The flavonoid resokaempferol improves insulin secretion from healthy and dysfunctional pancreatic ß-cells.

BACKGROUND AND PURPOSE: The pharmacology of flavonoids on ß-cell function is largely undefined especially in the context of defective secretion of insulin. We sought to identify flavonoids that increased the insulin-secreting function of ß-cells and to explore the underlying mechanisms. EXPERIMENTAL APPROACH: INS-1 ß-cells in culture and islets of Langerhans isolated from control and diabetic male rats were used for insulin secretion experiments. Pharmacological and electrophysiological approaches were used for mechanistic studies. KEY RESULTS: Among a set of flavonoids, exposure of INS-1 ß-cells to resokaempferol (ResoK) enhanced glucose-stimulated insulin secretion and therefore we further characterised its activity and its pharmacological mechanism. ResoK glucose-dependently enhanced insulin secretion in INS-1 ß-cells and pancreatic islets isolated from rats. Mechanistically, whole cell patch clamp recordings in INS-1 cells showed that ResoK rapidly and dose-dependently enhanced the L-type Ca2+ current whereas it was inactive towards T-type Ca2+ current. Accordingly, pharmacological inhibition of L-type Ca2+ current but not T-type Ca2+ current blocked the effects of ResoK on glucose-stimulated insulin secretion. ResoK was still active on dysfunctional ß-cells as it ameliorated glucose-stimulated insulin secretion in glucotoxicity-induced dysfunctional INS-1 cells and in pancreatic islets isolated from diabetic rats. CONCLUSION AND IMPLICATIONS: ResoK is a glucose-dependent activator of insulin secretion. Our results indicated that the effects of ResoK on insulin secretion involved its capacity to stimulate L-type Ca2+ currents in cultured ß-cells. As ResoK was also effective on dysfunctional ß-cells, our work provides a new approach to stimulating insulin secretion, using compounds based on the structure of ResoK.

Liver-Expressed Antimicrobial Peptide 2 antagonizes the insulinostatic effect of ghrelin in rat isolated pancreatic islets.

The hormone ghrelin is the endogenous agonist of the G protein-coupled receptor (GPCR) termed growth hormone secretagogue receptor (GHSR). Ghrelin inhibits glucose-stimulated insulin secretion by activating pancreatic GHSR. Recently, Liver-Expressed Antimicrobial Peptide 2 (LEAP2) was recognized as an endogenous GHSR ligand that blocks ghrelin-induced actions. Nonetheless, the effect of LEAP2 on glucose-stimulated insulin secretion from pancreatic islets is unknown. We aimed at exploring the activity of LEAP2 on glucose-stimulated insulin secretion. Islets of Langerhans isolated from rat pancreas were exposed to glucose in the presence or in the absence of LEAP2 and ghrelin and then insulin secretion was assayed. LEAP2 did not modulate glucose-stimulated insulin secretion. However, LEAP2 blocked the insulinostatic action of ghrelin. Our data show that LEAP2 behaves as an antagonist of pancreatic GHSR.

Heptafluoroisobutyronitrile (C4F7N), a gas used for insulating and arc quenching in electrical switchgear, is neurotoxic in the mouse brain.

Fluoronitrile gas (C4F7N, CAS number 42532-60-5) is one of the most promising candidates as insulating and/or breaking medium in high and medium voltage electrical equipment. Besides its promising properties, C4F7N gas is however not devoid of acute toxicity when used pure or in gas mixtures. The toxicity was not extensively analyzed and reported. The aim of the present study was to analyze in mice the consequences of a single exposure to C4F7N gas, at different concentrations and different timepoints after exposure. Male and female Swiss mice were exposed to breathable air or C4F7N gas, at 800 ppmv or 1500 ppmv, for 4 h on day 0. Behavioral tests (spontaneous alternation in the Y-maze and object recognition) were performed on days 1, 7 and 14 to assess memory alterations. The animals were then sacrificed and their brains dissected for biochemical analyses or fixed with paraformaldehyde for histology and immunohistochemistry. Results showed behavioral impairments and memory deficits, with impairments of alternation at days 1 and 7 and object recognition at day 14. Histological alterations of pyramidal neuronal layer in the hippocampus, neuroinflammatory astroglial reaction, and microglial alterations were observed, more marked in female than male mice. Moreover, the biochemical analyses done in the brain of 1500 ppmv exposed female mice showed a reductive stress with decreased lipid peroxidation and release of cytochrome c, leading to apoptosis with increases in caspase-9 cleavage and γ-H2AX/H2AX ratio. Finally, electrophysiological analyses using a multi-electrode array allowed the measure of the extracellular activity of pyramidal neurons in the CA2 area and revealed that exposure to the gas not only prevented the induction of long-term potentiation but even provoked an epileptoid-like activity in some neurons suggesting major alterations of synaptic plasticity. This study therefore showed that an acute exposure of mice to C4F7N gas provoked, particularly in female animals, memory alterations and brain toxicity characterized by a reductive stress, microglial toxicity, loss of synaptic plasticity and apoptosis. Its use in industrial installations must be done with extreme caution.

