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Assessment of the Role of Interstitial Glucagon in the Acute Glucose Secretory Responsiveness of In Situ Pancreatic ß-Cells

¹ Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
² Department of Chemistry, University of Arizona, Tucson, Arizona

Glucagon is a potent stimulator of insulin release in the presence of a permissive glucose concentration, activating ß-cells in vitro via both glucagon- and glucagon-like peptide-1 (GLP-1)-receptors. It is still unclear whether locally released glucagon amplifies the secretory responsiveness of neighboring ß-cells in the intact pancreas. The present study investigates this question in the perfused pancreas by examining the effects of antagonists for glucagon receptors ([des-His¹,des-Phe⁶,Glu⁹]glucagon-NH₂, 10 µmol/l) and GLP-1-receptors [exendin-(9-39)-NH₂, 1 µmol/l] on the insulin secretory response to glucose. The specificity of both antagonists was demonstrated by their selective interaction with glucagon-receptor signaling in rat hepatocytes and GLP-1-receptor signaling in Chinese hamster lung (CHL) fibroblasts. In purified rat ß-cells, the glucagon-receptor antagonist (10 µmol/l) inhibited the effect of 1 nmol/l glucagon upon glucose-induced insulin release by 78 ± 6%. In the perfused rat pancreas, neither of these antagonists inhibited the potent secretory response to 20 mmol/l glucose, although they effectively suppressed the potentiating effect of, respectively, an infusion of glucagon (1 nmol/l) or GLP-1 (1 nmol/l) on insulin release. When endogenous glucagon release was enhanced by isoproterenol (100 nmol/l), no amplification was seen in the simultaneous or subsequent insulin secretory response to glucose. It is concluded that, at least under the present selected conditions, the glucose-induced insulin release by the perfused rat pancreas seems to occur independent of an amplifying glucagon signal from neighboring -cells.

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