Insulin signaling regulates mitochondrial function in pancreatic beta-cells

Siming Liu; Terumasa Okada; Anke Assmann; Jamie Soto; Chong Wee Liew; Heiko Bugger; Orian S Shirihai; E Dale Abel; Rohit N Kulkarni

doi:10.1371/journal.pone.0007983

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Insulin signaling regulates mitochondrial function in pancreatic beta-cells

Journal article

Open access

Peer reviewed

Insulin signaling regulates mitochondrial function in pancreatic beta-cells

Siming Liu, Terumasa Okada, Anke Assmann, Jamie Soto, Chong Wee Liew, Heiko Bugger, Orian S Shirihai, E Dale Abel and Rohit N Kulkarni

PloS one, Vol.4(11), pp.e7983-e7983

11/24/2009

DOI: 10.1371/journal.pone.0007983

PMCID: PMC2776992

PMID: 19956695

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Abstract

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.

Cyclic AMP-Dependent Protein Kinases - metabolism

Phosphorylation

Signal Transduction

Humans

Mitochondria - metabolism

Diabetes Mellitus, Type 2 - metabolism

Glucokinase - metabolism

Serine - chemistry

Mice, Knockout

Insulin - metabolism

Insulin-Secreting Cells - metabolism

Animals

Receptor, Insulin - genetics

Islets of Langerhans - cytology

Cytosol - metabolism

Insulin-Secreting Cells - cytology

Mice

Details

Title: Subtitle: Insulin signaling regulates mitochondrial function in pancreatic beta-cells
Creators: Siming Liu - Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
Terumasa Okada
Anke Assmann
Jamie Soto
Chong Wee Liew
Heiko Bugger
Orian S Shirihai
E Dale Abel
Rohit N Kulkarni
Resource Type: Journal article
Publication Details: PloS one, Vol.4(11), pp.e7983-e7983
DOI: 10.1371/journal.pone.0007983
PMID: 19956695
PMCID: PMC2776992
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: R01 DK067536 / NIDDK NIH HHS R01 DK068721 / NIDDK NIH HHS P30 DK036836 / NIDDK NIH HHS HL RO1 73167 / NHLBI NIH HHS P30DK36836 / NIDDK NIH HHS R01 68721 / PHS HHS R01 DK056690 / NIDDK NIH HHS R01 DK035914 / NIDDK NIH HHS R01 HL073167 / NHLBI NIH HHS DK RO1 67536 / NIDDK NIH HHS
Language: English
Date published: 11/24/2009
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024511202771

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