Pioglitazone does not modify ANP levels of type 2 diabetic patients


Background: The atrial natriuretic peptide (ANP) regulates fluid volume redistribution between heart and the pulmonary vessels. In diabetic patients the physiological action of ANP appears to be seriously altered. Methods: 12 subjects (gender 6M/6F, age 47 ± 2 years, BMI 29.1 ± 0.1 kg/m2), with type 2 diabetes and under stable conditions, were studied after one month of pioglitazione treatment (30 mg/die) by means of isotonic blood volume expansion. Results: After one month of pioglitazone treatment the meta- bolic profile of the subjects improved (decrease dia- stolic blood pressure: p = 0.05, total cholesterol: p = 0.01, triglycerides: p = 0.03 and blood glucose: p = 0.01) as the expansion of their plasma volume was found associated with the decrease of hematocrit (p < 0.05). The statistical comparison before versus after pioglitazone showed a significant decrease in the ba- sal aldosterone levels post-treatment (p < 0.04). Nonetheless ANP plasma levels were similar before and after therapy. Conclusions: The inappropriately high concentrations of ANP induced by hyperglyce-mia and the abnormal responses to a physiological sti- mulus like an isotonic blood volume expansion are not reverted by one month of pioglitazone. This is in contrast with the brisk improvement of the metabolic profile seen for the same period of treatment. ANP secretion is modified by fluid load in diabetic patients. This anomaly is not reverted by pioglitazone.

Share and Cite:

Benedini, S. , Villa, P. , Luzi, L. and Bevilacqua, M. (2012) Pioglitazone does not modify ANP levels of type 2 diabetic patients. World Journal of Cardiovascular Diseases, 2, 277-282. doi: 10.4236/wjcd.2012.24043.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Salazar, F.J., Granger, J.P., Joyce, M.L.M., Burnett, J.C., Bove Jr., A.A. and Romero, J.C. (1986) Effects of hypertonic saline infusion and water drinking on atrial peptide. American Journal of Physiology, 251, R1091-R1094.
[2] Laine, M., Arajama, O., Voulteenaho, O., Ruskoaho, H. and Weckstrom, M. (1994) Block of stretch-activated atrial natriuretic peptide secretion by gadolinium in isolated rat atrium. The Journal of Physiology, 480, 553-561.
[3] Clark, B.A., Sclater, A., Epstein, F.H. and Elahi, D. (1993) Effect of glucose, insulin, and hypertonicity on atrial natriuretic peptide levels in man. Metabolism, 42, 224-228. doi:10.1016/0026-0495(93)90040-U
[4] Ohno, Y., Suzuki, H., Yamakawa, H., Nakamura, M., Kato, Y. and Saruta, T. (2001) Correlation of sodium-related factors with insulin sensitivity in young, lean, male offspring of hypertensive and normotensive subjects. Journal of Human Hypertension, 15, 393-399. doi:10.1038/sj.jhh.1001211
[5] Tanabe, A., Naruse, M., Wasada, T., Naruse, K., Yoshimoto, T., Omori, Y. and Demura, H. (1995) Effects of acute hyperinsulinemia on plasma atrial and brain natriuretic peptide concentrations. European Journal of Endocrinology, 132, 693-698. doi:10.1530/eje.0.1320693
[6] Bohlen, L., Ferrari, P., Papiri, M., Allemann, Y., Shaw, S. and Wiedmann, P. (1994) Atrial natriuretic factor increases in response to an acute glucose load. Journal of Human Hypertension, 12, 803-807.
[7] Reddy, S., Kelly, D., Cocineas, C. and Gyory, Z. (1988) Additive and synergistic interaction of atrial natriuretic peptide and volume expansion. American Journal of Physiology, 255, F66-F73.
