Improved Glucose-Stimulated Insulin Secretion by Selective Intraislet Inhibition of Angiotensin II Type 1 Receptor Expression in Isolated Islets of db/db Mice

Zhang, Zhen; Liu, Chunyan; Zhen-hua, Gan; Wang, Xinyi; Yi, Qiuyan; Liu, Yanqing; Wang, Yingzhijie; Lü, Bin; Du, Hong; Shao, Jianghua; Wang, Jun

doi:10.1155/2013/319586

Cited by 17 publications

(11 citation statements)

References 41 publications

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“…Collectively, these data demonstrate that early in the development of metabolic syndrome OLETF rats are afflicted by an increased pro-oxidant state in the pancreas and decreased plasma GLP-1 leading to an impairment in glucose-stimulated insulin secretion. It is important to note that while acute or chronic AT 1 blockade cannot reverse these detriments, RAS inhibition before the onset of dysregulated insulin secretion is protective (Nakayama, et al 2005; Rodriguez et al 2012; Zhang, et al 2013), suggesting that these detriments are irreversible without sufficiently early intervention. If so, identifying appropriate targets for improving therapies to reverse dysregulated pancreatic function associated with the manifestation of metabolic syndrome will be especially necessary.…”

Section: Discussionmentioning

confidence: 99%

Chronic AT1 blockade improves glucose homeostasis in obese OLETF rats

Rodríguez

Minas

Vázquez‐Medina

et al. 2018

Journal of Endocrinology

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Obesity is associated with the inappropriate activation of the renin-angiotensin system (RAS), which increases arterial pressure, impairs insulin secretion and decreases peripheral tissue insulin sensitivity. RAS blockade reverses these detriments; however, it is not clear whether the disease state of the organism and treatment duration determine the beneficial effects of RAS inhibition on insulin secretion and insulin sensitivity. Therefore, the objective of this study was to compare the benefits of acute vs chronic angiotensin receptor type 1 (AT) blockade started after the onset of obesity, hyperglycemia and hypertension on pancreatic function and peripheral insulin resistance. We assessed adipocyte morphology, glucose intolerance, pancreatic redox balance and insulin secretion after 2 and 11 weeks of AT blockade in the following groups of rats: (1) untreated Long-Evans Tokushima Otsuka (lean control; = 10), (2) untreated Otsuka Long-Evans Tokushima Fatty (OLETF; = 12) and (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day by oral gavage; = 12). Regardless of treatment duration, AT blockade decreased systolic blood pressure and fasting plasma triglycerides, whereas chronic AT blockade decreased fasting plasma glucose, glucose intolerance and the relative abundance of large adipocytes by 22, 36 and 70%, respectively. AT blockade, however, did not improve pancreatic oxidative stress or reverse impaired insulin secretion. Collectively, these data show that AT blockade after the onset of obesity, hyperglycemia and hypertension improves peripheral tissue insulin sensitivity, but cannot completely reverse the metabolic derangement characterized by impaired insulin secretion once it has been compromised.

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Section: Discussionmentioning

confidence: 99%

Chronic AT1 blockade improves glucose homeostasis in obese OLETF rats

Rodríguez

Minas

Vázquez‐Medina

et al. 2018

Journal of Endocrinology

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“…ARB lowers the expression of NADPH oxidase in db/db mice and restores insulin production in ␤-cells (129). The silencing of AT1Rs with small interfering RNA in isolated pancreatic islets from db/db mice results in increased GLUT2 and glucokinase protein levels (196). Extrapolated to the organismal level, AT1R blockade would enhance the glucose sensitivity of the ␤-cells.…”

