The renin–angiotensin–aldosterone system and glucose homeostasis
Open accessAbstract
The renin-angiotensin-aldosterone system (RAAS) is inappropriately activated in obesity. In individuals at risk for diabetes, RAAS inhibition protects against kidney and heart disease, and also reduces the incidence of diabetes in large clinical trials. At a cellular level, angiotensin II (Ang II) and aldosterone induce insulin resistance by increasing oxidative stress and altering insulin signaling, leading to decreased glucose transport. Ang II also contributes to oxidative stress, inflammation, and apoptosis in pancreatic β cells. Aldosterone diminishes glucose-stimulated insulin secretion in vivo and in vitro from isolated pancreatic islets and cultured β cells through a mineralocorticoid receptor (MR)-independent mechanism. We review these findings in the context of pharmacological strategies interrupting the RAAS to highlight the potential application of these strategies to the prevention of diabetes progression.
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The renin-angiotensin-aldosterone system induces insulin resistance on local and systemic levels, which explains why therapies that interfere with the RAAS reduce the incidence of type 2 diabetes mellitus.
“Apart from its major function of sodium and water retention, the RAAS was found to induce insulin resistance on local and systemic levels, which explains why therapies that interfere with the RAAS reduce the incidence of type 2 diabetes mellitus [71-73].”
From Interaction of the endocrine system with inflammation: a function of energy and volume regulation (2014) · cites this paper as [71]
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1 retracted
Effect of Captopril, Losartan, and Bradykinin on Early Steps of Insulin Action
Carvalho, C. R. D. O., Thirone, A. C. P., Gontijo, J. A. R., Velloso, L. A., & Saad, M. J. A. (1997) · Diabetes · doi:10.2337/diab.46.12.1950 · Cited by 117 · see citing works
RetractedReduction in the incidence of type 2 diabetes with lifestyle intervention or metformin
(2002) · New England Journal of Medicine · doi:10.1056/nejmoa012512 · Cited by 19,011 · see citing works
(2000) · New England Journal of Medicine · doi:10.1056/nejm200001203420301 · Cited by 8,663 · see citing works
Brenner, B. M., Cooper, M. E., de Zeeuw, D., Keane, W. F., Mitch, W. E., Parving, H.-H., Remuzzi, G., Snapinn, S. M., Zhang, Z., & Shahinfar, S. (2001) · New England Journal of Medicine · doi:10.1056/nejmoa011161 · Cited by 7,493 · see citing works
Haffner, S. M., Lehto, S., Rönnemaa, T., Pyörälä, K., & Laakso, M. (1998) · New England Journal of Medicine · doi:10.1056/nejm199807233390404 · Cited by 7,000 · see citing works
Mechanisms linking obesity to insulin resistance and type 2 diabetes
Kahn, S. E., Hull, R. L., & Utzschneider, K. M. (2006) · Nature · doi:10.1038/nature05482 · Cited by 5,448 · see citing works
The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy
Lewis, E. J., Hunsicker, L. G., Bain, R. P., & Rohde, R. D. (1993) · New England Journal of Medicine · doi:10.1056/nejm199311113292004 · Cited by 5,394 · see citing works
Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes
Nissen, S. E., & Wolski, K. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa072761 · Cited by 4,675 · see citing works
A genome-wide association study identifies novel risk loci for type 2 diabetes
Sladek, R., Rocheleau, G., Rung, J., Dina, C., Shen, L., Serre, D., Boutin, P., Vincent, D., Belisle, A., Hadjadj, S., et al. (2007) · Nature · doi:10.1038/nature05616 · Cited by 2,993 · see citing works
Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
Saxena, R., Voight, B. F., Lyssenko, V., Burtt, N. P., de Bakker, P. I. W., Chen, H., Roix, J. J., Kathiresan, S., Hirschhorn, J. N., Daly, M. J., et al. (2007) · Science · doi:10.1126/science.1142358 · Cited by 2,843 · see citing works
Pfeffer, M. A., McMurray, J. J. V., Velazquez, E. J., Rouleau, J.-L., Køber, L., Maggioni, A. P., Solomon, S. D., Swedberg, K., Van de Werf, F., White, H., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa032292 · Cited by 2,471 · see citing works
Obesity and Diabetes in the Developing World — A Growing Challenge
Hossain, P., Kawar, B., & El Nahas, M. (2007) · New England Journal of Medicine · doi:10.1056/nejmp068177 · Cited by 2,200 · see citing works
Weyer, C., Bogardus, C., Mott, D. M., & Pratley, R. E. (1999) · Journal of Clinical Investigation · doi:10.1172/jci7231 · Cited by 1,940 · see citing works
Home, P. D., Pocock, S. J., Beck-Nielsen, H., Curtis, P. S., Gomis, R., Hanefeld, M., Jones, N. P., Komajda, M., & McMurray, J. J. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60953-3 · Cited by 1,393 · see citing works
Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy
Parving, H., Persson, F., Lewis, J. B., Lewis, E. J., & Hollenberg, N. K. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0708379 · Cited by 1,092 · see citing works
Comparison of Candesartan, Enalapril, and Their Combination in Congestive Heart Failure
McKelvie, R. S., Yusuf, S., Pericak, D., Avezum, Á., Burns, R. J., Probstfield, J. L., Tsuyuki, R. T., White, M., Rouleau, J. L., Latini, R., et al. (1999) · Circulation · doi:10.1161/01.cir.100.10.1056 · Cited by 880 · see citing works
Effect of ramipril on the incidence of diabetes
(2006) · New England Journal of Medicine · doi:10.1056/nejmoa065061 · Cited by 737 · see citing works
Effect of valsartan on the incidence of diabetes and cardiovascular events
(2010) · New England Journal of Medicine · doi:10.1056/nejmoa1001121 · Cited by 660 · see citing works
Tuck, M. L., Sowers, J. R., Dornfeld, L., Kledzik, G. S., & Maxwell, M. H. (1981) · New England Journal of Medicine · doi:10.1056/nejm198104163041602 · Cited by 643 · see citing works
Weight Loss and the Renin-Angiotensin-Aldosterone System
Engeli, S., Böhnke, J., Gorzelniak, K., Janke, J., Schling, P., Bäder, M., Luft, F. C., & Sharma, A. M. (2005) · Hypertension · doi:10.1161/01.hyp.0000154361.47683.d3 · Cited by 625 · see citing works
Prevention of Type 2 Diabetes With Troglitazone in the Diabetes Prevention Program
The Diabetes Prevention Program Research Group* (2005) · Diabetes · doi:10.2337/diabetes.54.4.1150 · Cited by 474 · see citing works
Human adipocytes secrete mineralocorticoid-releasing factors
Ehrhart‐Bornstein, M., Lamounier‐Zepter, V., Schraven, A., Langenbach, J., Willenberg, H. S., Barthel, A., Hauner, H., McCann, S. M., Scherbaum, W. A., & Bornstein, S. R. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2336140100 · Cited by 443 · see citing works
Folli, F. B., Kahn, C. R., Hansen, H. F., Bouchie, J. L., & Feener, E. P. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119752 · Cited by 424 · see citing works
The adipose-tissue renin–angiotensin–aldosterone system: role in the metabolic syndrome?
Engeli, S., Schling, P., Gorzelniak, K., Boschmann, M., Janke, J., Ailhaud, G. P., Teboul, M., Massiéra, F., & Sharma, A. M. (2003) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(02)00311-4 · Cited by 415 · see citing works
Cross-talk between the insulin and angiotensin signaling systems.
