Drugs

, Volume 64, Issue 22, pp 2537–2565 | Cite as

Prevention of Type 2 Diabetes Mellitus Through Inhibition of the Renin-Angiotensin System

Review Article

Abstract

Type 2 diabetes mellitus is becoming a major health problem associated with excess morbidity and mortality. As the prevalence of type 2 diabetes is rapidly increasing, prevention of the disease should be considered as a key objective in the near future. Besides lifestyle changes, various pharmacological treatments have proven their efficacy in placebo-controlled clinical trials, including antidiabetic drugs such as metformin, acarbose and troglitazone, or antiobesity agents such as orlistat. Arterial hypertension, a clinical entity in which insulin resistance is common, is strongly associated with type 2 diabetes and may precede the disease by several years. While antihypertensive agents such as diuretics or β-adrenoceptor antagonists may worsen insulin resistance and impair glucose tolerance, newer antihypertensive agents exert neutral or even slightly positive metabolic effects. Numerous clinical trials have investigated the effects of ACE inhibitors or angiotensin II receptor antagonists (ARAs) on insulin sensitivity in hypertensive patients, with or without diabetes, with no consistent results. Almost half of the studies with ACE inhibitors in hypertensive nondiabetic individuals demonstrated a slight but significant increase in insulin sensitivity as assessed by insulin-stimulated glucose disposal during a euglycaemic hyperinsulinaemic clamp, while the other half failed to reveal any significant change. The effects of ARAs on insulin sensitivity are neutral in most studies.

Mechanisms of improvement of glucose tolerance and insulin sensitivity through the inhibition of the renin-angiotensin system (RAS) are complex. They may include improvement of blood flow and microcirculation in skeletal muscles and, thereby, enhancement of insulin and glucose delivery to the insulin-sensitive tissues, facilitating insulin signalling at the cellular level and improvement of insulin secretion by the β cells.

Six recent large-scale clinical studies reported a remarkably consistent reduction in the incidence of type 2 diabetes in hypertensive patients treated with either ACE inhibitors or ARAs for 3–6 years, compared with a thiazide diuretic, β-adrenoceptor antagonist, the calcium channel antagonist amlodipine or even placebo. The relative risk reduction averaged 14% (p = 0.034) in the CAPPP (Captopril Prevention Project) with captopril compared with a thiazide or β1-adrenoceptor antagonist, 34% (p < 0.001) in the HOPE (Heart Outcomes Prevention Evaluation) study with ramipril compared with placebo, 30% (p < 0.001) in the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) with lisinopril compared with chlortalidone, 25% (p < 0.001) in the LIFE (Losartan Intervention For Endpoint reduction in hypertension study) with losartan compared with atenolol, and 25% (p = 0.09) in the SCOPE (Study on Cognition and Prognosis in the Elderly) with candesartan cilexetil compared with placebo, and 23% (p < 0.0001) in the VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trial with valsartan compared with amlodipine. All these studies considered the development of diabetes as a secondary endpoint, except the HOPE trial where it was a post hoc analysis. These encouraging observations led to the initiation of two large, prospective, placebo-controlled randomised clinical trials whose primary outcome is the prevention of type 2 diabetes: the DREAM (Diabetes REduction Approaches with ramipril and rosiglitazone Medications) trial with the ACE inhibitor ramipril and the NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research) trial with the ARA valsartan. Finally, ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) will also investigate as a secondary endpoint whether it is possible to prevent the development of type 2 diabetes by blocking the RAS with either an ACE inhibitor or an ARA or a combination of both. Thus, the recent consistent observations of a 14–34% reduction of the development of diabetes in hypertensive patients receiving ACE inhibitors or ARAs are exciting. From a theoretical point of view, they emphasise that there are many aspects of the pathogenesis, prevention and treatment of type 2 diabetes that still need to be uncovered. From a practical point of view, they may offer a new strategy to reduce the ongoing epidemic and burden of type 2 diabetes.

References

  1. 1.
    Harris MI. Health care and health status and outcomes for patients with type 2 diabetes. Diabetes Care 2000; 23: 754–8PubMedCrossRefGoogle Scholar
  2. 2.
    Massi-Benedetti M, editor. The cost of diabetes type II in Europe: the CODE-2 study. Diabetologia 2002; 45 Suppl. 1: S1–28PubMedCrossRefGoogle Scholar
  3. 3.
    Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease. Hypertension 2001; 37: 1053–9PubMedCrossRefGoogle Scholar
  4. 4.
    Harris R, Donahue K, Rathore SS, et al. Screening adults for type 2 diabetes: a review of the evidence for the US Preventive Services Task Force. Ann Intern Med 2003; 138: 215–29PubMedGoogle Scholar
  5. 5.
    Scheen AJ, Lefèbvre PJ. Pathophysiology of type 2 diabetes. In: Kuhlmann J, Puls W, editors. Handbook of experimental pharmacology, oral antidiabetics. Berlin: Springer Verlag, 1996: 7–42Google Scholar
  6. 6.
    King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care 1998; 21: 1414–31PubMedCrossRefGoogle Scholar
  7. 7.
    Scheen AJ, Lefèbvre PJ. Insulin resistance versus insulin deficiency: which one comes first? The old question revisited. In: Di Mario U, Leonetti F, Pugliese G, et al., editors. Diabetes in the new millennium. New York: Wiley & Sons, 2000: 101–13Google Scholar
  8. 8.
    Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 2003; 46: 3–19PubMedCrossRefGoogle Scholar
  9. 9.
    The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20: 1183–97Google Scholar
  10. 10.
    Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595–607PubMedCrossRefGoogle Scholar
  11. 11.
    DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173–94PubMedCrossRefGoogle Scholar
  12. 12.
    McFarlane SI, Banerji M, Sowers JR. Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 2001; 86: 713–8PubMedCrossRefGoogle Scholar
  13. 13.
    Medalie JH, Papier CM, Goldbourt U, et al. Major factors in the development of diabetes mellitus in 10,000 men. Arch Intern Med 1975; 135: 811–7PubMedCrossRefGoogle Scholar
  14. 14.
    Skarfors ET, Selinus KI, Lithell HO. Risk factors for developing non-insulin dependent diabetes: a 10 year follow up of men in Uppsala. BMJ 1991; 303: 755–60PubMedCrossRefGoogle Scholar
  15. 15.
