title: Durable islet effects on insulin secretion and protein kinase A expression following exendin-4 treatment of high-fat diet-fed mice.
abstract: Glucagon-like peptide 1 (GLP-1) augments glucose-stimulated insulin secretion (GSIS) through cAMP-induced activation of protein kinase A (PKA), and stimulates beta-cell proliferation and reduces beta-cell apoptosis in rodent islets. This study explored islet GSIS, PKA expression, and markers of apoptosis (caspase 3/7 activity) and proliferation (PKBalpha and pancreatic and duodenal homeobox gene 1, Pdx-1) after 2 weeks of treatment with the GLP-1 receptor agonist exendin-4 (2 nmol/kg once daily) in female mice with high-fat diet-induced insulin resistance (HFD; 58% fat by energy). Islets were isolated 20 h after the last exendin-4 injection, when effects of circulating exendin-4 had vanished. The glucose responsiveness in islets from HFD-fed mice at 8.3 mM glucose was reduced compared with islets from control mice fed a normal diet due to increased basal insulin secretion. However, GSIS increased in islets from HFD-fed exendin-4-treated animals (0.124+/-0.012 ng/h per islet in HFD-Ex-4 versus 0.062+/-0.010 in HFD, P=0.006). Furthermore, the insulin response to forskolin was increased (2.7+/-0.3 in HFD-Ex-4 versus 2.0+/-0.2 ng/h per islet in HFD, P=0.011) and PKAcat expression was increased, while PKAreg was reduced in islets from exendin-4-treated mice. In contrast, protein expression of PKBalpha, Pdx-1, and caspase 3/7 activity was not affected by exendin-4 treatment. We conclude that GLP-1 receptor activation in HFD-fed mice has durable effects on GSIS, in association with augmented signaling through the PKA pathway. These effects are seen beyond those induced by circulating exendin-4 already after 2 weeks of once-daily treatment in mice, whereas markers for islet proliferation and apoptosis were unaffected by this treatment.
authors.affiliation: Division of Medicine, Department of Clinical Sciences, Lund University, BMC, B11, SE-221 84 Lund, Sweden. maria.sorhede_winzell@med.lu.se
authors.forename: Maria Sörhede
authors.initials: MS
authors.lastname: Winzell
authors.forename: Bo
authors.initials: B
authors.lastname: Ahrén
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose; D001835:Body Weight / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004032:Diet; D000077270:Exenatide; D005227:Fatty Acids / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D010477:Perfusion; D014688:Venoms / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D005227:Fatty Acids; D007328:Insulin; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; D017868:Cyclic AMP-Dependent Protein Kinases; D053148:Caspase 3; D053179:Caspase 7