Glucose homeostasis, insulin secretion, and islet phospholipids in mice that overexpress iPLA2beta in pancreatic beta-cells and in iPLA2beta-null mice.

Bao S, Jacobson DA, Wohltmann M, Bohrer A, Jin W, Philipson LH, Turk J
Am J Physiol Endocrinol Metab. 2008 294 (2): E217-29

PMID: 17895289 · PMCID: PMC2268609 · DOI:10.1152/ajpendo.00474.2007

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.

MeSH Terms (30)

Animals Arachidonic Acid Blood Glucose Blotting, Western Calcium Cell Line, Tumor DNA, Complementary Fasting Gene Expression Regulation, Enzymologic Genotype Glucose Tolerance Test Group IV Phospholipases A2 Homeodomain Proteins Homeostasis Insulin Insulin-Secreting Cells Insulinoma Insulin Secretion Islets of Langerhans Kv1.2 Potassium Channel Mice Mice, Knockout Mice, Transgenic Microscopy, Fluorescence Pancreatic Neoplasms Patch-Clamp Techniques Phospholipids Reverse Transcriptase Polymerase Chain Reaction Spectrometry, Mass, Electrospray Ionization Trans-Activators

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