Beneficial effects of candesartan, an angiotensin II type 1 receptor blocker, on β-cell function and morphology in db/db mice

Shao, Jianghua; Iwashita, Noseki; Ikeda, Fuki; Ogihara, Takeshi; Uchida, Toyoyoshi; Shimizu, Tomoaki; Uchino, Hiroshi; Hirose, Takahisa; Kawamori, Ryuzo; Watada, Hirotaka

doi:10.1016/j.bbrc.2006.04.011

Cited by 84 publications

(81 citation statements)

References 36 publications

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“…Targeting islet microendothelium might improve b-cell function. Indeed, Shao et al (2006) and Lacraz et al (2009) have recently shown the beneficial effects of calderstan (an AT1R blocker) and IL1Ra treatments on b-cell function and morphology together with an improvement in islet vascularization in db/db mice and GK rats.…”

Section: Discussionmentioning

confidence: 99%

Glucose inhibits angiogenesis of isolated human pancreatic islets

Dubois

Madec

Mesnier

et al. 2010

Journal of Molecular Endocrinology

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Owing to strong interactions between pancreatic islets and the surrounding capillary network, we hypothesized that high glucose concentrations might affect key angiogenesis factors from isolated human islets, thus contributing to b-cell failure in diabetes. Human islets from eight distinct donors were studied following 96 h in culture in the presence of normal (5 . 5 mmol/l) or high (16 . 7 mmol/l) glucose concentrations. Similar studies were performed with HUVECs. Human angiogenesis-related genes and corresponding proteins were studied by real-time quantitative PCR (RT-qPCR) and protein arrays respectively. Angiogenesis and proliferation assays were also performed with HUVECs under the same culture conditions. RT-qPCR and proteome analysis of human islets incubated with 16 . 7 mM/l glucose revealed a significant decrease in pro-angiogenic factors including vascular endothelial growth factor (VEGF) mRNA by 20% and VEGF protein levels by 42% as well as additional proteins such as fibroblast growth factor-4 by 41%, MMP9 by 18%, monocyte chemoattractant protein-1 by 21%, and prolactin by 25%. In contrast, we observed a 17% increase in thrombospondin-1 (TSP-1, listed as THBS1 in the HUGO database) and a 37% increase in angiotensinogen gene expression levels, but neither angiotensin-converting enzyme nor angiotensin II type 1 receptor gene expression was affected. The amounts of anti-angiogenic proteins such as TSP-1 and serpin B5/maspin were also increased by 70 and 98% respectively as well as endostatin by 63%. Angiogenesis assays of HUVECS in the presence of high glucose concentrations revealed a 30% decrease in tree-like tubular network formation. These data suggest that glucose reduces key factors of islet angiogenesis, which might exacerbate b-cell failure.

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Section: Discussionmentioning

confidence: 99%

Glucose inhibits angiogenesis of isolated human pancreatic islets

Dubois

Madec

Mesnier

et al. 2010

Journal of Molecular Endocrinology

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“…Importantly, the effects of an ACE inhibitor and an ARB on glucose tolerance in type 2 diabetic animals, including db/db mice, have been controversial, and depend on severity of diabetes, the time of start of drug treatment and the duration of drug treatment [25,26,41,42]. Furthermore, a recent clinical trial [43] showed that the addition of aliskiren to losartan, an ARB, provided additive reduction of urinary albumin excretion in type 2 diabetic patients, suggesting that the combination of aliskiren plus an ARB may be a useful therapeutic strategy for diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 99%

“…Beta cell mass was determined on insulin-stained sections and was estimated by the following formula: beta cell mass (g) = [area of islets/the area of the whole pancreatic area] × pancreas weight, as described previously [26].…”

