Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Jun 15;97(12):2705–2713. doi: 10.1172/JCI118724

The effect of non-insulin-dependent diabetes mellitus and obesity on glucose transport and phosphorylation in skeletal muscle.

D E Kelley 1, M A Mintun 1, S C Watkins 1, J A Simoneau 1, F Jadali 1, A Fredrickson 1, J Beattie 1, R Thériault 1
PMCID: PMC507362  PMID: 8675680

Abstract

Defects of glucose transport and phosphorylation may underlie insulin resistance in obesity and non-insulin-dependent diabetes mellitus (NIDDM). To test this hypothesis, dynamic imaging of 18F-2-deoxy-glucose uptake into midthigh muscle was performed using positron emission tomography during basal and insulin-stimulated conditions (40 mU/m2 per min), in eight lean nondiabetic, eight obese nondiabetic, and eight obese subjects with NIDDM. In additional studies, vastus lateralis muscle was obtained by percutaneous biopsy during basal and insulin-stimulated conditions for assay of hexokinase and citrate synthase, and for immunohistochemical labeling of Glut 4. Quantitative confocal laser scanning microscopy was used to ascertain Glut 4 at the sarcolemma as an index of insulin-regulated translocation. In lean individuals, insulin stimulated a 10-fold increase of 2-deoxy-2[18F]fluoro-D-glucose (FDG) clearance into muscle and significant increases in the rate constants for inward transport and phosphorylation of FDG. In obese individuals, the rate constant for inward transport of glucose was not increased by insulin infusion and did not differ from values in NIDDM. Insulin stimulation of the rate constant for glucose phosphorylation was similar in obese and lean subjects but reduced in NIDDM. Insulin increased by nearly twofold the number and area of sites labeling for Glut 4 at the sarcolemma in lean volunteers, but in obese and NIDDM subjects translocation of Glut 4 was attenuated. Activities of skeletal muscle HK I and II were similar in lean, obese and NIDDM subjects. These in vivo and ex vivo assessments indicate that impaired glucose transport plays a key role in insulin resistance of NIDDM and obesity and that an additional impairment of glucose phosphorylation is evident in the insulin resistance of NIDDM.

