The hyperinsulinemia of obesity has generally been regarded as a compensatory adaptation to the peripheral insulin resistance that is characteristic of the obese state. More recent studies have shown that in the initial phase of obesity, hyperinsulinemia is not due to insulin resistance, but constitutes a primary metabolic alteration caused by beta-cell dysfunction or dysregulation. The first metabolic abnormality during the course of obesity is a postprandial hyperinsulinemia, resulting from a delayed and higher pulse of insulin after normocaloric mixed meals, while fasting insulin levels and insulin sensitivity are normal. Rapid weight gain occurs during this phase. Insulin resistance, with permanent hyperinsulinemia in the fed as well as the fasting state, develops only later during the course of chronic obesity.
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Several lines of evidence support a critical role for acute insulin secretion in mediating weight gain and the development of obesity. In humans, hyperinsulinemia is a potent predictor of weight gain and obesity, particularly among individuals who are sensitive to insulin. (...)
The mechanism whereby hyperinsulinemia precipitates weight gain is not clear. Most important seems the fact that insulin promotes fat storage and causes preferential oxidation of carbohydrate over fat in response to mixed meals. (...) Recurrent postprandial hyperinsulinemia would, therefore, promote continued fat accumulation, especially in the presence of high dietary fat intake. (...)
There is significant evidence that hyperinsulinemia not only promotes the development of obesity, but also causes insulin resistance.
From both the human and animal studies it appears that the primary lesion leading to the insulin-resistant state is a longterm rise in plasma insulin levels.(...)
The evidence presented suggests that postprandial hyperinsulinemia represents a major pathogenic factor for the development of obesity and insulin resistance...
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