title: Glucose homeostasis, insulin secretion, and islet phospholipids in mice that overexpress iPLA2beta in pancreatic beta-cells and in iPLA2beta-null mice.
abstract: Studies with genetically modified insulinoma cells suggest that group VIA phospholipase A(2) (iPLA(2)beta) participates in amplifying glucose-induced insulin secretion. INS-1 insulinoma cells that overexpress iPLA(2)beta, 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 iPLA(2)beta overexpression, and two characterized TG mouse lines exhibit similar phenotypes. Their pancreatic islet iPLA(2)beta expression is increased severalfold, as reflected by quantitative PCR of iPLA(2)beta mRNA, immunoblotting of iPLA(2)beta protein, and iPLA(2)beta enzymatic activity. Immunofluorescence microscopic studies of pancreatic sections confirm iPLA(2)beta overexpression in RIP-iPLA(2)beta-TG islet beta-cells without obviously perturbed islet morphology. Male RIP-iPLA(2)beta-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-iPLA(2)beta-TG mice exhibit greater amplification of glucose-induced insulin secretion by a cAMP-elevating agent than WT islets. In contrast, islets from male iPLA(2)beta-null mice exhibit blunted insulin secretion, and those mice have impaired glucose tolerance. Arachidonate incorporation into and the phospholipid composition of RIP-iPLA(2)beta-TG islets are normal, but they exhibit reduced Kv2.1 delayed rectifier current and prolonged glucose-induced action potentials and elevations of cytosolic Ca(2+) concentration that suggest a molecular mechanism for the physiological role of iPLA(2)beta to amplify insulin secretion.
authors: Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. jturk@wustl.edu
authors: Shunzhong
authors: S
authors: Bao
authors: David A
authors: DA
authors: Jacobson
authors: Mary
authors: M
authors: Wohltmann
authors: Alan
authors: A
authors: Bohrer
authors: Wu
authors: W
authors: Jin
authors: Louis H
authors: LH
authors: Philipson
authors: John
authors: J
authors: Turk
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism / Q000502:physiology*; D015153:Blotting, Western; D002118:Calcium / Q000502:physiology; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005215:Fasting / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005838:Genotype; D005951:Glucose Tolerance Test; D054513:Group IV Phospholipases A2 / Q000096:biosynthesis* / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006706:Homeostasis / Q000502:physiology*; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007340:Insulinoma / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D051663:Kv1.2 Potassium Channel / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010190:Pancreatic Neoplasms / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010743:Phospholipids / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D021241:Spectrometry, Mass, Electrospray Ionization; D015534:Trans-Activators / Q000235:genetics
chemical_list: D001786:Blood Glucose; D018076:DNA, Complementary; D018398:Homeodomain Proteins; D007328:Insulin; D051663:Kv1.2 Potassium Channel; D010743:Phospholipids; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D016718:Arachidonic Acid; D054513:Group IV Phospholipases A2; D002118:Calcium