, Volume 34, Issue 2, pp 119–125 | Cite as

ACE-inhibition increases hepatic and extrahepatic sensitivity to insulin in patients with Type 2 (non-insulin-dependent) diabetes mellitus and arterial hypertension

  • E. Torlone
  • A. M. Rambotti
  • G. Perriello
  • G. Botta
  • F. Santeusanio
  • P. Brunetti
  • G. B. Bolli


To assess the effects of ACE-inhibition on insulin action in Type 2 (non-insulin-dependent) diabetes mellitus associated with essential hypertension, 12 patients with Type 2 diabetes (on diet and oral hypoglycaemic agents) and arterial hypertension were examined on two occasions, in a single blind, cross-over study, after two days of treatment with either captopril or a placebo. The study consisted of a euglycaemic-hyperinsulinaemic clamp (two sequential steps of insulin infusion at the rates of 0.25 mU·kg−1·min−1 and 1 mU·kg−1·min−1, 2 h each step), combined with an infusion of 3-3H-glucose to measure the rate of hepatic glucose production and that of peripheral glucose utilization. The results show that blood pressure was lower after captopril (sitting, systolic 148±5 mmHg, diastolic 89±2 mm Hg) compared to placebo (155±6 and 94±2 mm Hg) (p<0.05). Captopril treatment resulted in a more suppressed hepatic glucose production (2.7±0.4 vs 4.94±0.55 μmol·kg−1·min−1), and a lower plasma non-esterified fatty acid concentration (0.143±0.05 vs 0.200±0.05 mmol/l) (captopril vs placebo, p<0.05) at the end of the first step of insulin infusion (estimated portal plasma insulin concentration 305±28 pmol/l); and in a greater glucose utilization (36.5±5.1 vs 28±3.6μmol·kg−1·min−1, p<0.001) at the end of the second step of insulin infusion (arterial plasma insulin concentration of 604±33 pmol/l). We conclude that captopril improved insulin sensitivity in Type 2 diabetes associated with hypertension at the level of the liver and extrahepatic tissues, primarily muscle and adipose tissue. Thus, in contrast to other antihypertensive drugs such as diuretics and beta-blockers which may have a detrimental effect on insulin action, ACE-inhibitors appear to improve insulin action in Type 2 diabetes and essential hypertension, at least on a short-term basis.

Key words

Insulin resistance ACE-inhibitors Type 2 (non-insulin-dependent) diabetes mellitus essential hypertension captopril 


