Inhibitors of phosphatidylinositol 3-kinase amplify insulin release from islets of lean but not obese mice.
We examined the effects of phosphatidylinositol 3-kinase (PI3K) inhibition by wortmannin or LY294002 on glucose-induced secretion from mouse islets. Islets were collagenase isolated and perifused or subjected to Western blot analyses and probed for insulin receptor-signaling components. In agreement with previous studies, mouse islets, when compared with rat islets, were minimally responsive to 10 mM glucose stimulation. The inclusion of 50 nM wortmannin or 10 microM LY294002 significantly amplified 10 mM glucose-induced release from mouse islets. The effect of wortmannin was abolished by the calcium channel antagonist nitrendipine or by lowering the glucose level to 3 mM. Wortmannin had no effect on 10 mM alpha-ketoisocaproate-induced secretion. In contrast to its potentiating effect on islets from CD-1 mice, wortmannin had no effect on 10 mM glucose-induced release from ob/ob mouse islets. Western blot analyses revealed the presence of the insulin receptor, insulin receptor substrate proteins 1 and 2 and PI3K in CD-1 islets. These results support the concept that a PI3K-dependent signaling pathway exists in beta-cells and that it may function to restrain glucose-induced insulin secretion from beta-cells. They also suggest that, as insulin resistance develops in peripheral tissues, a potential result of impaired PI3K activation, the same biochemical anomaly in beta-cells promotes a linked increase in insulin secretion to maintain glucose homeostasis.
Zawalich
W S
WS
Yale University School of Nursing, 100 Church Street South, New Haven, Connecticut 06536-0740, USA. Walter.Zawalich@Ylae.Edu
Tesz
G J
GJ
Zawalich
K C
KC
D000704:Analysis of Variance; D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D000078790:Insulin Secretion; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009025:Morpholines / Q000494:pharmacology*; D009568:Nitrendipine / Q000494:pharmacology; D009765:Obesity / Q000503:physiopathology*; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000032:analysis; D000077191:Wortmannin
D000730:Androstadienes; D002121:Calcium Channel Blockers; D002867:Chromones; D004791:Enzyme Inhibitors; D005947:Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D009568:Nitrendipine; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D011972:Receptor, Insulin; D000077191:Wortmannin; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; C526298:Irs2 protein, mouse; C526299:Irs2 protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one