Velloso, L. A., Folli, F. B., Sun, X., White, M. F., Saad, M. J. A., & Kahn, C. R. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.22.12490 · Cited by 402 · see citing works
Aldosterone: effects on the kidney and cardiovascular system
Briet, M. B., & Schiffrin, E. L. (2010) · Nature Reviews Nephrology · doi:10.1038/nrneph.2010.30 · Cited by 337 · see citing works
Angiotensin II-induced NADPH Oxidase Activation Impairs Insulin Signaling in Skeletal Muscle Cells
Wei, Y., Sowers, J. R., Nistala, R., Gong, H., Uptergrove, G. M., Clark, S. E., Morris, E. M., Szary, N. M., Manrique, C. M., & Stump, C. S. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601320200 · Cited by 297 · see citing works
Prevention of Type 2 Diabetes Mellitus Through Inhibition of the Renin-Angiotensin System
Scheen, A. J. (2004) · Drugs · doi:10.2165/00003495-200464220-00004 · Cited by 293 · see citing works
Selective Angiotensin II Receptor Antagonism Reduces Insulin Resistance in Obese Zucker Rats
Henriksen, E. J., Jacob, S., Kinnick, T. R., Teachey, M. K., & Krekler, M. (2001) · Hypertension · doi:10.1161/hy1101.092970 · Cited by 293 · see citing works
Angiotensin Blockade Prevents Type 2 Diabetes by Formation of Fat Cells
Sharma, A. M., Janke, J., Gorzelniak, K., Engeli, S., & Luft, F. C. (2002) · Hypertension · doi:10.1161/01.hyp.0000036448.44066.53 · Cited by 283 · see citing works
Hirata, A., Maeda, N., Hiuge, A., Hibuse, T., Fujita, K., Okada, T., Kihara, S., Funahashi, T., & Shimomura, I. (2009) · Cardiovascular Research · doi:10.1093/cvr/cvp191 · Cited by 235 · see citing works
Shiuchi, T., Iwai, M., Li, H.-S., Wu, L., Min, L., Li, J., Okumura, M., Cui, T., & Horiuchi, M. (2004) · Hypertension · doi:10.1161/01.hyp.0000125142.41703.64 · Cited by 224 · see citing works
Andreozzi, F., Laratta, E., Sciacqua, A., Perticone, F., & Sesti, G. (2004) · Circulation Research · doi:10.1161/01.res.0000126501.34994.96 · Cited by 208 · see citing works
Epoxy-Keto Derivative of Linoleic Acid Stimulates Aldosterone Secretion
Goodfriend, T. L., Ball, D. L., Egan, B. M., Campbell, W. B., & Nithipatikom, K. (2004) · Hypertension · doi:10.1161/01.hyp.0000113294.06704.64 · Cited by 205 · see citing works
ACE Inhibitor Improves Insulin Resistance in Diabetic Mouse Via Bradykinin and NO
Shiuchi, T., Cui, T., Wu, L., Hironori Nakagami, A., Takeda-Matsubara, Y., Iwai, M., & Horiuchi, M. (2002) · Hypertension · doi:10.1161/01.hyp.0000028979.98877.0c · Cited by 149 · see citing works
Yamaji, M., Tsutamoto, T., Kawahara, C., Nishiyama, K., Yamamoto, T., Fujii, M., & Horie, M. (2010) · American Heart Journal · doi:10.1016/j.ahj.2010.04.024 · Cited by 129 · see citing works
Lastra, G., Whaley-Connell, A., Manrique, C., Habibi, J., Gutweiler, A. A., Appesh, L., Hayden, M. R., Wei, Y., Ferrario, C., & Sowers, J. R. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00258.2007 · Cited by 119 · see citing works
Effects of eplerenone versus losartan in patients with low-renin hypertension
Weinberger, M. H., White, W. B., Ruilope, L. M., MacDonald, T. M., Davidson, R. C., Roniker, B., Patrick, J. L., & Krause, S. L. (2005) · American Heart Journal · doi:10.1016/j.ahj.2004.12.005 · Cited by 115 · see citing works
Wada, T., Ohshima, S., Fujisawa, E., Koya, D., Tsuneki, H., & Sasaoka, T. (2008) · Endocrinology · doi:10.1210/en.2008-1018 · Cited by 113 · see citing works
Pathogenesis of weight-related changes in blood pressure in dogs.
Rocchini, A. P., Moorehead, C., DeRemer, S. J., & Bondie, D. (1989) · Hypertension · doi:10.1161/01.hyp.13.6.922 · Cited by 110 · see citing works
Aldosterone decreases glucose-stimulated insulin secretion in vivo in mice and in murine islets
Luther, J. M., Luo, P., Kreger, M. T., Brissova, M., Dai, C., Whitfield, T. T., Kim, H. S., Wasserman, D. H., Powers, A. C., & Brown, N. J. (2011) · Diabetologia · doi:10.1007/s00125-011-2158-9 · Cited by 109 · see citing works
Self-citationKraus, D., Jäger*, J., Meier, B., Fasshauer, M., & Klein, J. C. (2005) · Hormone and Metabolic Research · doi:10.1055/s-2005-870240 · Cited by 102 · see citing works
Fujimoto, M., Masuzaki, H., Tanaka, T., Yasue, S., Tomita, T., Okazawa, K., Fujikura, J., Chusho, H., Ebihara, K., Hayashi, T., et al. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.09.027 · Cited by 100 · see citing works
Relationships Among Plasma Aldosterone, High-Density Lipoprotein Cholesterol, and Insulin in Humans
Goodfriend, T. L., Egan, B. M., Stepniakowski, K. T., & Ball, D. L. (1995) · Hypertension · doi:10.1161/01.hyp.25.1.30 · Cited by 98 · see citing works
Lastra, G., Habibi, J., Whaley‐Connell, A. T., Manrique, C. M., Hayden, M. R., Rehmer, J. M., Patel, K., Ferrario, C. M., & Sowers, J. R. (2009) · Endocrinology · doi:10.1210/en.2008-1391 · Cited by 97 · see citing works
van der Zijl, N. J., Moors, C. C. M., Goossens, G. H., Hermans, M. M. H., Blaak, E. E., & Diamant, M. (2011) · Diabetes Care · doi:10.2337/dc10-2224 · Cited by 94 · see citing works
Swaminathan, K., Davies, J. I., Casella, G., Rajendra, N. S., Morris, A. D., & Struthers, A. D. (2008) · Diabetologia · doi:10.1007/s00125-008-0972-5 · Cited by 79 · see citing works
Insulin action in primary hyperaldosteronism before and after surgical or pharmacological treatment
Šindelka, G., Widimsky, J., Jr., Haas, T., Prázný, M., Hilgertová, J., & Škrha, J. (2012) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/s-0032-1329211 · Cited by 74 · see citing works
Csibi, A., Communi, D., Müller, N., & Bottari, S. P. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010070 · Cited by 73 · see citing works
Dall’Asta, C., Vedani, P., Manunta, P., Pizzocri, P., Marchi, M., Paganelli, M., Folli, F. B., & Pontiroli, A. E. (2008) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2008.06.001 · Cited by 67 · see citing works
Angiotensin II Enhances Insulin Sensitivity in Vitro and in Vivo
Juan, C., Chien, Y., Wu, L.-Y., Yang, W.-M., Chang, C.-L., Lai, Y., Ho, P., Kwok, C., & Ho, L.-T. (2005) · Endocrinology · doi:10.1210/en.2004-1136 · Cited by 53 · see citing works
Angiotensin II Affects Basal, Pulsatile, and Glucose-Stimulated Insulin Secretion in Humans
Fliser, D., Schaefer, F. S., Schmid, D., Veldhuis, J. D., & Ritz, E. (1997) · Hypertension · doi:10.1161/01.hyp.30.5.1156 · Cited by 53 · see citing works
Muñoz, M. C., Giani, J. F., Dominici, F. P., Turyn, D., & Toblli, J. E. (2009) · Journal of Hypertension · doi:10.1097/hjh.0b013e3283310e1b · Cited by 49 · see citing works
Iwai, M., Kan‐no, H., Tomono, Y., Inaba, S., Senba, I., Furuno, M., Mogi, M., & Horiuchi, M. (2010) · Journal of Hypertension · doi:10.1097/hjh.0b013e32833bc420 · Cited by 48 · see citing works
Diamond-Stanic, M. K., & Henriksen, E. J. (2010) · Archives of Physiology and Biochemistry · doi:10.3109/13813451003758703 · Cited by 47 · see citing works
Aliskiren improves insulin resistance and ameliorates diabetic vascular complications in db/db mice
Kang, Y. S., Lee, M., Song, H. K., et al. (2010) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfq579 · Cited by 43 · see citing works
Effect of captopril, losartan, and bradykinin on early steps of insulin action
Carvalho, C. R. D. O., Thirone, A. C., Gontijo, J. A. R., et al. (1997) · Diabetes · doi:10.2337/diabetes.46.12.1950 · Cited by 39 · see citing works
Analysis of Insulin Sensitivity in Adipose Tissue of Patients with Primary Aldosteronism
