Glucose homeostasis, insulin secretion, and islet phospholipids in mice that overexpress iPLA2β in pancreatic β-cells and in iPLA2β-null mice

Abstract

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.