Full Text

The Full Text of this article is available as a PDF (222.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Annane D., Duboc D., Mazoyer B., Merlet P., Fiorelli M., Eymard B., Radvanyi H., Junien C., Fardeau M., Gajdos P. Correlation between decreased myocardial glucose phosphorylation and the DNA mutation size in myotonic dystrophy. Circulation. 1994 Dec;90(6):2629–2634. doi: 10.1161/01.cir.90.6.2629. [DOI] [PubMed] [Google Scholar]
  2. Baroni M. G., Oelbaum R. S., Pozzilli P., Stocks J., Li S. R., Fiore V., Galton D. J. Polymorphisms at the GLUT1 (HepG2) and GLUT4 (muscle/adipocyte) glucose transporter genes and non-insulin-dependent diabetes mellitus (NIDDM). Hum Genet. 1992 Mar;88(5):557–561. doi: 10.1007/BF00219344. [DOI] [PubMed] [Google Scholar]
  3. Bell G. I., Kayano T., Buse J. B., Burant C. F., Takeda J., Lin D., Fukumoto H., Seino S. Molecular biology of mammalian glucose transporters. Diabetes Care. 1990 Mar;13(3):198–208. doi: 10.2337/diacare.13.3.198. [DOI] [PubMed] [Google Scholar]
  4. Bonadonna R. C., Del Prato S., Saccomani M. P., Bonora E., Gulli G., Ferrannini E., Bier D., Cobelli C., DeFronzo R. A. Transmembrane glucose transport in skeletal muscle of patients with non-insulin-dependent diabetes. J Clin Invest. 1993 Jul;92(1):486–494. doi: 10.1172/JCI116592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bonadonna R. C., Saccomani M. P., Seely L., Zych K. S., Ferrannini E., Cobelli C., DeFronzo R. A. Glucose transport in human skeletal muscle. The in vivo response to insulin. Diabetes. 1993 Jan;42(1):191–198. doi: 10.2337/diab.42.1.191. [DOI] [PubMed] [Google Scholar]
  6. Butler P. C., Kryshak E. J., Marsh M., Rizza R. A. Effect of insulin on oxidation of intracellularly and extracellularly derived glucose in patients with NIDDM. Evidence for primary defect in glucose transport and/or phosphorylation but not oxidation. Diabetes. 1990 Nov;39(11):1373–1380. doi: 10.2337/diab.39.11.1373. [DOI] [PubMed] [Google Scholar]
  7. Choi W. H., O'Rahilly S., Buse J. B., Rees A., Morgan R., Flier J. S., Moller D. E. Molecular scanning of insulin-responsive glucose transporter (GLUT4) gene in NIDDM subjects. Diabetes. 1991 Dec;40(12):1712–1718. doi: 10.2337/diab.40.12.1712. [DOI] [PubMed] [Google Scholar]
  8. Colberg S. R., Simoneau J. A., Thaete F. L., Kelley D. E. Skeletal muscle utilization of free fatty acids in women with visceral obesity. J Clin Invest. 1995 Apr;95(4):1846–1853. doi: 10.1172/JCI117864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. DeFronzo R. A., Tobin J. D., Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214–E223. doi: 10.1152/ajpendo.1979.237.3.E214. [DOI] [PubMed] [Google Scholar]
  10. Dohm G. L., Tapscott E. B., Pories W. J., Dabbs D. J., Flickinger E. G., Meelheim D., Fushiki T., Atkinson S. M., Elton C. W., Caro J. F. An in vitro human muscle preparation suitable for metabolic studies. Decreased insulin stimulation of glucose transport in muscle from morbidly obese and diabetic subjects. J Clin Invest. 1988 Aug;82(2):486–494. doi: 10.1172/JCI113622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Echwald S. M., Bjørbaek C., Hansen T., Clausen J. O., Vestergaard H., Zierath J. R., Printz R. L., Granner D. K., Pedersen O. Identification of four amino acid substitutions in hexokinase II and studies of relationships to NIDDM, glucose effectiveness, and insulin sensitivity. Diabetes. 1995 Mar;44(3):347–353. doi: 10.2337/diab.44.3.347. [DOI] [PubMed] [Google Scholar]
  12. Evans W. J., Phinney S. D., Young V. R. Suction applied to a muscle biopsy maximizes sample size. Med Sci Sports Exerc. 1982;14(1):101–102. [PubMed] [Google Scholar]
  13. Finegood D. T., Bergman R. N., Vranic M. Modeling error and apparent isotope discrimination confound estimation of endogenous glucose production during euglycemic glucose clamps. Diabetes. 1988 Aug;37(8):1025–1034. doi: 10.2337/diab.37.8.1025. [DOI] [PubMed] [Google Scholar]
  14. Fowler J. S., Wolf A. P. 2-Deoxy-2-[18F]fluoro-D-glucose for metabolic studies: current status. Int J Rad Appl Instrum A. 1986;37(8):663–668. doi: 10.1016/0883-2889(86)90259-5. [DOI] [PubMed] [Google Scholar]
