Insulin protects islets from apoptosis via Pdx1 and specific changes in the human islet proteome.
Insulin is both a hormone regulating energy metabolism and a growth factor. We and others have shown that physiological doses of insulin initiate complex signals in primary human and mouse beta-cells, but the functional significance of insulin's effects on this cell type remains unclear. In the present study, the role of insulin in beta-cell apoptosis was examined. Exogenous insulin completely prevented apoptosis induced by serum withdrawal when given at picomolar or low nanomolar concentrations but not at higher concentrations, indicating that physiological concentrations of insulin are antiapoptotic and that insulin signaling is self-limiting in islets. Insulin treatment was associated with the nuclear localization of Pdx1 and the prosurvival effects of insulin were largely absent in islets 50% deficient in Pdx1, providing direct evidence that Pdx1 is a signaling target of insulin. Physiological levels of insulin did not increase Akt phosphorylation, and the protective effects of insulin were only partially altered in islets lacking 80% of normal Akt activity, suggesting the presence of additional insulin-regulated antiapoptotic pathways. Proteomic analysis of insulin-treated human islets revealed significant changes in multiple proteins. Bridge-1, a Pdx1-binding partner and regulator of beta-cell survival, was increased significantly at low insulin doses. Together, these data suggest that insulin can act as a master regulator of islet survival by regulating Pdx1.
Johnson
James D
JD
Diabetes Research Group, Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada V6T 1Z3. jimjohn@interchange.ubc.ca
Bernal-Mizrachi
Ernesto
E
Alejandro
Emilyn U
EU
Han
Zhiqiang
Z
Kalynyak
Tatyana B
TB
Li
Hong
H
Beith
Jennifer L
JL
Gross
Julia
J
Warnock
Garth L
GL
Townsend
R Reid
RR
Permutt
M Alan
MA
Polonsky
Kenneth S
KS
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D005455:Fluorescent Antibody Technique; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*
D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D051057:Proto-Oncogene Proteins c-akt