PMID:18234911
| Citation |
Winzell, MS and Ahrén, B (2008) Durable islet effects on insulin secretion and protein kinase A expression following exendin-4 treatment of high-fat diet-fed mice. J. Mol. Endocrinol. 40:93-100 |
|---|---|
| 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. |
| Links |
PubMed Online version:10.1677/JME-07-0121 |
| Keywords |
Animals; Apoptosis/drug effects; Biological Markers/metabolism; Blood Glucose; Body Weight/drug effects; Caspase 3/metabolism; Caspase 7/metabolism; Cell Proliferation/drug effects; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/metabolism; Cyclic AMP-Dependent Protein Kinases/metabolism; Diet; Fatty Acids/administration & dosage; Fatty Acids/pharmacology; Female; Insulin/secretion; Islets of Langerhans/cytology; Islets of Langerhans/drug effects; Islets of Langerhans/enzymology; Islets of Langerhans/secretion; Mice; Mice, Inbred C57BL; Peptides/administration & dosage; Peptides/pharmacology; Perfusion; Venoms/administration & dosage; Venoms/pharmacology |
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