| Summary: | In type 2 diabetes (T2D), insufficient secretion of insulin from the pancreatic β-cells contributes to high blood glucose levels, associated with metabolic dysregulation. Interest in natural products to complement or replace existing antidiabetic medications has increased. In this study, we examined the effect of <i>Astragalus membranaceus</i> extract (ASME) and its compounds <b>1</b>−<b>9</b> on glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. ASME and compounds <b>1</b>−<b>9</b> isolated from <i>A. membranaceus</i> stimulated insulin secretion in INS-1 cells without inducing cytotoxicity. A further experiment showed that compounds <b>2</b>, <b>3</b>, and <b>5</b> enhanced the phosphorylation of total insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), and Akt, and activated pancreatic and duodenal homeobox-1 (PDX-1) and peroxisome proliferator-activated receptor-γ (PPAR-γ), which are associated with β-cell function and insulin secretion. The data suggest that two isoflavonoids (<b>2</b> and <b>3)</b> and a nucleoside (compound <b>5</b>), isolated from the roots of <i>A. membranaceus</i>, have the potential to improve insulin secretion in β-cells, representing the first step towards the development of potent antidiabetic drugs.
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