Regulation of insulin sensitivity, insulin production, and pancreatic β cell survival by angiotensin-(1-7) in a rat model of streptozotocin-induced diabetes mellitus

He, Jun; Yang, Zhiming; Yang, Hui‐Yu; Wang, Li; Wu, Huilu; Fan, Yunjuan; Wang, Wei; Fan, Xin; Li, Xing

doi:10.1016/j.peptides.2014.12.012

Cited by 34 publications

(21 citation statements)

References 33 publications

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“…Apoptosis may be a proposed mechanism for hyperglycemia‐induced hepatic inflammation [Graves et al, ; Francés et al, ] and increases in Bax and decreased Bcl‐2 content have been associated with the diabetes‐related conditions [Podestà et al, ; Hasnan et al, ]. Similar findings were also noted in streptozotocin (STZ)‐induced diabetes [He et al, ]. Hyperglycemia may turn on p53, a tumor suppressor gene acting via the Bax/Bcl–2 pathway, thereby lead to the apoptotic hepatic inflammation that occurs in untreated diabetes.…”

Section: Introductionsupporting

confidence: 64%

Resveratrol Ameliorates the Components of Hepatic Inflammation and Apoptosis in a Rat Model of Streptozotocin‐Induced Diabetes

Pektaş

Sadı

Koca

et al. 2016

Drug Development Research

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Preclinical Research Trans-resveratrol has a wide range of biological effects that reflect its antioxidant, anti-inflammatory, anticarcinogenic and cardioprotective properties. This study was conducted to elucidate the potential role of resveratrol on hepatic inflammation and the apoptotic pathway components Bcl-2, Bax and p53 in a streptozotocin (STZ)-induced rat model of diabetes mellitus. Inflammatory and apoptotic biomarkers indicated a reduction in hepatic erythropoietin (1.26-fold) and increased asymmetric dimethylarginine (3.9-fold), visfatin (1.6-fold), inflammatory interleukins and TNF-α contents (approximately twofold each) in the diabetic animals. Induction of inducible nitric oxide synthase gene (2.04-fold) and protein expression (1.24-fold) was also observed. Immunohistochemical studies showed enhancement of the apoptotic biomarkers Bax and p53 in diabetic animals. STZ-induced diabetic male Wistar rats were treated with resveratrol (20 mg/kg/day i.p.). Resveratrol succeeded to recover most of these inflammatory and apoptotic elements. Therefore, inflammatory and apoptotic pathways were proved to be affected by STZ-induced diabetes in several aspects and resveratrol might contribute hepatoprotective effects as evidenced from this study.

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Section: Introductionsupporting

confidence: 64%

Resveratrol Ameliorates the Components of Hepatic Inflammation and Apoptosis in a Rat Model of Streptozotocin‐Induced Diabetes

Pektaş

Sadı

Koca

et al. 2016

Drug Development Research

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“…Angiotensin-(1–7) has been shown to enhance insulin secretion (16–18). To determine whether neprilysin activity is required for this effect, basal (2.8 mmol/L glucose) and glucose-stimulated (20 mmol/L glucose) insulin secretion was assessed after a 48-h culture of C57BL/6.NEP +/+ or C57BL/6.NEP −/− islets in the absence and presence of angiotensin-(1–7).…”

Section: Resultsmentioning

confidence: 99%

Neprilysin Is Required for Angiotensin-(1–7)’s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1–2)

et al. 2017

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Recent work has renewed interest in therapies targeting the renin-angiotensin system (RAS) to improve β-cell function in type 2 diabetes. Studies show that generation of angiotensin-(1–7) by ACE2 and its binding to the Mas receptor (MasR) improves glucose homeostasis, partly by enhancing glucose-stimulated insulin secretion (GSIS). Thus, islet ACE2 upregulation is viewed as a desirable therapeutic goal. Here, we show that, although endogenous islet ACE2 expression is sparse, its inhibition abrogates angiotensin-(1–7)–mediated GSIS. However, a more widely expressed islet peptidase, neprilysin, degrades angiotensin-(1–7) into several peptides. In neprilysin-deficient mouse islets, angiotensin-(1–7) and neprilysin-derived degradation products angiotensin-(1–4), angiotensin-(5–7), and angiotensin-(3–4) failed to enhance GSIS. Conversely, angiotensin-(1–2) enhanced GSIS in both neprilysin-deficient and wild-type islets. Rather than mediating this effect via activation of the G-protein–coupled receptor (GPCR) MasR, angiotensin-(1–2) was found to signal via another GPCR, namely GPCR family C group 6 member A (GPRC6A). In conclusion, in islets, intact angiotensin-(1–7) is not the primary mediator of beneficial effects ascribed to the ACE2/angiotensin-(1–7)/MasR axis. Our findings warrant caution for the concurrent use of angiotensin-(1–7) compounds and neprilysin inhibitors as therapies for diabetes.

