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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.

Computed tomographic (CT) findings obtained in 53 patients with progressive systemic sclerosis were correlated with functional parameters and bronchoalveolar lavage (BAL) results, and lung changes over time were assessed in 17 patients. CT findings were normal in 21 patients (group 1) with otherwise normal lung function, except for subclinical alveolitis in seven patients. CT depicted pleural and parenchymal abnormalities in 32 patients, grouped according to the absence (group 2) or presence (group 3) of honeycombing. In group 2 (n = 13), mean values of functional parameters were normal, and BAL showed a significant increase in neutrophils compared to group 1 (P < .05). Among patients in group 3 (n = 19) with limited extent of honeycombing (n = 12), the mean diffusing capacity value was lower in patients with a moderate ground-glass profusion score (n = 4) than in those with a mild score (n = 8) (68% +/- 4 [standard error of the mean] vs 80% +/- 3). CT is the method of choice for evaluating parenchymal destruction, and profusion and extent of ground-glass opacities can help in predicting the severity of lung damage in areas devoid of destructive changes.

The p44/p42 MAPKs (ERK1/2) cascade regulates beta-cell nuclear events, which modulates cell differentiation and gene transcription, whereas its implication in processes occurring in the cytoplasm, such as activation of the exocytotic machinery, is still unclear. Using the MIN6 beta-cell line and isolated rat islets of Langerhans, we investigated whether glucose, by activating the ERK1/2 cascade, induces phosphorylation of cytoplasmic proteins implicated in exocytosis of insulin granules such as synapsin I. We observed that the majority of ERK1/2 activity induced by glucose remains in the cytoplasm and physically interacts with synapsin I, allowing phosphorylation of the substrate. Therefore, we reexamined the potential requirement of ERK1/2 for insulin secretion. Blocking activation of ERK1/2 using MEK1/2, the MAPK kinase inhibitor PD98059 or using small interfering RNA-mediated silencing of ERK1 and ERK2 expressions resulted in partial inhibition of glucose-induced insulin release, indicating that ERK1/2 pathway participates also in the regulation of insulin secretion. Moreover, using the pancreatic islet perifusion model, we found that the ERK1/2 activity participates in the first and second phases of insulin release induced by glucose. Taken together, our results demonstrate new aspects of the glucose-dependent actions of ERK1/2 in beta-cells exerted on cytoplasmic proteins, including synapsin I, and participating in the overall glucose-induced insulin secretion.