Diabetes, Vol 45, Issue 7 915-925, Copyright © 1996 by American Diabetes Association

ARTICLES

Roles of glucose transport and glucose phosphorylation in muscle insulin resistance of NIDDM

RC Bonadonna, S Del Prato, E Bonora, MP Saccomani, G Gulli, A Natali, S Frascerra, N Pecori, E Ferrannini, D Bier, C Cobelli and RA DeFronzo
Division of Endocrinology and Metabolic Diseases, University of Verona School of Medicine, Italy.

Insulin resistance for glucose metabolism in skeletal muscle is a key feature in NIDDM. The quantitative role of the cellular effectors of glucose metabolism in determining this insulin resistance is still imperfectly known. We assessed transmembrane glucose transport and intracellular glucose phosphorylation in vivo in skeletal muscle in nonobese NIDDM patients. We performed euglycemic insulin clamp studies in combination with the forearm balance technique (brachial artery and deep forearm vein catheterization) in five nonobese NIDDM patients and seven age- and weight-matched control subjects (study 1). D-Mannitol (a nontransportable molecule), 3-O-[14C]methyl-D-glucose (transportable, but not metabolizable) and D[3-3H]glucose (transportable and metabolizable) were simultaneously injected into the brachial artery, and the washout curves were measured in the deep venous effluent blood. In vivo rates of transmembrane transport and intracellular phosphorylation of D-glucose in forearm muscle were determined by analyzing the washout curves with the aid of a multicompartmental model of glucose kinetics in forearm tissues. At similar steady-state concentrations of plasma insulin (approximately 500 pmol/l) and glucose (approximately 5.0 mmol/l), the rates of transmembrane influx (34.3 +/- 9.1 vs. 58.5 +/- 6.5 micromol x min(-1) x kg(-1), P < 0.05) and intracellular phosphorylation (5.4 +/- 1.6 vs. 38.8 +/- 5.1 micromol x min(-1) x kg(-1), P < 0.01) in skeletal muscle were markedly lower in the NIDDM patients than in the control subjects. In the NIDDM patients (study 2), the insulin clamp was repeated at hyperglycemia, (approximately 13 mmol/l) trying to match the rates of transmembrane glucose influx measured during the clamp in the controls. The rate of transmembrane glucose influx (62 +/- 15 micromol x min(-1) x kg(-1)) in the NIDDM patients was similar to the control subjects, but the rate of intracellular glucose phosphorylation (16.6 +/- 7.5 micromol x min(-1) x kg(-1)), although threefold higher than in the patients during study 1 (P < 0.05), was still approximately 60% lower than in the control subjects (P < 0.05). These data suggest that when assessed in vivo, both transmembrane transport and intracellular phosphorylation of glucose are refractory to insulin action and add to each other in determining insulin resistance in skeletal muscle of NIDDM patients. It will be of interest to compare the present results with the in vivo quantitation of the initial rate of muscle glucose transport when methodology to perform this measurement becomes available.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. K. Coletta, B. Balas, A. O. Chavez, M. Baig, M. Abdul-Ghani, S. R. Kashyap, F. Folli, D. Tripathy, L. J. Mandarino, J. E. Cornell, et al. Effect of acute physiological hyperinsulinemia on gene expression in human skeletal muscle in vivo Am J Physiol Endocrinol Metab, May 1, 2008; 294(5): E910 - E917. [Abstract] [Full Text] [PDF]

				M. Pendergrass, A. Bertoldo, R. Bonadonna, G. Nucci, L. Mandarino, C. Cobelli, and R. A. DeFronzo Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E92 - E100. [Abstract] [Full Text] [PDF]

				B. Sirikul, B. A. Gower, G. R. Hunter, D. E. Larson-Meyer, and B. R. Newcomer Relationship between insulin sensitivity and in vivo mitochondrial function in skeletal muscle Am J Physiol Endocrinol Metab, October 1, 2006; 291(4): E724 - E728. [Abstract] [Full Text] [PDF]