[8] Ationu, A., Burch, M., Singer, D., Littleton, P. and Carter, N. (1993) Cardiac transplantation affects ventricular expression of brain natriuretic peptide. Cardiovascular Research, 27, 188-191. doi:10.1093/cvr/27.2.188
[9] Geny, B., Piquard, F., Follenius, M., Thiranos, J.C., Charpentier, A., Epailly, E., Levy, F., Kretz, J.G., Eisenmann, B. and Haberey, P. (1998) Endothelin participates in increased circulating atrial natriuretic peptide early after human heart transplantation. The Journal of Heart and Lung Transplantation, 17, 167-175.
[10] Weston, M.W., Cintron, G.B., Giordano, A.T. and Vesely, D.L. (1994) Normalisation of circulating atrial natriuretic peptides in cardiac transplant recipients. American Heart Journal, 127, 129-142. doi:10.1016/0002-8703(94)90518-5
[11] Starling, R.C., O’Dorisio, T.M., Malarkey, W.B., Murray, K.D., Myerowitz, P.D. and Cody, R.J. (1991) Preserved atrial natriuretic peptide secretory function after cardiac transplantation. American Journal of Cardiology, 68, 237- 241.
[12] Benedini, S., Fiocchi, R., Battezzati, A., et al. (2007) A-trial natriuretic peptide in diabetic and nondiabetic patients with and without heart transplantation. Transplantation Proceedings, 39, 1580-1585. doi:10.1016/j.transproceed.2007.04.020
[13] Patel, K.P. (1997) Volume reflex in diabetes. Cardiovascular Research, 34, 81-90. doi:10.1016/S0008-6363(97)00012-6
[14] Oliveira, V.L., Moreira, E.D., Farah, V.M., et al. (1999) Cardiopulmonary reflex impairment in experimental dia- betes in rats. Hypertension, 34, 813-817. doi:10.1161/01.HYP.34.4.813
[15] Beretta-Piccoli, C., Elshater-Zanetti, F., Shaw, S., et al. (1994) Acute sodium loading in patients with uncomplicated diabetes mellitus: Renal and hormonal effects. Clinical Science, 86, 383-390
[16] Salas-Ramirez, M., Ariza Andraca, R., Frati Munari, A., et al. (1995) Effect of plasma volume expansion on auri-cular natriuretic peptide in non-dependent insulin diabetic patients with autonomic neuropathy. Archives of Medical Research, 26, 35-40.
[17] Trevisan, R., Fioretto, P., Semplicini, A., et al. (1990) Role of insulin and atrial natriuretic peptide in sodium retention in insulin-treated IDDM patients during iso-tonic volume expansion. Diabetes, 39, 289-298. doi:10.2337/diabetes.39.3.289
[18] Sechi, L., Valentin, J.P., Griffin, C.A., et al. (1995) Receptors for atrial natriuretic pep-tide are decreased in the kidney of rats with streptozocin-induced diabetes mellitus. The Journal of Clinical Investigation, 95, 2451-2457. doi:10.1172/JCI117945
[19] Asakawa, M., Takano, H., Nagai, T., et al. (2002) Peroxi-some proliferator-activated receptor-gamma plays a cri- tical role in inhibition of cardiac hyper-trophy in vitro and in vivo. Circulation, 105, 1240-1246. doi:10.1161/hc1002.105225
[20] Duan, S.Z., Ivashchenko, C.Y., Russel, M.W., et al. (2005) Cardiomyocyte-specific knockout and agonist of peroxi-some proliferators-activated receptor-gamma both induce cardiac hypertrophy in mice. Circulation Research, 97, 372- 379. doi:10.1161/01.RES.0000179226.34112.6d
[21] Waugh, J., Keating, G.M., Plosker, G.L., Easthope, S. and Robinson, D.M. (2006) Pioglitazone: A review of its use in type 2 diabetes mellitus. Drugs, 66, 85-109. doi:10.2165/00003495-200666010-00005
[22] Rennings, A.J., Smits, P., Stewart, M.W., et al. (2006) Fluid retention and vascular effects of rosiglitazone in obese, insulin-resistant, nondiabetic subjects. Diabetes Care, 29, 581-587. doi:10.2337/diacare.29.03.06.dc05-01467
[23] Zanchi, A., Chiolero, A., Maillard, M., et al. (2004) Effects of the peroxisome proliferators-activated receptor-gamma agonist Pioglitazone on renal and hormonal responses to salt in healty men. The Journal of Clinical Endocrinology & Metabolism, 89, 1140-1145. doi:10.1210/jc.2003-031526
[24] Decaux, G., Dumont, I., Naeije, N., et al. (1982) High uric acid clearance in cirrhosis secondary to increased “effective vascular volume”. American Journal of Medicine, 73, 328-334. doi:10.1016/0002-9343(82)90718-5
[25] Weinman, E.J., Eknoyan, G. and Suki, W.N. (1975) The influence of the extracellular fluid volume on the tubular reabsorption of uric acid. Journal of Clinical Investigation, 55, 283-291. doi:10.1172/JCI107931
[26] Nesto, R.W., Bell, D., Bonow, R.O., Fonseca, V., Grundy, S.M., Horton, E.S., et al. (2003) Thiazolidinedione use, fluid retention, and congestive heart failure: A consensus statement from the American Heart Asso-ciation and American Diabetes Association. Circulation, 108, 2941-2948.
