Phytochemical Genistein Promotes Beta Cell Survival, Insulin Secretory Function and Ameliorates Hyperglycemia in Streptozotocin Induced Diabetic Mice.

Fu, Zhuo; Liu, Dongmin

Loss of beta-cell mass and function caused by apoptosis is central to the development of type I diabetes. Therefore, finding a strategy to promote islet beta-cell survival is extremely important to delay or prevent the onset of type 1 diabetes. We recently found that genistein, a plant-derived natural compound, is a novel cAMP signaling agonist in pancreatic beta-cells. In the present study, we show that incubation of clonal beta-cells (INS1E) with genistein (5µM) increased cell viability by 35 ±6%, 56±6%, and 57±13% in the presence of cytokines (IL-1β, TNF-α, and INF-γ), actinomycin D or cycloheximide, respectively, as determined by resazurin reduction-based assay. We further demonstrated that genistein promoted the cell viability and reduced caspase-3 activity in cultured human islets. Genistein significantly induced Bc1-2 promoter activity and protein expression in beta-cells as determined by luciferase reporter gene assay and Western blotting, respectively, with a maximal effect at 1-5 µM genistein. In association with this effect, exposure of INS1E cells to genistein for 48 hours augmented rapid insulin secretion stimulated by glucose (20 mM), pyruvate or potassium chloride, while the insulin content was not altered. The induced insulin secretion by genistein was dependent on the cAMP signaling and protein synthesis as this effect was completely blocked by SQ22536, H89 or cycloheximide. Similarly, genistein also enhanced glucose-stimulated insulin secretion in cultured mouse and human islets, suggesting a non-species-specific and biologically relevant effect. Animal study shows that dietary supplementation of genistein significantly ameliorated hyperglycemia in multiple low doses of Streptozotocin (STZ) induced diabetic mice. By the 21st day after STZ injection, 87.5% of STZ-alone-treated mice became diabetic, whereas only 12.5% were diabetic in the STZ- and genistein-treated group. Accordingly, genistein prevented STZ induced body weight loss without altering food intake in diabetic mice. These findings provide evidence that genistein may be a novel bioactive compound that has anti-diabetic effect by inhibiting pancreatic beta-cell apoptosis and improving its function.

PHYTOCHEMICALS; PANCREATIC beta cells; INSULIN; HYPERGLYCEMIA; STREPTOZOTOCIN; DIABETES; LABORATORY mice

Diabetes, 2007, Vol 56, pA415

0012-1797

Academic Journal