Low insulin sensitivity (S(i) = 0) in diabetic and nondiabetic subjects in the insulin resistance atherosclerosis study: is it associated with components of the metabolic syndrome and nontraditional risk factors?

OBJECTIVE: To determine the meaning of S(i) = 0 derived from the frequently sampled intravenous glucose tolerance test. RESEARCH DESIGN AND METHODS: The issue of assessing insulin resistance in large studies is important because the most definitive method ("gold standard"), the hyperinsulinemic-euglycemic clamp, is expensive and invasive. The frequently sampled intravenous glucose tolerance test (FSIGTT) has been widely used, but in insulin-resistant subjects (especially diabetic subjects), it yields considerable numbers of subjects whose S(i) is zero. The interpretation of an S(i) equaling zero is unknown.
RESULTS: -To address this issue, we examined 1482 subjects from the Insulin Resistance Atherosclerosis Study (IRAS) using an insulin-modified FSIGTT and minimal model calculation of S(i). The proportion of insulin-resistant subjects (S(i) < 1.61 x 10(-4) [min(-1). microU(-1) x ml(-1)] based on the median of the nondiabetic population) was 38.6% in subjects with normal glucose tolerance (NGT), 74% in subjects with impaired glucose tolerance (IGT), and 92% in subjects with type 2 diabetes. The proportion of subjects with S(i) = 0 was 2.2% in subjects with NGT, 13.2% in subjects with IGT, and 35.7% in subjects with type 2 diabetes. In subjects with IGT, those with S(i) = 0 had significantly lower HDL cholesterol levels and higher BMI, waist circumference, fibrinogen, plasminogen-activator inhibitor 1 (PAI-1), C-reactive protein (CRP), and 2-h insulin levels than insulin-resistant subjects with S(i) > 0. In type 2 diabetes, subjects with S(i) = 0 had significantly greater BMI and waist circumference and higher triglyceride, PAI-1, CRP, fibrinogen, and fasting and 2-h insulin levels than insulin-resistant subjects with S(i) > 0. In addition, diabetic subjects with S(i) = 0 had more metabolic disorders related to the insulin resistance syndrome than diabetic insulin-resistant subjects with S(i) > 0.
CONCLUSIONS: We found very few subjects with S(i) = 0 among subjects with NGT and few subjects with S(i) = 0 among subjects with IGT. In contrast, S(i) = 0 was common in subjects with diabetes. Subjects with S(i) = 0 tended to have more features of the insulin resistance syndrome than other insulin-resistant subjects with S(i) > 0, as would be expected of subjects with almost no insulin-mediated glucose disposal, thus suggesting that subjects with S(i) = 0 are correctly classified as being very insulin resistant rather than having failed the minimal model program.