				C. Corporeau, C. L. Foll, M. Taouis, J.-P. Gouygou, J.-P. Berge, and J. Delarue Adipose tissue compensates for defect of phosphatidylinositol 3'-kinase induced in liver and muscle by dietary fish oil in fed rats Am J Physiol Endocrinol Metab, January 1, 2006; 290(1): E78 - E86. [Abstract] [Full Text] [PDF]

				Y.-B. Kim, O. D. Peroni, W. G. Aschenbach, Y. Minokoshi, K. Kotani, A. Zisman, C. R. Kahn, L. J. Goodyear, and B. B. Kahn Muscle-Specific Deletion of the Glut4 Glucose Transporter Alters Multiple Regulatory Steps in Glycogen Metabolism Mol. Cell. Biol., November 1, 2005; 25(21): 9713 - 9723. [Abstract] [Full Text] [PDF]

				R. A. DeFronzo, R. M. Bergenstal, W. T. Cefalu, J. Pullman, S. Lerman, B. W. Bode, L. S. Phillips, and for the Exubera Phase III Study Group Efficacy of Inhaled Insulin in Patients With Type 2 Diabetes not Controlled With Diet and Exercise: A 12-week, randomized, comparative trial Diabetes Care, August 1, 2005; 28(8): 1922 - 1928. [Abstract] [Full Text] [PDF]

				M. Flores-Diaz, A. Alape-Giron, G. Clark, B. Catimel, Y. Hirabayashi, E. Nice, J.-M. Gutierrez, R. Titball, and M. Thelestam A Cellular Deficiency of Gangliosides Causes Hypersensitivity to Clostridium perfringens Phospholipase C J. Biol. Chem., July 22, 2005; 280(29): 26680 - 26689. [Abstract] [Full Text] [PDF]

				P. T Fueger, J. Shearer, D. P Bracy, K. A Posey, R. R. Pencek, O. P McGuinness, and D. H Wasserman Control of muscle glucose uptake: test of the rate-limiting step paradigm in conscious, unrestrained mice J. Physiol., February 1, 2005; 562(3): 925 - 935. [Abstract] [Full Text] [PDF]

				V. B. Ritov, E. V. Menshikova, J. He, R. E. Ferrell, B. H. Goodpaster, and D. E. Kelley Deficiency of Subsarcolemmal Mitochondria in Obesity and Type 2 Diabetes Diabetes, January 1, 2005; 54(1): 8 - 14. [Abstract] [Full Text] [PDF]

				M. K Jayapaul and M. Walker Review: Mechanisms contributing to the development of type 2 diabetes The British Journal of Diabetes & Vascular Disease, July 1, 2004; 4(4): 227 - 231. [Abstract] [PDF]

				Y. Gosmain, E. Lefai, S. Ryser, M. Roques, and H. Vidal Sterol Regulatory Element-Binding Protein-1 Mediates the Effect of Insulin on Hexokinase II Gene Expression in Human Muscle Cells Diabetes, February 1, 2004; 53(2): 321 - 329. [Abstract] [Full Text]

				Y. Miyazaki, H. He, L. J. Mandarino, and R. A. DeFronzo Rosiglitazone Improves Downstream Insulin Receptor Signaling in Type 2 Diabetic Patients Diabetes, August 1, 2003; 52(8): 1943 - 1950. [Abstract] [Full Text] [PDF]

				K. V. Williams, A. Bertoldo, P. Kinahan, C. Cobelli, and D. E. Kelley Weight Loss-Induced Plasticity of Glucose Transport and Phosphorylation in the Insulin Resistance of Obesity and Type 2 Diabetes Diabetes, July 1, 2003; 52(7): 1619 - 1626. [Abstract] [Full Text] [PDF]

				M. A. Selak, B. T. Storey, I. Peterside, and R. A. Simmons Impaired oxidative phosphorylation in skeletal muscle of intrauterine growth-retarded rats Am J Physiol Endocrinol Metab, July 1, 2003; 285(1): E130 - E137. [Abstract] [Full Text] [PDF]

				M. E. Cleasby, P. A. T. Kelly, B. R. Walker, and J. R. Seckl Programming of Rat Muscle and Fat Metabolism by in Utero Overexposure to Glucocorticoids Endocrinology, March 1, 2003; 144(3): 999 - 1007. [Abstract] [Full Text] [PDF]

