Gastrectomy induces impaired insulin and glucagon secretion: evidence for a gastro‐insular axis in mice

Abstract

Hormones released from the digestive tract have been suggested to contribute to the metabolic disposal of ingested glucose. Thus, an oral glucose load is metabolized more rapidly than an intravenous glucose load, and more insulin is secreted after oral glucose than after an equivalent intravenous glucose load (McIntyre et al. 1964;Dupr e, 1991; Creutzfeldt & Nauck, 1992). Several intestinal hormones, including glucagon-like peptide_1-(7-36)-amide (GLP_1) and glucose-dependent insulinotrophic peptide (GIP), are thought to affect blood glucose by modulating the secretion of insulin and glucagon (Dupr e, 1991; Creutzfeldt & Nauck, 1992;Holst, 1994). However, the dysfunction of such intestinal hormone systems does not explain the alimentary hyperglycaemia often noted in patients who have undergone gastric surgery (Muir, 1949;Tobe et al. 1967). The possible existence of a gastro-insular axis prompted us to study the effect of gastrectomy in mice on the insulin and glucagon responses in vivo and in vitro to the three major types of regulators of islet hormone release, i.e. glucose (nutrient regulator), carbachol (phospholipase C regulator) and isobutylmethylxanthine (IBMX) or forskolin (cyclic AMP regulators). In addition, we tested the effect of a crude oxyntic mucosal extract on islet hormone release. We also monitored blood lipids since recent studies have indicated that free fatty acids may impair insulin release (Prentki & Corkey, 1996).

Secretory and electrophysiological characteristics of insulin cells from gastrectomized mice: Evidence for the existence of insulinotropic agents in the stomach

“…This has been studied previously in GX mice and in isolated pancreatic islets from GX mice [14]. From these data, we have suggested that the impairment might reflect the loss of a gastric regulatory peptide that serves to enhance the insulin response to oral as well as circulating glucose [14]. In that study we could show that the impaired insulin response to glucose in GX mice was associated with an enhanced responsiveness to cholinergic agents and to agents stimulating cAMP formation [14].…”

“…This has been studied previously in GX mice and in isolated pancreatic islets from GX mice [14]. From these data, we have suggested that the impairment might reflect the loss of a gastric regulatory peptide that serves to enhance the insulin response to oral as well as circulating glucose [14].…”

“…In the present study we have extended our previous investigation [14] in order to further explore the nature of the GX-induced defects in the insulin secretory machinery, especially with regard to the cAMP system. To this end, we determined cAMP in freshly isolated islets and studied the insulin response to glucose and to the adenylate cyclase activator forskolin as well as the ability of the islets to accumulate cAMP upon incubation in the presence of different concentrations of glucose.…”

“…Gastrectomy (GX), in patients as well as in animals, impairs the ability of the insulin cells to respond to a glucose challenge with appropriate insulin release [12][13][14][15][16]. This has been studied previously in GX mice and in isolated pancreatic islets from GX mice [14].…”

ADP mediates inhibition of insulin secretion by activation of P2Y13 receptors in mice

“…10 min prior to i.p. glucose injection of 1.2 g/kg with or without MRS2211 (50 mg/kg) i.p., and blood samples were collected at 0, 3, 10 and 40 min post glucose administration as previously described [27].…”