  1. 1.
    Fuller JH (1985) Epidemiology of hypertension associated with diabetes mellitus. Hypertension 7 [Suppl 2]: 3–7Google Scholar
  2. 2.
    The Working Group on Hypertension in Diabetes (1987) Statement on hypertension in diabetes mellitus. Arch Intern Med 147: 830–842CrossRefGoogle Scholar
  3. 3.
    The 1984 Report Of The Joint National Committee on Detection, Evaluation, and treatment of high blood pressure (1984). Arch Intern Med 144: 1405–1507Google Scholar
  4. 4.
    Furman BL (1981) Impairment of glucose tolerance produced by diuretics and other drugs. Pharmacol Ther 12: 613–649CrossRefPubMedGoogle Scholar
  5. 5.
    Dimitriadis G, Leighton B, Parry-Billings M, Newsholme EA (1988) Effects of the diuretic furosemide on the sensitivity of glycolysis and glycogen synthesis to insulin in the soleus muscle of the rat. Diabetologia 31: 58–61PubMedGoogle Scholar
  6. 6.
    Östman J (1983) Beta-adrenergic blockade and diabetes mellitus. A review. Acta Med Scand 672 [Suppl]: 69–77Google Scholar
  7. 7.
    Pollare T, Lithell H, Morlin C, Prantare H, Hvarfner A, Ljunghall S (1989) Metabolic effects of diltiazem and atenolol: results from a randomized double-blind study with parallel groups. J Hypertens 7: 551–559CrossRefPubMedGoogle Scholar
  8. 8.
    Giugliano D, Torella R, Cacciapuoti F, Gentile S, Verza M, Varricchio M (1980) Impairment of insulin secretion in man by nifedipine. Eur J Clin Pharmacol 18: 395–398CrossRefPubMedGoogle Scholar
  9. 9.
    De Marinis L, Barbarino A (1980) Calcium antagonists and hormone release. I. Effects of verapamil on insulin release in normal subjects and patients with islet-cell tumor. Metabolism 29: 599–604CrossRefPubMedGoogle Scholar
  10. 10.
    Charles S, Ketelslegers J-M, Buysschaert M, Lambert A (1981) Hyperglycaemic effects of nifedipine. Br Med J 283: 19–20CrossRefGoogle Scholar
  11. 11.
    Bhatnagar SK, Amin MMA, Al-Yusuf AR (1984) Diabetogenic effects of nifedipine. Br Med J 289: 19CrossRefGoogle Scholar
  12. 12.
    Donnelly T, Harrower AD (1980) Effect of nifedipine on glucose tolerance and insulin secretion in diabetic and non-diabetic patients. Curr Med Res Opin 6: 690–693CrossRefPubMedGoogle Scholar
  13. 13.
    Marre M, Bellet M, Leblanc H, Passa P (1986) Dissociated effects of nicardipine on vascular tone and insulin secretion. J Cardiovasc Pharmacol 8: 707–711PubMedGoogle Scholar
  14. 14.
    Collins WCJ, Cullon MJ, Ferley J (1987) Calcium channel blocker drugs and diabetic control. Clin Pharmacol Ther 42: 420–423CrossRefPubMedGoogle Scholar
  15. 15.
    Pasanisi F, Vaccaro O, Ferrara AL, Di Bonito P, Capaldo B, Iovine C, Mancini M (1989) Effect of nicardipine on insulin secretion, glucose and lipid metabolism in hypertensive, non-insulin dependent diabetes. Eur J Clin Pharmacol 36: 1–4CrossRefPubMedGoogle Scholar
  16. 16.
    Belleville I, Vaillant G, Farmer M, Brun JM (1987) La nicardipine peut avoir un effet délétère sur l'équilibre glycémique du diabétique non insulinodépendant. Presse Méd 16: 1760–1761PubMedGoogle Scholar
  17. 17.
    Skarfors ET, Lithell HO, Selinus I, Aberg H (1989) Do antihypertensive drugs precipitate diabetes in predisposed man? Br Med J 298: 1147–1152CrossRefGoogle Scholar
  18. 18.
    Schonfeld MR, Goldberger E (1986) Hypercholesterolemia induced by thiazides: a pilot study. Curr Ther Res 6: 180–184Google Scholar
  19. 19.
    Weidman P, Gerber A, Mordasini R (1983) Effects of antihypertensive therapy on serum lipoproteins. Hypertension 5 [Supl 3]: 120–131Google Scholar
  20. 20.
    Pollare T, Lithell H, Selinus I, Berne C (1989) Sensitivity to insulin treatment with atenolol and metoprolol: a randomised double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients. Br Med J 298: 1152–1157CrossRefGoogle Scholar
  21. 21.
    Jauch KW, Hartl W, Guenther B, Wicklmayr M, Rett K, Dietze G (1987) Captopril enhances insulin responsiveness of forearm muscle tissue in non-insulin-dependent diabetes mellitus. Eur J Clin Invest 17: 448–454CrossRefPubMedGoogle Scholar
  22. 22.
    Pollare T, Lithell H, Berne C (1989) A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med 321: 868–873CrossRefPubMedGoogle Scholar