[27] Lincoff, A.M., Wolski, K., Nicholls, S.J. and Nissen, S.E. (2007) Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: A meta-analysis of randomized trials. JAMA, 298, 1180-1188.
[28] Erdmann, E. and Wilcox, R.G. (2008) Weighing up the cardiovascular benefits of thiazolidinedione therapy: The impact of increased risk of heart failure. European Heart Journal, 29, 12-20. doi:10.1093/eurheartj/ehm529
[29] Schernthaner, G., Matthews, D.R., Charbonnel, B., et al. (2004) Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double- blind, randomized trial. The Journal of Clinical Endocrinology & Metabolism, 89, 6068-6076. doi:10.1210/jc.2003-030861
[30] St. John Sutton, M., Rendell, M., Dandona, P., et al. (2002) A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes. Diabetes Care, 25, 2058- 2064. doi:10.2337/diacare.25.11.2058
[31] Goldberg, R.B., Kendall, D.M., Deeg, M.A., et al. (2005) A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care, 28, 1547-1554. doi:10.2337/diacare.28.7.1547
[32] Dormandy, J.A., Charbonnel, B., Eckland, D.J., Erdmann, E., Massi-Benedetti, M., Moules, I.K., Skene, A.M., Tan, M.H., Lefèbvre, P.J., Murray, G.D., Standl, E., Wilcox, R.G., Wilhelmsen, L., Betteridge, J., Birkeland, K., Golay, A., Heine, R.J., Korányi, L., Laakso, M., Mokán, M., Norkus, A., Pirags, V., Podar, T., Scheen, A., Scherbaum, W., Schernthaner, G., Schmitz, O., Skrha, J., Smith, U. and Taton, J., (2005) PROactive investigators. Secondary prevention of macrovascular events in patients with type 2
[33] Berger, R., Strecker, K., Huelsmann, M., Moser, P., Frey, B., Bojic, A., Stanek, B. and Pacher, R. (2003) Prognostic power of neurohumoral parameters in chronic heart failure depends on clinical stage and observation period. The Journal of Heart and Lung Transplantation, 22, 1037- 1045. doi:10.1016/S1053-2498(02)00560-0
[34] Ballerman, B.J., Brenner, B.M. and George, E. (1986) Brown memorial lecture. Role of atrial peptides in body fluid homeostasis. Circulation Research, 58, 619-630. doi:10.1161/01.RES.58.5.619
[35] Goenka, N., Kotonya, C., Penney, M.D., Randeva, H.S. and O’Hare, J.P. (2008) Thiazolidinediones and the renal and hormonal response to water immersion-induced volume expansion in type 2 diabetes mellitus. American Journal of Physiology—Endocrinology and Metabolism, 294, 733-739. doi:10.1152/ajpendo.00583.2007

Copyright © 2021 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.