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.