    Morales PA, Mitchell BD, Valdez RA, et al. Incidence of NIDDM and impaired glucose tolerance in hypertensive subjects: the San Antonio Heart Study. Diabetes 1993; 42: 154–61PubMedCrossRefGoogle Scholar
  16. 16.
    Hypertension in Diabetes Study (HDS). I: prevalence of hypertension in newly presenting type 2 diabetic patients and the association with risk factors for cardiovascuar and diabetic complications. J Hypertens 1993; 11: 309–17CrossRefGoogle Scholar
  17. 17.
    Mykkanen L, Haffner SM, Kuusisto J, et al. Microalbuminuria precedes the development of NIDDM. Diabetes 1994; 43: 552–7PubMedCrossRefGoogle Scholar
  18. 18.
    WHO Study Group. Prevention of diabetes mellitus: report of WHO study group. World Health Organ Tech Rep Ser 1994; 844: 1–100Google Scholar
  19. 19.
    Donelly R, Garber A, editors. Progression of type 2 diabetes: inevitable or preventable? Diabetes Obes Metab 2001; 3 Suppl. 1: S1–S43CrossRefGoogle Scholar
  20. 20.
    American Diabetes Association and National Institute of Diabetes, Digestive and Kidney Diseases. The prevention or delay of type 2 diabetes. Diabetes Care 2002; 25: 742–9CrossRefGoogle Scholar
  21. 21.
    Tuomilehto J, Lindström J, Ericksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance: Finnish Diabetes Prevention Study Group. N Engl J Med 2001; 344: 1343–50PubMedCrossRefGoogle Scholar
  22. 22.
    Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393–403CrossRefGoogle Scholar
  23. 23.
    Scheen AJ. Current management strategies for coexisting diabetes mellitus and obesity. Drugs 2003; 63: 1165–84PubMedCrossRefGoogle Scholar
  24. 24.
    Scheen AJ, Paquot N, Letiexhe MR, et al. Approches pharmacologiques de prévention du diabète de type 2. Med Hyg 2002; 60: 1480–4Google Scholar
  25. 25.
    Freemark M. Pharmacologic approaches to the prevention of type 2 diabetes in high risk pédiatric patients. J Clin Endocrinol Metab 2003; 88: 3–13PubMedCrossRefGoogle Scholar
  26. 26.
    Chiasson J-L, Josse RG, Gomis R, et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial: the STOP-NIDDM Trial Research Group. Lancet 2002; 359: 2072–7PubMedCrossRefGoogle Scholar
  27. 27.
    Scheen AJ. Is there a role for α-glucosidase inhibitors in the prevention of type 2 diabetes? Drugs 2003; 63: 933–51PubMedCrossRefGoogle Scholar
  28. 28.
    Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 2002; 51: 2796–803PubMedCrossRefGoogle Scholar
  29. 29.
    Keating GM, Jarvis B. Orlistat: in the prevention and treatment of type 2 diabetes mellitus. Drugs 2001; 61: 2107–19PubMedCrossRefGoogle Scholar
  30. 30.
    Torgerson JS, Hauptman J, Boldrin MN, et al. Xenical in the prevention of diabetes in obese subjects (XENDOS) study: a randomised study of orlistat as an adjunct to lifestyle for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004; 27: 155–61PubMedCrossRefGoogle Scholar
  31. 31.
    Paquot N, Scheen AJ, Lefèbvre PJ. Contribution hémodynamique à l’insulinorésistance: du concept physiopathologique aux perspectives thérapeutiques. Med Hyg 1995; 53: 1633–7Google Scholar
  32. 32.
    Scheen AJ. Le concept d’insulinosensibilité. Diabetes Metab 2001; 27: 193–200PubMedGoogle Scholar
  33. 33.
    Wheatcroft SB, Williams IL, Shah AM, et al. Pathophysiological implications of insulin resistance on vascular endothelial function. Diabet Med 2003; 20: 255–68PubMedCrossRefGoogle Scholar
  34. 34.
    Lefèbvre PJ, Scheen AJ. Improving the action of insulin. Clin Invest Med 1995; 18: 340–7PubMedGoogle Scholar
  35. 35.
    Katovich MJ, Pachori A. Effects of inhibition of the renin-angiotensin system on the cardiovascular actions of insulin. Diabetes Obes Metab 2000; 2: 3–14PubMedCrossRefGoogle Scholar
  36. 36.
    Carey RM, Siragy HM. Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation. Endocr Rev 2003; 24: 261–71PubMedCrossRefGoogle Scholar
  37. 37.
    Zanella MT, Salgado BJ, Kohlmann Jr O, et al. Angiotensin-converting enzyme (ACE) inhibition: therapeutic option for diabetic hypertensive patients. Drugs 1990; 39 Suppl. 2: 33–9PubMedCrossRefGoogle Scholar
  38. 38.
    Kaplan NM. Management of hypertension in patients with type 2 diabetes mellitus: guidelines based on current evidence. Ann Intern Med 2001; 135: 1079–83PubMedGoogle Scholar
  39. 39.
    Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. The JNC 7 report. JAMA 2003; 289: 2560–72Google Scholar
  40. 40.
    Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy: The Collaborative Group. N Engl J Med 1993; 329: 1456–62PubMedCrossRefGoogle Scholar
  41. 41.
    Yki-Järvinen H. Management of type 2 diabetes mellitus and cardiovascular risk: lessons from intervention trials. Drugs 2000; 60: 975–83PubMedCrossRefGoogle Scholar
  42. 42.
    Podar T, Tuomilehto J. The role of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists in the management of diabetic complications. Drugs 2002; 62: 2007–12PubMedCrossRefGoogle Scholar
  43. 43.
    Gilbert RE, Krum H, Wilkinson-Berka J, et al. The renin-angiotensin system and the long-term complications of diabetes: pathophysiological and therapeutic considerations. Diabet Med 2003; 20: 607–21PubMedCrossRefGoogle Scholar
  44. 44.
    Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861–9PubMedCrossRefGoogle Scholar
  45. 45.
    Pollare TG, 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: 868–73PubMedCrossRefGoogle Scholar
  46. 46.
    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: 611–6PubMedCrossRefGoogle Scholar
  47. 47.
    Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients: the Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342: 145–53PubMedCrossRefGoogle Scholar
  48. 48.
