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

Detta är en avhandling från Stockholm : Karolinska Institutet, false

Sammanfattning: Control of food intake and satiety are physiologically complex processes, thatonly partly are understood. Several hormonal peptides have been proposed to mediatesatiety. Islet amyloid polypeptide (IAPP) is a recently discovered 37 amino acidpeptide, mainly produced by the pancreatic ß-cells. Initially, IAPP was shownto impair glucose tolerance at supra-physiological plasma concentrations and wasspeculated to be involved in the development of type-2 diabetes. More recent studiesof IAPP administration at pharmacological doses, demonstrate that IAPP can inhibitfood intake in the rat. In the present study the anorectic effect of LAPP is furtherevaluated, with the hypothesis that IAPP is a satiety factor that plays a hormonalrole 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 eithermanually or continuously by computer, enabling analysis of meal patterns. A novelindwelling aortic catherization technique was developed. This new technique allowedfrequent and rapid blood sampling for up to two months. Plasma levels of IAPP weredetermined by radioimmunoassay in all studies. In addition, the catheterization techniquemade it possible to in the same animals determine the threshold dose of IAPP forsuppression of food intake, the plasma response to this IAPP dose, and compare thisresponse to plasma concentrations of IAPP obtained during feeding. Furthermore, theeffect of IAPP on peripheral glucose utilization was measured by hyperinsulinemiceuglycernic clamp at plasma con-centrations of IAPP that reduced food intake. Inaddition, the response to anorectic IAPP doses on satiety related neurotransmittersand neuropeptides was investigated. Both acute and chronic IAPP administration potently inhibited food intake in adose response manner. Inhibition of food intake occurred at lower doses than previouslyreported. Analysis of meal pattern following both acute and chronic IAPP administrationrevealed that the reduced food intake was caused by a decreased meal frequency ratherthan meal size. In the chronic meal pattern experiment, the effects were most prominentduring the light phase. It was demonstrated that plasma concentrations of IAPP duringfeeding were not sufficient to inhibit food intake. However, the threshold dose resultedin circulating IAPP levels that were close to those levels that were observed duringphysiological conditions and well within the range of what has been reported in anorecticpancreatic cancer patients. Chronic administration of low anorectic doses of IAPPdid not induce hyperglycemia or insulin resistance, and did not alter levels of neurotransmittersand neuropeptides in the hypothalamus, hippocampus, striatum, left cortex, and rightcortex of the rat brain. In conclusion, IAPP potently and dose-dependently inhibits food intake by reducingmeal frequency. The postprandial rise in plasma IAPP that was obtained in this studyis not sufficient to reduce food intake, but exogenously administered IAPP that producesplasma concentrations similar to what is observed in pancreatic cancer patients inhibitsfood intake. This study provides evidence to suggest that the anorectic effect ofIAPP can not be explained by a reduction in glucose utilization or marked, sustained,changes in neurotransmitters or neuropeptides in rat brain. Keywords: body weight, glucose metabolism, IAPP, meal patterns, monoamines, neuropeptides,radioimmunoassay, rats, satiety ISBN 91-628-2778-2

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