Heart and skeletal muscle insulin resistance but not myocardial blood flow reserve could be related to chronic use of thiazolidione in patients with type-2 diabetes

Ikuo Yokoyama, Toshiyuki Moritan, Yusuke Inoue

Department of Cardiovascular Medicine, Clinical Research Center, Sanno Hospital and Sanno Medical Center, International University of Health and Welfare, Tokyo, Japan.
Department of Clinical Engineering, Faculty of Medical Engineering, Suzuka University of Medical Science, Suzuka, Japan.
Department of Radiology, Graduate School of Medicine, Kitasato University, Sagamihara, Japan.

DOI: 10.4236/jbise.2013.62018                

Abstract

Heart and skeletal muscle insulin resistance and abnormal myocardial flow reserve (MFR) occurs in patients with type-II diabetes. Improvement of heart and skeletal muscle insulin resistance with rosiglitazone use over 16 weeks have been reported. However, it is not clear whether chronic use of troglitazone can improve heart and skeletal muscle insulin resistance and MFR. Materials and Methods: To test the hypothesis whether effects of troglitazone on heart and skeletal muscle insulin resistance and MFR in patients with type-II diabetes, rest and dipyridamole stress perfusion positron emission tomography (PET) with ¹³N-ammonia and heart and skeletal muscle ¹⁸FDG PET scans under insulin clamping were undertaken before and 12 month after the initiation of troglitazone therapy (400 mg/day) in 23 patients with type-II diabetes. Twenty patients with type-II diabetes without CAD and without medications were served as controls. In controls, any medications were not added from the first PET study and 12 months after the second PET study. Results: Baseline myocardial blood flow (MBF) was comparable before and after the troglitazone group as was the controls. MBF during dipyridamole administration (0.56 mg/min/kg) was not significantly improved in troglitazone group and controls. MFR was not improved in troglitazone group and controls. In troglitazone group, whole body glucose disposal rate (GDR; μmole/min/kg) significantly improved (pre; 19.0 ± 9.55, post; 28.7 ± 15.3, p < 0.05) as did the skeletal muscle glucose utilization rate (SMGU (μmole/min/kg); pre; 20.3 ± 12.0, post; 34.8 ± 10.6, p < 0.05) and the myocardial glucose utilization rate (MGU (μmole/min/kg); pre; 339.7 ± 105.2 vs. post; 410.0 ± 240.0, p < 0.05). GDR, SMGU and MGU were unchanged in controls. Conclusions: Troglitazone can improve heart and skeletal muscle insulin resistance in patients with type-II diabetes but not MFR showing that co-existence of heart and skeletal muscle insulin resistance is implicated in patients with type-II diabetes and impaired MFR is uncoupled with insulin resistance in the whole body and heart and skeletal muscle in patients with type-II diabetes.

Keywords

Insulin Resistance; Myocardial Insulin Resistance; Glucose; FDG; PET; Type-II Diabetes; Flow Reserve

