Impaired metabolism-secretion coupling in pancreatic beta-cells: role of determinants of mitochondrial ATP production.
Glucose-induced insulin secretion from beta-cells is often impaired in diabetic condition and by exposure to diabetogenic pharmacological agents. In pancreatic beta-cells, intracellular glucose metabolism regulates exocytosis of insulin granules, according to metabolism-secretion coupling in which glucose-induced mitochondrial ATP production plays an essential role. Impaired glucose-induced insulin secretion often results from impaired glucose-induced ATP elevation in beta-cells. Mitochondrial ATP production is driven by the proton-motive force including mitochondrial membrane potential (DeltaPsi(m)) generated by the electron transport chain. These electrons are derived from reducing equivalents, generated in the Krebs cycle and transferred from cytosol by the shuttles. Here, roles of the determinants of mitochondrial ATP production in impaired glucose-induced insulin secretion are discussed. Cytosolic alkalization, H(+) leak in the inner membrane by uncoupler (e.g. free fatty acid exposure), decrease in the supply of electron donors including NADH and FADH(2) to the respiratory chain, and endogenous mitochondrial ROS (e.g. Na(+)/K(+)-ATPase inhibition) all reduce hyperpolarlization of DeltaPsi(m) and ATP production, causing decresed glucose-induced insulin release. The decrease in the supply of NADH and FADH(2) to the respiratory chain derives from impairments in glucose metabolism including glycolysis (e.g. MODY2 and exposure to NO) and the shuttles (e.g. diabetic state and exposure to ketone body).
Fujimoto
Shimpei
S
Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. fujimoto@metab.kuhp.kyoto-u.ac.jp
Nabe
Koichiro
K
Takehiro
Mihoko
M
Shimodahira
Makiko
M
Kajikawa
Mariko
M
Takeda
Tomomi
T
Mukai
Eri
E
Inagaki
Nobuya
N
Seino
Yutaka
Y
D000255:Adenosine Triphosphate / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D017382:Reactive Oxygen Species
D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D005947:Glucose