Section: Vessel Ring Preparation and Organ Chamber Experimentsmentioning

confidence: 99%

Aliskiren prevents cardiovascular complications and pancreatic injury in a mouse model of obesity and type 2 diabetes

et al. 2009

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Aims/hypothesis The effect of renin inhibition on type 2 diabetes is still unclear. The present study was undertaken to examine the efficacy of aliskiren, a direct renin inhibitor, on cardiovascular injuries, glucose intolerance and pancreatic injury in a mouse model of type 2 diabetes. Methods Groups of db/db mice, with obesity and type 2 diabetes, were treated with aliskiren (3, 6, 12 and 25 mg kg −1 day −1 ) or hydralazine (80 mg kg −1 day −1 ) for 6 weeks, and the protective effects were extensively compared among groups.Results All sub-pressor and hypotensive doses of aliskiren significantly attenuated cardiac fibrosis, macrophage infiltration and coronary remodelling, and improved vascular endothelial function in db/db mice. These protective effects of aliskiren were attributed to the attenuation of cardiac p22 phox -related NADPH oxidase-induced superoxide and the restoration of vascular endothelial nitric oxide synthase (eNOS) production. Aliskiren at the highest dose (25 mg kg), but not at lower doses, partially reduced glucose intolerance in db/db mice. Furthermore, the highest dose of aliskiren significantly attenuated the decreases in pancreatic islet insulin content and beta cell mass, and prevented pancreatic islet fibrosis in db/db mice, being associated with the reduction of 8-hydroxy-2′-deoxyguanosine-positive cells and Nox2 (also known as Cybb) expression in pancreatic islets by aliskiren. Conclusions/interpretation Our work provides the first evidence that direct renin inhibition with aliskiren protects against cardiovascular complications and pancreatic injury, through the attenuation of oxidative stress. Thus, we propose that aliskiren may be a promising therapeutic agent for type 2 diabetes.

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“…Similar effects were observed in other models of diabetes and glucose intolerance. [5][6][7] This effect of AT 1 receptor blockade on glucose intolerance was not caused by the change in insulin secretion. However, the glucose uptake in insulin-sensitive tissues is increased by ARBs especially in skeletal muscles.…”

Section: Ras and Insulin Resistancementioning

confidence: 77%

“…Moreover, it has been reported that ARB could protect the pancreas in type II diabetic animal model with enhanced insulin secretion. 10 In the following parts, we will review mainly the roles of angiotensin II receptor subtype in adipose tissue.…”

Section: Ras and Insulin Resistancementioning

confidence: 99%

Role of renin–angiotensin system in adipose tissue dysfunction

Iwai

Horiuchi

2009

Hypertens Res

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Blockade of angiotensin II type 1 (AT 1 ) receptor improves insulin sensitivity and diabetic condition. In short-term regulation, angiotensin II changes lipid metabolism and in long-term regulation, it affects insulin sensitivity and adipocyte differentiation in adipose tissue. These effects are mainly mediated by AT 1 receptor. AT 1 receptor blocker improves insulin sensitivity and induces adipocyte differentiation by increasing peroxisome proliferator-activated receptor-c (PPARc) and transcription factors in adipose tissue in diabetic and atherosclerotic models. Clinical studies indicate that AT 1 receptor blockers prevent the new onset of diabetes and improve insulin sensitivity. On the other hand, AT 2 receptor stimulation appears to cause antagonistic actions against AT 1 receptor signaling. Although further investigations are necessary on the AT 2 receptor function in adipose tissue, studies using AT 2 receptor agonists, in addition to those using AT 1 receptor blockers, would contribute to the treatment of metabolic syndrome and associated pathological disorders.

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Beneficial effects of candesartan, an angiotensin II type 1 receptor blocker, on β-cell function and morphology in db/db mice

Cited by 84 publications

References 36 publications

Glucose inhibits angiogenesis of isolated human pancreatic islets

Glucose inhibits angiogenesis of isolated human pancreatic islets

Aliskiren prevents cardiovascular complications and pancreatic injury in a mouse model of obesity and type 2 diabetes

Role of renin–angiotensin system in adipose tissue dysfunction

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