Urolithin C increases glucose-induced ERK activation which contributes to insulin secretion.

Polyphenols exert pharmacological actions through protein-mediated mechanisms and by modulating intracellular signalling pathways. We recently showed that a gut-microbial metabolite of ellagic acid named urolithin C is a glucose-dependent activator of insulin secretion acting by facilitating L-type Ca2+ channel opening and Ca2+ influx into pancreatic ß-cells. However, it is still unknown whether urolithin C regulates key intracellular signalling proteins in ß-cells. Here, we report that urolithin C enhanced glucose-induced extracellular signal-regulated kinases 1/2 (ERK1/2) activation as shown by higher phosphorylation levels in INS-1 ß-cells. Interestingly, inhibition of ERK1/2 with two structurally distinct inhibitors led to a reduction in urolithin C effect on insulin secretion. Finally, we provide data to suggest that urolithin C-mediated ERK1/2 phosphorylation involved insulin signalling in INS-1 cells. Together, these data indicate that the pharmacological action of urolithin C on insulin secretion relies, in part, on its capacity to enhance glucose-induced ERK1/2 activation. Therefore, our study extends our understanding of the pharmacological action of urolithin C in ß-cells. More generally, our findings revealed that urolithin C modulated the activation of key multifunctional intracellular signalling kinases which participate in the regulation of numerous biological processes.

The ellagitannin metabolite urolithin C is a glucose-dependent regulator of insulin secretion through activation of L-type calcium channels.

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 Cav 1.2 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.

Chicoric acid, a new compound able to enhance insulin release and glucose uptake.

Caffeic acid and chlorogenic acid (CGA), a mono-caffeoyl ester, have been described as potential antidiabetic agents. Using in vitro studies, we report the effects of a dicaffeoyl ester, chicoric acid (CRA) purified from Cichorium intybus, on glucose uptake and insulin secretion. Our results show that CRA and CGA increased glucose uptake in L6 muscular cells, an effect only observed in the presence of stimulating concentrations of insulin. Moreover, we found that both CRA and CGA were able to stimulate insulin secretion from the INS-1E insulin-secreting cell line and rat islets of Langerhans. In the later case, the effect of CRA is only observed in the presence of subnormal glucose levels. Patch clamps studies show that the mechanism of CRA and CGA was different from that of sulfonylureas, as they did not close K(ATP) channels. Chicoric acid is a new potential antidiabetic agent carrying both insulin sensitizing and insulin-secreting properties.

Grape Pomace: Antioxidant Activity, Potential Effect Against Hypertension and Metabolites Characterization after Intake.

Observational studies indicate that the intake of polyphenol-rich foods improves vascular health, thereby significantly reducing the risk of hypertension and cardiovascular disease (CVD). Therefore, the aim of this study was to analyse the remained potential of grape by-products from important Rhône Valley red wine cultivars: Grenache, Syrah, Carignan, Mourvèdre and Alicante. For that, six different extracts from grape pomaces, selected by their antioxidant activity, were studied in vivo during six weeks with spontaneously hypertensive rats (SHR). Extracts used in SHR1, SHR2 and SHR6 groups presented a « rebound effect » on systolic blood pressure, whereas the other extracts do not change it significantly. The bioavailability of Grenache (GRE1) (EA70) seed pomace extract (SHR1 group), Mouvendre (MOU) (EA70) skin pomace extract (SHR5 group) and Alicante (ALI) (EA70) skin pomace extract (SHR6 group) was studied by High Performance Liquid Chromatography with Photodiode Array detector and Electrospray Ionization Mass Spectrometer (HPLC-PDA-ESI-MSn) in urine, plasma and tissues to search differences on the metabolism of the different extracts intake.

