Genistein Acutely Stimulates Insulin Secretion in Pancreatic -Cells Through a cAMP-Dependent Protein Kinase Pathway

Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA.
Diabetes (Impact Factor: 8.1). 05/2006; 55(4):1043-50. DOI: 10.2337/diabetes.55.04.06.db05-1089
Source: PubMed


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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    • "Instead, this insulinotropic effect of genistein was shown to primarily rely on an increase in intracellular cAMP and thus an activation of PKA suggesting that this isoflavone directly targets pancreatic b-cells (Liu et al. 2006). Daidzein (2.5 lM), an analogue of genistein that does not inhibit PTK, also significantly increased GIIS and PKA activity, albeit not as potently as genistein (Liu et al. 2006). A few years later, Lee et al. (2009b) reported that genistein potentiated insulin secretion following the stimulation of INS-1 cells with various energy-generating nutrients such as leucine/glutamine (Leu/Gln). "
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    ABSTRACT: Diabetes mellitus is a complex metabolic disorder and is considered a fast-growing global health problem. Type 2 diabetes (T2D) represents the majority of total diabetes prevalence and β-cell dysfunction has been described as a crucial point for this disease development and progression. To date, all of the common anti-hyperglycaemic drugs used for diabetes management cause undesirable side effects or problems with long-term efficacy or safety and the development of alternative approaches for the prevention as well as for the treatment of T2D might be a valuable solution to meet this rising demand. In this regards, numerous epidemiological studies indicate that exposure to certain polyphenol compounds is associated with the prevention of chronic diseases, including diabetes. Here, we review growing evidence suggesting that polyphenols can modulate the activity of various molecular targets, which are known to control β-cell function, involved in the development and the progression of this diabetes. The protective effects of polyphenols on β-cell function is reported with a particular focus on the mechanism of action behind polyphenol putative bioactivity. Animal and in vitro studies selected in this review, reporting about both flavonoid and non-flavonoid compounds, highlight the direct action of polyphenols on pancreatic β-cells, stimulating insulin secretion through the activation of specific cellular targets and protecting these cells from damages mediated by oxidative stress and inflammation, both typically elevated in diabetes. Some of the reviewed studies describe polyphenol effects comparable to those exerted by many drugs commonly used in diabetes treatment, and, in some occasions, synergistic polyphenol-drug interactions. Finally, future studies need to be addressed to the effects of specific polyphenol human and microbial metabolites, which are still poorly studied, in order to better define the preventive and therapeutic approach to contrast β-cell failure and diabetes progression.
    Phytochemistry Reviews 07/2015; 14(6). DOI:10.1007/s11101-015-9429-x · 2.41 Impact Factor
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    • "The results of mRNA and western blotting showed that 7WA-induced enhancement of GSIS is mediated, at least partially, by the cAMP-PKA dependent pathway. Therefore, to examine which pathway(s) is involved in 7WA-induced enhancement of GSIS, RIN-5F cells were pretreated with 10 ␮mol/L SQ22536 (an AC inhibitor) (Liu et al., 2006 "
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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 · 4.07 Impact Factor
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    • "Likewise, polyphenols have the potential to trigger phosphatidylinositide 3-kinase (PI3K), an intracellular signal transducer for the upregulation of blood glucose uptake (Kumar et al., 2009). The antihyperglycemic effect of genistein did not correlate with induction of insulin biosynthesis, glucose transporter-2 expression, or glycolytic pathway, rather than it acts as a novel agonist in cAMP-dependent protein kinase signaling, which is an important physiological inducer of pancreatic b-cells for glucose-induced insulin secretion (Liu et al., 2006). Genistein, an isoflavone, demonstrated antidiabetic effect by positively harmonizing the pancreatic b-cell functions through activation of cyclic AMP/PKA-dependent ERK1/2 signaling pathway (Fu et al., 2010). "
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    ABSTRACT: Context: Polyphenol-rich marine macroalgae are gaining dietary importance due to their influence over diabetes mellitus and the role as a vital source of high-value nutraceuticals. Their assorted beneficial effects on human health include competitive inhibition of digestive enzymes, varying the activity of hepatic glucose-metabolizing enzymes, lowering the plasma glucose levels, and lipid peroxidation, delaying the aging process. Objective: In this paper, we review the health beneficial effects of polyphenols and phlorotannins from brown seaweeds with special emphasis on their inhibitory effects on carbohydrate-metabolizing enzymes. Methods: A survey of literature from databases such as Sciencedirect, Scopus, Pubmed, Springerlink, and Google Scholar from the year 1973 to 2013 was done to bring together the information relating to drug discovery from brown seaweeds as a source for diabetes treatment. Results: Over the past two decades, 20 different bioactive polyphenols/phlorotannins have been isolated and studied from 10 different brown algae. Discussion of the positive effect on the inhibition of enzymes metabolizing carbohydrates in both in vitro and in vivo experiments are included. Conclusion: Despite the recent advancements in isolating bioactive compounds from seaweeds with potential health benefit or pharmaceutical behavior, studies on the polyphenol effectiveness on glucose homeostasis in human beings are very few in response to their functional characterization. Added research in this area is required to confirm the close connection of polyphenol rich seaweed-based diet consumption with glucose homeostasis and the exciting possibility of prescribing polyphenols to treat the diabetes pandemic.
    Pharmaceutical Biology 01/2015; 53(8). DOI:10.3109/13880209.2014.959615 · 1.24 Impact Factor
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