BACKGROUND AND PURPOSEQuercetin lowers plasma glucose, normalizes glucose tolerance tests and preserves pancreatic b-cell integrity in diabetic rats. However, its mechanism of action has never been explored in insulin-secreting b-cells. Using the INS-1 b-cell line, the effects of quercetin were determined on glucose-or glibenclamide-induced insulin secretion and on b-cell dysfunctions induced by hydrogen peroxide (H2O2). These effects were analysed along with the activation of the extracellular signal-regulated kinase (ERK)1/2 pathway. N-acetyl-L-cysteine (NAC) and resveratrol, two antioxidants also known to exhibit some anti-diabetic properties, were used for comparison. EXPERIMENTAL APPROACHInsulin release was quantified by the homogeneous time resolved fluorescence method and ERK1/2 activation tested by Western blot experiments. Cell viability was estimated by the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) colorimetric assay. KEY RESULTSQuercetin (20 mmol·L ), protected b-cell function and viability against oxidative damage induced by 50 mmol·L -1 H2O2 and induced a major phosphorylation of ERK1/2. In the same conditions, resveratrol or NAC were ineffective. CONCLUSION AND IMPLICATIONSQuercetin potentiated glucose and glibenclamide-induced insulin secretion and protected b-cells against oxidative damage. Our study suggested that ERK1/2 played a major role in those effects. The potential of quercetin in preventing b-cell dysfunction associated with diabetes deserves further investigation.

We previously showed that grape extracts enriched in different polyphenolic families were similarly able to prevent reactive oxygen species (ROS) production, although having differential effects on various features of metabolic syndrome when administered at a dose of 21 mg/kg to the fructose (60%)-fed rat (a model of metabolic syndrome). In the present work, we analyzed on the same model the effect of pure polyphenolic molecules (catechin, resveratrol, delphinidin, and gallic acid) administered at a dose of 2.1 mg/kg. Delphinidin and gallic acid prevented insulin resistance, while gallic acid prevented the elevation of blood pressure. All molecules prevented cardiac ROS overproduction and NADPH overexpression. We also showed that fructose feeding was associated with cardiac fibrosis (accumulation of collagen I) and expression of osteopontin, a factor induced by ROS and a collagen I expression inducer. Collagen I and osteopontin expressions were prevented by the administration of all polyphenolic molecules. The potential use of polyphenols in the prevention of cardiac fibrosis should be further explored.

Background and Purpose The pharmacology of polyphenol metabolites on beta‐cell function is largely undetermined. We sought to identify polyphenol metabolites that enhance the insulin‐secreting function of beta‐cells and to explore the underlying mechanisms. Experimental Approach INS‐1 beta‐cells and rat isolated islets of Langerhans or perfused pancreas preparations were used for insulin secretion experiments. Molecular modelling, intracellular Ca2+ monitoring, and whole‐cell patch‐clamp recordings were used for mechanistic studies. Key Results Among a set of polyphenol metabolites, we found that exposure of INS‐1 beta‐cells to urolithins A and C enhanced glucose‐stimulated insulin secretion. We further characterized the activity of urolithin C and its pharmacological mechanism. Urolithin C glucose‐dependently enhanced insulin secretion in isolated islets of Langerhans and perfused pancreas preparations. In the latter, enhancement was reversible when glucose was lowered from a stimulating to a non‐stimulating concentration. Molecular modelling suggested that urolithin C could dock into the Cav1.2 L‐type Ca2+ channel. Calcium monitoring indicated that urolithin C had no effect on basal intracellular Ca2+ but enhanced depolarization‐induced increase in intracellular Ca2+ in INS‐1 cells and dispersed cells isolated from islets. Electrophysiology studies indicated that urolithin C dose‐dependently enhanced the L‐type Ca2+ current for levels of depolarization above threshold and shifted its voltage‐dependent activation towards more negative potentials in INS‐1 cells. Conclusion and Implications Urolithin C is a glucose‐dependent activator of insulin secretion acting by facilitating L‐type Ca2+ channel opening and Ca2+ influx into pancreatic beta‐cells. Our work paves the way for the design of polyphenol metabolite‐inspired compounds aimed at ameliorating beta‐cell function.