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	DeFronzo, R.A., Gunnarsson, R. Bjorkman, O., et al. (1985) Effect of insulin on peripheral and splanchnic glucose metabolism in non-insulin dependent (type II) diabetes mellitus. The Journal of Clinical Investigation, 76, 149-155. doi:10.1172/JCI111938
[2]	DeFronzo, R.A. (1992) Insulin resistance, hyperinsuline mia, and coronary artery disease: A complex metabolic web. Journal of Cardiovascular Pharmacology, 20, S1 S16. doi:10.1097/00005344-199200111-00002
[3]	Voipio-Pulkki, L.M., Nuutila, P., Knuuti, J.M., et al. (1993) Heart and skeletal muscle glucose disposal in type 2 diabetic patients as determined by positron emission tomography. Journal of Nuclear Medicine, 34, 2064-2067.
[4]	Yokoyama, I., Ohtake, T., Momomura, S., et al. (1998) Organ specific insulin resistance in patients with non-insulin dependent diabetes mellitus and hypertension. Journal of Nuclear Medicine, 39, 884-889.
[5]	Yokoyama, I., Yonekura, K., Ohtake, T., et al. (2000) Effect of insulin resistance on heart and skeletal muscle FDG uptake in type II diabetics. Journal of Nuclear Cardiology, 7, 242-248. doi:10.1016/S1071-3581(00)70013-4
[6]	Yokoyama, I., Ohtake, T., Momomura, S., et al. (1997) Reduced myocardial flow reserve in patients with non insulin dependent diabetes mellitus. Journal of the American College of Cardiology, 30, 1472-1477. doi:10.1016/S0735-1097(97)00327-6
[7]	Yokoyama, I., Ohtake, T., Momomura, S., et al. (1998) Hyperglycemia rather than insulin resistance is related to coronary flow reserve in patients with non-insulin dependent diabetes mellitus. Diabetes, 47, 119-124. doi:10.2337/diabetes.47.1.119
[8]	Yokoyama, I., Yonekura, K., Ohtake, T., et al. (2000) Myocardial flow reserve in angiographically normal coronary arteries in non-insulin-dependent diabetics was related to glycemic control and was more prominently reduced in those with microvascular angina than in those with coronary artery disease. Journal of Nuclear Cardiology, 41, 978-985.
[9]	Lautamaki, R., Airaksinen, K.E., Seppanen, M., et al. (2005) Rosiglitazone improves myocardial glucose up take in patients with type 2 diabetes and coronary artery disease: A 16-week randomized, double-blind, placebo controlled study. Diabetes, 54, 2787-2794. doi:10.2337/diabetes.54.9.2787
[10]	Naoumova, R.P., Kindler, H., Leccisotti, L., et al. (2007) Pioglitazone improves myocardial blood flow and glucose utilization in nondiabetic patients with combined hyperlipidemia. A randomized, double-blind, placebo controlled study. Journal of the American College of Cardiology, 50, 2051-2058. doi:10.1016/j.jacc.2007.07.070
[11]	Yokoyama, I., Moritan, T. and Inoue, Y. (2012) Heart and skeletal muscle insulin resistance during troglitazone therapy in type-2 diabetes. Journal of Biomedical Science and Engineering, 512A, 829-835. doi:10.4236/jbise.2012.512A105
[12]	Krivokapitch, J., Smith, G.T., Huang, S.C., et al. (1989) 13N-ammonia myocardial imaging at rest and with exer cise in normal volunteers. Circulation, 80, 1328-1337. doi:10.1161/01.CIR.80.5.1328
[13]	Ehrenkaufer, R.E., Potocki, J.F. and Jewett, D.M. (1989) Simple synthesis of F-18 labeled 2-fluoro-2-deoxy-D-glu cose. Journal of Nuclear Medicine, 25, 333-337.
[14]	Ohtake, T., Kosaka, N., Watanabe, T., et al. (1991) Non invasive method to obtain input function for measuring tissue glucose utilization of thoracic and abdominal organs. Journal of Nuclear Medicine, 32, 1432-1438.
[15]	Patlak, C.S., Blasberg, R.G. and Fenstermacher, J.D. (1983) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Journal of Cerebral Blood Flow & Metabolism, 3, 1-7. doi:10.1038/jcbfm.1983.1
[16]	Ng, C.K., Soufer, R. and McNulty, P.H. (1998) Effect of hyperinsulinemia on myocardial fluorine-18-FDG uptake. Journal of Nuclear Medicine, 39, 379-383.
[17]	Utriainen, T., Lovisatti, S., M?kimattila, S., et al. (2000) Direct measurement of the lumped constant for 2-deoxy [1-14C]glucose in vivo in human skeletal muscle. American Journal of Physiolofy: Endocrinology and Metabolism, 279, E228-E233.
[18]	Yokoyama, I., Moritan, T. and Inoue, Y. (2013) Measurement of lumbar muscle glucose utilization rate can be as useful in estimating skeletal muscle Insulin resistance as that of thigh muscle. Journal of Biomedical Sciences and Engineering, 6, 201-208. (in press) doi:10.4236/jbise.2013.62024
