Functional imaging of skeletal muscle glucose metabolism by ¹⁸FDG PET to characterize insulin resistance in patients at high risk for coronary artery disease

Ikuo Yokoyama, Toshiyuki Moritan, Yusuke Inoue

Department of Cardiovascular Medicine, Clinical Research Center, Sanno Hospital of 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, Kitasato University Graduate School of Medicine, Sagamihara, Japan.

DOI: 10.4236/jbise.2012.512A103                

Abstract

Insulin resistance is associated with several coronary risk factors and is thought to play a critical role for the development of coronary artery disease. Insulin resistance has several causes, including an impaired skeletal muscle glucose utilization rate (SMGU), reduced peripheral blood flow, and altered fatty tissue metabolism, with SMGU being considered the most important. Nonetheless, insulin resistance has only been estimated by the glucose disposal rate (GDR) in previous studies. Methods: Skeletal muscle metabolic imaging with ¹⁸FDG and positron emission tomography (PET) was undertaken to measure SMGU during hyperinsulinemiceuglycemic clamping in 22 normotensive type-2 diabetics under no medications (T2- DM), 17 normotensive non-diabetic hypertriglyceridemics, 22 patients with hypertension, and 12 agematched controls. Whole body insulin resistance was assessed by the GDR during hyperinsulinemiceuglycemic insulin clamping. Results: The SMGU and GDR were significantly reduced in T2DM (32.1 ± 16.6 μmol/min/kg and 24.3 ± 13.0 μmol/min/kg, respectively), hypertriglyceridemics (36.5 ± 13.5 μmol/min/ kg and 22.7 ± 8.07 μmol/min/kg respectively) and patients with hypertension (35.4 ± 26.6 μmol/min/kg and 29.0 ± 9.90 μmol/min/kg, respectively) compared with controls (72.2 ± 44.1 μmol/min/kg and 43.0 ± 22.9 μmol/min/kg, p < 0.01, respectively). In all groups studied, SMGU was significantly correlated with GDR (r = 0.76, p < 0.01) and GDR (F = 13.9) was independently related to SMGU (r = 0.81, p < 0.01). Conclusion: Insulin resistance is significantly associated with SMGU to a similar degree among patients with T2DM, essential hypertension and hypertriglyceridemia. ¹⁸FDG PET functional imaging allows insulin resistance to be assessed.

Keywords

Insulin Resistance; Glucose Metabolism; Skeletal Muscle; Coronary Risk Factor; Type II Diabetes Mellitus; Hypertension; Hyperlipidemia;¹⁸F-FDG; PET