Effect of Sclerocarya birrea (Anacardiaceae) stem bark methylene chloride/methanol extract on streptozotocin-diabetic rats.

Sclerocarya birrea (Anacardiaceae) is used as a traditional treatment of diabetes in Cameroon. In this study, we investigated the possible antidiabetic effect of the stem bark extract in diabetic rats. Diabetes was induced by intravenous injection of streptozotocin (STZ, 55 mg/kg) to male Wistar rats. Experimental animals (six per group), were treated by oral administration of plant extract (150 and 300 mg/kg body weight) and metformin (500 mg/kg; reference drug) for comparison, during 21 days. The stem bark methanol/methylene chloride extract of Sclerocarya birrea exhibited at termination, a significant reduction in blood glucose and increased plasma insulin levels in diabetic rats. The extract also prevented body weight loss in diabetic rats. The effective dose of the plant extract (300 mg/kg) tended to reduce plasma cholesterol, triglyceride and urea levels toward the normal levels. Four days after diabetes induction, an oral glucose tolerance test (OGTT) was also performed in experimental diabetic rats. The results showed a significant improvement in glucose tolerance in rats treated with Sclerocarya birrea extract. Metformin, a known antidiabetic drug (500 mg/kg), significantly decreased the integrated area under the glucose curve. These data indicate that Sclerocarya birrea treatment may improve glucose homeostasis in STZ-induced diabetes which could be associated with stimulation of insulin secretion.

Development and validation of a liquid chromatography-electrospray ionization-tandem mass spectrometry method for the determination of urolithin C in rat plasma and its application to a pharmacokinetic study.

Urolithins are microflora human metabolites of dietary ellagic acid derivatives. There is now a growing interest in the biological activities of these compounds. Several studies suggest that urolithins have potential antioxidant, anti-inflammatory, anticancer and anti-glycative activities. Recently, our group investigated the role of urolithins as potential anti-diabetic treatments; among the four urolithins, urolithin C was the most promising compound. The purpose of this paper was to develop a rapid, sensitive and specific liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method for the determination of urolithin C in rat plasma. To date, no method is reported for the quantification of urolithin C in any of the matrices. Plasma samples were extracted with ethyl acetate. Urolithin D was selected as the internal standard. The separation was carried out on a C18 Kinetex EVO column (2.1mm×150mm, 2.6µm) using a mobile phase of acetonitrile-1% aqueous formic acid solution (30:70, v/v). A triple quadrupole mass spectrometer in the negative ion mode was used for the determination of the target analyte. The monitored ion transitions were m/z 243→187 for urolithin C and m/z 259→213 for the internal standard. The calibration curve range was 4.95-1085µg/L (r2>0.994). The intra- and inter-day precisions were less than 10%; accuracies ranged from 96.6 to 109%. The mean extraction recovery of urolithins C and D was greater than 91%. No significant matrix effects and no carryover effects were observed. Small changes in LC-ESI-MS/MS conditions did not have significant effect on the determination of urolithin C. Stability tests under various conditions were also investigated. This highly specific and sensitive method was used to analyze samples collected during preclinical pharmacokinetic studies in rats. Glucuronyl and sulfate conjugates of urolithin C were the main metabolites detected in plasma.

Involvement of oxidative stress and NADPH oxidase activation in the development of cardiovascular complications in a model of insulin resistance, the fructose-fed rat.

Growing evidences suggest a role of oxidative stress in hypertension and cardiac hypertrophy. The fructose (60%)-fed rat represents a model of metabolic syndrome, associating insulin resistance and high blood pressure. In this model, hypertension, cardiac and vessels hypertrophy and markers of oxidative stress were determined. In addition, the production of reactive oxygen species (ROS) was evaluated at different times after the initiation of fructose-enriched diet in aorta, heart and polymorphonuclear cells. High fructose feeding was associated with an early (1-week) increase in ROS production by aorta, heart and circulatory polymorphonuclear cells, in association with enhanced markers of oxidative stress. Vascular and cardiac hypertrophy was also rapidly observed, while the rise in blood pressure was significant only after 3 weeks. In summary, our study suggests that the production of reactive oxygen species can be a key-event in the initiation and development of cardiovascular complications associated with insulin resistance.

Extracts enriched in different polyphenolic families normalize increased cardiac NADPH oxidase expression while having differential effects on insulin resistance, hypertension, and cardiac hypertrophy in high-fructose-fed rats.