[19]	Park, K.S., Claraldi, T.P., Abramas-Carter, L., et al. (1998) Troglitazone regulation of glucose metabolism in human skeletal muscle cultures from obese type II diabetic subjects. The Journal of Clinical Endocrinology & Metabolism, 83, 1636-1643. doi:10.1210/jc.83.5.1636
[20]	Yokoyama, I., Yonekura, K., Moritan, T., et al. (2001) Troglitazone improves whole-body insulin resistance and skeletal muscle glucose use in type II diabetic patients. Journal of Nuclear Medicine, 42, 1005-1010.
[21]	Jagnasia, D., Whiting, J.M., Concato, J., Pfau, S. and McNulty, P.M. (2001) Effects of non-insulin dependent diabetes mellitus on myocardial insulin responsiveness in patients with ischemic heart isease. Circulation, 103, 1734 1739. doi:10.1161/01.CIR.103.13.1734
[22]	Kim, J.K., Wi, J.K. and Youn, J.H. (1996) Plasma free fatty acids decrease insulin-stimulated skeletal muscle glucose uptake by suppressing glycolysis in conscious rats. Diabetes, 45, 446-453. doi:10.2337/diabetes.45.4.446
[23]	Boden, G., Chen, X., Ruiz, J., et al. (1994) Mechanisms of fatty acid-induced inhibition of glucose uptake. Journal of Clinical Investigation, 93, 2438-2446. doi:10.1172/JCI117252
[24]	Racete, S.B., Davis, A.O., McGill, J.B. and Klein, S. (2002) Thiazolidiones enhance insulin-mediated suppression of fatty acid flux in type 2 diabetes mellitus. Metabolism, 51, 169-174. doi:10.1053/meta.2002.29981
[25]	Nuutila, P., Koivisto, V.A., Knuuti, J., et al. (1992) The glucose free fatty acid cycle operates in human heart and skeletal muscle in vivo. Journal of Clinical Investigation, 89, 1767-1744. doi:10.1172/JCI115780
[26]	Okuno, A., Tamemoto, H., Tobe, K., et al. (1998) Tro glitazone increases the number of small adipocytes with out the change of white adipose tissue mass in obese Zucker rats. Journal of Clinical Investigation, 101, 1354 1361. doi:10.1172/JCI1235
[27]	Yokoyama, I., Momomura, S., Ohtake, T., et al. (1999) Improvement of myocardial vasodilatation in hypelipi demics due to diffuse coronary arterosclerosis after lipid lowering therapy. Circulation, 100, 117-122. doi:10.1161/01.CIR.100.2.117
[28]	Yokoyama, I., Yonekura, K., Inoue, Y., Ohtomo, K. and Nagai, R. (2001) Long-term effect of simvastatin on the improvement of impaired myocardial flow reserve in pa tients with familial hypercholesterolemia without gender variance. Journal of Nuclear Cardiology, 8, 445-451. doi:10.1067/mnc.2001.115517
[29]	Yokoyama, I., Inoue, Y., Moritan, T., Ohtomo, K. and Nagai, R. (2004) Impaired myocardial vasodilatation dur ing hyperaemic stress is improved by simvastatin but not by pravastatin in patients with hypercholesterolaemia. European Heart Journal, 25, 671-679. doi:10.1016/j.ehj.2004.02.017
[30]	Guethlin, M., Kasel, A.M., Coppenrath, K., Ziegler, S., Delius, W. and Schwaiger, M. (1999) Delayed response of myocardial flow reserve to lipid-lowering therapy with fluvastatin. Circulation, 99, 475-481. doi:10.1161/01.CIR.99.4.475
[31]	Baller, D., Notohamiprodjo, G., Gleichmann, U., Holzinger, J., Weise, R. and Lehmann, J. (1999) Improvement in coronary flow reserve determined by positron emission tomography after 6 months of cholesterol-lowering therapy in patients with early stages of coronary atherosclerosis. Circulation, 99, 2871-2875. doi:10.1161/01.CIR.99.22.2871
[32]	Camici, P.G. and Crea, F. (2007) Coronary microvascular dysfunction. New England Journal of Medicine, 356, 830 840. doi:10.1056/NEJMra061889
[33]	Hariharan, R., Bray, M., Ganim, R., Doenst, T., Goodwin, G.W. and Taegtmeyer, H. (1995) Foundamental limitation of 18F2-deoxy-2-fluoro-D-glucose for assessing myocardial glucose uptake. Circulation, 91, 2435-2444. doi:10.1161/01.CIR.91.9.2435
[34]	Ng, C.K., Holden, J.E., Degrado, T.R., et al. (1991) Sensitivity of myocardial fluorodeoxyglucose lumped constant to glucose and insulin. The American Journal of Physiology, 260, H593-H603.
[35]	Yokoyama, I., Ohtake, T., Momomuram, S., et al. (1999) Insulin action on Heart and skeletal muscle FDG uptake in patients with hypertriglyceridemia. Journal of Nuclear Medicine, 40, 1116-1121.