    Yusuf S, Gerstein H, Hoogwerf B, et al. Ramipril and the development of diabetes. JAMA 2001; 286: 1882–5PubMedCrossRefGoogle Scholar
  49. 49.
    The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. 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). JAMA 2002; 288: 2981–97CrossRefGoogle Scholar
  50. 50.
    Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For End-point reduction in hypertension study (LIFE): a randomised trial against atenolol. The LIFE Study Group. Lancet 2002; 359: 995–1003Google Scholar
  51. 51.
    Lindholm LH, Ibsen H, Borch-Johnsen K, et al. Risk of new onset-diabetes in the Losartan Intervention For Endpoint reduction in hypertension study: the LIFE Study Group. J Hypertens 2002; 20: 1879–86PubMedCrossRefGoogle Scholar
  52. 52.
    Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. The SCOPE Study Group. J Hypertens 2003; 21: 875–86Google Scholar
  53. 53.
    Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipidne: the VALUE randomised trial. Lancet 2004; 363: 2022–31PubMedCrossRefGoogle Scholar
  54. 54.
    Scheen AJ, Paquot N, Castillo MJ, et al. How to measure insulin action in vivo. Diabetes Metab Rev 1994; 10: 151–88PubMedCrossRefGoogle Scholar
  55. 55.
    Modan M, Halkin H, Almog S, et al. Hyperinsulinemia: a link between hypertension, obesity, and glucose intolerance. J Clin Invest 1985; 75: 809–17PubMedCrossRefGoogle Scholar
  56. 56.
    Ferrannini E, Buzzigoli G, Bonadonna R, et al. Insulin resistance in essential hypertension. N Engl J Med 1987; 317: 350–7PubMedCrossRefGoogle Scholar
  57. 57.
    Swislocki ALM, Hoffman BB, Reaven GM. Insulin resistance, glucose intolerance and hyperinsulinemia in patients with hypertension. Am J Hypertens 1989; 2: 419–23PubMedGoogle Scholar
  58. 58.
    Ferrari P, Weidmann P. Insulin, insulin sensitivity, and hypertension. J Hypertens 1990; 8: 491–500PubMedCrossRefGoogle Scholar
  59. 59.
    Bühler FR, Julius S, Reaven GM, et al. A dimension in hypertension: role of insulin resistance. J Cardiovasc Pharmacol 1990; 15 Suppl. 5: S1–3PubMedGoogle Scholar
  60. 60.
    Donahue RP, Skyler JS, Schneiderman B, et al. Hyperinsulinemia and elevated blood pressure: cause, confounder, or coincidence? Am J Epidemiol 1990; 132: 827–36PubMedGoogle Scholar
  61. 61.
    Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities: the role of insulin resistance and the sympathoadrenal system. N Engl J Med 1996; 334: 374–81PubMedCrossRefGoogle Scholar
  62. 62.
    Landsberg L. Insulin resistance and hypertension. Clin Exp Hypertens 1999; 21: 885–94PubMedCrossRefGoogle Scholar
  63. 63.
    Julius S, Gudbrandsson T, Jamerson K, et al. The haemodynamic link between insulin resistance and hypertension. J Hypertens 1991; 9: 983–6PubMedCrossRefGoogle Scholar
  64. 64.
    Baron AD, Bretchel-Hook G, Johnson A, et al. Skeletal muscle blood flow: a possible link between insulin resistance and blood pressure. Hypertension 1992; 21: 129–35CrossRefGoogle Scholar
  65. 65.
    Olsen MH, Andersen UB, Wachtell K, et al. A possible link between endothelial dysfunction and insulin resistance in hypertension: a LIFE substudy. Losartan Intervention For End-point-Reduction in Hypertension. Blood Press 2000; 9: 132–9Google Scholar
  66. 66.
    Gaboury CL, Simonson DC, Seely EW, et al. Relation of pressor responsiveness to angiotensin II and insulin resistance in hypertension. J Clin Invest 1994; 94: 2295–3000PubMedCrossRefGoogle Scholar
  67. 67.
    Gress TW, Nieto FJ, Shahar E, et al. Hypertension and anti-hypertensive therapy as risk factors for type 2 diabetes mellitus: the Atherosclerosis Risk in Communities Study. N Engl J Med 2000; 342: 905–12PubMedCrossRefGoogle Scholar
  68. 68.
    Psaty BM, Smith NL, Siscivick DS, et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA 1997; 277: 739–45PubMedCrossRefGoogle Scholar
  69. 69.
    Blood Pressure Lowering Treatment Trialist’s Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet 2000; 355: 1955–64CrossRefGoogle Scholar
  70. 70.
    Shapiro AP, Benedek TG, Small JL. Effect of thiazides on carbohydrate metabolism in patients with hypertension. N Engl J Med 1961; 265: 1028–33CrossRefGoogle Scholar
  71. 71.
    Bengtsson C, Blohme G, Lapidus L, et al. Do antihypertensive drugs precipitate diabetes? BMJ 1984; 289: 1495–7PubMedCrossRefGoogle Scholar
  72. 72.
    Baba T, Neugebauer S. The link between insulin resistance and hypertension: effects of antihypertensive and antihyper-lipidaemic drugs on insulin sensitivity. Drugs 1994; 47: 383–404PubMedCrossRefGoogle Scholar
  73. 73.
    Teuscher AU, Weidmann PU. Requirements for antihypertensive therapy in diabetic patients: metabolic aspects. J Hypertens Suppl 1997; 15 Suppl. 2: S67–75PubMedGoogle Scholar
  74. 74.
    Padwal R, Laupacis A. Antihypertensive therapy and incidence of type 2 diabetes: a systematic review. Diabetes Care 2004; 27: 247–55PubMedCrossRefGoogle Scholar
  75. 75.
    Gurwitz JH, Bohn RL, Glynn RJ, et al. Antihypertensive drug therapy and the initiation of treatment for diabetes mellitus. Ann Intern Med 1993; 118: 273–8PubMedGoogle Scholar
  76. 76.
    Berne C, Pollare T, Lithell H. Effects of antihypertensive treatment on insulin sensitivity with special reference to ACE inhibitors. Diabetes Care 1991; 14: 39–47PubMedGoogle Scholar
  77. 77.
    Donnelly R. Angiotensin-converting enzyme inhibitors and insulin sensitivity: metabolic effects in hypertension, diabetes, and heart failure. J Cardiovasc Pharmacol 1992; 20 Suppl. 11: S38–44PubMedCrossRefGoogle Scholar
  78. 78.
