Abstract
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 IRS2by 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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis
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Cell Line
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Cell Survival*
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Colforsin / pharmacology
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Cyclic AMP / metabolism*
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism*
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Diabetes Mellitus / etiology
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Diabetes Mellitus / metabolism
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Diabetes Mellitus / pathology
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Gene Expression Regulation
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Glucagon / metabolism
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Glucagon-Like Peptide 1
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Glucose / metabolism
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Glucose Intolerance
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Humans
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Insulin / blood
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Insulin / metabolism
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Insulin Receptor Substrate Proteins
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Insulin-Like Growth Factor I / pharmacology
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Intracellular Signaling Peptides and Proteins
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Islets of Langerhans / metabolism
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Islets of Langerhans / physiology*
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Mice
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Mice, Transgenic
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Peptide Fragments / metabolism
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Phosphoproteins / genetics*
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Phosphoproteins / metabolism*
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Phosphorylation
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Promoter Regions, Genetic
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Protein Precursors / metabolism
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Signal Transduction
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Transfection
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Transgenes
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Tumor Cells, Cultured
Substances
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Cyclic AMP Response Element-Binding Protein
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IRS2 protein, human
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Insulin
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Irs2 protein, mouse
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Peptide Fragments
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Phosphoproteins
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Protein Precursors
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Proto-Oncogene Proteins
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Colforsin
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Insulin-Like Growth Factor I
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Glucagon-Like Peptide 1
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Glucagon
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Cyclic AMP
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Glucose