Effects of ghrelin on insulin and glucagon secretion: a study of isolated pancreatic islets and intact mice
Introduction
There is a suspicion that the stomach harbours peptide hormones that contribute to the control of pancreatic hormone release. This suspicion is based on reports describing impaired insulin release following resection of the stomach both in man and experimental animals [1], [2], [3]. Recently, a growth hormone-releasing peptide named ghrelin was identified in extracts of the rat stomach [4] and found to be produced and stored in a population of peptide hormone-producing cells referred to as A-like cells [5], [6], [7]. Circulating concentrations of ghrelin are elevated by food deprivation and lowered by food intake [6], [8], [9]. The signals that regulate the secretion of ghrelin from the A-like cells have not yet been identified. Whether the A-like cells and ghrelin participate in the control of islet hormone secretion remains an unresolved issue although some reports have appeared, suggesting that ghrelin either stimulates [10], [11] or inhibits [12], [13], [14] insulin secretion. There have been claims that insulin (and/or glucose) lowers circulating ghrelin [15], [16], [17], [18], [19] (for a different view, see Ref. [20]). There are surprisingly few data on the effect of ghrelin on glucagon release; however, it was recently reported that ghrelin is without effect on glucagon secretion in the perfused rat pancreas [13].
The purpose of the present study was to examine the effects of ghrelin on insulin and glucagon release from freshly isolated pancreatic islets from mice and to further investigate effects of ghrelin on insulin and glucagon secretion in intact, freely moving mice using different blood sampling times and different doses with or without administration of glucose and various insulin and glucagon secretagogues.
Section snippets
Drugs and chemicals
Rat ghrelin-28 was a kind gift from Professors N. Yanaihara and C. Yanaihara at the Yanaihara Institute, Shizuoka, Japan. Collagenase (CLS-4) from Worthington Biochemicals (Freehold, NJ, USA) was used to prepare the pancreatic islets. Bovine serum albumin (BSA) was from ICN Biomedical (High Wycombe, UK). All other chemicals were from British Drug Houses (Poole, UK) or Merck (Darmstadt, Germany). Radioimmunoassay kits for determination of insulin were obtained from Diagnostika (Falkenberg,
Insulin and glucagon secretion in response to varying concentrations of ghrelin at a fixed glucose concentration
Fig. 1 illustrates the concentration–response curves for the effect of ghrelin on insulin and glucagon secretion from isolated islets in the presence of a glucose concentration (12 mmol l−1) that in itself has a modest stimulating effect on insulin secretion. Insulin release was suppressed in the presence of low concentrations of ghrelin (1–100 pmol l−1), while concentrations of 0.1 and 1 μmol l−1 stimulated insulin secretion. However, within the range of circulating ghrelin concentrations (0.5
Discussion
In an earlier report [3], we suggested that the stomach harbours a peptide hormone that serves to enhance the glucose-stimulated insulin response and potentiate the glucose-induced suppression of glucagon secretion. This suggestion is in line with the fact that the oxyntic mucosa of the stomach is rich in peptide hormone-producing endocrine cells, such as ECL cells and A-like cells [29], [30]. The putative peptide hormone of the ECL cells is unknown, whereas ghrelin has been identified as the
Acknowledgements
The study was supported by grants from the Swedish Research Council (grants 4286 and 04x-1007), the Albert Påhlsson foundation, the Crafoord foundation, the Golje foundation, the Magnus Bergvall foundation, the Novo Nordisk foundation and the Medical Faculty of Lund.
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