Insulin resistance and oxidative stress act synergistically in the development of cardiovascular complications. The present study compared the efficacy of three polyphenolic extracts in their capacity to prevent hypertension, cardiac hypertrophy, increased production of reactive oxygen species (ROS) by the aorta or the heart, and increased expression of cardiac NAD(P)H oxidase in a model of insulin resistance. Rats were fed a 60%-enriched fructose food and were treated once a day (gavage) for 6 weeks with 10 mL/kg of water only (F group) or the same amount of solution containing a red grape skin polyphenolic extract enriched in anthocyanins (ANT), a grape seed extract enriched in procyanidins and rich in galloylated procyanidins (PRO), or the commercial preparation Vitaflavan (VIT), rich in catechin oligomers. All treatments were administered at the same dose of 21 mg/kg of polyphenols. Our data indicate that (a) the ANT treatment prevented hypertension, cardiac hypertrophy, and production of ROS, (b) the PRO treatment prevented insulin resistance, hypertriglyceridemia, and overproduction of ROS but had only minor effects on hypertension or hypertrophy, while (c) Vitaflavan prevented hypertension, cardiac hypertrophy, and overproduction of ROS. All polyphenolic treatments prevented the increased expression of the p91phox NADPH oxidase subunit. In summary, our study suggest that (a) the pathogeny of cardiac hypertrophy in the fructose-fed rat disease involves both hypertension and hyperproduction of ROS, (b) polyphenolic extracts enriched in different types of polyphenols possess differential effects on insulin resistance, hypertension, and cardiac hypertrophy, and (c) polyphenols modulate the expression of NAD(P)H oxidase.

Effect of a polyphenols-enriched chardonnay white wine in diabetic rats.

A Chardonnay white wine enriched in polyphenols was obtained by modification of winemaking and characterized by its enrichment in total polyphenolic content (1346 mg/L as compared to 316 mg/L for traditional Chardonnay) and in various individual polyphenols (catechin, epicatechin, procyanidins dimers B1-B4, gallic acid, cafeic acid, and caftaric acid), as determined from HPLC coupled to a diode array detector. The polyphenols-enriched white wine (W) or its ethanol-free derivative (EFW) was then administered by gavage (10 mL/kg, twice a day) for 6 weeks to rats that have been rendered diabetic by a single iv injection of streptozotocin (55 mg/kg). Treatments had no effect on the symptoms associated with hyperglycemia. However, while a reduction in plasma antioxidant capacity was associated with the diabetic state, administration of W or EFW restored plasma antioxidant capacities to a level not significantly different from that of nondiabetic control animals. In addition, the effect of both treatments was manifested by the enlargement of mesenteric arteries, as determined by quantitative histomorphometry. In summary, our study indicates that white wine, when enriched in polyphenols, is able to induce ethanol-independent in vivo effects in a model of insulin-deficient diabetes characterized by a major oxidative stress.

Red wine polyphenols alone or in association with ethanol prevent hypertension, cardiac hypertrophy, and production of reactive oxygen species in the insulin-resistant fructose-fed rat.

The effects of a red wine polyphenolic extract (RWPE), ethanol, or both combined were evaluated in insulin resistant rats. Rats were fed for 6 weeks with fructose (60%)-enriched food and force-fed with (a) water only (F group), (b) aqueous solution of RWPE (100 mg/kg, FP group), (c) 10% (v/v) mixture of ethanol and water (FE group), or (d) solution containing the same amount of the RWPE and ethanol (FPE group). Animals fed a standard chow (C group) were used for comparison purpose. After 6 weeks, blood pressure was higher in F (130.0 x b1 1.7 mm Hg) than in C animals (109.6 x b1 0.9 mm Hg) and similar to the C group in all other fructose-fed treatment groups. Relative heart weight was higher in F (3.10 x b1 0.05) than in C (2.78 x b1 0.07) and significantly lower in FP (2.92 x b1 0.04) and FPE (2.87 x b1 0.08 mg/g) than in F animals. Left ventricle and aorta productions of reactive oxygen species (O2*-) were higher in F than in C groups and lowered by the RWPE but not by the ethanol treatment. Ethanol but not the RWPE treatment reduced the degree of insulin resistance in the fructose-fed rats. In summary, our study showed that polyphenols are able to prevent cardiac hypertrophy and production of reactive oxygen species in the insulin resistant fructose-fed rat.

Antidiabetic activity of red wine polyphenolic extract, ethanol, or both in streptozotocin-treated rats.

