T. improves ␤-cell mass and glucose disposal in streptozotocin-induced diabetic mice and activates cAMP/PKA/␤-catenin signaling in ␤-cells in vitro. Recent studies have demonstrated that the COOH-terminal fragment of the incretin hormone glucagonlike 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 ␤-cells remains largely unknown. Here, we show that in a

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... induced mouse diabetes model, GLP-1(28 -36)amide improved glucose disposal and increased pancreatic ␤-cell mass and ␤-cell proliferation. An in vitro investigation revealed that GLP-1(28 -36)amide stimulates ␤-catenin (␤-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 ␤-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 ␤-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 ␤-cells in vitro and in vivo. Our observations suggest that GLP-1(28 -36)amide may exert its effect through the PKA/␤-catenin signaling pathway. glucagon-like peptide-1; protein kinase A; Wnt; cAMP response element-binding protein; insulin; bromodeoxyuridine