				K. V. Williams, A. Bertoldo, B. Mattioni, J. C. Price, C. Cobelli, and D. E. Kelley Glucose Transport and Phosphorylation in Skeletal Muscle in Obesity: Insight from a Muscle-Specific Positron Emission Tomography Model J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1271 - 1279. [Abstract] [Full Text] [PDF]

				R. A Defronzo Impaired glucose tolerance: do pharmacological therapies correct the underlying metabolic disturbance? The British Journal of Diabetes & Vascular Disease, January 1, 2003; 3(1_suppl): S24 - S40. [Abstract] [PDF]

				G. W. Cline, K. Johnson, W. Regittnig, P. Perret, E. Tozzo, L. Xiao, C. Damico, and G. I. Shulman Effects of a Novel Glycogen Synthase Kinase-3 Inhibitor on Insulin-Stimulated Glucose Metabolism in Zucker Diabetic Fatty (fa/fa) Rats Diabetes, October 1, 2002; 51(10): 2903 - 2910. [Abstract] [Full Text] [PDF]

				B. R. Barnes, J. W. Ryder, T. L. Steiler, L. G.D. Fryer, D. Carling, and J. R. Zierath Isoform-Specific Regulation of 5' AMP-Activated Protein Kinase in Skeletal Muscle From Obese Zucker (fa/fa) Rats in Response to Contraction Diabetes, September 1, 2002; 51(9): 2703 - 2708. [Abstract] [Full Text] [PDF]

				D. E. Kelley, K. V. Williams, J. C. Price, T. M. McKolanis, B. H. Goodpaster, and F. L. Thaete Plasma Fatty Acids, Adiposity, and Variance of Skeletal Muscle Insulin Resistance in Type 2 Diabetes Mellitus J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5412 - 5419. [Abstract] [Full Text] [PDF]

				A. Bertoldo, P. Peltoniemi, V. Oikonen, J. Knuuti, P. Nuutila, and C. Cobelli Kinetic modeling of [18F]FDG in skeletal muscle by PET: a four-compartment five-rate-constant model Am J Physiol Endocrinol Metab, September 1, 2001; 281(3): E524 - E536. [Abstract] [Full Text] [PDF]

				K. V. Williams, J. C. Price, and D. E. Kelley Interactions of Impaired Glucose Transport and Phosphorylation in Skeletal Muscle Insulin Resistance: A Dose-Response Assessment Using Positron Emission Tomography Diabetes, September 1, 2001; 50(9): 2069 - 2079. [Abstract] [Full Text] [PDF]

				L. M. Perriott, T. Kono, R. R. Whitesell, S. M. Knobel, D. W. Piston, D. K. Granner, A. C. Powers, and J. M. May Glucose uptake and metabolism by cultured human skeletal muscle cells: rate-limiting steps Am J Physiol Endocrinol Metab, July 1, 2001; 281(1): E72 - E80. [Abstract] [Full Text] [PDF]

				A. Basu, R. Basu, P. Shah, A. Vella, C. M. Johnson, M. Jensen, K. S. Nair, W. F. Schwenk, and R. A. Rizza Type 2 Diabetes Impairs Splanchnic Uptake of Glucose but Does Not Alter Intestinal Glucose Absorption During Enteral Glucose Feeding: Additional Evidence for a Defect in Hepatic Glucokinase Activity Diabetes, June 1, 2001; 50(6): 1351 - 1362. [Abstract] [Full Text]

				E. Bonora, G. Targher, M. Alberiche, R. C. Bonadonna, M. B. Zenere, F. Saggiani, and M. Muggeo Intracellular Partition of Plasma Glucose Disposal in Hypertensive and Normotensive Subjects with Type 2 Diabetes Mellitus J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2073 - 2079. [Abstract] [Full Text]

				P. Iozzo, T. Pratipanawatr, H. Pijl, C. Vogt, V. Kumar, R. Pipek, M. Matsuda, L. J. Mandarino, K. J. Cusi, and R. A. DeFronzo Physiological hyperinsulinemia impairs insulin-stimulated glycogen synthase activity and glycogen synthesis Am J Physiol Endocrinol Metab, May 1, 2001; 280(5): E712 - E719. [Abstract] [Full Text] [PDF]