    Oksa A, Gajdos M, Fedelesova V, et al. Effects of angiotensin-converting enzyme inhibitors on glucose and lipid metabolism in essential hypertension. J Cardiovasc Pharmacol 1994; 23: 79–86PubMedCrossRefGoogle Scholar
  79. 79.
    Trost BN, Weidmann P. Effects of calcium antagonists on glucose homeostasis and serum lipids in non-diabetic and diabetic subjects: a review. J Hypertens 1987; 5: S81–104CrossRefGoogle Scholar
  80. 80.
    Neaton JD, Grimm Jr RH, Prineas RJ, et al. Treatment of Mild Hypertension Study: final results. JAMA 1993; 270: 713–24PubMedCrossRefGoogle Scholar
  81. 81.
    Sowers JR, Bakris GL. Antihypertensive therapy and the risk of type 2 diabetes mellitus. N Engl J Med 2000; 342: 969–70PubMedCrossRefGoogle Scholar
  82. 82.
    Staessen JA, Ginocchio G, Guang Wang J, et al. Genetic variability in the renin-angiotensin system: prevalence of alleles and genotypes. J Cardiovasc Risk 1997; 4: 401–22PubMedCrossRefGoogle Scholar
  83. 83.
    Sheu WH, Lee WJ, Jeng CY, et al. Angiotensinogen gene polymorphism is associated with insulin resistance in nondiabetic men with or without coronary heart disease. Am Heart J 1998; 136: 125–31PubMedCrossRefGoogle Scholar
  84. 84.
    Bengtsson K, Orho-Melander M, Lindblad U, et al. Polymorphism in the angiotensin converting enzyme but not in the angiotensinogen gene is associated with hypertension and type 2 diabetes: the Skaraborg Hypertension and Diabetes project. J Hypertens 1999; 17: 1569–75PubMedCrossRefGoogle Scholar
  85. 85.
    Cong ND, Hamaguchi K, Saikawa T, et al. The I/D polymorphism of angiotensin-converting enzyme gene but not the angiotensinogen gene is associated with insulin response to oral glucose in Japanese. Proc Soc Exp Biol Med 1999; 220: 46–51PubMedCrossRefGoogle Scholar
  86. 86.
    Tiret L, Rigat B, Visvikis S, et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet 1992; 51: 197–205PubMedGoogle Scholar
  87. 87.
    Zingone A, Dominijanni A, Mele E, et al. Deletion polymorphism in the gene for angiotensin converting enzyme is associated with elevated fasting blood glucose levels. Hum Genet 1994; 94: 207–9PubMedCrossRefGoogle Scholar
  88. 88.
    Huang X-H, Rantalaiho V, Wirta O, et al. Relationship of the angiotensin-converting enzyme gene polymorphism to glucose intolerance, insulin resistance, and hypertension in NIDDM. Hum Genet 1998; 102: 372–8PubMedCrossRefGoogle Scholar
  89. 89.
    Jeng JR, Shieh S-M, Harn J-J, et al. Angiotensin I converting enzyme gene polymorphism and insulin resistance in patients with hypertension. J Hypertens 1997; 15: 963–8PubMedCrossRefGoogle Scholar
  90. 90.
    Perticone F, Ceravolo R, Iacopino S, et al. Relationship between angiotensin-converting enzyme gene polymorphism and insulin resistance in never-treated hypertensive patients. J Clin Endocrinol Metab 2001; 86: 172–8PubMedCrossRefGoogle Scholar
  91. 91.
    Thamer C, Koch M, Haap M, et al. Association of the ACE gene I/D polymorphism with insulin sensitivity depends on the presence of additional macroangiopathic risk factors [letter]. Atherosclerosis 2002; 160: 257–8PubMedCrossRefGoogle Scholar
  92. 92.
    Katsuya T, Horiuchi M, Chen YDI, et al. Relation between deletion polymorphism of the angiotensin-converting enzyme gene and insulin resistance, glucose intolerance, hyperinsulinemia and dyslipidemia. Arterioscler Thromb Vasc Biol 1995; 15: 779–82PubMedCrossRefGoogle Scholar
  93. 93.
    Panahloo A, Andres C, Mohamed-Ali V, et al. The insertion allele of the ACE gene I/D polymorphism: a candidate gene for insulin resistance? Circulation 1995; 92: 3390–3PubMedCrossRefGoogle Scholar
  94. 94.
    Takezato T, Saku K, Zhang B, et al. Angiotensin I converting enzyme gene polymorphism and insulin resistance in patients with angina pectoris. Am J Hypertens 1999; 12: 291–7CrossRefGoogle Scholar
  95. 95.
    Chiu KC, McCarthy JE. The insertion allele at the angiotensin I-converting enzyme gene locus is associated with insulin resistance. Metabolism 1997; 46: 395–9PubMedCrossRefGoogle Scholar
  96. 96.
    Thomas GN, Tomlinson B, Chan JCN, et al. Renin-angiotensin system gene polymorphisms, blood pressure, dyslipidemia, and diabetes in Hong Kon Chinese: a significant association of the ACE insertion/deletion polymorphism with type 2 diabetes. Diabetes Care 2001; 24: 356–61PubMedCrossRefGoogle Scholar
  97. 97.
    Lee Y-J, Tsai JCR. ACE gene insertion/deletion polymorphism associated with 1998 World Health Organization definition of metabolic syndrome in Chinese type 2 diabetic patients. Diabetes Care 2002; 25: 1002–8PubMedCrossRefGoogle Scholar
  98. 98.
    Viitanen L, Pihlajamäki J, Halonen P, et al. Association of angiotensin converting enzyme and plasminogen activator inhibitor-1 promoter gene polymorphisms with features of the insulin resistance syndrome in patients with premature coronary heart disease. Atherosclerosis 2001; 157: 57–64PubMedCrossRefGoogle Scholar
  99. 99.
    Strazzullo P, Iacone R, Iacoviello L, et al. Genetic variation in the renin-angiotensin system and abdominal adiposity in men: the Olivetti Prospective Heart Study. Ann Intern Med 2003; 138: 17–23PubMedGoogle Scholar
  100. 100.