Section: E441mentioning

confidence: 99%

Modulation of glucose metabolism by the renin-angiotensin-aldosterone system

Favrè

Esnault

Obberghen

2015

American Journal of Physiology-Endocrinology and Metabolism

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The renin-angiotensin-aldosterone system (RAAS) is an enzymatic cascade functioning in a paracrine and autocrine fashion. In animals and humans, RAAS intrinsic to tissues modulates food intake, metabolic rate, adiposity, insulin sensitivity, and insulin secretion. A large array of observations shows that dysregulation of RAAS in the metabolic syndrome favors type 2 diabetes. Remarkably, angiotensin-converting enzyme inhibitors, suppressing the synthesis of angiotensin II (ANG II), and angiotensin receptor blockers, targeting the ANG II type 1 receptor, prevent diabetes in patients with hypertensive or ischemic cardiopathy. These drugs interrupt the negative feedback loop of ANG II on the RAAS cascade, which results in increased production of angiotensins. In addition, they change the tissue expression of RAAS components. Therefore, the concept of a dual axis of RAAS regarding glucose homeostasis has emerged. The RAAS deleterious axis increases the production of inflammatory cytokines and raises oxidative stress, exacerbating the insulin resistance and decreasing insulin secretion. The beneficial axis promotes adipogenesis, blocks the production of inflammatory cytokines, and lowers oxidative stress, thereby improving insulin sensitivity and secretion. Currently, drugs targeting RAAS are not given for the purpose of preventing diabetes in humans. However, we anticipate that in the near future the discovery of novel means to modulate the RAAS beneficial axis will result in a decisive therapeutic breakthrough.

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“…glycemia in vivo in models of T2D. 8,12 Previous studies in experimental models where β-cell function was markedly deteriorated, such as islets isolated from db/db mice 8,10 or diabetic rats, 27,28 demonstrated beneficial effects of RAS inhibition on β-cell function. In this study, C57BL/6 mice fed a HF diet for 15 weeks continued to exhibit hyperinsulinemia associated with glucose intolerance.…”

Section: Discussionmentioning

confidence: 99%

“…AngII inhibited glucosestimulated insulin secretion in isolated islets, 7,8 while blockade or silencing of AT1R improved insulin secretion. [8][9][10] In contrast, infusion of AngII enhanced in vivo insulin secretion in mice fed standard murine diet. 11 In animal models of T2D, whole-body inhibition of the RAS consistently improves insulin sensitivity and glucose homeostasis.…”

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confidence: 97%

Pancreatic AT1aR Deficiency Decreases Insulin Secretion in Obese C57BL/6 Mice

Shoemaker

Alsiraj

Chen

et al. 2019

American Journal of Hypertension

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BACKGROUND Previously, we demonstrated that obese mice have marked elevations in systemic concentrations of angiotensin II (AngII). Drugs that inhibit the renin-angiotensin system (RAS), including angiotensin type 1 receptor (AT1R) antagonists, have been reported to delay the onset of type 2 diabetes (T2D), suggesting improvements in insulin sensitivity or regulation of pancreatic insulin secretion. Pancreatic islets possess components of the RAS, including AT1R, but it is unclear if AngII acts at islets to regulate insulin secretion during the development of T2D. METHODS We deleted AT1aR from pancreatic islets and examined effects on insulin secretion in mice fed a low-fat (LF) or high-fat (HF) diet. In separate studies, to exacerbate the system, we infused HF-fed mice of each genotype with AngII. RESULTS Pancreatic AT1aR deficiency impaired glucose tolerance and elevated plasma glucose concentrations in HF, but not LF-fed mice. In HF-fed mice, high glucose increased insulin secretion from islets of AT1aR fl/fl , but not AT1aR pdx mice. In AngII-infused mice, following glucose challenge, plasma glucose or insulin concentrations were not significantly different between genotypes. Moreover, high glucose stimulated insulin secretion from islets of AT1aR fl/fl and AT1aR pdx mice, presumably related to weight loss, and improved insulin sensitivity in both groups of AngII-infused HF-fed mice. CONCLUSIONS Our results suggest that during the adaptive response to insulin resistance from HF feeding, AngII promotes insulin secretion from islets through an AT1aR mechanism. These results suggest the timing of initiation of AT1R blockade may be important in the progression from prediabetes to T2D with β-cell failure.

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Improved Glucose-Stimulated Insulin Secretion by Selective Intraislet Inhibition of Angiotensin II Type 1 Receptor Expression in Isolated Islets of db/db Mice

Cited by 17 publications

References 41 publications

Chronic AT1 blockade improves glucose homeostasis in obese OLETF rats

Chronic AT1 blockade improves glucose homeostasis in obese OLETF rats

Modulation of glucose metabolism by the renin-angiotensin-aldosterone system

Pancreatic AT1aR Deficiency Decreases Insulin Secretion in Obese C57BL/6 Mice

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