  15. Garvey W. T., Huecksteadt T. P., Matthaei S., Olefsky J. M. Role of glucose transporters in the cellular insulin resistance of type II non-insulin-dependent diabetes mellitus. J Clin Invest. 1988 May;81(5):1528–1536. doi: 10.1172/JCI113485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Garvey W. T., Maianu L., Hancock J. A., Golichowski A. M., Baron A. Gene expression of GLUT4 in skeletal muscle from insulin-resistant patients with obesity, IGT, GDM, and NIDDM. Diabetes. 1992 Apr;41(4):465–475. doi: 10.2337/diab.41.4.465. [DOI] [PubMed] [Google Scholar]
  17. Gumà A., Zierath J. R., Wallberg-Henriksson H., Klip A. Insulin induces translocation of GLUT-4 glucose transporters in human skeletal muscle. Am J Physiol. 1995 Apr;268(4 Pt 1):E613–E622. doi: 10.1152/ajpendo.1995.268.4.E613. [DOI] [PubMed] [Google Scholar]
  18. Hamacher K., Coenen H. H., Stöcklin G. Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution. J Nucl Med. 1986 Feb;27(2):235–238. [PubMed] [Google Scholar]
  19. Hansen P. A., Gulve E. A., Holloszy J. O. Suitability of 2-deoxyglucose for in vitro measurement of glucose transport activity in skeletal muscle. J Appl Physiol (1985) 1994 Feb;76(2):979–985. doi: 10.1152/jappl.1994.76.2.979. [DOI] [PubMed] [Google Scholar]
  20. Hickey M. S., Weidner M. D., Gavigan K. E., Zheng D., Tyndall G. L., Houmard J. A. The insulin action-fiber type relationship in humans is muscle group specific. Am J Physiol. 1995 Jul;269(1 Pt 1):E150–E154. doi: 10.1152/ajpendo.1995.269.1.E150. [DOI] [PubMed] [Google Scholar]
  21. Hofmann S., Pette D. Low-frequency stimulation of rat fast-twitch muscle enhances the expression of hexokinase II and both the translocation and expression of glucose transporter 4 (GLUT-4). Eur J Biochem. 1994 Jan 15;219(1-2):307–315. doi: 10.1111/j.1432-1033.1994.tb19942.x. [DOI] [PubMed] [Google Scholar]
  22. Howald H., Pette D., Simoneau J. A., Uber A., Hoppeler H., Cerretelli P. Effect of chronic hypoxia on muscle enzyme activities. Int J Sports Med. 1990 Feb;11 (Suppl 1):S10–S14. doi: 10.1055/s-2007-1024847. [DOI] [PubMed] [Google Scholar]
  23. Huang S. C., Williams B. A., Barrio J. R., Krivokapich J., Nissenson C., Hoffman E. J., Phelps M. E. Measurement of glucose and 2-deoxy-2-[18F]fluoro-D-glucose transport and phosphorylation rates in myocardium using dual-tracer kinetic experiments. FEBS Lett. 1987 May 25;216(1):128–132. doi: 10.1016/0014-5793(87)80770-6. [DOI] [PubMed] [Google Scholar]
  24. Kahn B. B. Facilitative glucose transporters: regulatory mechanisms and dysregulation in diabetes. J Clin Invest. 1992 May;89(5):1367–1374. doi: 10.1172/JCI115724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Katz A., Nyomba B. L., Bogardus C. No accumulation of glucose in human skeletal muscle during euglycemic hyperinsulinemia. Am J Physiol. 1988 Dec;255(6 Pt 1):E942–E945. doi: 10.1152/ajpendo.1988.255.6.E942. [DOI] [PubMed] [Google Scholar]
  26. Katz A., Raz I. Hexokinase kinetics in human skeletal muscle after hyperinsulinaemia, hyperglycaemia and hyperepinephrinaemia. Acta Physiol Scand. 1994 Aug;151(4):527–530. doi: 10.1111/j.1748-1716.1994.tb09775.x. [DOI] [PubMed] [Google Scholar]
  27. Katzen H. M., Soderman D. D., Wiley C. E. Multiple forms of hexokinase. Activities associated with subcellular particulate and soluble fractions of normal and streptozotocin diabetic rat tissues. J Biol Chem. 1970 Aug 25;245(16):4081–4096. [PubMed] [Google Scholar]
  28. Kelley D. E., Mandarino L. J. Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in noninsulin-dependent diabetes mellitus. J Clin Invest. 1990 Dec;86(6):1999–2007. doi: 10.1172/JCI114935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kelley D. E., Reilly J. P., Veneman T., Mandarino L. J. Effects of insulin on skeletal muscle glucose storage, oxidation, and glycolysis in humans. Am J Physiol. 1990 Jun;258(6 Pt 1):E923–E929. doi: 10.1152/ajpendo.1990.258.6.E923. [DOI] [PubMed] [Google Scholar]
  30. Kelley D. E., Simoneau J. A. Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus. J Clin Invest. 1994 Dec;94(6):2349–2356. doi: 10.1172/JCI117600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Klip A., Pâquet M. R. