Glucagon-like peptide-1 but not glucagon-like peptide-2 stimulates insulin release from isolated rat pancreatic islets

The mechanism of synergism between glucose and adenosine 3',5'-cyclic monophosphate (cAMP) on insulin release has been studied. Synergism may result from 1) inhibition of Na+-Ca2+ exchange by glucose and 2) a cAMP-induced sensitization of the release machinery to Ca2+. To distinguish between these two possibilities, isolated rat pancreatic islets were perifused with agents that raise intracellular levels of cAMP [3-isobutyl-1-methylxanthine (IBMX) and forskolin] and others that increase intracellular concentrations of Ca2+ either by blocking Na2+-Ca2+ exchange (ouabain and choline-Ringer solution) or by causing increased Ca2+ influx (KCl, carbachol, and 10 mM Ca2+). The results indicate that both the combination of cAMP and increased Ca2+ influx or blocked Na2-Ca2+ exchange and increased Ca2+ influx potentiated insulin release. When the relative potentiating abilities of cAMP and blocked Na2+-Ca2+ exchange were compared by determining the individual effects of IBMX and 1 mM ouabain (a concentration that causes similar inhibition of 45C2+ efflux as 16.7 mM glucose) in the presence of carbachol, cAMP was only 1.4 times more potent as a potentiating agent than blocked Na+-Ca2+ exchange. The greatest potentiation of insulin release was observed when Na+-Ca2+ exchange was blocked in the presence of increased levels of intracellular cAMP.

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Lack of effect of incretin hormones on insulin release from pancreatic islets in the bile duct-ligated rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.280.1.e59 ◽

2001 ◽

Vol 280 (1) ◽

pp. E59-E64 ◽

Cited By ~ 2

Author(s):

Tae Niwa ◽

Yuji Nimura ◽

Ichiro Niki

Keyword(s):

Bile Duct ◽

Pancreatic Islets ◽

G Protein ◽

Insulin Release ◽

Statistical Significance ◽

Serum Levels ◽

Hepatobiliary Diseases ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Insulinotropic Peptide

Hyperglycemia associated with obstructive jaundice seriously affects the prognosis of patients with hepatobiliary diseases. We investigated secretory properties of isolated islets from bile duct-ligated (BDL) rats. Pancreatic islets from BDL rats lost their secretory responses to glucagon-like peptide-1 (GLP-1), although their responses to glucose were normal. Loss of potentiation of insulin release was also observed in glucagon and glucose-dependent insulinotropic peptide (GIP), whereas modulation of the release by forskolin, dibutyryl cAMP, or epinephrine remained unaffected. cAMP production by BDL islets was not increased by these insulinotropic hormones. Serum levels of glucagon, but not GIP, were increased in BDL rats. GLP-1 levels were also elevated, although they did not reach statistical significance. Immunoblotting of trimeric G protein subunits demonstrated that GsαL and GsαS, but not Giα1/2 and Giα3/oα, were less expressed in BDL islets. Therefore, unresponsiveness of the β-cell to cAMP-raising hormones is involved in glucose intolerance under cholestasis. It results from diminished expression of α-subunits of the relevant G protein, Gs, and desensitization of receptors of these hormones.

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