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      Angiotensin(1–7) activates MAS-1 and upregulates CFTR to promote insulin secretion in pancreatic β-cells: the association with type 2 diabetes

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          Abstract

          Objective

          The beneficial effect of angiotensin(1–7) (Ang(1–7)), via the activation of its receptor, MAS-1, has been noted in diabetes treatment; however, how Ang(1–7) or MAS-1 affects insulin secretion remains elusive and whether the endogenous level of Ang(1–7) or MAS-1 is altered in diabetic individuals remains unexplored. We recently identified an important role of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl − channel, in the regulation of insulin secretion. Here, we tested the possible involvement of CFTR in mediating Ang(1–7)’s effect on insulin secretion and measured the level of Ang(1–7), MAS-1 as well as CFTR in the blood of individuals with or without type 2 diabetes.

          Methods

          Ang(1–7)/MAS-1/CFTR pathway was determined by specific inhibitors, gene manipulation, Western blotting as well as insulin ELISA in a pancreatic β-cell line, RINm5F. Human blood samples were collected from 333 individuals with ( n  = 197) and without ( n  = 136) type 2 diabetes. Ang(1–7), MAS-1 and CFTR levels in the human blood were determined by ELISA.

          Results

          In RINm5F cells, Ang(1–7) induced intracellular cAMP increase, cAMP-response element binding protein (CREB) activation, enhanced CFTR expression and potentiated glucose-stimulated insulin secretion, which were abolished by a selective CFTR inhibitor, RNAi-knockdown of CFTR, or inhibition of MAS-1. In human subjects, the blood levels of MAS-1 and CFTR, but not Ang(1–7), were significantly higher in individuals with type 2 diabetes as compared to those in non-diabetic healthy subjects. In addition, blood levels of MAS-1 and CFTR were in significant positive correlation in type-2 diabetic but not non-diabetic subjects.

          Conclusion

          These results suggested that MAS-1 and CFTR as key players in mediating Ang(1–7)-promoted insulin secretion in pancreatic β-cells; MAS-1 and CFTR are positively correlated and both upregulated in type 2 diabetes.

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          Most cited references25

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          Oxidative stress and diabetic complications.

          Ferdinando Giacco, Michael Brownlee, Ann Marie Schmidt (2010)
          Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. This increased superoxide production causes the activation of 5 major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of AGEs (advanced glycation end products), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. It also directly inactivates 2 critical antiatherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways, increased intracellular reactive oxygen species (ROS) cause defective angiogenesis in response to ischemia, activate a number of proinflammatory pathways, and cause long-lasting epigenetic changes that drive persistent expression of proinflammatory genes after glycemia is normalized ("hyperglycemic memory"). Atherosclerosis and cardiomyopathy in type 2 diabetes are caused in part by pathway-selective insulin resistance, which increases mitochondrial ROS production from free fatty acids and by inactivation of antiatherosclerosis enzymes by ROS. Overexpression of superoxide dismutase in transgenic diabetic mice prevents diabetic retinopathy, nephropathy, and cardiomyopathy. The aim of this review is to highlight advances in understanding the role of metabolite-generated ROS in the development of diabetic complications.
          Article 0 comments Cited 894 times – based on 0 reviews     Review now
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            Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system.

            Robson A S Santos, Anderson J. Ferreira, Thiago Verano-Braga … (2013)
            Angiotensin (Ang)-(1-7) is now recognized as a biologically active component of the renin-angiotensin system (RAS). Ang-(1-7) appears to play a central role in the RAS because it exerts a vast array of actions, many of them opposite to those attributed to the main effector peptide of the RAS, Ang II. The discovery of the Ang-converting enzyme (ACE) homolog ACE2 brought to light an important metabolic pathway responsible for Ang-(1-7) synthesis. This enzyme can form Ang-(1-7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1-9) with subsequent Ang-(1-7) formation by ACE. In addition, it is now well established that the G protein-coupled receptor Mas is a functional binding site for Ang-(1-7). Thus, the axis formed by ACE2/Ang-(1-7)/Mas appears to represent an endogenous counterregulatory pathway within the RAS, the actions of which are in opposition to the vasoconstrictor/proliferative arm of the RAS consisting of ACE, Ang II, and AT(1) receptor. In this brief review, we will discuss recent findings related to the biological role of the ACE2/Ang-(1-7)/Mas arm in the cardiovascular and renal systems, as well as in metabolism. In addition, we will highlight the potential interactions of Ang-(1-7) and Mas with AT(1) and AT(2) receptors.
            Article 0 comments Cited 198 times – based on 0 reviews     Review now
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              Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse?

