The Gastrointestinal Stimulus to Insulin Secretion in Lean and Obese Hyperglycaemic Mice

Abstract

A shortened, simplified modification of the insulin radioimmunoassay method of Hales & Randle has been established. Intraperitoneal glucose tolerance tests (ipGIT) confirmed hyperglycaemia, hyperinsulinaemia and impaired glucose tolerance in obese hyperglycaemic mice. Secretin and pancreozymin, but not gastrin, elevated plasma insulin levels and reduced blood glucose levels during ipGIT. Secretin, pancreozymin and glucagon stimulated the secretion of insulin from both lean and obese mouse islets in static incubation and during perifusion. Pancreozymin and glucagon-stimulated insulin secretion was accompanied by a parallel rise and fall in islet cyclic AMP content and efflux. Glucose and secretin did not significantly influence islet cyclic AMP content. It is suggested that gastrointestinal hormones might stimulate the secretion of insulin from a small labile pool via cyclic AMP, providing an early warning signal to the β-cell and a fine-tuning of glucose-induced insulin secretion. Although obese mouse islets showed an exaggerated insulin response to glucose and gastrointestinal hormones, lean and obese mouse islet cyclic AMP levels were not significantly different. The incorporation of lean and obese mouse everted jejunal sacs into the islet perifusion system indicated that factors released from the jejunum in response to glucose and amino acid might be capable of stimulating the release of insulin. Obese mouse duodenal-jejunal extracts contained higher insulin trophic activity and higher levels of bio assayable secretin and pancreozymin than extracts from lean mice. Histological and electron microscopical studies on lean and obese mouse intestine confirmed the presence of enteroendocrine cells. The possible role of the entero-insular axis in the development of hyperinsulinism and the pathogenesis of the obese-hyperglycaemic syndrome in mice has been discussed.