A polyphenol extract from a Corbières (France) red wine (P, 200 mg/kg), ethanol (E, 1 mL/kg), or a combination of both (PE) was administered by daily gavage for 6 weeks to healthy control or streptozotocin (60 mg/kg i.v.)-induced diabetic rats (180-200 g). Treatment groups included C or D (untreated control or diabetic) and CP, CE, or CPE (treated control) or DP, DE, or DPE (treated diabetic). P treatment induced a reduction in body growth, food intake, and glycemia in both CP and DP groups. In DP, hyperglycemia was reduced when measured 1 h after daily treatment but not at sacrifice (no treatment on that day). The hyperglycemic response to the oral glucose tolerance test (OGTT) and plasma insulin at sacrifice were impaired similarly in DP and D groups. In contrast, in DE or DPE, body growth was partially restored while hyperglycemia was reduced both during treatment and at sacrifice. In addition, hyperglycemia response to OGTT was reduced and plasma insulin was higher in DE or DPE than in D animals, indicating a long-term correction of diabetes in ethanol-treated animals. Morphometric studies showed that ethanol partially reversed the enlarging effect of diabetes on the mesenteric arterial system while the polyphenolic treatment enhanced it in the absence of ethanol. In summary, our study shows that (i). a polyphenol extract from red wine ("used at a pharmacological" dose) reduces glycemia and decreases food intake and body growth in diabetic and nondiabetic animals and (ii). ethanol ("nutritional" dose) administered alone or in combination with polyphenols is able to correct the diabetic state. Some of the effects of polyphenols were masked by the effects of ethanol, notably in diabetic animals. Further studies will determine the effect of "nutritional" doses of polyphenols as well as their mechanism of action.

Levels of stilbene oligomers and astilbin in French varietal wines and in grapes during noble rot development.

Phenolics from grapes and wines can play a role against oxidation and development of atherosclerosis. Stilbenes have been shown to have cancer chemopreventive activity and to protect lipoproteins from oxidative damage. A method for the direct determination of stilbene oligomers (viniferin and pallidol) as well as astilbin in different types of wine using high-performance liquid chromatography with UV detection is described. In a survey of 21 commercial wines from the south of France, levels of pallidol and viniferin are reported for the first time in different types of wines. Viniferin was found to be present only in red and botrytized sweet white wines with levels between 0.1 and 1.63 mg/L; pallidol was not found in dry and sweet white wines but only in wines made by maceration with stems, with levels between 0.38 and 2.22 mg/L. Highest levels of astilbin were found in Egiodola (15.13 mg/L), Merlot (11.61 mg/L), and Cabernet Sauvignon (8.24 mg/L) for red wines and in Sauvignon (5.04 mg/L) for white varietal wines. Astilbin levels are highest for recent vintages, but pallidol is not found in older vintages. During noble rot development in Sauvignon or Sémillon grapes from the Sauternes area, levels of trans-astringin, trans-resveratrol, trans-piceid, and pallidol are quite low (<0.5 mg/kg of grapes). Viniferin and astilbin levels become optimum at 2 and 30 mg/kg, respectively, during spot grape and speckle grape stages.

Phenolics from commercialized grape extracts prevent early atherosclerotic lesions in hamsters by mechanisms other than antioxidant effect.

The aim of this study was to evaluate the antiatherosclerotic effect of commercially available phenolic-rich extracts from grape seeds (ExGrape seeds, EGS; grape seed extract, GSE) and marc (ExGrape total, EGT) in cholesterol-fed hamsters and to investigate possible operating mechanisms. These extracts fed at a moderate dose mimicking two glasses of red wine per meal reduced plasma cholesterol (-11% on average) but did not affect plasma antioxidant capacity of hamsters. The extracts prevented the development of aortic atherosclerosis by 68% (EGS), 63% (EGT), and 34% (GSE). Elsewhere, in an ex vivo experiment using rat aortic rings, EGS (7 microg/mL) induced 77% endothelium-dependent relaxation, whereas EGT and GSE (30 microg/mL) induced 84 and 72%, respectively. These results suggests that phenolic extracts from grape seeds and marc are beneficial in inhibiting atherosclerosis by indirect mechanism(s).

Leaf methanol extract of Bidens pilosa prevents and attenuates the hypertension induced by high-fructose diet in Wistar rats.

