The incretin hormone GLP1 promotes islet-cell survival via the second messenger cAMP. Here we show that mice deficient in the activity of CREB, caused by expression of a dominant-negative A-CREB transgene in pancreatic beta-cells, develop diabetes secondary to beta-cell apoptosis. Remarkably, A-CREB severely disrupted expression of IRS2, an insulin signaling pathway component that is shown here to be a direct target for CREB action in vivo. As induction of IRS2 by cAMP enhanced activation of the survival kinase Akt in response to insulin and IGF-1, our results demonstrate a novel mechanism by which opposing pathways cooperate in promoting cell survival.
机构:
Univ Toronto, Toronto Gen Hosp, Dept Med, Banting & Best Diabet Ctr,Univ Hlth Network, Toronto, ON M5G 2C4, CanadaUniv Toronto, Toronto Gen Hosp, Dept Med, Banting & Best Diabet Ctr,Univ Hlth Network, Toronto, ON M5G 2C4, Canada
机构:
Univ Toronto, Toronto Gen Hosp, Dept Med, Banting & Best Diabet Ctr,Univ Hlth Network, Toronto, ON M5G 2C4, CanadaUniv Toronto, Toronto Gen Hosp, Dept Med, Banting & Best Diabet Ctr,Univ Hlth Network, Toronto, ON M5G 2C4, Canada