title: Dipeptidyl peptidase-4 inhibition in diabetic rats leads to activation of the transcription factor CREB in β-cells.
abstract: Incretin therapies are effective in controlling blood glucose levels in type 2 diabetic patients by improving the survival and function of β-cells. They include dipeptidyl peptidase-4 (DPP-4) inhibitors and long-acting glucagon-like peptide-1 (GLP-1) analogs. We have previously reported that GLP-1 enhances the survival of cultured human islets by activation of the transcription factor CREB. To test the in vivo relevance of these findings, we examined the effects of alogliptin, a DPP-4 inhibitor, in Zucker Diabetic rats, a model for type 2 diabetes. The plasma levels of GLP-1 increased in alogliptin-treated diabetic rats leading to normoglycemia. Pancreatic islets of untreated diabetic rats were characterized by decreased immunostaining for insulin and PDX-1. Elevation of GLP-1 in treated diabetic rats resulted in the improved survival of β-cells. Dual immunofluorescent staining showed phosphorylation/activation of CREB in insulin-positive β-cells of islets. This led to increases in the levels of CREB targets including Bcl-2, an antiapoptotic mitochondrial protein, BIRC3, a caspase inhibitor and IRS-2, an adapter protein needed for insulin signaling. Findings from this study suggest potential activation of cytoprotective CREB by GLP-1 in pancreatic β-cells of diabetic patients undergoing incretin-based therapies.
authors.affiliation: Veterans Affairs Medical Center, Denver, CO, United States; Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States. Electronic address: subbiah.pugazhenthi@ucdenver.edu.
authors.forename: Subbiah
authors.initials: S
authors.lastname: Pugazhenthi
authors.affiliation: Veterans Affairs Medical Center, Denver, CO, United States.
authors.forename: LiMei
authors.initials: L
authors.lastname: Qin
authors.affiliation: Veterans Affairs Medical Center, Denver, CO, United States; Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Ron
authors.initials: R
authors.lastname: Bouchard
mesh_terms: D000818:Animals; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001786:Blood Glucose / Q000032:analysis; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011924:Rats, Zucker; D014280:Triglycerides / Q000097:blood; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D017362:Cyclic AMP Response Element-Binding Protein; D054873:Dipeptidyl-Peptidase IV Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C491584:Irs3 protein, rat; D010880:Piperidines; D019253:Proto-Oncogene Proteins c-bcl-2; D014280:Triglycerides; D014498:Uracil; D052216:Glucagon-Like Peptide 1; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494836:Birc3 protein, rat; C520853:alogliptin
keywords: CREB and β-cells; Diabetes; Dipeptidyl peptidase-4; GLP-1; Insulin