OBJECTIVE -The prospective association between insulin levels and risk of cardiovascular disease (CVD) is controversial. The objective of the present study was to investigate the relationship of the homeostasis model assessment of insulin resistance (HOMA-IR), as well as insulin levels, with risk of nonfatal and fatal CVD over the 8-year follow-up of the San Antonio Heart Study. -Between 1984 and 1988, randomly selected Mexican-American and non-Hispanic white residents of San Antonio participated in baseline examinations that included fasting blood samples for glucose, insulin, and lipids, a glucose tolerance test, anthropometric measurements, and a lifestyle questionnaire. Between 1991 and 1996, 2,569 subjects who were free of diabetes at baseline were reexamined using the same protocol. RESEARCH DESIGN AND METHODSRESULTS -Over the follow-up period, 187 subjects experienced an incident cardiovascular event (heart attack, stroke, heart surgery, angina, or CVD death). Logistic regression analysis indicated that risk of a CVD event increased across quintiles of HOMA-IR after adjustment for age, sex, and ethnicity (P for trend Ͻ0.0001; quintile 5 vs. quintile 1, odds ratio [OR] 2.52, 95% CI 1.46 -4.36). Additional adjustment for LDL, triglyceride, HDL, systolic blood pressure, smoking, alcohol consumption, exercise, and waist circumference only modestly reduced the magnitude of these associations (P for trend 0.02; quintile 5 vs. quintile 1, OR 1.94, 95% CI 1.05-3.59). Furthermore, there were no significant interactions between HOMA-IR and ethnicity, sex, hypertension, dyslipidemia, glucose tolerance (impaired glucose tolerance versus normal glucose tolerance), or obesity. The magnitude and direction of the relationship between insulin concentration and incident CVD were similar.CONCLUSIONS -We found a significant association between HOMA-IR and risk of CVD after adjustment for multiple covariates. The topic remains controversial, however, and additional studies are required, particularly among women and minority populations.
The utility of the disposition index as a measure of β-cell compensatory capacity rests on the established hyperbolic relationship between its component insulin secretion and sensitivity measures as derived from the intravenous glucose tolerance test (IVGTT). If one is to derive an analogous measure of β-cell compensation from the oral glucose tolerance test (OGTT), it is thus necessary to first establish the existence of this hyperbolic relationship between OGTT-based measures of insulin secretion and insulin sensitivity. In this context, we tested five OGTT-based measures of secretion (insulinogenic index, Stumvoll first phase, Stumvoll second phase, ratio of total area-underthe-insulin-curve to area-under-the-glucose-curve (AUC ins/gluc ), and incremental AUC ins/gluc ) with two measures of sensitivity (Matsuda index and 1/Homeostasis Model of Assessment for insulin resistance (HOMA-IR)). Using a model of log(secretion measure) = constant + β × log(sensitivity measure), a hyperbolic relationship can be established if β is approximately equal to −1, with 95% confidence interval (CI) excluding 0. In 277 women with normal glucose tolerance (NGT), the pairing of total AUC ins/gluc and Matsuda index was the only combination that satisfied these criteria (β = −0.99, 95% CI (−1.66, −0.33)). This pairing also satisfied hyperbolic criteria in 53 women with impaired glucose tolerance (IGT) (β = −1.02, (−1.72, −0.32)). In a separate data set, this pairing yielded distinct hyperbolae for NGT (n = 245) (β = −0.99, (−1.67, −0.32)), IGT (n = 116) (β = −1.18, (−1.84, −0.53)), and diabetes (n = 43) (β = −1.37, (−2.46, −0.29)). Moreover, the product of AUC ins/gluc and Matsuda index progressively decreased from NGT (212) to IGT (193) to diabetes (104) (P < 0.001), consistent with declining β-cell function. In summary, a hyperbolic relationship can be demonstrated between OGTT-derived AUC ins/gluc and Matsuda index across a range of glucose tolerance. Based on these findings, the product of these two indices emerges as a potential OGTT-based measure of β-cell function.
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