Glucose homeostasis, insulin secretion, and islet phospholipids in mice that overexpress iPLA<sub>2</sub>β in pancreatic β-cells and in iPLA<sub>2</sub>β-null mice

American Journal of Physiology - Endocrinology and Metabolism - Tập 294 Số 2 - Trang E217-E229 - 2008
Shunzhong Bao1, David A. Jacobson2,3,4, Mary Wohltmann2,3,4, Alan Bohrer2,3,4, Wu Jin2,3,4, Louis H. Philipson2,3,4, John Turk2,3,4
1Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
21Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110
32Department of Medicine, University of Chicago, Chicago, Illinois 60637
4Washington University School of Medicine, Box 8127, 660 S. Euclid Ave., St. Louis, MO 63110;

Tóm tắt

Studies with genetically modified insulinoma cells suggest that group VIA phospholipase A2(iPLA2β) participates in amplifying glucose-induced insulin secretion. INS-1 insulinoma cells that overexpress iPLA2β, for example, exhibit amplified insulin-secretory responses to glucose and cAMP-elevating agents. To determine whether similar effects occur in whole animals, we prepared transgenic (TG) mice in which the rat insulin 1 promoter (RIP) drives iPLA2β overexpression, and two characterized TG mouse lines exhibit similar phenotypes. Their pancreatic islet iPLA2β expression is increased severalfold, as reflected by quantitative PCR of iPLA2β mRNA, immunoblotting of iPLA2β protein, and iPLA2β enzymatic activity. Immunofluorescence microscopic studies of pancreatic sections confirm iPLA2β overexpression in RIP-iPLA2β-TG islet β-cells without obviously perturbed islet morphology. Male RIP-iPLA2β-TG mice exhibit lower blood glucose and higher plasma insulin concentrations than wild-type (WT) mice when fasting and develop lower blood glucose levels in glucose tolerance tests, but WT and TG blood glucose levels do not differ in insulin tolerance tests. Islets from male RIP-iPLA2β-TG mice exhibit greater amplification of glucose-induced insulin secretion by a cAMP-elevating agent than WT islets. In contrast, islets from male iPLA2β-null mice exhibit blunted insulin secretion, and those mice have impaired glucose tolerance. Arachidonate incorporation into and the phospholipid composition of RIP-iPLA2β-TG islets are normal, but they exhibit reduced Kv2.1 delayed rectifier current and prolonged glucose-induced action potentials and elevations of cytosolic Ca2+concentration that suggest a molecular mechanism for the physiological role of iPLA2β to amplify insulin secretion.

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American Journal of Physiology - Endocrinology and Metabolism

Tập 294 Số 2

E217-E229

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