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ORIGINAL RESEARCH ARTICLE

Leptin Constrains Phospholipase C-Protein Kinase C-Induced Insulin Secretion via a Phosphatidylinositol 3-Kinase-Dependent Pathway

Joo-Won Lee^*, Andrew G. Swick and Dale R. Romsos^*,1

^* Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824–1224, and
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, Connecticut 06340

Leptin-deficient Lep^ob/Lep^obmice hypersecrete insulin in response to acetylcholine stimulation of the phospholipase C-protein kinase C (PLC-PKC) pathway, and leptin constrains this hypersecretion. Leptin has been reported to activate phosphatidylinositol 3-kinase (PI 3-K) and subsequently phosphodiesterase (PDE) to impair protein kinase A (PKA)-induced insulin secretion from cultured islets of neonatal rats. We determined if PKA-induced insulin secretion was also hyperresponsive in islets fromLep^ob/Lep^obmice, and if leptin impaired this pathway in islets from these mice. Additionally, the possible role for PI 3-K and PDE in leptin-induced control of acetylcholine-induced insulin secretion was examined. Stimulation of insulin secretion with GLP-1, forskolin (an activator of adenylyl cyclase), or IBMX (an inhibitor of PDE) did not cause hypersecretion of insulin from islets of youngLep^ob/Lep^obmice, and leptin did not inhibit GLP-1-induced insulin secretion from islets of these mice. Inhibition of PDE with IBMX also did not block leptin-induced inhibition of acetylcholine-mediated insulin secretion from islets ofLep^ob/Lep^obmice. But, preincubation of islets with wortmannin, an inhibitor of PI 3-K activity, blocked the ability of leptin to constrain acetylcholine-induced insulin secretion from islets ofLep^ob/Lep^obmice. We conclude that the capacity of the PKA pathway to stimulate insulin secretion is not increased in islets from youngLep^ob/Lep^obmice, and that leptin does not regulate this pathway in islets from mice. Leptin may stimulate PI 3-K to constrain PLC-PKC-induced insulin secretion from islets ofLep^ob/Lep^obmice.

Key Words: Insulin secretion • Lep^ob/Lep^ob mice • leptin • phosphatidylinositol 3-kinase • phospholipase C-protein kinase C

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