    Nagi DK, Foy CA, Mohamed-Ali V, et al. Angiotensin-1-converting enzyme (ACE) gene polymorphism, plasma ACE levels, and their association with the metabolic syndrome and electrocardiographic coronary artery disease in Pima Indian. Metabolism 1998; 47: 622–6PubMedCrossRefGoogle Scholar
  101. 101.
    Ryan AS, Nicklas BJ, Berman DM, et al. The insertion/deletion polymorphism of the ACE gene is related to insulin sensitivity in overweight women. Diabetes Care 2001; 24: 1646–52PubMedCrossRefGoogle Scholar
  102. 102.
    Feng Y, Niu T, Xu X, et al. Insertion/deletion polymorphism of the ACE gene is associated with type 2 diabetes. Diabetes 2002; 51: 1986–8PubMedCrossRefGoogle Scholar
  103. 103.
    Morris AD, Donnelly R. Angiotensin II: an insulin-sensitising vasoactive hormone? J Clin Endocrinol Metab 1996; 81: 1303–6PubMedCrossRefGoogle Scholar
  104. 104.
    Ferrannini E, Seghieri G, Muscelli E. Insulin and the renin-angiotensin-aldosterone system: influence of ACE inhibition. J Cardiovasc Pharmacol 1994; 24 Suppl. 3: S61–9PubMedCrossRefGoogle Scholar
  105. 105.
    Ferriere M, Lachkar H, Richard JL, et al. Captopril and insulin sensitivity [letter]. Ann Intern Med 1985; 102: 134PubMedGoogle Scholar
  106. 106.
    Torlone E, Rambotti AM, Perriello G, et al. ACE-inhibition increases hepatic and extrahepatic sensitivity to insulin in patients with type 2 (non-insulin-dependent) diabetes mellitus and arterial hypertension. Diabetologia 1991; 34: 119–25PubMedCrossRefGoogle Scholar
  107. 107.
    Torlone E, Britta M, Rambotti AM, et al. Improved insulin action and glycémic control after long-term angiotensin-converting enzyme inhibition in subjects with arterial hypertension and type 2 diabetes. Diabetes Care 1993; 16: 1347–55PubMedCrossRefGoogle Scholar
  108. 108.
    Petrie JR, Morris AD, Ueda S, et al. Trandolapril does not improve insulin sensitivity in patients with hypertension and type 2 diabetes: a double-blind, placebo-controlled crossover trial. J Clin Endocrinol Metab 2000; 85: 1882–9PubMedCrossRefGoogle Scholar
  109. 109.
    Heart Outcomes Prevention Evaluation Study Investigators. Effect of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355: 253–9CrossRefGoogle Scholar
  110. 110.
    Herings RMC, de Boer A, Strieker BHC, et al. Hypoglycemia associated with use of inhibitors of angiotensin converting enzyme. Lancet 1995; 345: 1195–8PubMedCrossRefGoogle Scholar
  111. 111.
    Morris AD, Boyle DI, McMahon AD, et al. ACE inhibitor use is associated with hospitalization for severe hypoglycemia in patients with diabetes. DARTS-MEMO Collaboration. Diabetes Audit and Research in Tayside, Scotland. Medicines monitoring unit. Diabetes Care 1997; 20: 1363–7Google Scholar
  112. 112.
    Thamer M, Ray NF, Taylor T, et al. Association between antihypertensive drug use and hypoglycemia: a case-control study of diabetic users of insulin or sulfonylureas. Clin Ther 1999; 21: 1387–400PubMedCrossRefGoogle Scholar
  113. 113.
    Kodama J, Katayama S, Tanaka K, et al. Effect of captopril on glucose concentration: possible role of augmented post-prandial forearm blood flow. Diabetes Care 1990; 13: 1109–11PubMedCrossRefGoogle Scholar
  114. 114.
    Ludvik B, Kueenburg E, Brunnbauer M, et al. The effects of ramipril on glucose tolerance, insulin secretion and insulin sensitivity in patients with hypertension. J Cardiovasc Pharmacol 1991; 18 Suppl. 2: S157–9PubMedGoogle Scholar
  115. 115.
    Santoro D, Natali A, Palombo C, et al. Effects of chronic angiotensin converting enzyme inhibition on glucose tolerance and insulin sensitivity in essential hypertension. Hypertension 1992; 20: 181–91PubMedCrossRefGoogle Scholar
  116. 116.
    Haenni A, Andersson PE, Lind L, et al. Electrolyte changes and metabolic effects of lisinopril/bendrofluazide treatment: results from a randomized, double-blind study with parallel groups. Am J Hypertens 1994; 7: 615–22PubMedGoogle Scholar
  117. 117.
    Reneland R, Andersson PE, Haenni A, et al. Metabolic effects of long-term angiotensin-converting enzyme inhibition with fosinopril in patients with essential hypertension: relationship to angiotensin-converting enzyme inhibition. Eur J Clin Pharmacol 1994; 46: 431–6PubMedCrossRefGoogle Scholar
  118. 118.
    Paolisso G, Balbi V, Gambardella A, et al. Lisinopril administration improves insulin action in aged patients with hypertension. J Hum Hypertens 1995; 9: 541–6PubMedGoogle Scholar
  119. 119.
    Falkner B, Canessa M, Anzalone D. Effect of angiotensin converting enzyme inhibitor (lisinopril) on insulin sensitivity and sodium transport in mild hypertension. Am J Hypertens 1995; 8: 454–60PubMedCrossRefGoogle Scholar
  120. 120.
    Andersson PE, Lithell H. Metabolic effects of doxazosin and enalapril in hypertriglyceridemic, hypertensive men: relationship to changes in skeletal muscle blood flow. Am J Hypertens 1996; 9: 323–33PubMedCrossRefGoogle Scholar
  121. 121.
    Fogari R, Zoppi A, Corradi L, et al. Comparative effects of lisinopril and losartan on insulin sensitivity in the treatment of non diabetic hypertensive patients. Br J Clin Pharmacol 1998; 46: 467–71PubMedCrossRefGoogle Scholar
  122. 122.
    Wiggam IM, Hunter SJ, Brew Atkinson A, et al. Captopril does not improve insulin action in essential hypertension: a double-blind placebo-controlled study. J Hypertens 1998; 16: 1651–7PubMedCrossRefGoogle Scholar
  123. 123.