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Steiner, G., Morita, S. and Vranic, M. (1980) Resistance to insulin but not to glucagon in lean human hypertri-glyceridemics. Diabetes, 29, 899-905 doi:10.2337/diabetes.29.11.899
[2]	Defronzo, R.A., Gunnarsson, R., Bjorkman, O., Olson, M. and Wahren, J. (1985) Effect of insulin on peripheral and splanchnic glucose metabolism in non-insulin dependent (type II) diabetes mellitus. Journal of Clinical Investigation, 76, 149-155. doi:10.1172/JCI111938
[3]	Reaven, G.M. (1988) Role of insulin resistance in human disease. Diabetes, 37, 1595-1607. doi:10.2337/diabetes.37.12.1595
[4]	Kaplan, N.M. (1989) The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Archives of Internal Medicine, 149, 514-520. doi:10.1001/archinte.1989.00390070054005
[5]	Reaven, G.M., Meheab, K., Villaume, C., Drouin, P. and Debry, G. (1983) Plasma glucose and insulin responses to oral glucose in nonobese subjects and patients with edo- geneous hypertriglyceridemia. Metabolism, 32, 447-450 doi:10.1016/0026-0495(83)90005-7
[6]	Yki-Jaervinen, H. and Taskinen, M.-R. (1988) Interrelationships among insulin’s antilipolytic and glucoregula- tory effects and plasma triglycerides in non-diabetic patients with endogenous hypertriglyceridemia. Diabetes, 37, 1271-1278. doi:10.2337/diabetes.37.9.1271
[7]	McKane, W.R., Stevens, A.B., Woods, R., Andrews, W.J., Henry, R.W. and Bell, P.M. (1990) The assessment of he- patic and peripheral insulin sensitivity in hypertriglyceri- demia. Metabolism, 39, 1240-1245 doi:10.1016/0026-0495(90)90177-E
[8]	Widén, E., Ekstrand, A., Saloranta, C., Franssila-Kallunki, A., Eriksson, J., Schalin-J?ntti, C. and Groop, L. (1992) Insulin resistance in type 2 (non-insulin-dependent) diabetic patients with hypertriglyceridemia. Diabetologia, 35, 1140-1145. doi:10.1007/BF00401367
[9]	Ferrannini, E., Buzzigoli, G., Bonadonna, R., Giorico, M.A., Oleggini, M., Graziadei, L., Pedrinelli, R., Brandi, L. and Bevilacqua, S. (1987) Insulin resistance in essen- tial hypertension. The New England Journal of Medicine, 317, 350-357. doi:10.1056/NEJM198708063170605
[10]	Shen, D.C., Shieh, S.-M., Fuh, M.M.-T., Wu, D.-A., Chen, Y.-DI and Reaven. G.M. (1998) Resistance to insulin sti- mulated glucose uptake in patients with hypertension. The Journal of Clinical Endocrinology & Metabolism, 66, 580-583. doi:10.1210/jcem-66-3-580
[11]	Eliasson, B., Taskinen, M.R. and Smith, U. (1996) Long term use of nicotine gum is associated with hyperinsu- linemia and insulin resistance. Circulation, 94, 878-881. doi:10.1161/01.CIR.94.5.878
[12]	Reaven, G.M. (1991) Insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension: parallels between human disease and rodent models. Diabetes Care, 14, 195-202. doi:10.2337/diacare.14.3.195
[13]	Laakso, M., Edelman, S.V., Brechtel, G. and Baron, A.D. (1990) Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. Journal of Clinical Investigation, 85, 1844-1852. doi:10.1172/JCI114644
[14]	Roden, M., Price, T.B., Perseghin, G., Petersen, K.F., Rothman, D.L., Cline, G.W. and Shulman, G.I. (1996) Mechanism of free fatty acid-induced insulin resistance in humans. Journal of Clinical Investigation, 15, 2859-2865. doi:10.1172/JCI118742
[15]	Boden, G. (1996) Fatty acids and insulin resistance. Dia- betes Care, 19, 394-395. doi:10.2337/diacare.19.4.394
[16]	Nuutila, P., Koivisto, V.A., Knuuti, J., Ruotsalainen, U., Ter?s, M., Haaparanta, M., Bergman, J., Solin, O., Voipio- Pulkki, L.M., Wegelius, U., et al. (1992) The glucose free fatty acid cycleoperates in human heart and skeletal mus- cle in vivo. Journal of Clinical Investigation, 89, 1767- 1744. doi:10.1172/JCI115780
[17]	Voipio-Pulkki, L.M., Nuutila, P., Knuuti, M.J., Ruotsa- lainen, U., Haaparanta, M., Ter?s, M., Wegelius, U. and Koivisto, V.A. (1993) Heart and skeletal muscle glucose disposal in type 2 diabetic patients as determined by posi- tron emission tomography. Journal of Nuclear Medicine, 34, 2064-2067.
[18]	Nuutila, P., M?ki, M., Laine, H., Knuuti, M.J., Ruotsalai- nen, U., Luotolahti, M., Haaparanta, M., Solin, O., Jula, A., Koivisto, V.A., et al. (1995) Insulin action on heart and skeletal muscle glucose uptake in essential hyperten- sion. Journal of Clinical Investigation, 96, 1003-1009. doi:10.1172/JCI118085
[19]	Yokoyama, I., Ohtake, T., Momomura, S., Yonekura, K., Yamada, N., Nishikawa, J., Sasaki, Y. and Omata, M. (1998) Organ specific insulin resistance in patients with non-insulin dependent diabetes mellitus and hypertension. Journal of Nuclear Medicine, 39, 884-889.
[20]	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, 26, 477-485.