  23. 23.
    De Fronzo R (1988) The triumvirate: B-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37: 667–687CrossRefGoogle Scholar
  24. 24.
    Ferrannini E, Buzzigoli G, Bonadonna R et al. (1987) Insulin resistance in essential hypertension. N Engl J Med 317: 350–357CrossRefPubMedGoogle Scholar
  25. 25.
    Ferriere M, Lachkar H, Richard JL, Bringer J, Orsetti A, Mirouza J (1985) Captopril and insulin sensitivity. Ann Intern Med 102: 134–135CrossRefPubMedGoogle Scholar
  26. 26.
    Lederle RM (1985) Captopril and hydrochlorothiazide in the fixed combination multicenter trial. J Cardiovasc Pharmacol 7 [Suppl]: 63–69CrossRefGoogle Scholar
  27. 27.
    McMurray J, Fraser DM (1986) Captopril, enalapril, and blood glucose, Lancet I: 1305Google Scholar
  28. 28.
    Sawicki PT, Mühlhauser I, Baba T, Berger M (1990) Do angiotensin converting enzyme inhibitors represent a progress in hypertension care in diabetes mellitus? Diabetologia 33: 121–124CrossRefPubMedGoogle Scholar
  29. 29.
    Andres R, Swerdloff T, Pozefsky T, Coleman D (1966) Manual feedback technique for the control of blood glucose concentration. In: Lt Skeggs Jr (Ed) Automatism in analytical chemistry. New York, Mediad, pp 486–491Google Scholar
  30. 30.
    McGuire E, Helderman J, Tobin R, Andres R, Berman M (1976) Effects of arterial versus venous sampling on analysis of glucose kinetics in man. J Appl Physiol 41: 565–573PubMedGoogle Scholar
  31. 31.
    De Feo P, Perriello G, Ventura MM et al. (1986) Studies on overnight insulin requirements and metabolic clearance rate of insulin in normal and diabetic man: relevance to the pathogenesis of the dawn phenomenon. Diabetologia 29: 475–480CrossRefPubMedGoogle Scholar
  32. 32.
    De Feo P, Perriello G, De Cosmo S et al. (1986) Comparison of glucose counterregulation during short-term and prolonged hypoglycemia in normal humans. Diabetes 35: 563–569CrossRefPubMedGoogle Scholar
  33. 33.
    Rizza A, Cryer PE, Gerich JE (1979) Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation: effects of somatostatin and combined a- and b-adrenergic blockade on plasma glucose recovery and glucose flux rates after insulin-induced hypoglycemia. J Clin Invest 64: 62–71CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Herbert V, Lav KS, Gottlieb G, Bleicher SJ (1965) Coated charcoal immunoassay of insulin. J Endocrinol Metab 25: 1375–1379CrossRefGoogle Scholar
  35. 35.
    Faber O, Binder C, Markussen J, Heding L, Naithand V, Kuzuya H, Blix P, Horwitz D, Rubenstein A (1978) Characterization of seven C-peptide antisera. Diabetes 27 [Suppl 1]: 170–177CrossRefPubMedGoogle Scholar
  36. 36.
    NEFA C. Enzymatic colorimetric method for the quantitative determination of FFA in serum. Wako Chemicals, NeussGoogle Scholar
  37. 37.
    De Bodo R, Steele R, Altzuler N, Dunn A, Bishop J (1963) On the hormonal regulation of carbohydrate metabolism: studies with C14 glucose. Recent Prog Horm Res 19: 445–448Google Scholar
  38. 38.
    Miles J, Haymond M, Gerich JE (1982) Effects of free fatty acids, insulin glucagon and adrenalin on ketone body production in humans. In: Metabolic acidosis, Ciba Foundation Symposium 87, Pitman, London, pp 192–213Google Scholar
  39. 39.
    Eaton R, Allen R, Shade D, Erickson K, Standefer J (1980) Prehepatic insulin production in man: kinetic analysis using peripheral connecting peptide behaviour. J Clin Endocrin Metab 51: 520–528CrossRefGoogle Scholar
  40. 40.
    Zar J (1984) Biostatistical analysis. Prentice Hall, Englewood Cliffs New YerseyGoogle Scholar
  41. 41.
    Miles JM, Rizza RA, Haymond MW, Gerich JE (1980) Effects of acute insulin deficiency on glucose and ketone body turnover in man. Diabetes 29: 926–930CrossRefPubMedGoogle Scholar
  42. 42.