    Hunter SJ, Harper R, Ennis C, et al. Effects of combination therapy with an angiotensin converting enzyme inhibitor and thiazide diuretic on insulin action in essential hypertension. J Hypertens 1998; 16: 103–9PubMedCrossRefGoogle Scholar
  124. 124.
    Fogari R, Zoppi A, Lazzari P, et al. ACE inhibition but not angiotensin II antagonism reduces plasma fibrinogen and insulin resistance in overweight hypertensive patients. J Cardiovasc Pharmacol 1998; 32: 616–20PubMedCrossRefGoogle Scholar
  125. 125.
    Miyazaki Y, Murakami H, Hirata A, et al. Effects of the angiotensin converting enzyme inhibitor temocapril on insulin sensitivity and its effects on renal sodium handling and the pressor system in essential hypertensive patients. Am J Hypertens 1998; 11: 962–70PubMedCrossRefGoogle Scholar
  126. 126.
    Heise T, Heinemann L, Kristahn K, et al. Insulin sensitivity in patients with essential hypertension: no influence of the ACE inhibitor enalapril. Horm Metab Res 1999; 31: 418–23PubMedCrossRefGoogle Scholar
  127. 127.
    Lender D, Arauz-Pacheco C, Breen L, et al. A double blind comparison of the effects of amlodipine and enalapril on insulin sensitivity in hypertensive patients. Am J Hypertens 1999; 12: 298–303PubMedCrossRefGoogle Scholar
  128. 128.
    Galletti F, Strazzullo P, Capaldo B, et al. Controlled study of the effect of angiotensin converting enzyme inhibition versus calcium-entry blockade on insulin sensitivity in overweight hypertensive patients: Trandolapril Italian Study (TRIS). J Hypertens 1999; 17: 439–45PubMedCrossRefGoogle Scholar
  129. 129.
    Reneland R, Alvarez E, Andersson PE, et al. Induction of insulin resistance by beta-blockade but not by ACE-inhibition: long-term treatment with atenolol or trandolapril. J Hum Hypertens 2000; 14: 175–80PubMedCrossRefGoogle Scholar
  130. 130.
    Malmqvist K, Kahan T, Isaksson H, et al. Regression of left ventricular mass with captopril and metoprolol, and the effects on glucose and lipid metabolism. Blood Press 2001; 10: 101–10PubMedCrossRefGoogle Scholar
  131. 131.
    Fogari R, Zoppi A, Preti P, et al. Differential effects of ACE-inhibition and angiotensin II antagonism on fibrinolysis and insulin sensitivity in hypertensive postmenopausal women. Am J Hypertens 2001; 14: 921–6PubMedCrossRefGoogle Scholar
  132. 132.
    Furuhashi M, Ura N, Higashiura K, et al. Blockade of the renin-angiotensin system increases adiponectin concentrations in patients with essential hypertension. Hypertension 2003; 42: 76–81PubMedCrossRefGoogle Scholar
  133. 133.
    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: 306–11PubMedCrossRefGoogle Scholar
  134. 134.
    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: 300–7PubMedCrossRefGoogle Scholar
  135. 135.
    Haenni A, Berglund L, Reneland R, et al. The alterations in insulin sensitivity during angiotensin-converting enzyme inhibitor treatment are related to changes in the calcium/magnesium balance. Am J Hypertens 1997; 10: 145–51PubMedCrossRefGoogle Scholar
  136. 136.
    Paolisso G, Gambardella A, Verza M, et al. ACE inhibition improves insulin-sensitivity in aged insulin-resistant hypertensive patients. J Hum Hypertens 1992; 6: 175–9PubMedGoogle Scholar
  137. 137.
    Moan A, Risanger T, Eide I, et al. The effect of angiotensin II receptor blockade on insulin sensitivity and sympathetic nervous system activity in primary hypertension. Blood Press 1994; 3: 185–8PubMedCrossRefGoogle Scholar
  138. 138.
    Moan A, Hoieggen A, Seljeflot I, et al. The effect of angiotensin II receptor antagonism with losartan on glucose metabolism and insulin sensitivity. J Hypertens 1996; 14: 1093–7PubMedCrossRefGoogle Scholar
  139. 139.
    Laakso M, Karjalainen L, Lempiainen-Kuosa P. Effects of losartan on insulin sensitivity in hypertensive subjects. Hypertension 1996; 28: 392–6PubMedCrossRefGoogle Scholar
  140. 140.
    Paolisso G, Tagliamonte MR, Gambardella A, et al. Losartan mediated improvement in insulin action is mainly due to an increase in non-oxidative glucose metabolism and blood flow in insulin-resistant hypertensive patients. J Hum Hypertens 1997; 11: 307–12PubMedCrossRefGoogle Scholar
  141. 141.
    Higashiura K, Ura N, Miyazaki Y, et al. Effect of an angiotensin II receptor antagonist, candesartan, on insulin resistance and pressor mechanisms in essential hypertension. J Hum Hypertens 1999; 13 Suppl. 1: S71–4PubMedCrossRefGoogle Scholar
  142. 142.
    Vermes E, Ducharme A, Bourassa MG, et al. Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the studies of left ventricular dysfunction (SOLVD). Circulation 2003; 107: 1291–6PubMedCrossRefGoogle Scholar
  143. 143.
    Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. The CHARM Investigators and Committees. Lancet 2003; 362: 759–66CrossRefGoogle Scholar
  144. 144.
    Paolisso G, De Riu S, Marrazzo G, et al. Insulin resistance and hyperinsulinemia in patients with chronic congestive heart failure. Metabolism 1991; 40: 972–7PubMedCrossRefGoogle Scholar
  145. 145.
    Hansson L, Lindholm LH, Ekblom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. The STOP-Hypertension-2 Study Group. Lancet 1999; 354: 1751–6Google Scholar
  146. 146.
    World Health Organization. Diabetes mellitus: report of a WHO Study Group. Technical Report Series 727. Geneva: WHO, 1985Google Scholar
  147. 147.
    Scheen AJ. CAPPP trial [letter]. Lancet 1999; 353: 1793–4PubMedCrossRefGoogle Scholar
  148. 148.
    World Health Organization. Department of Non-Communicable Disease Surveillance. WHO 1999 criteria for diagnosis of diabetes mellitus. Geneva: WHO, 1999: 1–59Google Scholar
  149. 149.
    Scheen AJ. VALUE: analysis of results (letter). Lancet 2004; 364: 932–3PubMedCrossRefGoogle Scholar
  150. 150.
