Assessment of the role of interstitial glucagon in the acute glucose secretory responsiveness of in situ pancreatic beta-cells.
Glucagon is a potent stimulator of insulin release in the presence of a permissive glucose concentration, activating beta-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 beta-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-His(1),des-Phe(6),Glu(9)]glucagon-NH(2), 10 micromol/l) and GLP-1-receptors [exendin-(9-39)-NH(2), 1 micromol/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 beta-cells, the glucagon-receptor antagonist (10 micromol/l) inhibited the effect of 1 nmol/l glucagon upon glucose-induced insulin release by 78 plus minus 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 alpha-cells.
Moens
Karen
K
Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
Berger
Veerle
V
Ahn
Jung-Mo
JM
Van Schravendijk
Chris
C
Hruby
Victor J
VJ
Pipeleers
Daniel
D
Schuit
Frans
F
D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D004357:Drug Synergism; D005110:Extracellular Space / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism; D005934:Glucagon / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008168:Lung; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction
C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D018027:Receptors, Glucagon; C080071:glucagonamide, desHis(1)-Glu(9)-; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose; D007545:Isoproterenol