Pancreatic β-cell lipoprotein lipase independently regulates islet glucose metabolism and normal insulin secretion

Lipid and glucose metabolism are adversely affected by diabetes, a disease characterized by pancreatic β-cell dysfunction. To clarify the role of lipids in insulin secretion, we generated mice with β-cell-specific overexpression (βLPL-TG) or inactivation (βLPL-KO) of lipoprotein lipase (LPL), a physiologic provider of fatty acids. LPL enzyme activity and triglyceride content were increased in βLPL-TG islets; decreased LPL enzyme activity in βLPL-KO islets did not affect islet triglyceride content. Surprisingly, both βLPL-TG and βLPL-KO mice were strikingly hyperglycemic during glucose tolerance testing. Impaired glucose tolerance in βLPL-KO mice was present at one month of age, whereas βLPL-TG mice did not develop defective glucose homeostasis until approximately five months of age. Glucose-simulated insulin secretion was impaired in islets isolated from both mouse models. Glucose oxidation, critical for ATP production and triggering of insulin secretion mediated by the ATP-sensitive potassium (K_ATP) channel, was decreased in βLPL-TG islets but increased in βLPL-KO islets. Islet ATP content was not decreased in either model. Insulin secretion was defective in both βLPL-TG and βLPL-KO islets under conditions causing calcium-dependent insulin secretion independent of the K_ATP channel. These results show that β-cell-derived LPL has two physiologically relevant effects in islets, the inverse regulation of glucose metabolism and the independent mediation of insulin secretion through effects distal to membrane depolarization.