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

摘要

First published September 27, 2007; doi:10.1152/ajpendo.00474.2007.-Studies with genetically modified insulinoma cells suggest that group VIA phospholipase A2 (iPLA2beta) participates in amplifying glucose-induced insulin secretion. INS~(-1) insulinoma cells that overexpress iPLA2beta, 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 IPLbeta overexpression, and two characterized TG mouse lines exhibit similar phenotypes. Their pancreatic islet iPLA2beta expression is increased severalfold, as reflected by quantitative PCR of iPLA2beta mRNA, immunoblotting of iPLA2beta protein, and iPLA2beta enzymatic activity. Immunofluorescence microscopic studies of pancreatic sections confirm iPLA2beta overexpression in RTP-iPLA2beta-TG islet beta-cells without obviously perturbed islet morphology. Male RTP-iPLA-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-iPLA2beta-TG mice exhibit greater amplification of glucose-induced insulin secretion by a cAMP-elevat-ing agent than WT islets. In contrast, islets from male iPLA2beta-nuII mice exhibit blunted insulin secretion, and those mice have impaired glucose tolerance. Arachidonate incorporation into and the phospholipid composition of RIP-iPLA-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 iPLA2beta to amplify insulin secretion.