    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: 1563–74PubMedCrossRefGoogle Scholar
  151. 151.
    Gerstein HC. Reduction of cardiovascular events and microvascular complications in diabetes with ACE inhibitor treatment: HOPE and MICRO-HOPE. Diabetes Metab Res Rev 2002; 18: S82–5PubMedCrossRefGoogle Scholar
  152. 152.
    The NAVIGATOR Trial Steering Committee. Nateglinide and valsartan in impaired glucose tolerance outcomes research, rationale and design of the NAVIGATOR trial [abstract]. Diabetes 2002; 51 Suppl. 2: A116Google Scholar
  153. 153.
    Top C, Cingozbay BY, Terekecci H, et al. The effects of valsartan on insulin sensitivity in patients with primary hyper-tension. J Int Med Res 2002; 30: 15–20PubMedGoogle Scholar
  154. 154.
    Yusuf S. From the HOPE to the ONTARGET and the TRANSCEND studies: challenges in improving prognosis. Am J Cardiol 2002; 89 Suppl. 2: 18A-26ACrossRefGoogle Scholar
  155. 155.
    The ONTARGET/TRANSCEND Investigators. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J 2004; 148: 52–61CrossRefGoogle Scholar
  156. 156.
    Chow L, De Gasparo M, Levens N. Improved glucose metabolism following blockade of angiotensin converting enzyme but not angiotensin AT1 receptors. Eur J Pharmacol 1995; 282: 77–86PubMedCrossRefGoogle Scholar
  157. 157.
    Conn JW. Hypertension, the potassium ion, and impaired carbohydrate tolerance. N Engl J Med 1965; 273: 1135–43PubMedCrossRefGoogle Scholar
  158. 158.
    Rowe JW, Tobin JD, Rose RM, et al. Effect of experimental potassium deficiency on glucose and insulin metabolism. Metabolism 1980; 29: 498–502PubMedCrossRefGoogle Scholar
  159. 159.
    Helderman JH, Elahi D, Andersen DK, et al. Prevention of the glucose intolerance of thiazide diuretics by maintenance of body potassium. Diabetes 1983; 32: 106–11PubMedCrossRefGoogle Scholar
  160. 160.
    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: 127–33PubMedCrossRefGoogle Scholar
  161. 161.
    Leung PS, Carlsson PO. Tissue renin-angiotensin system: its expression, localization, regulation and potential role in the pancreas. J Mol Endocrinol 2001; 26: 155–64PubMedCrossRefGoogle Scholar
  162. 162.
    Fliser D, Schäfer F, Schmid D, et al. Angiotensin II influences basal, pulsatile and glucose-stimulated insulin secretion in humans. Hypertension 1997; 30: 1156–61PubMedCrossRefGoogle Scholar
  163. 163.
    Fliser D, Dikow R, Demukaj S, et al. Opposing effects of angiotensin II on muscle and renal blood flow under eug-lycemic conditions. J Am Soc Nephrol 2000; 11: 2001–6PubMedGoogle Scholar
  164. 164.
    Henriksen EJ, Jacob S. Angiotensin converting enzyme inhibitors and modulation of skeletal muscle insulin resistance. Diabetes Obes Metab 2003; 5: 214–22PubMedCrossRefGoogle Scholar
  165. 165.
    Chen S, Noguchi Y, Izumida T, et al. A comparison of the hypotensive and hypoglycaemic actions of an angiotensin converting enzyme inhibitor, an AT1 antagonist and troglitazone. J Hypertens 1996; 14: 1325–30PubMedCrossRefGoogle Scholar
  166. 166.
    Wiernsperger N. Vascular defects in the aetiology of peripheral insulin resistance in diabetes: a critical review of hypotheses and facts. Diabetes Metab Rev 1994; 10: 287–307PubMedCrossRefGoogle Scholar
  167. 167.
    Feldman RD, Schmidt ND. Quinapril treatment enhances vascular sensitivity to insulin. J Hypertens 2001; 19: 113–8PubMedCrossRefGoogle Scholar
  168. 168.
    Steinberg HO, Chaker H, Learning R, et al. Obesity/insulin resistance is associated with endothelial dysfunction: implications for the syndrome of insulin resistance. J Clin Invest 1996; 97: 2601–10PubMedCrossRefGoogle Scholar
  169. 169.
    Jamerson KA, Nesbitt SD, Amerena JV, et al. Angiotensin mediates forearm glucose uptake by hemodynamic rather than direct effects. Hypertension 1996; 27: 854–8PubMedCrossRefGoogle Scholar
  170. 170.
    Richey JM, Ader M, Moore D, et al. Angiotensin II induces insulin resistance independent of changes in interstitial insulin. Am J Physiol 1999; 277: E920–6PubMedGoogle Scholar
  171. 171.
    Erdos EG, Deddish PA, Marcic BM. Potentiating of bradykinin action by ACE inhibitors. Trends Endocrinol Metab 1999; 10: 223–9PubMedCrossRefGoogle Scholar
  172. 172.
    Gavras I, Gavras H. Metabolic effects of angiotensin-converting enzyme inhibition: the role of bradykinin. Curr Opin Endocrinol Diabetes 2002; 9: 323–8CrossRefGoogle Scholar
  173. 173.
    Gainer JV, Morrow JD, Loveland A, et al. Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 1998; 339: 1285–92PubMedCrossRefGoogle Scholar
  174. 174.
    Dietze GJ, Wicklmayr M, Rett K, et al. Potential role of bradykinin in forearm muscle metabolism in humans. Diabetes 1996; 45 Suppl. 1: S110–4PubMedGoogle Scholar
  175. 175.
    Duka I, Shenouda S, Johns C, et al. Role of the B2 receptor of bradykinin on insulin sensitivity. Hypertension 2001; 38: 1355–60PubMedCrossRefGoogle Scholar
  176. 176.
    Tomiyama H, Kushiro T, Abeta H, et al. Kinins contribute to the improvement of insulin sensitivity during treatment with angiotensin converting enzyme inhibitor. Hypertension 1994; 23: 450–5PubMedCrossRefGoogle Scholar
  177. 177.
    Henriksen EJ, Jacob S, Kinnick TR, et al. ACE inhibition and glucose transport in insulin resistant muscle: roles of bradykinin and nitric oxide. Am J Physiol 1999; 277: R332–6PubMedGoogle Scholar
  178. 178.
