Insulin signaling regulates mitochondrial function in pancreatic beta-cells.
Insulin/IGF-I signaling regulates the metabolism of most mammalian tissues including pancreatic islets. To dissect the mechanisms linking insulin signaling with mitochondrial function, we first identified a mitochondria-tethering complex in beta-cells that included glucokinase (GK), and the pro-apoptotic protein, BAD(S). Mitochondria isolated from beta-cells derived from beta-cell specific insulin receptor knockout (betaIRKO) mice exhibited reduced BAD(S), GK and protein kinase A in the complex, and attenuated function. Similar alterations were evident in islets from patients with type 2 diabetes. Decreased mitochondrial GK activity in betaIRKOs could be explained, in part, by reduced expression and altered phosphorylation of BAD(S). The elevated phosphorylation of p70S6K and JNK1 was likely due to compensatory increase in IGF-1 receptor expression. Re-expression of insulin receptors in betaIRKO cells partially restored the stoichiometry of the complex and mitochondrial function. These data indicate that insulin signaling regulates mitochondrial function and have implications for beta-cell dysfunction in type 2 diabetes.
Liu
Siming
S
Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
Okada
Terumasa
T
Assmann
Anke
A
Soto
Jamie
J
Liew
Chong Wee
CW
Bugger
Heiko
H
Shirihai
Orian S
OS
Abel
E Dale
ED
Kulkarni
Rohit N
RN
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005941:Glucokinase / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000235:genetics; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction
D007328:Insulin; D012694:Serine; D005941:Glucokinase; D011972:Receptor, Insulin; D017868:Cyclic AMP-Dependent Protein Kinases