              M H Shanik, Y. Xu, J Skrha … (2008)
              Insulin resistance, recently recognized as a strong predictor of disease in adults, has become the leading element of the metabolic syndrome and renewed as a focus of research. The condition exists when insulin levels are higher than expected relative to the level of glucose. Thus, insulin resistance is by definition tethered to hyperinsulinemia. The rising prevalence of medical conditions where insulin resistance is common has energized research into the causes. Many causes and consequences have been identified, but the direct contributions of insulin itself in causing or sustaining insulin resistance have received little sustained attention. We examine situations where insulin itself appears to be a proximate and important quantitative contributor to insulin resistance. 1) Mice transfected with extra copies of the insulin gene produce basal and stimulated insulin levels that are two to four times elevated. The mice are of normal weight but show insulin resistance, hyperglycemia, and hypertriglyceridemia. 2) Somogyi described patients with unusually high doses of insulin and hyperglycemia. Episodes of hypoglycemia with release of glucose-raising hormones, postulated as the culprits in early studies, have largely been excluded by studies including continuous glucose monitoring. 3) Rats and humans treated with escalating doses of insulin show both hyperinsulinemia and insulin resistance. 4) The pulsatile administration of insulin (rather than continuous) results in reduced requirements for insulin. 5) Many patients with insulinoma who have elevated basal levels of insulin have reduced (but not absent) responsiveness to administered insulin. In summary, hyperinsulinemia is often both a result and a driver of insulin resistance.
              Article 0 comments Cited 129 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Endocr Connect
                Journal ID (iso-abbrev): Endocr Connect
                Journal ID (hwp): EC
                Title: Endocrine Connections
                Publisher: Bioscientifica Ltd (Bristol )
                ISSN (Electronic): 2049-3614
                Publication date (Electronic): 26 November 2021
                Publication date Collection: 01 January 2022
                Volume: 11
                Issue: 1
                Electronic Location Identifier: e210357
                Affiliations
                [1 ]Department of Endocrinology , Beijing Tongren Hospital, Capital Medical University, Beijing, China
                [2 ]Department of Physiology , School of Medicine, Jinan University, Guangzhou, China
                [3 ]Department of Biomedical Engineering , Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong, China
                [4 ]Department of Transfusion Medicine , Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China
                [5 ]Epithelial Cell Biology Research Center , The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China
                [6 ]Cell-Gene Therapy Translational Medicine Research Center , The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
                Author notes
                Correspondence should be addressed to H Chen or J Guo: chenh567@ 123456mail.sysu.edu.cn or guojh@ 123456jnu.edu.cn
                Author information
                http://orcid.org/0000-0002-7783-9811
                Article
                Publisher ID: EC-21-0357
                DOI: 10.1530/EC-21-0357
                PMC ID: 8789014
                PubMed ID: 34825893
                SO-VID: c0da8624-5378-43ff-b317-6982b9936841
                Copyright © © The authors
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                History
                Date received : 01 November 2021
                Date accepted : 26 November 2021
                Categories
                Subject: Research

                Keywords: type 2 diabetes,insulin,angiotensin(1–7),mas-1,cftr,p-creb
                Data availability:
                Keywords: type 2 diabetes, insulin, angiotensin(1–7), mas-1, cftr, p-creb

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