Islet amyloid polypeptide in the control of food intake : an experimental study in the rat

Control of food intake and satiety are physiologically complex processes, that only partly are understood. Several hormonal peptides have been proposed to mediate satiety. Islet amyloid polypeptide (IAPP) is a recently discovered 37 amino acid peptide, mainly produced by the pancreatic ß-cells. Initially, IAPP was shown to impair glucose tolerance at supra-physiological plasma concentrations and was speculated to be involved in the development of type-2 diabetes. More recent studies of IAPP administration at pharmacological doses, demonstrate that IAPP can inhibit food intake in the rat. In the present study the anorectic effect of LAPP is further evaluated, with the hypothesis that IAPP is a satiety factor that plays a hormonal role in the control of food intake.

To test the hypothesis a series of in vivo experiments in rats were performed. IAPP was administered both acutely and chronically. Food intake was registered either manually or continuously by computer, enabling analysis of meal patterns. A novel indwelling aortic catherization technique was developed. This new technique allowed frequent and rapid blood sampling for up to two months. Plasma levels of IAPP were determined by radioimmunoassay in all studies. In addition, the catheterization technique made it possible to in the same animals determine the threshold dose of IAPP for suppression of food intake, the plasma response to this IAPP dose, and compare this response to plasma concentrations of IAPP obtained during feeding. Furthermore, the effect of IAPP on peripheral glucose utilization was measured by hyperinsulinemic euglycemic clamp at plasma concentrations of IAPP that reduced food intake. In addition, the response to anorectic IAPP doses on satiety related neurotransmitters and neuropeptides was investigated.

Both acute and chronic IAPP administration potently inhibited food intake in a dose response manner. Inhibition of food intake occurred at lower doses than previously reported. Analysis of meal pattern following both acute and chronic IAPP administration revealed that the reduced food intake was caused by a decreased meal frequency rather than meal size. In the chronic meal pattern experiment, the effects were most prominent during the light phase. It was demonstrated that plasma concentrations of IAPP during feeding were not sufficient to inhibit food intake. However, the threshold dose resulted in circulating IAPP levels that were close to those levels that were observed during physiological conditions and well within the range of what has been reported in anorectic pancreatic cancer patients. Chronic administration of low anorectic doses of IAPP did not induce hyperglycemia or insulin resistance, and did not alter levels of neurotransmitters and neuropeptides in the hypothalamus, hippocampus, striatum, left cortex, and right cortex of the rat brain.

In conclusion, IAPP potently and dose-dependently inhibits food intake by reducing meal frequency. The postprandial rise in plasma IAPP that was obtained in this study is not sufficient to reduce food intake, but exogenously administered IAPP that produces plasma concentrations similar to what is observed in pancreatic cancer patients inhibits food intake. This study provides evidence to suggest that the anorectic effect of IAPP cannot be explained by a reduction in glucose utilization or marked, sustained, changes in neurotransmitters or neuropeptides in rat brain.