one drink) was associated with an 8% lower 2-hour post-glucose-load insulin (P<.01) in a multiple regression analysis for twin data, adjusted for age, body mass index, waist-to-hip ratio, total caloric intake, and family history of diabetes. With genetic influences removed by matched analysis of the subset of 98 monozygotic twin pairs, an intrapair difference of 12 g of alcohol per day was associated with a 12.4% intrapair decrement in postload insulin (P<.01). Inverse associations were also seen for fasting insulin. Alcohol consumption was inversely associated with postload glucose but not with fasting glucose in unmatched (P=.05) and matched (P=.005) analyses. A significant positive association of alcohol intake with high-density lipoprotein cholesterol and an inverse relation of alcohol intake with triglycerides were each independent of insulin levels (Ps.02 in the matched models). Neither systolic nor diastolic blood pressures were related to alcohol consumption in this sample, perhaps because of the rather low level of alcohol intake in the study population (median, 4 g/d). ConclusionsWithin the range of light to moderate drinking habits, alcohol consumption was inversely related to fasting and postload insulin levels. This relation did not explain associations of alcohol intake with lipid levels and may instead reflect an additional mechanism by which moderate alcohol consumption impacts cardiovascular disease risk.

Prevalence and Risk Factors of Diabetic Retinopathy in Non-Hispanic Whites and Hispanics With NIDDM: San Luis Valley Diabetes Study

Diabetic retinopathy (DR) is the leading cause of blindness in adults in the United States. Because photocoagulation can reduce the incidence of blindness from severe DR by ∼50%, it is important to identify people at increased risk for DR so that appropriate treatment can be accomplished. Use of populations at increased risk for diabetes may identify groups at increased risk for complications. A recent report from the San Antonio Heart Study showed that Mexican Americans were at greater risk for servere DR than non-Hispanic Whites. To compare the prevalence of DR between non-Hispanics and Hispanics in southern Colorado, 279 people with non-insulindependent diabetes mellitus (NIDDM) were identified, and retinal photographs identified the presence and severity of retinopathy. The worse eye was used to classify the severity of DR for each patient. Ninety percent of the subjects (166 Hispanics and 85 non-Hispanic Whites) were classified by retinopathy level. The duration-adjusted prevalence of any DR was 41.8% in Hispanics and 54.1% in non-Hispanic Whites. Severe DR (preproliferative and proliferative) occurred in 18.5% of the Hispanics and in 21.3% of the non-Hispanic Whites. The odds ratio for any DR, comparing Hispanics with non-Hispanic Whites adjusted for other risk factors, was 0.40 (95% confidence interval = 0.21, 0.76). Other risk factors for the presence of any retinopathy included use of exogenous insulin, increased duration of diabetes, younger age at diagnosis, increased glycosylated hemoglobin level, and increased systolic blood pressure. These data suggest that, compared with non-Hispanic Whites, Hispanics in Colorado may be at decreased risk for diabetic retinopathy.

Relationship Between Habitual Physical Activity and Insulin Levels Among Nondiabetic Men and Women: San Luis Valley Diabetes Study

Objective To determine whether higher levels of physical activity would be associated with lower fasting insulin and C-peptide levels in a free-living nondiabetic population. Research Design and Methods A cross-sectional study was conducted with a Hispanic and non-Hispanic white population of 442 men and 489 women with normal glucose tolerance (by World Health Organization criteria) in two rural Colorado counties. Total physical activity was assessed by a 7-day physical activity recall from which metabolic equivalents were estimated. Relationships between metabolic equivalents and fasting insulin and C-peptide were assessed while considering obesity, age, and other risk factors known to influence fasting insulin levels. Results Among all subjects, univariate analyses showed that higher activity levels were associated with lower mean fasting insulin and C-peptide levels (P < or equal to 0.05). Multiple linear regression showed that higher activity was significantly associated with lower values of log fasting insulin and C-peptide levels in men only (P < 0.001) independent of obesity, fat distribution, and age. Men in the highest tertile of activity had an adjusted mean fasting insulin level of 59.2 pM and fasting C-peptide level of 0.5 nM compared with a fasting insulin level of 72.7 pM and fasting C-peptide level of 0.6 mM for men in the lowest tertile of activity. The magnitude of the inverse association between activity and insulin was greatest in older rather than younger men. Physical activity was not associated with fasting insulin or C-peptide levels in women in the multivariate analyses. Conclusions Based on cross-sectional data, we conclude that higher levels of habitual physical activity are associated with lower fasting insulin and C-peptide levels in Hispanic and non-Hispanic white men.

Heritability of factors of the insulin resistance syndrome in women twins

The insulin resistance syndrome (IRS) is characterized by a combination of interrelated coronary heart disease (CHD) risk factors, including low high‐density lipoprotein cholesterol (HDL‐C) levels, obesity and increases in triglyceride (TG), blood pressure, small low‐density lipoprotein particles (LDL), and both fasting and postload plasma insulin and glucose. Using factor analysis, we previously identified 3 uncorrelated factors that explained 66% of the variance among these variables, based on data from women participating in examination 2 of the Kaiser Permanente Women Twins Study in Oakland. CA during 1989–1990. The factors were interpreted as: 1) body mass/fat distribution, 2) insulin/glucose, and 3) lipids: TG, HDL‐C, LDL peak particle diameter. In this analysis, heritability of each of the factors was estimated based on data from 140 monozygotic and 96 dizygotic pairs of non‐diabetic women twins. Heritability estimates were calculated using the classical approach, the analysis of variance (ANOVA) approach, and the maximum likelihood approach. For the body mass/fat distribution factor heritability estimates suggest moderate genetic influences: 0.61 (P < 0.001), 0.14 (P > 0.05), and 0.71 (P < 0.001), respectively. The insulin/glucose factor appeared to be highly heritable, with estimates of 0.87,0.92, and 0.57 (all P < 0.001), respectively. The heritability estimates for the lipid factor were moderate and consistent across methods: 0.25 (P < 0.10), 0.32 (P < 0.05), and 0.30 (P < 0.05), respectively. These results are consistent with genetic influences on each of the 3 “factors,” and suggest that both genetic and environmental effects are involved in the clustering of IRS risk factors. Genet. Epidemiol. 14:241–253,1997.

