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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?

¹ Department of Medicine, University of Texas Health Science Center, San Antonio, Texas
² Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
³ Department of Biophysics and Physiology, University of Southern California, Los Angeles, California
⁴ Kaiser Research Center, Northern California, Oakland, California
⁵ Department of Medicine, UCLA School of Medicine, Los Angeles, California

Address correspondence and reprint requests to Steven M. Haffner, MD, Department of Medicine, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. E-mail: haffner{at}uthscsa.edu

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 1,482 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 · µU^-1 · 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.

Abbreviations: CRP, C-reactive protein • FSIGTT, frequently sampled intravenous glucose tolerance test • IGT, impaired glucose tolerance • IRAS, Insulin Resistance Atherosclerosis Study • NCEP, National Cholesterol Education Program • NGT, normal glucose tolerance • PAI-1, plasminogen activator inhibitor 1

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