title: mTOR links incretin signaling to HIF induction in pancreatic beta cells.
abstract: Under feeding conditions, the incretin hormone GLP-1 promotes pancreatic islet viability by triggering the cAMP pathway in beta cells. Increases in PKA activity stimulate the phosphorylation of CREB, which in turn enhances beta cell survival by upregulating IRS2 expression. Although sustained GLP-1 action appears important for its salutary effects on islet function, the transient nature of CREB activation has pointed to the involvement of additional nuclear factors in this process. Following the acute induction of CREB-regulated genes, cAMP triggers a second delayed phase of gene expression that proceeds via the HIF transcription factor. Increases in cAMP promote the accumulation of HIF1α in beta cells by activating the mTOR pathway. As exposure to rapamycin disrupts GLP-1 effects on beta cell viability, these results demonstrate how a pathway associated with tumor growth also mediates salutary effects of an incretin hormone on pancreatic islet function.
authors.affiliation: The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Van de Velde
authors.forename: Meghan F
authors.initials: MF
authors.lastname: Hogan
authors.forename: Marc
authors.initials: M
authors.lastname: Montminy
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D054795:Incretins / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D054795:Incretins; D055504:Insulin Receptor Substrate Proteins; C526299:Irs2 protein, rat; D034741:RNA, Small Interfering; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases