Modulation of insulin resistance by renin angiotensin system inhibitors: implications for cardiovascular prevention



Insulin resistance (IR) and the related hyperinsulinamia play a key role in the genesis and progression of the continuum of cardiovascular (CV) disease. Thus, it is reasonable to pursue in primary and secondary CV prevention, the pharmacological strategies that are capable to interfere with the development of IR. The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathogenesis of IR. In particular, angiotensin II (Ang II) through the generation of reactive oxygen species, induces a low grade of inflammation, which impairs the insulin signal transduction. The angiotensin converting enzyme (ACE) inhibitors are effective not only as blood pressure-lowering agents, but also as modulators of metabolic abnormalities. Indeed, experimental evidence indicates that in animal models of IR, ACE inhibitors are capable to ameliorate the insulin sensitivity. The Ang II receptor blockers (ARBs) modulate the peroxisome proliferator-activated receptor (PPAR)-γ activity. PPAR–γ is a transcription factor that controls the gene expression of several key enzymes of glucose metabolism. A further mechanism that accounts for the favorable metabolic properties of ARBs is the capability to modulate the hypothalamic–pituitary-adrenal (HPA) axis. The available clinical evidence is consistent with the concept that both ACE inhibitors and ARBs are able to interfere with the development of IR and its consequences like type 2 diabetes. In addition, pharmacological inhibition of the RAAS has favourable effects on dyslipidaemias, metabolic syndrome and obesity. Therefore, the pharmacological antagonism of the RAAS, nowadays, represents the first choice in the prevention of cardio-metabolic diseases.



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Reaven G. The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. EndocrinolMetabClin North Am 2004;33:283-303. DOI:

Olefsky J, Farquhar JW, Reaven G. Relationship between fasting plasma insulin level and resistance to insulin-mediated glucose uptake in normal and diabetic subjects. Diabetes 1973;22:507-13. DOI:

Sowers JR, Standley PR, Ram JL, et al. Hyperinsulinemia, insulin resistance, and hyperglycemia: contributing factors in the pathogenesis of hypertension and atherosclerosis. Am J Hypertens 1993;6:260S-70. DOI:

Wierzbicki AS, Oben J. Nonalcoholic fatty liver disease and lipids. Curr Opin Lipidol 2012;23:345-52. DOI:

Verdecchia P, Reboldi G, Schillaci G, et al. Circulating insulin and insulin growth factor-1 are independent determinants of left ventricular mass and geometry in essential hypertension. Circulation 1999;100:1802-7. DOI:

Xu H, Carrero JJ. Insulin resistance in chronic kidney disease. Nephrology (Carlton) 2017;224:31-4. DOI:

DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia 2010;53:1270-7.

Strisciuglio T, Izzo R, Barbato E, et al. Insulin resistance predicts severity of coronary atherosclerotic disease in non-diabetic patients. J Clin Med 2020;9:2144. DOI:

Lempiäinen P, Mykkänen L, Pyörälä K, et al. Insulin resistance syndrome predicts coronary heart disease events in elderly nondiabetic men. Circulation 1999;100:123-8. DOI:

Jing J, Pan Y, Zhao X, et al. insulin resistance and prognosis of nondiabetic patients with ischemic stroke: The ACROSS-China Study (Abnormal Glucose Regulation in patients with acute stroke across China). Stroke 2017;48:887-93. DOI:

Ago T, Matsuo R, Hata J, et al. Insulin resistance and clinical outcomes after acute ischemic stroke. Neurology 2018;90:e1470-7. DOI:

Uetani T, Amano T, Harada K, et al. Impact of insulin resistance on post-procedural myocardial injury and clinical outcomes in patients who underwent elective coronary interventions with drug-eluting stents. JACC Cardiovasc Interv 2012;5:1159-67. DOI:

Swan JW, Anker SD, Walton C, et al. Insulin resistance in chronic heart failure: relation to severity and etiology of heart failure. J Am Coll Cardiol 1997;30:527-32. DOI:

Morisco C, Lembo G, Trimarco B. Insulin resistance and cardiovascular risk: New insights from molecular and cellular biology. Trends Cardiovasc Med 2006;16:183-8. DOI:

Fiordelisi A, Iaccarino G, Morisco C, et al. NFkappaB is a key player in the crosstalk between inflammation and cardiovascular diseases. Int J Mol Sci 2019;20:1599. DOI:

Erdös EG. Angiotensin I convertingenzyme. Circ Res 1975;36:247-55. DOI:

Fryer LG, Hajduch E, Rencurel F, et al. Activation of glucose transport by AMP-activated protein kinase via stimulation of nitric oxide synthase. Diabetes 2000;49:1978-85. DOI:

Henriksen EJ, Jacob S, Kinnick TR, et al. ACE inhibition and glucose transport in insulinresistant muscle: roles of bradykinin and nitric oxide. Am J Physiol 1999;277:R332-6. DOI:

Morel Y, Gadient A, Keller U, et al. Insulin sensitivity in obese hypertensive dyslipidemic patients treated with enalapril or atenolol. J Cardiovasc Pharmacol 1995;26:306-11. DOI:

Pollare T, Lithell H, Berne C. A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med 1989;321:868-73. DOI:

Sharma AM, Janke J, Gorzelniak K, et al. Angiotensin blockade prevents type 2 diabetes by formation of fat cells. Hypertension 2002;40:609-11. DOI:

Carlsson PO, Berne C, Jansson L. Angiotensin II and the endocrine pancreas: effects on islet blood flow and insulin secretion in rats. Diabetologia 1998;41:127-33. DOI:

Arbin V, Claperon N, Fournié-Zaluski MC, et al. Acute effect of the dual angiotensin-converting enzyme and neutral endopeptidase 24-11 inhibitor mixanpril on insulin sensitivity in obese Zucker rat. Br J Pharmacol 2001;133:495-502. DOI:

Uehara M, Kishikawa H, Isami S, et al. Effect on insulin sensitivity of angiotensin converting enzyme inhibitors with or without a sulphydryl group: bradykinin may improve insulin resistance in dogs and humans. Diabetologia 1994;37:300-7. DOI:

Dal Ponte DB, Fogt DL, Jacob S, Henriksen EJ. Interactions of captopril and verapamil on glucose tolerance and insulin action in an animal model of insulin resistance. Metabolism 1998;47:982-7. DOI:

Steen MS, Foianini KR, Youngblood EB, et al. Interactions of exercise training and ACE inhibition on insulin action in obese Zucker rats. J Appl Physiol (1985) 1999;86:2044-51. DOI:

Nawano M, Anai M, Funaki M, et al. Imidapril, an angiotensin-converting enzyme inhibitor, improves insulin sensitivity by enhancing signal transduction via insulin receptor substrate proteins and improving vascular resistance in the Zucker fatty rat. Metabolism 1999;48:1248-55. DOI:

Shiuchi T, Cui TX, Wu L, et al. ACE inhibitor improves insulin resistance in diabetic mouse via bradykinin and NO. Hypertension 2002;40:329-34. DOI:

Henriksen EJ, Jacob S. Effects of captopril on glucose transport activity in skeletal muscle of obese Zucker rats. Metabolism 1995;44:267-72. DOI:

Jacob S, Henriksen EJ, Fogt DL, Dietze GJ. Effects of trandolapril and verapamil on glucose transport in insulin-resistant rat skeletal muscle. Metabolism 1996;45:535-41. DOI:

Rett K, Wicklmayr M, Dietze GJ, Häring HU. Insulin-induced glucose transporter (GLUT1 and GLUT4) translocation in cardiac muscle tissue is mimicked by bradykinin. Diabetes 1996;45:S66-9. DOI:

Mazzone G, Morisco C, Lembo V, et al. Dietary supplementation of vitamin D prevents the development of western diet-induced metabolic, hepatic and cardiovascular abnormalities in rats. United European Gastroenterol J 2018;6:1056-64. DOI:

Toblli JE, Muñoz MC, Cao G, et al. ACE inhibition and AT1 receptor blockade prevent fatty liver and fibrosis in obese Zucker rats. Obesity (Silver Spring) 2008;16:770-6. DOI:

Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999;353:611-6. DOI:

Heart Outcomes Prevention Evaluation Study Investigators, Yusuf S, Sleight P, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. [Errata in: in 2000 May 4;342:1376 - N Engl J Med 2000;342:748]. N Engl J Med 2000;342:145-53. DOI:

ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [Errata in JAMA 2003;289:178 - JAMA 2004;291:2196]. JAMA 2002;288:2981-97. DOI:

Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351:2058-68. DOI:

Borém LMA, Neto JFR, Brandi IV, et al. The role of the angiotensin II type I receptor blocker telmisartan in the treatment of non-alcoholic fatty liver disease: a brief review. Hypertens Res 2018;41:394-405. DOI:

Schupp M, Janke J, Clasen R, et al. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation 2004;109:2054-57. DOI:

Schupp M, Lee LD, Frost N, et al. Regulation of peroxisome proliferator-activated receptor gamma activity by losartan metabolites. Hypertensio. 2006;47:586-9. DOI:

Guerre-Millo M, Gervois P, RAASpé E, et al. Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem 2000;275:16638-42. DOI:

Chou CJ, Haluzik M, Gregory C, et al. WY14,643, a peroxisome proliferator-activated receptor alpha (PPARalpha ) agonist, improves hepatic and muscle steatosis and reverses insulin resistance in lipoatrophic A-ZIP/F-1 mice. J Biol Chem 2002;277:24484-9. DOI:

Müller-Fielitz H, Hübel N, Mildner M, et al. Chronic blockade of angiotensin AT₠receptors improves cardinal symptoms of metabolic syndrome in diet-induced obesity in rats. Br J Pharmacol 2014;171:746-60. DOI:

Abuissa H, Jones PG, Marso SP, O'Keefe JH Jr. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials. J Am Coll Cardiol 2005;46:821-6. DOI:

Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis [Erratum in: Lancet 2007;369:1518]. Lancet 2007;369:201-7.

Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators, Yusuf S, Teo K, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial [Erratum in: Lancet 2008;372:1384] Lancet 2008;372:1174-83. DOI:

Carpinella G, Pagano G, Buono F, et al. Prognostic value of combined target-organ damage in patients with essential hypertension. Am J Hypertens 2015;28:127-34. DOI:

Daugherty A, Rateri DL, Lu H, et al. Hypercholesterolemia stimulates angiotensin peptide synthesis and contributes to atherosclerosis through the AT1A receptor. Circulation 2004;110:3849-57. DOI:

Kanome T, Watanabe T, Nishio K, et al. Angiotensin II upregulates acyl-CoA: cholesterol acyltransfeRAASe-1 via the angiotensin II Type 1 receptor in human monocyte-macrophages. Hypertens Res 2008;31:1801-10. DOI:

Putnam K, Shoemaker R, Yiannikouris F, Cassis LA. The renin-angiotensin-aldosterone system: a target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome. Am J Physiol Heart Circ Physiol 2012;302:H1219-30. DOI:

Li D, Saldeen T, Romeo F, Mehta JL. Oxidized LDL upregulates angiotensin II type 1 receptor expression in cultured human coronary artery endothelial cells: the potential role of transcription factor NF-kappaB. Circulation 2000;102:1970-6. DOI:

Buono F, Spinelli L, Giallauria F, et al. Usefulness of satisfactory control of low-density lipoprotein cholesterol to predict left ventricular remodeling after a first ST-elevation myocardial infarction successfully reperfused. Am J Cardio. 2011;107:1772-8. DOI:

Kyvelou SM, Vyssoulis GP, Karpanou EA, et al. Effects of antihypertensive treatment with angiotensin II receptor blockers on lipid profile: an open multi-drug comparison trial. Hellenic J Cardiol 2006;47:21-8.

Olsen MH, Wachtell K, Beevers G, et al. Effects of losartan compared with atenolol on lipids in patients with hypertension and left ventricular hypertrophy: the Losartan Intervention For Endpoint reduction in hypertension study. J Hypertens 2009;27:567574. DOI:

Lindholm LH, Persson M, Alaupovic P, et al. Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study). J Hypertens 2003;21:1563-74. DOI:

Parhofer KG, Münzel F, Krekler M. Effect of the angiotensin receptor blocker irbesartan on metabolic parameters in clinical practice: the DO-IT prospective observational study. Cardiovasc Diabetol 2007;6:36. DOI:

Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995;91:2844-50. DOI:

Celi A, Cianchetti S, Dell'Omo G, Pedrinelli R. Angiotensin II, tissue factor and the thrombotic paradox of hypertension. Expert Rev Cardiovasc Ther 2010;8:1723-9. DOI:

Gigante B, Bellis A, Visconti R, et al. Retrospective analysis of coagulation factor II receptor (F2R) sequence variation and coronary heart disease in hypertensive patients. Arterioscler Thromb Vasc Biol 2007;27:1213-9. DOI:

Yi X, Wu P, Liu J, et al.. Identification of the potential key genes for adipogenesis from human mesenchymal stem cells by RNA-seq. J Cell Physiol 2019;234 20217-27. DOI:

Buono F, Crispo S, Pagano G, et al. Determinants of left ventricular hypertrophy in patients with recent diagnosis of essential hypertension. J Hypertens 2014;32:166-73. DOI:

Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med 2002;347:305-13. DOI:

Rexrode KM, Carey VJ, Hennekens CH, et al. Abdominal adiposity and coronary heart disease in women. JAMA 1998;280:1843-8. DOI:

Pazos F. Range of adiposity and cardiorenal syndrome. World J Diabetes 2020;11:322-50. DOI:

Nistala R, Whaley-Connell A. Resistance to insulin and kidney disease in the cardiorenal metabolic syndrome; role for angiotensin II. Mol Cell Endocrinol 2013;378:53-8. DOI:

Meccariello A, Buono F, Verrengia E, et al. Microalbuminuria predicts the recurrence of cardiovascular events in patients with essential hypertension. J Hypertens 2016;34:646-53. DOI:

Gerstein HC, Mann JF, Yi Q, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 2001;286:421-6. DOI:

Lau DC, Dhillon B, Yan H, et al. Adipokines: molecular links between obesity and atheroslcerosis. Am J Physiol Heart Circ Physiol 2005;288:H2031-41. DOI:

Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004;92:347355. DOI:

Jones BH, Standridge MK, Taylor JW, Moustaïd N. Angiotensinogen gene expression in adipose tissue: analysis of obese models and hormonal and nutritional control. Am J Physiol 1997;273:R236-42. DOI:

Engeli S, Sharma AM. Role of adipose tissue for cardiovascular-renal regulation in health and disease. Horm Metab Res 2000;32:485-99. DOI:

Gorzelniak K, Engeli S, Janke J, Luft FC, Sharma AM. Hormonal regulation of the human adipose-tissue renin-angiotensin-aldosterone system: relationship to obesity and hypertension. J Hypertens 2002;20:965-73. DOI:

Sola S, Mir MQ, Cheema FA, et al. Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study. Circulation 2005;111:343-8. DOI:

Bähr IN, Tretter P, Krüger J, et al. High-dose treatment with telmisartan induces monocytic peroxisome proliferator-activated receptor-γ target genes in patients with the metabolic syndrome. Hypertension 2011;58:725-32. DOI:

Martinez-Martin FJ, Rodriguez-Rosas H, Peiro-Martinez I, et al. Olmesartan/amlodipine vs olmesartan/hydrochlorothiazide in hypertensive patients with metabolic syndrome: the OLAS study. J Hum Hypertens 2011;25:346-53. DOI:

Fernandes T, Hashimoto NY, Magalhães FC, et al. Aerobic exercise training-induced left ventricular hypertrophy involves regulatory MicroRNAs, decreased angiotensin-converting enzyme-angiotensin ii, and synergistic regulation of angiotensin-converting enzyme 2-angiotensin (1-7). Hypertension 2011;58:182-9. DOI:

Iaccarino G, Franco D, Sorriento D, et al. Modulation of insulin sensitivity by exercise training: Implications for cardiovascular prevention. J Cardiovasc Transl Res 2020. doi: 10.1007/s12265-020-10057-w. Online ahead of print. DOI:

Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:537-44. DOI:

Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;34:1343-50. DOI:

Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403. DOI:

Hamman RF, Wing RR, Edelstein SL, et al. Effect of weight loss with lifestyle intervention on risk of diabetes. Diabetes Care 2006;29:2102-7. DOI:

Lao XQ, Deng HB, Liu X, et al. Increased leisure-time physical activity associated with lower onset of diabetes in 44 828 adults with impaired fasting glucose: a population-based prospective cohort study. Br J Sports Med 2019;53:895-900. DOI:

Aune D, Norat T, Leitzmann M, et al. Physical activity and the risk of type 2 diabetes: a systematic review and dose-response meta-analysis. Eur J Epidemiol 2015;30:529-42. DOI:

Orozco LJ, Buchleitner AM, Gimenez-Perez G, et al. Exercise or exercise and diet for preventing type 2 diabetes mellitus. Cochrane Database Syst Rev 2008;(3):CD003054. DOI:

Chudyk A, Petrella RJ. Effects of exercise on cardiovascular risk factors in type 2 diabetes: a meta-analysis. Diabetes Care 2011;34:1228-37. DOI:

Campbell WW, Kraus WE, Powell KE, et al. High-intensity interval training for cardiometabolic disease prevention. Med Sci Sports Exerc 2019;5:1220-6. DOI:

American Diabetes Association. 3. Prevention or delay of type 2 diabetes: Standards of medical care in diabetes-2020. Diabetes Care 2020;43:S32-6. DOI:

Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2007;30:162-72. DOI:

Borges L, Passos MEP, Silva MBB, et al. Dance training improves cytokine secretion and viability of neutrophils in diabetic patients. Mediators Inflamm 2019;2019:2924818 DOI:

Melo KCB, Araújo FS, Cordeiro Júnior CCM, et al. Pilates method training: functional and blood glucose responses of older women with type 2 diabetes. J Strength Cond Res 2020;34:1001-7. DOI:

Cugusi L, Cadeddu C, Nocco S, et al. Effects of an aquatic-based exercise program to improve cardiometabolic profile, quality of life, and physical activity levels in men with type 2 diabetes mellitus. PM R 2015;7:141-8; quiz 148. DOI:

Krishnan S, Tokar TN, Boylan MM, et al. Zumba® dance improves health in overweight/obese or type 2 diabetic women. Am J Health Behav 2015;39:109-20. DOI:

Crisafulli A, Pagliaro P, Roberto S, et al. Diabetic cardiomyopathy and ischemic heart disease: Prevention and therapy by exercise and conditioning. Int J Mol Sci 2020;21:2896. DOI:

Colaiori I, Izzo R, Barbato E, et al. Severity of coronary atherosclerosis and risk of diabetes mellitus. J Clin Med 2019;8:1069. DOI:

Izzo R, de Simone G, Chinali M, et al. Insufficient control of blood pressure and incident diabetes. Diabetes Care 2009;32:845-50. DOI:

Izzo R, de Simone G, Trimarco V, et al. Hypertensive target organ damage predicts incident diabetes mellitus. Eur Heart J 2013;34:3419-26. DOI:


Cardiology - Reviews
ACE inhibitors, Angiotensin II receptor blockers, Type 2 diabetes, Metabolic syndrome, Obesity, Atherosclerosis, Vascular inflammation
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How to Cite
Valente, Valeria, Raffaele Izzo, Maria Virginia Manzi, Maria Rosaria De Luca, Emanuele Barbato, and Carmine Morisco. 2021. “Modulation of Insulin Resistance by Renin Angiotensin System Inhibitors: Implications for Cardiovascular Prevention”. Monaldi Archives for Chest Disease 91 (2).

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