Telmisartan, an angiotensin II type 1 receptor blocker, prevents the development of diabetes in male Spontaneously Diabetic Torii rats

Hasegawa, Goji; Fukui, Michiaki; Hosoda, Hiroko; Asano, Mai; Harusato, Ichiko; Tanaka, Muhei; Shiraishi, Emi; Senmaru, Takashi; Sakabe, Kazumi; Yamasaki, Masahiro; Kitawaki, Jo; Fujinami, Aya; Ohta, Mitsuhiro; Obayashi, Hiroshi; Nakamura, Naoto

doi:10.1016/j.ejphar.2009.01.001

Cited by 34 publications

(25 citation statements)

References 26 publications

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“…Ang II binds to AGTR1, which is a major Ang II receptor in pancreatic b-cells. AGTR1 was also upregulated in animal models of T2D (Nakayama et al 2005, Chu et al 2006 and AGTR1 blocker improved b-cell mass and function in T2D (Chu et al 2006, Hasegawa et al 2009. Therefore, pancreatic RAAS may be another pathological mechanism of glucotoxicity-induced pancreatic b-cell apoptosis.…”

Section: Discussionmentioning

confidence: 95%

Testosterone reduces AGTR1 expression to prevent β-cell and islet apoptosis from glucotoxicity

Kooptiwut¹,

Hanchang²,

Semprasert³

et al. 2014

Journal of Endocrinology

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Hypogonadism in men is associated with an increased incidence of type 2 diabetes. Supplementation with testosterone has been shown to protect pancreatic b-cell against apoptosis due to toxic substances including streptozotocin and high glucose. One of the pathological mechanisms of glucose-induced pancreatic b-cell apoptosis is the induction of the local rennin-angiotensin-aldosterone system (RAAS). The role of testosterone in regulation of the pancreatic RAAS is still unknown. This study aims to investigate the protective action of testosterone against glucotoxicity-induced pancreatic b-cell apoptosis via alteration of the pancreatic RAAS pathway. Rat insulinoma cell line (INS-1) cells or isolated male mouse islets were cultured in basal and high-glucose media in the presence or absence of testosterone, losartan, and angiotensin II (Ang II), then cell apoptosis, cleaved caspase 3 expression, oxidative stress, and expression of angiotensin II type 1 receptor (AGTR1) and p47 phox mRNA and protein were measured. Testosterone and losartan showed similar effects in reducing pancreatic b-cell apoptosis. Testosterone significantly reduced expression of AGTR1 protein in INS-1 cells cultured in high-glucose medium or high-glucose medium with Ang II. Testosterone decreased the expression of AGTR1 and p47 phox mRNA and protein in comparison with levels in cells cultured in high-glucose medium alone. Furthermore, testosterone attenuated superoxide production when co-cultured with high-glucose medium. In contrast, when cultured in basal glucose, supplementation of testosterone did not have any effect on cell apoptosis, oxidative stress, and expression of AGT1R and p47 phox .In addition, high-glucose medium did not increase cleaved caspase 3 in AGTR1 knockdown experiments. Thus, our results indicated that testosterone prevents pancreatic b-cell apoptosis due to glucotoxicity through reduction of the expression of ATGR1 and its signaling pathway.

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Section: Discussionmentioning

confidence: 95%

Testosterone reduces AGTR1 expression to prevent β-cell and islet apoptosis from glucotoxicity

Kooptiwut¹,

Hanchang²,

Semprasert³

et al. 2014

Journal of Endocrinology

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“…It has been shown in experimental animals that treatment with telmisartan reduces oxidative stress and protects against islet b-cell damage and dysfunction (35).…”

Section: Discussionmentioning

confidence: 99%

Effect of telmisartan on selected adipokines, insulin sensitivity, and substrate utilization during insulin-stimulated conditions in patients with metabolic syndrome and impaired fasting glucose

