Acute Postchallenge Hyperinsulinemia Predicts Weight Gain: A Prospective Study

The relationships of insulin secretion and insulin action to body weight are incompletely understood. Obesity is associated with reduced sensitivity to insulin and high fasting and postprandial serum insulin levels. However, it is unknown whether insulin secretion rises to compensate for insulin resistance or high insulin secretion promotes body weight gain and the development of insulin resistance. To shed light on this question, we examined weight gain over an interval of 16.7 +/- 3.9 years (mean +/- SD) in 107 glucose-tolerant offspring (48 men, 59 women) of two parents with NIDDM. The offspring had a baseline intravenous glucose tolerance test, at which time they were aged 32.9 +/- 9.7 years, and only those who did not develop diabetes during the follow-up period were included. We estimated insulin sensitivity with the insulin sensitivity index from Bergman's minimal model of glucose disposal and acute insulin secretion from the incremental area under the insulin curve in the first 10 min of the intravenous glucose tolerance test. Weight-gain rate (g/year) was defined as the regression slope of each subject's body weight over time. High acute insulin secretion, young age, and low baseline percent ideal body weight (IBW) were each associated with a high rate of weight gain. After adjustment for differences in age and IBW, statistically significant effects of insulin sensitivity (P = 0.05) as well as acute insulin secretion (P = 0.001) were obtained. To estimate the effects of acute insulin secretion and insulin sensitivity on the average rate of weight gain (adjusting for age and IBW), the study group was stratified into four subgroups by dividing it at the medians of these two variables. Among those with low acute insulin secretion, weight-gain rate was the same regardless of whether insulin sensitivity was low or high (176 and 152 g/year, respectively). Among those with high acute insulin secretion, mean weight-gain rate was still rather low in those with low insulin sensitivity (271 g/year), but it was quite high in those with high insulin sensitivity (672 g/year; significantly higher than in all other subgroups). Therefore a high first-phase insulin response to intravenous glucose is a risk factor for long-term weight gain, and this effect is particularly manifested in insulin-sensitive individuals.