Study of genetic prediabetic south Indian subjects. Importance of hyperinsulinemia and beta-cell dysfunction

To study 1) whether abdominal adiposity was present in adult offspring of two NIDDM parents, 2) whether abdominal adiposity was associated with the development of glucose intolerance, and 3) the association of pancreatic beta-cell function with impaired glucose tolerance (IGT) and NIDDM in these groups.

One hundred offspring whose parents both had NIDDM were studied (60 men, 40 women, mean age 34 +/- 6.9 years, BMI 27.4 +/- 4.1 kg/m2). None had a history of glucose intolerance. Nondiabetic control subjects with no family history of diabetes were also studied for comparison (21 men, 19 women, age 36 +/- 10.3 years, BMI 26 +/- 3.7 kg/m2). A standard oral glucose tolerance test was done for all, and plasma glucose, C-peptide, and insulin responses were measured. Abdominal fat measurements at L4-L5 were made using a computed axial tomography scan. Subcutaneous fat (SF), visceral fat (VF), and total fat (TF) areas were measured and VF/SF ratio was calculated. An index of insulin secretion (delta I/G) was derived as the ratio of incremental insulin at 30 min divided by 30-min plasma glucose.

IGT was detected in 32 offspring and diabetes in 21 offspring. Diabetic men had a higher TF area than the other groups. SF, VF, and VF/SF ratios were similar in control men and in offspring with normal glucose tolerance (NGT), IGT, or diabetes. Among control subjects, women had significantly lower VF than men. Female offspring had higher VF than the control subjects, but intragroup variations were absent. Fasting insulin and all C-peptide responses were higher in NGT compared with control subjects (P < 0.02). The 2-h insulin and C-peptide responses were higher in IGT subjects (P < 0.005). In diabetic subjects, the insulin-to-glucose ratio, C-peptide-to-glucose ratio, and delta I/G were significantly low compared with all other groups (P < 0.005). Multiple logistic regression analysis showed that the area of insulin response had a positive association and delta I/G had a negative association with diabetes, while age, sex, BMI, waist-to-hip ratio, abdominal fat areas, fasting and 2-h insulin, area of insulin, and the C-peptide measurements did not show independent associations. Two-hour insulin showed a positive association with IGT, while increasing area of insulin showed a negative association.

Visceral adiposity seemed to precede glucose intolerance only in women, but it had no independent association with IGT or NIDDM. Insulin resistance, indicated by higher plasma insulin response, and insulin secretory defect, indicated by low delta I/G at 30 min, were associated with diabetes. beta-cell defect was not independently associated with IGT. Increased abdominal visceral adiposity does not appear to be a prerequisite for development of IGT or diabetes in Asian Indians with a strong genetic predisposition for diabetes.