Wohl

Krusinova

Hill

et al. 2010

European Journal of Endocrinology

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Objective: Telmisartan improves glucose and lipid metabolism in rodents. This study evaluated the effect of telmisartan on insulin sensitivity, substrate utilization, selected plasma adipokines and their expressions in subcutaneous adipose tissue (SAT) in metabolic syndrome. Design and methods: Twelve patients with impaired fasting glucose completed the double-blind, randomized, crossover trial. Patients received telmisartan (160 mg/day) or placebo for 3 weeks and vice versa with a 2-week washout period. At the end of each period, a hyperinsulinemic euglycemic clamp (HEC) combined with indirect calorimetry was performed. During HEC (0, 30, and 120 min), plasma levels of adipokines were measured and a needle biopsy (0 and 30 min) of SAT was performed. Results: Fasting plasma glucose was lower after telmisartan compared with placebo (P!0.05). There were no differences in insulin sensitivity and substrate utilization. We found no differences in basal plasma adiponectin, resistin and tumour necrosis factor a (TNFa), but an increase was found in basal leptin, after telmisartan treatment. Insulin-stimulated plasma adiponectin (P!0.05), leptin and resistin (P!0.001) were increased, whereas TNFa was decreased (P!0.05) after telmisartan treatment. Expression of resistin, but not adiponectin, TNFa and leptin was increased after telmisartan treatment. Conclusions: Despite the decrease in fasting plasma glucose, telmisartan does not improve insulin sensitivity and substrate utilization. Telmisartan increases plasma leptin as well as insulin-stimulated plasma adiponectin, leptin and resistin, and decreases plasma TNFa during HEC. Changes in plasma adipokines cannot be explained by their expressions in SAT. The changes in plasma adipokines might be involved in the metabolic effects of telmisartan in metabolic syndrome.

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“…For instance, both ACEi and angiotensin receptor antagonists have been shown to ameliorate islet fibrosis and dysfunction during long-term oral treatment of Zucker diabetic fatty rats and other animal models of Type 2 diabetes [26][27][28][29][30][31]. Specifically, telmisartan effectively prevented the development of glucose intolerance and diabetes in spontaneously non-obese Type 2 diabetic rats, possibly by down-regulating islet RAS components contributing to oxidative stress [32]. Mechanistically, telmisartan was found to attenuate lipotoxicity-induced islet formation of ROS (reactive oxygen species), PKC (protein kinase C) activation and NADPH oxidase activity [33], thereby improving islet cell viability and function.…”

Section: Figure 3 Effects Of Ramipril and Telmisartan On Pbf In Type mentioning

confidence: 99%

Acute regulation of pancreatic islet microcirculation and glycaemia by telmisartan and ramipril: discordant effects between normal and Type 2 diabetic rats

et al. 2013

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Diabetic patients are often treated with an ACEi (angiotensin-converting enzyme inhibitor) or angiotensin receptor antagonist against hypertension or albuminuria. These drugs also have a positive impact on glucose tolerance, but the mechanism for this remains elusive. Hypothesizing a positive non-additive effect, we studied whether the angiotensin receptor antagonist telmisartan or the ACEi ramipril acutely influence insulin secretion and glycaemia in vivo in healthy and Type 2 diabetic rats through effects on islet blood perfusion. Telmisartan and ramipril were injected intravenously into anaesthetized non-diabetic Wistar rats or Type 2 diabetic GK (Goto-Kakizaki) rats. In non-diabetic Wistar rats, neither whole PBF (pancreatic blood flow) nor IBF (islet blood flow) were significantly influenced by telmisartan and ramipril, alone or in combination. Renal blood flow was enhanced significantly by telmisartan and ramipril when used in combination, whereas ABF (adrenal blood flow) was not affected by any of the drugs. Telmisartan and ramipril both significantly increased serum insulin levels, but did not influence glycaemia. In Type 2 diabetic GK rats, both whole PBF and IBF were significantly decreased by telmisartan and ramipril, but only when used in combination. Renal blood flow was enhanced significantly by telmisartan and ramipril alone, but not when used in combination, whereas ABF was not affected by any of the drugs. Telmisartan and ramipril both significantly decreased serum insulin levels, and non-additively elevated blood glucose levels. In conclusion, the present study suggests that a local pancreatic RAS (renin-angiotensin system), sensitive to acute administration of telmisartan and ramipril, controls pancreatic IBF and insulin secretion and thereby has an impact on glucose tolerance. Our findings indicate unexpected significant differences in the effects of these agents on islet microcirculation, in vivo insulin secretion and glycaemia between healthy and Type 2 diabetic rats.

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Telmisartan, an angiotensin II type 1 receptor blocker, prevents the development of diabetes in male Spontaneously Diabetic Torii rats

Cited by 34 publications

References 26 publications

Testosterone reduces AGTR1 expression to prevent β-cell and islet apoptosis from glucotoxicity

Testosterone reduces AGTR1 expression to prevent β-cell and islet apoptosis from glucotoxicity

Effect of telmisartan on selected adipokines, insulin sensitivity, and substrate utilization during insulin-stimulated conditions in patients with metabolic syndrome and impaired fasting glucose

Acute regulation of pancreatic islet microcirculation and glycaemia by telmisartan and ramipril: discordant effects between normal and Type 2 diabetic rats

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