Urbanet, R., Pilon, C., Calcagno, A., Peschechera, A., Hubert, E.-L., Giacchetti, G., Gomez-Sanchez, C., Mulatero, P., Toffanin, M., Sonino, N., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-0097 · Cited by 38 · see citing works
Effects of renin-angiotensin system blockade on islet function in diabetic rats
Li, Y., Li, X., Xu, G., et al. (2010) · Journal of Endocrinological Investigation · doi:10.1007/bf03346544 · Cited by 35 · see citing works
Saitoh, Y., Hongwei, W., Ueno, H., Mizuta, M., & Nakazato, M. (2010) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2010.06.005 · Cited by 24 · see citing works
Leung, P. S. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-90-481-9060-7_6 · Cited by 10 · see citing works
Arase, Y., Suzuki, F., Suzuki, Y., Akuta, N., Kobayashi, M., Kawamura, Y., Yatsuji, H., Sezaki, H., Hosaka, T., Hirakawa, M., et al. (2009) · Journal of Medical Virology · doi:10.1002/jmv.21572 · Cited by 8 · see citing works
Calcium antagonist stopped in ABCD study
Husten, L. (1998) · The Lancet · doi:10.1016/s0140-6736(05)78505-6 · Cited by 4 · see citing works
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- [1]International Diabetes Federation 2006 Diabetes Atlas 3rd Edition edn International Diabetes Federation
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Rochette, L., Lorin, J., Zeller, M., Guilland, J.-C., Lorgis, L., Cottin, Y., & Vergely, C. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.07.004 · Cited by 456 · see citing works
Interaction of the endocrine system with inflammation: a function of energy and volume regulation
Straub, R. H. (2014) · Arthritis Research & Therapy · doi:10.1186/ar4484 · Cited by 121 · see citing works
“It seems that hormones of the RAAS exert these effects via intracellular induction of reactive oxygen species [71,72].”
BackgroundModulation of glucose metabolism by the renin-angiotensin-aldosterone system
Favre, G. A., Esnault, V. L. M., & Van Obberghen, E. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00391.2014 · Cited by 114 · see citing works
Aldosterone excess impairs first phase insulin secretion in primary aldosteronism
Fischer, E., Adolf, C., Pallauf, A., Then, C., Bidlingmaier, M., Beuschlein, F., Seissler, J., & Reincke, M. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3934 · Cited by 88 · see citing works
Loloi, J., Miller, A. J., Bingaman, S. S., Silberman, Y., & Arnold, A. C. (2018) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00281.2018 · Cited by 30 · see citing works
Luther, J. M., Byrne, L. M., Yu, C., Wang, T. J., & Brown, N. J. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-2122 · Cited by 26 · see citing works
Self-citation
- Authors
- Luther, J. M., & Brown, N. J.
- Affiliations
- Vanderbilt University Medical Center (US)
- Venue
- Trends in Pharmacological Sciences
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 32
- Issue
- 12
- Pages
- 734-739
- ISSN
- 0165-6147 (ISSN-L)
- PMC
- PMC3223326
- OpenAlex
- W2092003450
- Cited by
- 185
- References
- 64
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 12 · 2023: 21 · 2022: 11 · 2021: 11 · 2020: 14 · 2019: 8 · 2018: 15 · 2017: 9 · 2016: 10 · 2015: 7 · 2014: 12 · 2013: 18 · 2012: 12
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Trends in Pharmacological Sciences (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL060906)
- National Institute of Diabetes and Digestive and Kidney Diseases (K23DK081662)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- renin-angiotensin-aldosterone system, glucose homeostasis, angiotensin II, aldosterone, insulin resistance, oxidative stress, insulin signaling, glucose transport, pancreatic beta cells, apoptosis, inflammation, mineralocorticoid receptor, glucose-stimulated insulin secretion, diabetes prevention, obesity
- MeSH terms
- Angiotensin-Converting Enzyme Inhibitors, Animals, Diabetes Mellitus, Humans, Insulin Resistance, Obesity, Renin-Angiotensin System, Glucose Metabolism Disorders, Angiotensin II Type 1 Receptor Blockers, Insulin-Secreting Cells, Molecular Targeted Therapy
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