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

Kirk L. Pappan, Zhijun Pan, Guim Kwon, Connie A. Marshall, Trey Coleman, Ira J. Goldberg, Michael L. McDaniel, Clay F. Semenkovich

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43 Scopus citations

Abstract

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 (KATP) 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 KATP 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.

Original languageEnglish
Pages (from-to)9023-9029
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number10
DOIs
StatePublished - Mar 11 2005

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