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Beneficial effects of an antioxidant (N-acetyl-i,-cysteine, NAC) and an angiotensin 1-converting enzyme (ACE) inhibitor (ramipril) were assessed in a rat model of insulin resistance induced by 10% glucose feeding for 20 weeks. Treatments with NAC (2 g/kg per day) and ramipril (1 mg/kg per day) were initiated at 16 weeks in the drinking fluid. Systolic blood pressure, plasma levels of insulin and glucose, and insulin resistance were significantly higher in rats treated with glucose for 20 weeks. This was associated with a higher production of superoxide anion and NADPH oxidase activity in aorta and liver and with a marked reduction in protein expression of skeletal muscle insulin receptor substrate-1 (IRS-1) in the gastrocnemius muscle. NAC prevented all these alterations. Although ramipril also reversed high blood pressure, it had a lesser effect on insulin resistance (including IRS-1) and blocked superoxide anion production only in aorta. Ramipril, in contrast to NAC, did not reduce NADPH oxidase activity in aorta and liver or plasma levels of 4-hydroxynonenal and malondialdehyde. Results suggest that the inhibition of the oxidative stress in hypertensive and insulin-resistant states contributes to the therapeutic effects of NAC and ramipril. Whereas NAC exerts effective antioxidant activity in multiple tissues, ramipril appears to preferentially target the vasculature. Key words: ACE inhibitor, hypertension, insulin resistance, N-acetyl-i,-cysteine, oxidative stress, ramipril. On a evalue les effets benefiques d'un antioxydant (N-acetyl-i,-cysteine, NAC) et d'un inhibiteur de l'enzyme de conversion de l'angiotensine-1 (ECA) (Rmpril) dans un modele de rats presentant une resistance a l'insuline induite par l'ingestion de 10 % de glucose pendant 20 semaines. On a incorpore la NAC (2 g/kg par jour) et le ramipril (1 mgikg par jour) durant la 16' semaine dans le liquide de consommation. La pression arterielle systolique, les taux plasmatiques d'insuline et de glucose et la resistance a l'insuline ont ete significativement plus eleves chez les rats traites avec le glucose pendant 20 semaines. Ce resultat a ete associe a une augmentation de la production d'anions superoxyde et de l'activite de la NADPH oxydase dans l'aorte et le foie, et a une reduction marquee de l'expression de la proteine substrat du recepteur de l'insuline (IRS-1) musculaire squelettique dans le muscle gastrocnemien. La NAC a prevenu toutes ces modifications. Bien que le ramipril ait aussi renverse l'hypertension, il a eu un plus faible effet sur la resistance a l'insuline (y compris 1'IRS-1) et a bloque la production d'anions superoxyde dans l'aorte seulement. Le ramipril n'a pas diminue l'activite de la NADPH oxydase dans l'aorte et le foie ou les taux plasmatiques de 4-hydroxynonenal et de malondialdehyde, contrairement a la NAC. Les resultats donnent a penser que l'inhibition du stress oxydatif durant l'hypertension et la resistance a l'insuline contribue aux effets therapeutiques de la NAC et du ramipril. La NAC exerce une activite antioxydante efficace dans de multiples tissus, alors que le ramipril semble davantage cibler le systeme vasculaire. Mots-cles : inhibiteur de PECA, hypertension, resistance a l'insuline, N-acetyl-i,-cysteine, stress oxydatif, ramipril. [Traduit par la Redaction], Introduction The 'metabolic syndrome' is an emerging epidemic worldwide that consists of an association of multiple cardiovascular risk factors (Giugliano et al. 1995). These factors, including hypertension, insulin resistance, and [...]

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Bradykinin (BK) promotes insulin sensitivity and glucose uptake in adipocytes and other cell types. We demonstrated that in rat adipocytes BK enhances insulin-stimulated glucose transport via endothelial nitric oxide synthase, nitric oxide (NO) generation, and decreased activity of the mitogen-activated protein kinase (MAPK) JNK (c-Jun NH 2 -terminal kinase). In endothelial cells, NO increases soluble guanylate cyclase (sGC) activity, which, in turn, activates protein kinase G (PKG) by increasing cGMP levels. In this study, we investigated whether BK acts via the sGC-cGMP-PKG pathway to inhibit the negative effects of JNK on insulin signaling and glucose uptake in rat adipocytes. BK augmented cGMP concentrations. The BK-induced enhancement of insulin-stimulated glucose uptake was mimicked by the sGC activator YC-1 and a cell-permeable cGMP analog, CPT-cGMP, and inhibited by the sGC inhibitor ODQ and the PKG inhibitor KT 5823. Transfection of dominant-negative PKG reduced the BK augmentation of insulin-induced Akt phosphorylation. The activation of JNK and ERK1/2 by insulin was attenuated by BK, which was mediated by the sGC-cGMP-PKG pathway. Whereas insulin-stimulated phosphorylation of upstream activators of JNK and ERK, i.e., MKK4 and MEK1/2, was unaffected, BK augmented insulin-mediated induction of MKP-5 mRNA and protein levels. Furthermore, zaprinast, a phosphodiesterase inhibitor, enhanced cGMP and MKP-5 and prolonged the action of BK. These data indicate that BK enhances insulin action by inhibition of negative feedback by JNK and ERK via upregulation of MKP-5, mediated by the sGC-cGMP-PKG signaling pathway., (Copyright © 2017 the American Physiological Society.)

Background: Mechanisms underlying the attenuation of body weight gain and insulin resistance in response to high fat diet (HFD) by the curry compound curcumin need to be further explored. Although the attenuation of the inflammatory pathway is an accepted mechanism, a recent study suggested that curcumin stimulates Wnt signaling pathway and hence suppresses adipogenic differentiation. This is in contrast with the known repressive effect of curcumin on Wnt signaling in other cell lineages., Methodology and Principal Findings: We conducted the examination on low fat diet, or HFD fed C57BL/6J mice with or without curcumin intervention for 28 weeks. Curcumin significantly attenuated the effect of HFD on glucose disposal, body weight/fat gain, as well as the development of insulin resistance. No stimulatory effect on Wnt activation was observed in the mature fat tissue. In addition, curcumin did not stimulate Wnt signaling in vitro in primary rat adipocytes. Furthermore, curcumin inhibited lipogenic gene expression in the liver and blocked the effects of HFD on macrophage infiltration and the inflammatory pathway in the adipose tissue., Conclusions and Significance: We conclude that the beneficial effect of curcumin during HFD consumption is mediated by attenuating lipogenic gene expression in the liver and the inflammatory response in the adipose tissue, in the absence of stimulation of Wnt signaling in mature adipocytes.