[21]	Ohtake, T., Kosaka, N., Watanabe, T., Yokoyama, I., Moritan, T., Masuo, M., Iizuka, M., Kozeni, K., Momose, T., Oku, S., Nishikawa, J., Sasaki, Y. and Iio, M. (1991) Noninvasive method to obtain input function for measuring tissue glucose utilization of thoracic and abdominal organs. Journal of Nuclear Medicine, 32, 1432-1438.
[22]	Yokoyama, I., Inoue, Y., Moritan, T., Ohtomo, K. and Nagai, R. (2005) Measurement of skeletal muscle glucose utilization by dynamic 18F-FDG PET without arteial blood sampling. Nuclear Medicine Communications, 26, 31-37. doi:10.1097/00006231-200501000-00006
[23]	Yokoyama, I., Ohtake, T., Momomura, S., Yonekura, K., Woo-Soo, S., Nishikawa, J., Sasaki, Y. and Omata, M. (1998) Hyperglycemia rather than insulin resistance is re- lated to coronary flow reserve in patients with non-insulin dependent diabetes mellitus. Diabetes, 47, 119-124. doi:10.2337/diabetes.47.1.119
[24]	Capaldo, B., Lembo, G., Napoli, R., Rendina, V., Albano, G., Sacca, L. and Trimarco, B. (1991) Skeletal muscle is a primary site of insulin resistance in essential hyperten- sion. Metabolism, 40, 1320-1322. doi:10.1016/0026-0495(91)90036-V
[25]	Natali, A., Quinones, G.A, Pecori, N., Sanna, G., Toschi, E. and Ferrannini, E. (1998) Vasodilation with sodium nitroprusside does not improve insulin action in essential hypertension. Hypertension, 31, 632-636. doi:10.1161/01.HYP.31.2.632
[26]	Laine, H., Ykiarvinen, H., Kirvela, O., Tolvanen, T., Raitakari, M., Solin, O., Haaparanta, M., Knuuti, J. and Nuutila, P. (1998) Insulin resistance of glucose uptake in skeletal muscle cannot be ameliorated by enhancing endothelium-dependent blood flow in obesity. Journal of Clinical Investigation, 101, 1156-1162. doi:10.1172/JCI1065
[27]	Paternostro, G., Camici, P.G., Lammerstma, A.A., Ma- rinho, N., Baliga, R.R., Kooner, J.S., Radda, G.K. and Ferrannini, E. (1996) Cardiac and skeletal muscle insulin resistance in patients with heart disease. Journal of Clinical Investigation, 98, 2094-2099. doi:10.1172/JCI119015
[28]	Defronzo, R.A. and Ferrannini, E. (1991) Insulin resistance. A multifacted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care, 14, 173-194 doi:10.2337/diacare.14.3.173
[29]	Rodnick, K.J., Henriksen, E.J., James, D.E. and Holloszy, J.O. (1992) Exercise training, glucose transporters, and glucose transport in rat skeletal muscles. American Journal of Physiology, 262, C9-C14.
[30]	Matsui, H., Okumura, K., Kawakami, K., Hibino, M. and Ito, T. (1997) Improved insulin sensitivity by bezafibrate in rats: Relationship to fatty acid composition of skeletal muscle t3riglycerides. Diabetes, 46, 348-353. doi:10.2337/diabetes.46.3.348
[31]	Rivellese, A.A., Maffettone, A., Iovine, C., DiMarino, L., Annuzzi, G., Mancini, M. and Ricardi, G. (1996) Long term effects of fish oil on insulin resistance and plasma lipoproteins in NIDDM patients with hypertriglyceridemia. Diabetes Care, 19, 1207-1213. doi:10.2337/diacare.19.11.1207
[32]	Matsuhisa, M., Shi, Z.Q., Wan, C., Lekas, M., Rodgers, C.D., Giacca, A., Kawamori, R. and Vranic, M. (1997) The effect of pioglitazone on hepatic glucose uptake measured with indirect and direct methods in alloxan-induced diabetic dogs. Diabetes, 46, 224-231. doi:10.2337/diabetes.46.2.224
[33]	Nestel, P.J., Pomeroy, S.E., Sasahara, T., Yamashita, T., Liang, Y.L., Dart, A.M., Jennings, G.L., Abbey, M. and Cameron, J.D. (1997) Arterial compliance in obese subjects is improved with dietary plant n-3 fatty acid from flaxseed oil despite increased LDL oxidizability. Arte- riosclerosis, Thrombosis, and Vascular Biology, 17, 1163-1170.
[34]	Fujiwara, T., Yoshioka, S., Yoshioka, T., Ushiyama, I. and Horikoshi, H. (1988) Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes, 37, 1549-1558. doi:10.2337/diabetes.37.11.1549
[35]	Iwamoto, Y., Kuzuya, T., Matsuda, A., Awata, T., Kuma-kura, S., Inooka, G. and Shiraishi, I. (1991) Effect of new oral antidiabetic agent CS-045 on glucose tolerance and insulin secretion in patients with NIDDM. Diabetes Care, 14, 1083-1086. doi:10.2337/diacare.14.11.1083
[36]	Nolan, J.J., Ludvik, B., Beerdsen, P., Joyce, M. and Olefsky, J. (1994) Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. The New England Journal of Medicine, 331, 1188-1193. doi:10.1056/NEJM199411033311803
[37]	Yokoyama, I., Yonekura, K., Ohtake, T., Yang, W., Shin, W.S., Yamada, N., Ohtomo, K. and Nagai, R. (2001) Troglitazone can improve impaired femoral muscle glucose utilization in type II diabetics with or without hypertension. Journal of Nuclear Medicine, 42, 1005-1010.