    Bolli GB, Tsalikian E, Haymond MW, Cryer PE, Gerich JE (1984) Defective glucose counterregulation after subcutaneous insulin in non-insulin dependent diabetes mellitus: paradoxical suppression of glucose utilization and lack of compensatory increase in glucose production, roles of insulin resistance, abnormal neuroendocrine responses, and islet paracrine interactions. J Clin Invest 73: 1532–1541CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Rizza M, Mandarino L, Gerich J (1981) Dose-response characteristics for effects of insulin on production and utilization of glucose in man. Am J Physiol 240: E630-E639PubMedGoogle Scholar
  44. 44.
    Nurjhan N, Campbell PJ, Kennedy FP, Miles JM, Gerich JE (1986) Insulin dose-response characteristics for suppression of glycerol release and conversion to glucose in humans. Diabetes 35: 1326–1331CrossRefPubMedGoogle Scholar
  45. 45.
    Cobelli C, Mari A, Ferrannini E (1987) The non-steady state problem: error analysis of Steele's model and new development for glucose kinetics. Am J Physiol 252: E679-E689PubMedGoogle Scholar
  46. 46.
    Perriello G, De Feo P, Torlone E, Fanelli C, Santeusanio F, Brunetti P, Bolli GB (1990) Nocturnal spikes of growth hormone secretion cause the dawn phenomenon in Type 1 (insulin-dependent) diabetes mellitus by decreasing hepatic (and extrahepatic) sensitivity to insulin in the absence of insulin waning. Diabetologia 33: 52–59CrossRefPubMedGoogle Scholar
  47. 47.
    Gerich JE (1988) Role of insulin resistance in the pathogenesis of NIDDM. Balliere's Clin Endocrinol Metab 2: 307–326CrossRefGoogle Scholar
  48. 48.
    Trovati M, Mularoni E, Massucco P, Burzacca S, Malvaso MR, Anfossi G, Emanuelli G (1989) Study on the occurrence of blood glucose concentrations under the target of 4.4 mmol/l in a cohort of 463 Type 2 diabetic patients. Diabetologia 32: 549AGoogle Scholar
  49. 49.
    Douglas WW (1985) Polypeptides-angiotensin, plasma kinins and others. In: Goodman LS and Gilman JAG (eds) The pharmacological basis of therapeutics. MacMillan, New York, pp 639–659Google Scholar
  50. 50.
    Pollare T, Lithell H, Selinus I, Berne C (1988) Application of prazosin is associated with an increase of insulin sensitivity in obese patients with hypertension. Diabetologia 31: 415–420CrossRefPubMedGoogle Scholar
  51. 51.
    Dietze GJ (1982) Modulation of the action of insulin in relation to the energy state in skeletal muscle. Possible involvement of kinins and prostaglandins. Mol Cell Endocrinol 25: 127–149CrossRefPubMedGoogle Scholar
  52. 52.
    Jauch K-W, Guenther B, Hartl W, Rett K, Wicklmayr M, Dietze G (1986) Improvement of impaired postoperative insulin action by bradykinin. Biol Chem Hoppe-Seyler 367: 207–210CrossRefPubMedGoogle Scholar
  53. 53.
    De Feo P, Bolli GB, Motolese M, Brunetti P (1989) Benazepril improves glycaemic control in patients with Type 2 diabetes and essential hypertension. The International Symposium on ACE-inhibition, London, February 14–17, Abs F078Google Scholar
  54. 54.
    Seefeldt T, Orskov L, Rasmussen O, Pedersen MM, Moller N, Christiansen JS, Schmitz O (1990) Lack of effects of angiotensinconverting enzyme inhibitors on glucose metabolism in insulindependent diabetes mellitus. Diabetic Med 7: 700–704CrossRefPubMedGoogle Scholar
  55. 55.
    Unger R, Grundy S (1985) Hyperglycemia as an inducer as well as a consequence of impaired islet function and insulin resistance: implication for the management of diabetes. Diabetologia 28: 119–121CrossRefPubMedGoogle Scholar
  56. 56.
    Stout RW (1985) Overview of the association between insulin and atherosclerosis. Metabolism 34 [Suppl 1]: 7–12CrossRefPubMedGoogle Scholar
  57. 57.
    Wingard DL, Barrett-Connor E (1987) Family history of diabetes and cardiovascular disease risk factors and mortality among euglycemic, borderline hyperglycemic and diabetic adults. Am J Epidemiol 125: 948–958PubMedGoogle Scholar
  58. 58.
    Ferrannini E, De Fronzo R (1989) The association of hypertension, diabetes, and obesity: a review. J Nephrol 1: 3–15Google Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • E. Torlone
    • 1
  • A. M. Rambotti
    • 1
  • G. Perriello
    • 1
  • G. Botta
    • 1
  • F. Santeusanio
    • 1
  • P. Brunetti
    • 1
  • G. B. Bolli
    • 1
  1. 1.Istituto di Patologia Speciale Medica e Metodologia ClinicaUniversità di PerugiaPerugiaItaly

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