Metabolic consequence of long-term exposure of pancreatic beta cells to free fatty acid with special reference to glucose insensitivity.
Long-term exposure of the pancreatic beta cells to free fatty acid (FFA) reportedly inhibits glucose-stimulated insulin secretion. We here studied the impact of FFA on glucose and lipid metabolism in pancreatic beta cells with special reference to insulin secretion. Pancreatic beta-cell line MIN6 was exposed to various concentrations of palmitate for 3 days. Glucose-stimulated insulin secretion and insulin content were decreased corresponding to the concentration of the palmitate exposed. Glycolytic flux and ATP synthesis was unchanged, but pyruvate-stimulated change in NAD(P)H concentration was decreased. Pyruvate carboxylase was decreased at the protein level, which was restored by the removal of palmitate or the inhibition of beta-oxidation. Intracellular content of triglyceride and FFA were elevated, beta-oxidation was increased, and de novo lipogenesis from glucose was decreased. NADPH content and citrate output into the medium, which reflected pyruvate malate shuttle flux, were decreased, but malic enzyme activity was unaffected. The malic enzyme inhibitor alone inhibited insulin response to glucose. In conclusion, long-term exposure of FFA to beta cells inhibits glucose-stimulated insulin secretion via the decreased NADPH contents due to the inhibition of pyruvate carboxylase and malate pyruvate shuttle flux.
Iizuka
Katsumi
K
Department of Internal Medicine, Graduate School of Medicine, Osaka University, Suita, Japan.
Nakajima
Hiromu
H
Namba
Mitsuyoshi
M
Miyagawa
Jun ichiro
Ji
Miyazaki
Junichi
J
Hanafusa
Toshiaki
T
Matsuzawa
Yuji
Y
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D050356:Lipid Metabolism; D009243:NAD / Q000378:metabolism; D010168:Palmitates / Q000494:pharmacology; D011766:Pyruvate Carboxylase / Q000032:analysis / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; D007328:Insulin; D010168:Palmitates; D009243:NAD; D011766:Pyruvate Carboxylase; D005947:Glucose; D002118:Calcium