title: Feedback inhibition of CREB signaling promotes beta cell dysfunction in insulin resistance.
abstract: Although persistent elevations in circulating glucose concentrations promote compensatory increases in pancreatic islet mass, unremitting insulin resistance causes deterioration in beta cell function that leads to the progression to diabetes. Here, we show that mice with a knockout of the CREB coactivator CRTC2 in beta cells have impaired oral glucose tolerance due to decreases in circulating insulin concentrations. CRTC2 was found to promote beta cell function in part by stimulating the expression of the transcription factor MafA. Chronic hyperglycemia disrupted cAMP signaling in pancreatic islets by activating the hypoxia inducible factor (HIF1)-dependent induction of the protein kinase A inhibitor beta (PKIB), a potent inhibitor of PKA catalytic activity. Indeed, disruption of the PKIB gene improved islet function in the setting of obesity. These results demonstrate how crosstalk between nutrient and hormonal pathways contributes to loss of pancreatic islet function.
authors.affiliation: Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Emilie
authors.initials: E
authors.lastname: Blanchet
authors.affiliation: Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Van de Velde
authors.affiliation: Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Matsumura
authors.affiliation: Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Ergeng
authors.initials: E
authors.lastname: Hao
authors.affiliation: Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Genetics, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5156, USA.
authors.forename: John
authors.initials: J
authors.lastname: LeLay
authors.affiliation: Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Genetics, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5156, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Kaestner
authors.affiliation: Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: montminy@salk.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Montminy
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005951:Glucose Tolerance Test; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D051473:Maf Transcription Factors, Large / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: C492004:Creb1 protein, mouse; C504923:Crtc2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D051793:Hypoxia-Inducible Factor 1; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D014157:Transcription Factors; D000242:Cyclic AMP