    Di Mattia G, Ferri C, Laurenti O, et al. Circulating catecho-lamines and metabolic effects of captopril in NIDDM patients. Diabetes Care 1996; 19: 226–30PubMedCrossRefGoogle Scholar
  179. 179.
    Paolisso G, Scheen A, D’Onofrio F, et al. Magnesium and glucose homeostasis. Diabetologia 1990; 33: 511–4PubMedCrossRefGoogle Scholar
  180. 180.
    Paolisso G, Sgambato S, Pizza G, et al. Improved insulin response and action by chronic magnesium administration in aged NIDDM subjects. Diabetes Care 1989; 12: 265–9PubMedCrossRefGoogle Scholar
  181. 181.
    Bernobich E, de Angelis L, Lerin C, et al. The role of the angiotensin system in cardiac glucose homeostasis: therapeutic implications. Drugs 2002; 62: 1295–314PubMedCrossRefGoogle Scholar
  182. 182.
    Velloso LA, Folli F, Sun XJ, et al. Cross-talk between the insulin and angiotensin signaling systems. Proc Natl Acad Sci U S A 1996; 93: 12490–5PubMedCrossRefGoogle Scholar
  183. 183.
    Folli F, Saad MJ, Velloso L, et al. Cross-talk between the insulin and angiotensin II signaling system. Exp Clin Endocrinol Diabetes 1999; 107: 133–9PubMedCrossRefGoogle Scholar
  184. 184.
    Ogihara T, Asano T, Ando K, et al. Angiotensin II-induced insulin resistance is associated with enhanced insulin signaling. Hypertension 2002; 40: 872–9PubMedCrossRefGoogle Scholar
  185. 185.
    Hoenack C, Roesen P. Inhibition of angiotensin type 1 receptor prevents decline of glucose transporter (GLUT4) in diabetic rat heart. Diabetes 1996; 45 Suppl. 1: S82–7PubMedGoogle Scholar
  186. 186.
    Henriksen EJ, Jacob S. Modulation of metabolic control by angiotensin converting enzyme (ACE) inhibition. J Cell Physiol 2003; 196: 171–9PubMedCrossRefGoogle Scholar
  187. 187.
    Jacob S, Henriksen EJ, Fogt DL, et al. Effects of trandolapril and verapamil on glucose transport in insulin-resistant rat skeletal muscle. Metabolism 1996; 45: 535–41PubMedCrossRefGoogle Scholar
  188. 188.
    Nawano M, Anai M, Funaki M, et al. Imadapril, 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: 1248–55PubMedCrossRefGoogle Scholar
  189. 189.
    Carvalho CRO, Thirone ACP, Gontijo JAR, et al. Effect of captopril, losartan, and bradykinin on early steps of insulin action. Diabetes 1997; 46: 1950–7PubMedCrossRefGoogle Scholar
  190. 190.
    Häring HU, Tippmer S, Kellerer M, et al. Potential mechanisms of a cross-talk between bradykinin and insulin receptor. Diabetes 1996; 45 Suppl. 1: S115–9PubMedGoogle Scholar
  191. 191.
    Dal Ponte DB, Fogt DL, Jacob S, et al. Interaction of captopril and verapamil on glucose tolerance and insulin action in an animal model of insulin resistance. Metabolism 1998; 47: 982–7CrossRefGoogle Scholar
  192. 192.
    Hennes MMI, O’Shaughnessy IM, Kelly TM, et al. Insulin-resistant lipolysis in abdominally obese hypertensive individuals: role of the renin-angiotensin system. Hypertension 1996; 28: 120–6PubMedCrossRefGoogle Scholar
  193. 193.
    Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997; 45: 3–10CrossRefGoogle Scholar
  194. 194.
    Chandran M, Phillips SA, Ciaraldi T, et al. Adiponectin more than just another fat cell hormone? Diabetes Care 2003; 26: 2442–50PubMedCrossRefGoogle Scholar
  195. 195.
    Engeli S, Negrel R, Sharma AM. Physiology and physiopathology of the adipose tissue renin-angiotensin system. Hypertension 2000; 35: 1270–7PubMedCrossRefGoogle Scholar
  196. 196.
    Gorzelniak K, Engeli S, Janke J, et al. Hormonal regulation of the human adipose-tissue renin-angiotensin system: relationship to obesity and hypertension. J Hypertens 2002; 20: 965–73PubMedCrossRefGoogle Scholar
  197. 197.
    Sharma AM, Janke J, Gorzelniak K, et al. Angiotensin blockade prevents type 2 diabetes by formation of fat cells. Hypertension 2002; 40: 609–11PubMedCrossRefGoogle Scholar
  198. 198.
    Lewis GF, Carpentier A, Adeli K, et al. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 2002; 23: 201–29PubMedCrossRefGoogle Scholar
  199. 199.
    Picard F, Auwerx J. PPAR (gamma) and glucose homeostasis. Annu Rev Nutr 2002; 22: 167–97PubMedCrossRefGoogle Scholar
  200. 200.
    Yki-Järvinen H. Thiazolidinediones. N Engl J Med 2004; 351: 1106–18PubMedCrossRefGoogle Scholar
  201. 201.
    Schupp M, Janke J, Clasen R, et al. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-γ activity. Circulation 2004; 109: 2054–7PubMedCrossRefGoogle Scholar
  202. 202.
    Benson SC, Pershadsingh HA, Ho CI, et al. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARγ-modulating activity. Hypertension 2004; 43: 1–10CrossRefGoogle Scholar
  203. 203.
    Pershadsingh HA, Kurtz TW. Insulin-sensitizing effects of telmisartan: implications for treating insulin resistant-hypertension and cardiovascular disease [letter]. Diabetes Care 2004; 27: 1015PubMedCrossRefGoogle Scholar
  204. 204.
    Ura N, Higashiura K, Shimamoto K. The mechanisms of insulin sensitivity improving effects of angiotensin converting enzyme inhibitor. Immunopharmacology 1999; 44: 153–9PubMedCrossRefGoogle Scholar

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© Adis Data Information BV 2004

Authors and Affiliations

  1. 1.Division of Diabetes, Department of Medicine, Nutrition and Metabolic DisordersCHU Sart Tilman (B35)Liège 1Belgium

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