				T. Utriainen, S. Lovisatti, S. Makimattila, A. Bertoldo, S. Weintraub, R. DeFronzo, C. Cobelli, and H. Yki-Jarvinen Direct measurement of the lumped constant for 2-deoxy-[1-14C]glucose in vivo in human skeletal muscle Am J Physiol Endocrinol Metab, July 1, 2000; 279(1): E228 - E233. [Abstract] [Full Text] [PDF]

				A. A. Osman, M. Pendergrass, J. Koval, K. Maezono, K. Cusi, T. Pratipanawatr, and L. J. Mandarino Regulation of MAP kinase pathway activity in vivo in human skeletal muscle Am J Physiol Endocrinol Metab, June 1, 2000; 278(6): E992 - E999. [Abstract] [Full Text] [PDF]

				R. A. DeFronzo Pharmacologic Therapy for Type 2 Diabetes Mellitus Ann Intern Med, August 17, 1999; 131(4): 281 - 303. [Abstract] [Full Text] [PDF]

				D. E. Kelley, K. V. Williams, and J. C. Price Insulin regulation of glucose transport and phosphorylation in skeletal muscle assessed by PET Am J Physiol Endocrinol Metab, August 1, 1999; 277(2): E361 - E369. [Abstract] [Full Text] [PDF]

				G. W. Cline, K. F. Petersen, M. Krssak, J. Shen, R. S. Hundal, Z. Trajanoski, S. Inzucchi, A. Dresner, D. L. Rothman, and G. I. Shulman Impaired Glucose Transport as a Cause of Decreased Insulin-Stimulated Muscle Glycogen Synthesis in Type 2 Diabetes N. Engl. J. Med., July 22, 1999; 341(4): 240 - 246. [Abstract] [Full Text] [PDF]

				H. Ardehali, R. L. Printz, R. R. Whitesell, J. M. May, and D. K. Granner Functional Interaction between the N- and C-terminal Halves of Human Hexokinase II J. Biol. Chem., June 4, 1999; 274(23): 15986 - 15989. [Abstract] [Full Text] [PDF]

				E. Ferrannini Insulin Resistance versus Insulin Deficiency in Non-Insulin-Dependent Diabetes Mellitus: Problems and Prospects Endocr. Rev., August 1, 1998; 19(4): 477 - 490. [Abstract] [Full Text] [PDF]

				M. Pendergrass, E. Fazioni, D. Collins, and R. A. DeFronzo IGF-I increases forearm blood flow without increasing forearm glucose uptake Am J Physiol Endocrinol Metab, August 1, 1998; 275(2): E345 - E350. [Abstract] [Full Text] [PDF]

				R. C. Bonadonna, M. P. Saccomani, S. Del Prato, E. Bonora, R. A. DeFronzo, and C. Cobelli Role of Tissue-Specific Blood Flow and Tissue Recruitment in Insulin-Mediated Glucose Uptake of Human Skeletal Muscle Circulation, July 21, 1998; 98(3): 234 - 241. [Abstract] [Full Text] [PDF]

				M. Christopher, F. L. Hew, M. Oakley, C. Rantzau, and F. Alford Defects of Insulin Action and Skeletal Muscle Glucose Metabolism in Growth Hormone-Deficient Adults Persist after 24 Months of Recombinant Human Growth Hormone Therapy J. Clin. Endocrinol. Metab., May 1, 1998; 83(5): 1668 - 1681. [Abstract] [Full Text]

				C. Vogt, H. Yki-Jarvinen, P. Iozzo, R. Pipek, M. Pendergrass, J. Koval, H. Ardehali, R. Printz, D. Granner, R. DeFronzo, et al. Effects of Insulin on Subcellular Localization of Hexokinase II in Human Skeletal Muscle in Vivo J. Clin. Endocrinol. Metab., January 1, 1998; 83(1): 230 - 234. [Abstract] [Full Text]