The physiology of a local renin–angiotensin system in the pancreas

Leung, Po Sing

doi:10.1113/jphysiol.2006.126193

Cited by 141 publications

(112 citation statements)

References 49 publications

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“…Testosterone and angiotensin II receptor blocker decreased apoptosis of pancreatic b-cells induced by high-glucose medium and Ang II Previous studies have reported that Ang II production was increased in mice with T2D, which might be produced by pancreatic islet RAAS (Lau et al 2004, Leung 2007 We further confirmed our cell apoptosis results using the levels of cleaved caspase 3. INS-1 cells were cultured in basal-and high-glucose media with or without testosterone or in the presence or absence of losartan.…”

Section: Testosterone Decreased Apoptosis Of Pancreatic B-cells Cultusupporting

confidence: 79%

“…In the pancreas, the local RAAS is divided into the acinar RAAS and islet RAAS. The acinar RAAS regulates exocrine function and the islet RAAS has a role in glucose homeostasis by regulating glucose-induced insulin secretion (Leung 2007). The expression of RAAS components, such as angiotensinogen (AGT), angiotensin-converting enzyme, angiotensin II type 1 receptor (AGTR1) and AGTR2, in human and mouse islets has been demonstrated (Lam & Leung 2002, Lau et al 2004.…”

Section: Introductionmentioning

confidence: 99%

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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: Testosterone Decreased Apoptosis Of Pancreatic B-cells Cultusupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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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“…Local RAS can affect islet cell function and structure in the adult pancreas as well as the proliferation and differentiation of pancreatic stem/progenitor cells during development (43,44). In fact, RAS blockade significantly attenuates islet damage and restores the b-cell mass by reducing oxidative stress, apoptosis, and attenuating profibrotic pathways (42,45).…”

Section: Discussionmentioning

confidence: 99%

Insulin Receptor Substrate-2 (Irs2) in Endothelial Cells Plays a Crucial Role in Insulin Secretion

et al. 2014

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Endothelial cells are considered to be essential for normal pancreatic β-cell function. The current study attempted to demonstrate the role of insulin receptor substrate-2 (Irs2) in endothelial cells with regard to insulin secretion. Endothelial cell–specific Irs2 knockout (ETIrs2KO) mice exhibited impaired glucose-induced, arginine-induced, and glucagon-induced insulin secretion and showed glucose intolerance. In batch incubation and perifusion experiments using isolated islets, glucose-induced insulin secretion was not significantly different between the control and the ETIrs2KO mice. In contrast, in perfusion experiments, glucose-induced insulin secretion was significantly impaired in the ETIrs2KO mice. The islet blood flow was significantly impaired in the ETIrs2KO mice. After the treatment of these knockout mice with enalapril maleate, which improved the islet blood flow, glucose-stimulated insulin secretion was almost completely restored to levels equal to those in the control mice. These data suggest that Irs2 deletion in endothelial cells leads to a decreased islet blood flow, which may cause impaired glucose-induced insulin secretion. Thus, Irs2 in endothelial cells may serve as a novel therapeutic target for preventing and ameliorating type 2 diabetes and metabolic syndrome.

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“…29,42 Interestingly, it has also been reported that RAS-mediated insulin resistance can be exerted directly at the major insulin-responsive glucose-metabolizing tissue, ie, skeletal muscle, via interference with insulin signaling. 35 Moreover, there are potentially diabetogenic effects of elevated RAS activity involving pancreatic ␤-cell function and insulin secretion, 43 and thiazides can impair insulin secretion. 4 However, we found no consistent differences between the ARB and thiazide (ie, RAS blockade versus amplification) with respect to acute insulin response on glucose challenge.…”

Section: Discussionmentioning

confidence: 99%

Hydrochlorothiazide, but not Candesartan, Aggravates Insulin Resistance and Causes Visceral and Hepatic Fat Accumulation

et al. 2008

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Abstract-Treatment with angiotensin II receptor blockers is associated with lower risk for the development of type 2 diabetes mellitus compared with thiazide diuretics. The Mechanisms for the Diabetes Preventing Effect of Candesartan Study addressed insulin action and secretion and body fat distribution after treatment with candesartan, hydrochlorothiazide, and placebo. Twenty-six nondiabetic, abdominally obese, hypertensive patients were included in a multicenter 3-way crossover trial, and 22 completers (by predefined criteria; 10 men and 12 women) were included in the analyses. They underwent 12-week treatment periods with candesartan (C; 16 to 32 mg), hydrochlorothiazide (H; 25 to 50 mg), and placebo (P), respectively, and the treatment order was randomly assigned and double blinded. Intravenous glucose tolerance tests and euglycemic hyperinsulinemic (56 mU/m 2 per minute) clamps were performed. Intrahepatic and intramyocellular and extramyocellular lipid content and subcutaneous and visceral abdominal adipose tissue were measured using proton magnetic resonance spectroscopy and MRI. Insulin sensitivity (M-value) was reduced following H versus C and P (6.07Ϯ2.05, 6.63Ϯ2.04, and 6.90Ϯ2.10 mg/kg of body weight per minute, meanϮSD; PՅ0.01). Liver fat content was higher (PϽ0.05) following H than both P and C. The subcutaneous to visceral abdominal adipose tissue ratio was reduced following H versus C and P (PϽ0.01). Glycosylated hemoglobin, alanine aminotransferase, aspartate aminotransferase, and high-sensitivity C-reactive protein levels were higher (PϽ0.05) after H, but not C, versus P. There were no changes in body fat, intramyocellular lipid, extramyocellular lipid, or first-phase insulin secretion. Blood pressure was reduced similarly by C and H versus P. In conclusion, visceral fat redistribution, liver fat accumulation, low-grade inflammation, and aggravated insulin resistance were demonstrated after hydrochlorothiazide but not candesartan treatment. These findings can partly explain the diabetogenic potential of thiazides. Key Words: insulin resistance Ⅲ visceral obesity Ⅲ liver fat Ⅲ glucose clamp Ⅲ magnetic resonance H ypertension is associated with an increased risk of development of type 2 diabetes mellitus (T2DM), and it is also an important component of the metabolic syndrome. 1 Obesity and insulin resistance appear to be central perturbations in this cluster of cardiovascular risk factors. 2 Among antihypertensive drugs, ␤-blocking agents and thiazide diuretics have been reported to impair insulin sensitivity and potentially increase the risk for T2DM. [3][4][5] The diabetogenic potential of thiazides has been implicated for single, as well as combination, therapy. 3,6 It has been attributed to increased hepatic glucose production, impaired peripheral glucose uptake, and hypokalemia-mediated ␤-cell dysfunction. 6 -8 In contrast, there are several studies suggesting that inhibition of the renin-angiotensin system (RAS) with angiotensinconverting enzyme inhibitors or blockers of the type 1 angioten...

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The physiology of a local renin–angiotensin system in the pancreas

Cited by 141 publications

References 49 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

Insulin Receptor Substrate-2 (Irs2) in Endothelial Cells Plays a Crucial Role in Insulin Secretion

Hydrochlorothiazide, but not Candesartan, Aggravates Insulin Resistance and Causes Visceral and Hepatic Fat Accumulation

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