Pancreatic β-cell dysfunction plays an important role in the pathogenesis of both type 1 and type 2 diabetes. Insulin, which is produced in β-cells, is a critical regulator of metabolism. Insulin is synthesized as preproinsulin and processed to proinsulin. Proinsulin is then converted to insulin and C-peptide and stored in secretary granules awaiting release on demand. Insulin synthesis is regulated at both the transcriptional and translational level. The cis-acting sequences within the 5′ flanking region and trans-activators including paired box gene 6 (PAX6), pancreatic and duodenal homeobox-1(PDX-1), MafA, and B-2/Neurogenic differentiation 1 (NeuroD1) regulate insulin transcription, while the stability of preproinsulin mRNA and its untranslated regions control protein translation. Insulin secretion involves a sequence of events in β-cells that lead to fusion of secretory granules with the plasma membrane. Insulin is secreted primarily in response to glucose, while other nutrients such as free fatty acids and amino acids can augment glucose-induced insulin secretion. In addition, various hormones, such as melatonin, estrogen, leptin, growth hormone, and glucagon like peptide-1 also regulate insulin secretion. Thus, the β-cell is a metabolic hub in the body, connecting nutrient metabolism and the endocrine system. Although an increase in intracellular [Ca2+] is the primary insulin secretary signal, cAMP signaling-dependent mechanisms are also critical in the regulation of insulin secretion. This article reviews current knowledge on how β-cells synthesize and secrete insulin. In addition, this review presents evidence that genetic and environmental factors can lead to hyperglycemia, dyslipidemia, inflammation, and autoimmunity, resulting in β-cell dysfunction, thereby triggering the pathogenesis of diabetes.

Flavonoids are polyphenolic compounds that are abundant in fruits and vegetables and increasing evidence demonstrates a positive relationship between consumption of flavonoid-rich foods and disease prevention. Epidemiological, in vitro and animal studies support the beneficial effects of dietary flavonoids on glucose and lipid homeostasis. It is encouraging that the beneficial effects of some flavonoids are at physiological concentrations and comparable to clinically-used anti-diabetic drugs; however, clinical research in this field and studies on the anti-diabetic effects of flavonoid metabolites are limited. Flavonoids act on various molecular targets and regulate different signaling pathways in pancreatic β-cells, hepatocytes, adipocytes, and skeletal myofibers. Flavonoids may exert beneficial effects in diabetes by (i) enhancing insulin secretion and reducing apoptosis and promoting proliferation of pancreatic β-cells, (ii) improving hyperglycemia through regulation of glucose metabolism in hepatocytes, (iii) reducing insulin resistance, inflammation and oxidative stress in muscle and fat, and (iv) increasing glucose uptake in skeletal muscle and white adipose tissue. This review highlights recent findings on the anti-diabetic effects of dietary flavonoids, including flavan-3-ols, flavanones, flavonols, anthocyanidins, flavones, and isoflavones, with particular emphasis on the studies that investigated the cellular and molecular mechanisms involved in the beneficial effects of the compounds.

The adrenal steroid dehydroepiandrosterone (DHEA) has no known cellular receptor or unifying mechanism of action, despite evidence suggesting beneficial vascular effects in humans. Based on previous data from our laboratory, we hypothesized that DHEA binds to specific cell-surface receptors to activate intracellular Gproteins and endothelial nitric-oxide synthase (eNOS). We now pharmacologically characterize a putative plasma membrane DHEA receptor and define its associated G-proteins. The physiological role of the adrenal steroid dehydroepiandrosterone (DHEA) 1 is not known. There are widespread data suggesting a beneficial effect of DHEA on vascular function. Extensive epidemiologic evidence shows an inverse correlation between circulating DHEA levels and the prevalence of atherosclerotic and cardiovascular diseases (1-5). There are few human intervention studies focused on vascular outcomes of DHEA administration, and these are not of a size or duration to define whether DHEA therapy has an effect on cardiovascular morbidity or mortality. Available studies do suggest a beneficial effect on atherosclerosis (6). Studies of the short term effect of DHEA on human vascular function, using sophisticated assays of vascular function, are beginning to emerge. Williams et al. (7) showed a significant increase in flow-mediated dilatation and systemic arterial compliance in postmenopausal women taking DHEA for 3 months. DHEA reduces atherosclerosis, decreases the accumulation of cholesterol in aortic and coronary arteries (8, 9), and inhibits platelet aggregation (10) in various animal models. DHEA also affects growth factor-induced mitogenesis and proliferation of vascular smooth muscle cells (11-13). However, the molecular mechanisms by which DHEA acts to protect from atherosclerotic and cardiovascular diseases are still unknown. Furthermore, it is unclear whether the effect on vascular tissues is related to DHEA or to its metabolites, which include estradiol.Steroid hormones are known to bind specific intracellular receptors, which function as ligand-dependent gene transcription factors (14). However, previous efforts to isolate an intracellular receptor for DHEA have failed (15-18). In contrast to this classical pathway of steroid hormone action, there are also rapid, plasma membrane-dependent, non-genomic effects of steroids in various tissues, which lead to important physiological responses (19 -24). Plasma membrane-associated receptors are postulated to mediate these non-genomic actions of steroids. Functional plasma membrane binding sites have been identified for several steroids, including estrogen, vitamin D, and progesterone (25-28). However, besides the receptor for estrogen, no plasma membrane steroid receptor has yet been unequivocally identified and characterized.We have found that DHEA stimulates nitric oxide (NO) generation within minutes from bovine aortic endothelial cells (BAEC).2 Furthermore, DHEA conjugated to bovine serum albumin (BSA) had similar effects. These cellular responses to DHEA were spe...

Genistein, a flavonoid in legumes and some herbal medicines, has various biological actions. However, studies on whether genistein has an effect on pancreatic beta-cell function are very limited. In the present study, we investigated the effect of genistein on beta-cell proliferation and cellular signaling related to this effect and further determined its antidiabetic potential in insulin-deficient diabetic mice. Genistein induced both INS1 and human islet beta-cell proliferation after 24 h of incubation, with 5 mum genistein inducing a maximal 27% increase. The effect of genistein on beta-cell proliferation was neither dependent on estrogen receptors nor shared by 17beta-estradiol or a host of structurally related flavonoid compounds. Pharmacological or molecular intervention of protein kinase A (PKA) or ERK1/2 completely abolished genistein-stimulated beta-cell proliferation, suggesting that both molecules are essential for genistein action. Consistent with its effect on cell proliferation, genistein induced cAMP/PKA signaling and subsequent phosphorylation of ERK1/2 in both INS1 cells and human islets. Furthermore, genistein induced protein expression of cyclin D1, a major cell-cycle regulator essential for beta-cell growth. Dietary intake of genistein significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in streptozotocin-induced diabetic mice, concomitant with improved islet beta-cell proliferation, survival, and mass. These results demonstrate that genistein may be a natural antidiabetic agent by directly modulating pancreatic beta-cell function via activation of the cAMP/PKA-dependent ERK1/2 signaling pathway.

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