title: GLP-1(28-36) improves β-cell mass and glucose disposal in streptozotocin-induced diabetic mice and activates cAMP/PKA/β-catenin signaling in β-cells in vitro.
abstract: Recent studies have demonstrated that the COOH-terminal fragment of the incretin hormone glucagon-like peptide-1 (GLP-1), a nonapeptide GLP-1(28-36)amide, attenuates diabetes and hepatic steatosis in diet-induced obese mice. However, the effect of this nonapeptide in pancreatic β-cells remains largely unknown. Here, we show that in a streptozotocin-induced mouse diabetes model, GLP-1(28-36)amide improved glucose disposal and increased pancreatic β-cell mass and β-cell proliferation. An in vitro investigation revealed that GLP-1(28-36)amide stimulates β-catenin (β-cat) Ser(675) phosphorylation in both the clonal INS-1 cell line and rat primary pancreatic islet cells. In INS-1 cells, the stimulation was accompanied by increased nuclear β-cat content. GLP-1(28-36)amide was also shown to increase cellular cAMP levels, PKA enzymatic activity, and cAMP response element-binding protein (CREB) and cyclic AMP-dependent transcription factor-1 (ATF-1) phosphorylation. Furthermore, GLP-1(28-36)amide treatment enhanced islet insulin secretion and increased the growth of INS-1 cells, which was associated with increased cyclin D1 expression. Finally, PKA inhibition attenuated the effect of GLP-1(28-36)amide on β-cat Ser(675) phosphorylation and cyclin D1 expression in the INS-1 cell line. We have thus revealed the beneficial effect of GLP-1(28-36)amide in pancreatic β-cells in vitro and in vivo. Our observations suggest that GLP-1(28-36)amide may exert its effect through the PKA/β-catenin signaling pathway.
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institutes, University Health Network, Toronto, Ontario, Canada;
authors.forename: Weijuan
authors.initials: W
authors.lastname: Shao
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Wang
authors.forename: Wilfred
authors.initials: W
authors.lastname: Ip
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Chiang
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Xiong
authors.forename: Tuanyao
authors.initials: T
authors.lastname: Chai
authors.forename: Catherine
authors.initials: C
authors.lastname: Xu
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
authors.forename: Tianru
authors.initials: T
authors.lastname: Jin
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015195:Drug Design; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology*; D064546:Protein Kinase C beta / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D001786:Blood Glucose; D010446:Peptide Fragments; C560057:glucagon-like peptide-1(28-36)amide; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D064546:Protein Kinase C beta
keywords: Wnt; bromodeoxyuridine; cAMP response element-binding protein; glucagon-like peptide-1; insulin; protein kinase A