Chronic fructose treatment in rats has repeatedly been shown to elevate blood pressure in association with insulin resistance and hyperinsulinemia. The purpose of the current study was to investigate the effect of the leaf methanol extract of Bidens pilosa on systolic blood pressure (SBP) and plasma glucose, insulin, cholesterol, triglycerides and creatinine levels in rats with fructose-induced hypertension. Wistar rats that drank a 10% fructose solution for 3-6 weeks showed significant increase not only in plasma insulin and cholesterol levels but also in SBP. B. pilosa extract was able to prevent the establishment of hypertension and lower elevated blood pressure levels. The extract also reduced the highly elevated plasma insulin levels provoked by the high fructose diet. These results suggest that the leaf methanol extract of B. pilosa exerts its antihypertensive effect in part by improving insulin sensitivity.

MAP Kinase cross talks in oxidative stress-induced impairment of insulin secretion. Involvement in the protective activity of quercetin.

Insulin secretion preservation is a major issue for the prevention or treatment of type 2 diabetes. We previously showed on ß-cells that quercetin (Q), but not resveratrol (R) or N-acetyl cysteine (NAC), amplified glucose-induced insulin secretion in a calcium- and ERK1/2-dependent manner. Quercetin, but not resveratrol or NAC, also protected ß-cell function and hyperamplified ERK1/2 phosphorylation in oxidative stress conditions. As quercetin may interfere with other stress-activated protein kinases (JNK and p38 MAPK), we further explored MAPK cross talks and their relationships with the mechanism of the protective effect of quercetin against oxidative stress. In INS-1 insulin-secreting ß-cells, using pharmacological inhibitors of MAPK pathways, we found that under oxidative stress (50 µm H2O2) and glucose-stimulating insulin secretion conditions: (i) p38 MAPK phosphorylation was increased and regulated by ERK1/2 (positively) and JNK (negatively), although p38 MAPK activation did not seem to play any significant role in oxidative stress-induced insulin secretion impairment; (ii) the JNK pathway appeared to inhibit both ERK1/2 activation and insulin secretion, although JNK phosphorylation was not significantly changed in our experimental conditions; (iii) the functionality of ß-cell in the presence of oxidative stress was closely linked to the level of ERK1/2 activation, (iv) quercetin, resveratrol, or NAC inhibited H2O2 -induced p38 MAPK phosphorylation. The preservation of ß-cell function against oxidative stress appears dependent on the balance between ERK1/2 and JNK activation. The protecting effect of quercetin appears due to ERK1/2 hyperactivation, possibly induced by L-type calcium channel opening as we recently showed.

Phytochemical profiles of black, red, brown, and white rice from the Camargue region of France.

Secondary metabolites in black, red, brown, and white rice grown in the Camargue region of France were investigated using HPLC-PDA-MS(2). The main compounds in black rice were anthocyanins (3.5 mg/g), with cyanidin 3-O-glucoside and peonidin 3-O-glucoside predominating, followed by flavones and flavonols (0.5 mg/g) and flavan-3-ols (0.3 mg/g), which comprised monomeric and oligomeric constituents. Significant quantities of γ-oryzanols, including 24-methylenecycloartenol, campesterol, cycloartenol, and ß-sitosterol ferulates, were also detected along with lower levels of carotenoids (6.5 µg/g). Red rice was characterized by a high amount of oligomeric procyanidins (0.2 mg/g), which accounted >60% of secondary metabolite content with carotenoids and γ-oryzanol comprising 26.7%, whereas flavones, flavonols and anthocyanins were <9%. Brown and white rice contained lower quantities of phytochemicals, in the form of flavones/flavonols (21-24 µg/g) and γ-oryzanol (12.3-8.2 µg/g), together with trace levels of the carotenoids lutein and zeaxanthin. Neither anthocyanins nor procyanidins were detected in brown and white rice. By describing the profile of the heterogeneous mixture of phytochemicals present in different rice varieties, this study provides a basis for defining the potential health effects related to pigmented and nonpigmented rice consumption by humans.

Short-term intravenous insulin infusion is associated with reduced expression of NADPH oxidase p47(phox) subunit in monocytes from type 2 diabetes patients.

Hyperglycemia is a well-known inducing factor of oxidative stress through activation of NADPH oxidase. In addition to its plasma glucose lowering effect, insulin may also have antioxidant activity and was shown to downregulate NADPH oxidase expression in vitro. In this study, we show that a short-term (3-day) intravenous insulin infusion in patients with type 2 diabetes induces normalization of both glycemia and mRNA expression of circulating monocyte p47(phox) subunit.