Microvascular Complications of NIDDM in Hispanics and Non-Hispanic Whites: San Luis Valley Diabetes Study

The goal of this article was to examine the differences in the rates of microvascular complications of non-insulin-dependent diabetes mellitus (NIDDM) in Hispanic and non-Hispanic white subjects. This was a geographically based case-control study where prevalent cases of NIDDM were identified in medical records. Subjects attended a 4-h clinic to confirm NIDDM diagnosis and assess complication end points. Retinopathy was defined by stereofundus photographs. Distal symmetric neuropathy was determined by standardized clinical examination. Nephropathy was indicated by serum creatinine level, urine protein-creatinine ratio, and urine albumin concentration. This study consisted of 279 NIDDM subjects confirmed by oral glucose tolerance test and World Health Organization criteria aged 20–74 yr (187 Hispanic and 92 non-Hispanic white subjects). Duration-adjusted prevalence of retinopathy was significantly higher in non-Hispanic white subjects (54.1 per 100, 95% confidence interval [CI] 44.4–63.7) than in Hispanics (41.8 per 100, 95% CI 34.8–48.8). This excess occurred only in non-Hispanic white subjects with background retinopathy but not in those with more severe retinopathy. Hispanics and non-Hispanic white subjects did not differ significantly for the prevalence of neuropathy (31.6 per 100 in non-Hispanic white subjects and 26.3 per 100 in Hispanics) or nephropathy by any measure. There were no significant differences in duration of diabetes or mean glycohemoglobin levels between ethnic groups. Microvascular complications of NIDDM are not in excess among Colorado Hispanics, and retinopathy may be somewhat more common in non-Hispanic white people.

Relationship Between Habitual Physical Activity and Insulin Area Among Individuals With Impaired Glucose Tolerance: The San Luis Valley Diabetes Study

OBJECTIVE To determine whether higher levels of physical activity are associated with lower fasting insulin levels and lower insulin areas under the oral glucose tolerance curve in individuals with impaired glucose tolerance (IGT) in a community setting. RESEARCH DESIGN AND METHODS Data from a cross-sectional study of a population consisting of 219 Hispanic and non-Hispanic white men and women with IGT (by World Health Organization criteria) in two rural Colorado counties were analyzed. Total physical activity was assessed by a 7-day physical activity recall, from which metabolic equivalents (METs) were estimated (expressed as MET h/week). Relationships of MET h/week with fasting insulin levels and insulin areas were assessed while considering obesity, age, and other risk factors known to influence fasting insulin level and insulin area. RESULTS Among all subjects, univariate analyses showed that higher physical activity levels were associated with lower mean insulin areas and fasting insulin levels (both P ≤ 0.05). Multiple linear regression showed that higher levels of physical activity were significantly associated with lower values of of the insulin area (P < 0.001) but not with fasting insulin levels. The relationship between insulin area and habitual physical activity was independent of obesity, fat distribution, and age. CONCLUSIONS On the basis of cross-sectional data, we conclude that higher levels of habitual physical activity are associated with lower insulin areas in a population of individuals with IGT. Understanding the impact of physical activity on markers of insulin action in individuals with IGT is important because of the greatly enhanced risk of non-insulin-dependent diabetes mellitus and, hence, cardiovascular disease in this population.

The role of insulin and body fat in associations of physical activity with lipids and lipoproteins in a biethnic population. The San Luis Valley Diabetes Study.

It has been postulated that the positive effects of physical activity on high density lipoprotein cholesterol (HDL-C) and HDL-C subfraction 2 (HDL-C2) are mediated through insulin action because increased activity lowers insulin levels and lower insulin levels are associated with higher HDL-C. These relations were evaluated in a rural population of Hispanic and non-Hispanic white (NHW) adults in Colorado. Included were 138 men and 152 women with normal glucose tolerance confirmed by World Health Organization criteria. Total physical activity was assessed by 7-day recall interviews. No significant associations were observed among women. Among men, activity was inversely associated with fasting insulin (r = -0.17, p less than 0.05). From analysis of covariance models including the interaction term activity x ethnicity, total HDL-C was 43.4 mg/dl (95% confidence interval [CI] = 39.1, 47.7) in the low tertile of activity and 50.4 mg/dl (95% CI = 46.3, 54.5) in the high tertile for NHW men, after adjustment for fasting insulin, fasting glucose, body mass index (BMI), waist to hip ratio (WHR), and age. For Hispanic men, adjusted HDL-C was 43.4 mg/dl (95% CI = 38.6, 48.2) and 49.1 mg/dl (95% CI = 44.0, 54.2) in the low and high tertiles, respectively. Adjusted HDL-C2 levels were 52% higher in the most compared with the least active NHW men, whereas there was no difference by activity for Hispanic men. Higher adjusted mean levels of HDL-C3 were observed for the high compared with the low activity tertile in both ethnic groups. Ethnicity-specific models showed that for NHW men, activity explained 12% (p = 0.01), fasting insulin explained 5% (p = 0.05), and BMI explained 6% (p = 0.04) of the variability in total HDL-C, after adjustment for fasting glucose, WHR, and age. These models confirmed that effects of insulin and body fat did not explain the observed associations between activity and total HDL-C and its subfractions.