Losartan, an angiotensin II type 1 receptor blocker, protects human islets from glucotoxicity through the phospholipase C pathway

Madec, Anne-Marie; Cassel, R.; Dubois, Séverine; Ducreux, Sylvie; Vial, Guillaume; Chauvin, Marie-Agnès; Mesnier, Aurélia; Chikh, Karim; Bosco, Domenico; Rieusset, Jennifer; Coppenolle, Fabien Van; Thivolet, Charles

doi:10.1096/fj.13-234104

Cited by 30 publications

(26 citation statements)

References 36 publications

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“…Thus, there may be a connection between AGTR1 activation and ER stress. This notion was supported by results from a recent study which indicated that high levels of glucose up-regulated the expression of AGTR1 and AGT mRNA in human islets, leading to the activation of islet RAAS (Madec et al 2013). AGTR1 was activated through phospholipase C and caused the depletion of ER calcium.…”

Section: Discussionmentioning

confidence: 60%

“…The reduction in ER calcium levels induced ER stress, which then induced b-cell dysfunction and apoptosis. Losartan showed a protective effect against glucotoxicity via inhibition of expression of AGTR1 and reduction of ER stress (Madec et al 2013). All of these lines of evidence indicated that testosterone and losartan inhibit similar aspects of high-glucose activated AGTR1.…”

Section: Discussionmentioning

confidence: 87%

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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: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 87%

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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“…Increased IP3R2 amounts may reflect important changes in Ca 2+ homeostasis and release of Ca 2+ from the ER. We have previously shown that exposure of human islets to high glucose concentrations led to increased levels of IP3R2 both at the mRNA and protein levels, as well as reduced levels of sarco-endoplasmic reticulum Ca 2+ ATPase 2b (SERCA 2b) pump [21]. Depletion of reticular Ca 2+ stores results in dysfunction of protein folding activation of the unfolded protein response (UPR), which leads to ER stress and may also alter mitochondria [22].…”

Section: Discussionmentioning

confidence: 99%

Reduction of endoplasmic reticulum- mitochondria interactions in beta cells from patients with type 2 diabetes

et al. 2017

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Type 2 diabetes develops when beta cells are not able to fulfill insulin needs. The role of the endoplasmic reticulum–mitochondria junction in coordinating the functions of these two organelles throughout the natural history of type 2 diabetes is determinant and may explain the alterations of insulin biosynthesis. Our goal was to study endoplasmic reticulum and mitochondrial interactions in human beta cells from organ donors with type 2 diabetes. Pancreas samples were obtained via the network for pancreatic organ donors with diabetes (nPOD) based on disease status with 12 subjects with type 2 diabetes and 9 non-diabetic controls. We examined pancreatic specimens by immunofluorescence, in situ hybridization and in situ proximity ligation assay and compared the results to an in vitro model of beta-cell dysfunction. Expression of proteins that enable tethering and exchanges between endoplasmic reticulum (ER) and mitochondria and quantification of interconnection through mitochondria associated membranes (MAM) was investigated. In beta cells from type 2 diabetic cases as compared to controls, there was a significant increase in reticular expression of inositol triphosphate receptor-2 (IP3R2) both at the protein and mRNA levels, no difference in mitochondrial transit peptide receptor TOM20 and mitofusin-2 expressions, and a decrease in the expression of voltage-dependent anion channel-1 (VDAC-1). The number of IP3R2-VDAC-1 complexes identified by in situ proximity ligation assay was significantly lower in diabetic islets and in beta cells of diabetics as compared to controls. Treatment of Min6-B1 cells with palmitate altered glucose-stimulated insulin secretion, increased ER stress and significantly reduced ER-mitochondrial interactions. We can conclude that specific changes in reticular and mitochondrial beta cell proteins characterize human type 2 diabetes with reduction in organelle interactions. This finding opens new targets of intervention.

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“…[5][6][7][8][9] On the other hand, ARBs, the first line antihypertensive agents in T2DM patients, have recently been shown to exert beneficial effects on pancreatic β-cell function as well as on the insulin signaling cascades in skeletal muscle cells and hepatocytes. [16][17][18][19] It is therefore clinically relevant to determine whether the beneficial effects of DPP-4 inhibitor on pancreatic β-cell function could be observed in T2DM patients treated with ARBs. Our findings demonstrated for the first time that the DPP-4 inhibitor sitagliptin improved pancreatic β-cell function in ARB-treated T2DM patients.…”

Section: Discussionmentioning

confidence: 99%

“…14,15 In addition, ARBs have recently been reported not only to improve insulin sensitivity, but also to preserve pancreatic β-cell function in both animal experiments and clinical studies. [16][17][18][19] Therefore, it is clinically relevant to investigate whether the beneficial effect of DDP-4 inhibitors could be exerted in ARB-treated T2DM patients.…”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl peptidase-4 inhibitor sitagliptin improves pancreatic β-cell function in hypertensive diabetic patients treated with angiotensin receptor blockers

Fukui

Kawahito

Wakana

et al. 2015

J Renin Angiotensin Aldosterone Syst

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Introduction: Dipeptidyl peptidase (DPP)-4 inhibitors, a novel oral anti-diabetic agents, exert a protective effect on pancreatic β-cell function in patients with type 2 diabetic mellitus (T2DM). However, their beneficial effect in hypertensive T2DM patients treated with angiotensin receptor blockers (ARBs) has not been investigated. Methods: In this open-label multicenter randomized study, a total of 55 hypertensive T2DM patients treated with ARBs were randomly assigned to receive the DPP-4 inhibitor sitagliptin or sulfonylurea (SU). Results: After 24 weeks of treatment, a significant reduction in fasting blood glucose was only observed in the sitagliptin group, while HbA1c was significantly reduced in both groups. Homeostasis model assessment of insulin resistance was not significantly improved in either group. Indicators of pancreatic β-cell function, including proinsulin to insulin ratio and homeostasis model assessment of β-cell function, were significantly improved in the sitagliptin group, but not in the SU group. The beneficial effects of sitagliptin were observed in hypoglycemic drug naïve patients, but not in patients who had received SU monotherapy prior to the study. Conclusion: Treatment with the DPP-4 inhibitor sitagliptin might exert beneficial effects on pancreatic β-cell function in ARB-treated T2DM patients and its efficacy might be more pronounced in hypoglycemic drug naïve patients.

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Losartan, an angiotensin II type 1 receptor blocker, protects human islets from glucotoxicity through the phospholipase C pathway

Cited by 30 publications

References 36 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

Reduction of endoplasmic reticulum- mitochondria interactions in beta cells from patients with type 2 diabetes

Dipeptidyl peptidase-4 inhibitor sitagliptin improves pancreatic β-cell function in hypertensive diabetic patients treated with angiotensin receptor blockers

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