Pancreatic beta-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 beta-cell dysfunction. To clarify the role of lipids in insulin secretion, we generated mice with beta-cell-specific overexpression (betaLPL-TG) or inactivation (betaLPL-KO) of lipoprotein lipase (LPL), a physiologic provider of fatty acids. LPL enzyme activity and triglyceride content were increased in betaLPL-TG islets; decreased LPL enzyme activity in betaLPL-KO islets did not affect islet triglyceride content. Surprisingly, both betaLPL-TG and betaLPL-KO mice were strikingly hyperglycemic during glucose tolerance testing. Impaired glucose tolerance in betaLPL-KO mice was present at one month of age, whereas betaLPL-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 betaLPL-TG islets but increased in betaLPL-KO islets. Islet ATP content was not decreased in either model. Insulin secretion was defective in both betaLPL-TG and betaLPL-KO islets under conditions causing calcium-dependent insulin secretion independent of the KATP channel. These results show that beta-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.
Pappan
Kirk L
KL
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Pan
Zhijun
Z
Kwon
Guim
G
Marshall
Connie A
CA
Coleman
Trey
T
Goldberg
Ira J
IJ
McDaniel
Michael L
ML
Semenkovich
Clay F
CF
D000818:Animals; D002462:Cell Membrane / Q000502:physiology; D018076:DNA, Complementary; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007700:Kinetics; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D012016:Reference Values; D014280:Triglycerides / Q000378:metabolism
D018076:DNA, Complementary; D007328:Insulin; D014280:Triglycerides; D008071:Lipoprotein Lipase; D005947:Glucose