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“…Ang II (via AT1R), the predominant component of RAS, induces insulin resistance through variety of mechanisms including inhibition of insulin signaling and insulin mediated glucose uptake in the skeletal muscle, decreased insulin secretion from pancreatic beta cells and alternation in adipocyte homeostasis [ 27 , 28 ]. In contrast to the Ang II/AT1R axis, other components of RAS, such as Ang (1-7), AT2R or AT4R may have alternate effects on insulin sensitivity and vascular function [ 29 - 31 ]. For example, Ang- (1-7) improves insulin sensitivity and pancreatic β cell survival in STZ-induced diabetic mice [ 31 ] and deletion of AT2R may reverse diabetes-induced endothelial function and vascular injury [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle insulin resistance in salt-sensitive hypertension: role of angiotensin II activation of NFκB

Zhou

Liu

Tian

et al. 2015

Cardiovasc Diabetol

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BackgroundWe have previously shown that in hypertensive Dahl salt-sensitive (DS) rats, impaired endothelium-dependent relaxation to acetylcholine and to insulin is mechanistically linked to up-regulation of angiotensin (Ang) II actions and the production of reactive oxygen species (ROS) and to activation of the proinflammatory transcription factor (NF)κB. Here we investigated whether Ang II activation of NFκB contributed to insulin resistance in the skeletal muscle of this animal model.MethodsDS rats were fed either a normal (NS, 0.5% NaCl) or high (HS, 4% NaCl) salt diet for 6 weeks. In addition, 3 separate groups of HS rats were given angiotensin receptor 1 blocker candesartan (ARB, 10 mg/kg/day in drinking water), antioxidant tempol (1 mmol/L in drinking water) or NFκB inhibitor PDTC (150 mg/kg in drinking water).ResultsDS rats manifested an increase in soleus muscle Ang II content, ROS production and phosopho-IκBα/IκBα ratio, ARB or tempol reduced ROS and phospho-IκBα/IκBα ratio. Hypertensive DS rats also manifested a reduction in glucose infusion rate, impaired insulin-induced Akt phosphorylation and Glut-4 translocation in the soleus muscle, which were prevented with treatment of either ARB, tempol, or PDTC. Data from the rat diabetes signaling pathway PCR array showed that 8 genes among 84 target genes were altered in the muscle of hypertensive rats with the increase in gene expression of ACE1 and 5 proinflammatory genes, and decrease of 2 glucose metabolic genes. Incubation of the muscle with NFκB SN50 (a specific peptide inhibitor of NFκB) ex vivo reversed changes in hypertension-induced gene expression.ConclusionThe current findings strongly suggest that the activation of NFκB inflammatory pathway by Ang II play a critical role in skeletal muscle insulin resistance in salt-sensitive hypertension.

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Regulation of insulin sensitivity, insulin production, and pancreatic β cell survival by angiotensin-(1-7) in a rat model of streptozotocin-induced diabetes mellitus

Cited by 34 publications

References 33 publications

Resveratrol Ameliorates the Components of Hepatic Inflammation and Apoptosis in a Rat Model of Streptozotocin‐Induced Diabetes

Resveratrol Ameliorates the Components of Hepatic Inflammation and Apoptosis in a Rat Model of Streptozotocin‐Induced Diabetes

Neprilysin Is Required for Angiotensin-(1–7)’s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1–2)

Skeletal muscle insulin resistance in salt-sensitive hypertension: role of angiotensin II activation of NFκB

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