Genistein Acutely Stimulates Insulin Secretion in Pancreatic β-Cells Through a cAMP-Dependent Protein Kinase Pathway
ABSTRACT Although genistein, a soy isoflavone, has beneficial effects on various tissues, it is unclear whether it plays a role in physiological insulin secretion. Here, we present evidence that genistein increases rapid glucose-stimulated insulin secretion (GSIS) in both insulin-secreting cell lines (INS-1 and MIN6) and mouse pancreatic islets. Genistein elicited a significant effect at a concentration as low as 10 nmol/l with a maximal effect at 5 micromol/l. The effect of genistein on GSIS was not dependent on estrogen receptor and also not related to an inhibition of protein tyrosine kinase (PTK). Consistent with its effect on GSIS, genistein increases intracellular cAMP and activates protein kinase A (PKA) in both cell lines and the islets by a mechanism that does not involve estrogen receptor or PTK. The induced cAMP by genistein, at physiological concentrations, may result primarily from enhanced adenylate cyclase activity. Pharmacological or molecular intervention of PKA activation indicated that the insulinotropic effect of genistein is primarily mediated through PKA. These findings demonstrated that genistein directly acts on pancreatic beta-cells, leading to activation of the cAMP/PKA signaling cascade to exert an insulinotropic effect, thereby providing a novel role of soy isoflavones in the regulation of insulin secretion.
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ABSTRACT: A water-soluble polysaccharide, 7WA, with an average molecular mass of 7.1×10(4)Da, was isolated from the leaves of green tea. Monosaccharide composition analysis indicated that 7WA mainly contained Arabinose and Galactose in the molar ratio of 1.0:0.96. By using the methods of methylation analysis, partial hydrolysis, and NMR, 7WA was characterized to possess a backbone consisting of 1,3- and 1,6-linked galactopyranosyl residues, with branches attached to O-3 of 1,6-linked galactose residues, and O-4 and O-6 of 1,3-linked galactose residues. The results of glucose-stimulated insulin secretion (GSIS) showed that 7WA significantly augmented insulin secretion at high glucose level (25mM), however, such effect was not seen at low glucose level (5mM). The mechanism study results indicated 7WA, a type II arabinogalactan from Green Tea, enhances GSIS through cAMP-PKA pathway. Copyright © 2015 Elsevier Ltd. All rights reserved.Carbohydrate Polymers 06/2015; 124:98-108. DOI:10.1016/j.carbpol.2015.01.070 · 3.92 Impact Factor
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ABSTRACT: 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 further show that exposure of clonal insulin secreting (INS-1E) cells to genistein for 48 h enhanced glucose-stimulated insulin secretion (GSIS), whereas insulin content was not altered, suggesting that genistein-enhanced GSIS is not due to a modulation of insulin synthesis. This genistein effect is protein tyrosine kinase- and K(ATP) channel-independent. In addition, genistein had no effect on glucose transporter-2 expression or cellular ATP production, but similarly augmented pyruvate-stimulated insulin secretion in INS-1E cells, indicating that the improvement of insulin secretory function by long-term genistein exposure is not related to an alternation in glucose uptake or the glycolytic pathway. The enhanced insulin secretion by genistein was associated with elevated intracellular Ca(2+) concentration and dependent on protein kinase A and new protein synthesis as this effect was completely blocked by N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide or cycloheximide. Similarly, 48 h of genistein exposure also enhanced GSIS in freshly isolated mouse and human pancreatic islets, suggesting a non-species-specific and biologically relevant effect. These findings provide evidence that genistein may be a novel bioactive compound that has an anti-diabetic effect by improving insulin secretion from pancreatic beta-cells.European journal of pharmacology 07/2009; 616(1-3):321-7. DOI:10.1016/j.ejphar.2009.06.005 · 2.68 Impact Factor
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ABSTRACT: Diabetic vascular complications are related to a combination of oxidative stress and hyperglycemia. Here we investigate the effect and mechanism of soy isoflavones on oxidative stress-induced endothelial cell injury. Oxidative stress was modeled in primary cultured human umbilical vein endothelial cells by incubation with H(2)O(2) and high glucose. Genistein and daidzein protected the cells against H(2)O(2)-induced apoptosis and their protective actions were abolished by ICI 182780, an estrogen receptor antagonist. The inhibition of cell proliferation by oxidative stress was prevented by genistein and daidzein under normal glucose conditions, but they were less effective at high glucose levels. Genistein and daidzein upregulated the estrogen receptor ERbeta and increased Bcl-2 expression. Silencing of Bcl-2 with siRNA abolished the protection of genistein. Moreover, inhibition of the PI3K and Rho A/Rho kinase pathways by wortmannin and Y-27632 altered the effects of genistein and daidzein on cell survival. We conclude that oxidative stress-induced apoptosis and cell proliferation inhibition can be prevented by soy isoflavones via the regulation of ERbeta and Bcl-2/Bax expression and modulation of cell survival signaling, such as the PI3K pathway. These findings imply that multiple mechanisms are involved in the beneficial effects of soy isoflavone supplements for diabetic endothelial injury.Free Radical Biology and Medicine 05/2009; 47(2):167-75. DOI:10.1016/j.freeradbiomed.2009.04.021 · 5.71 Impact Factor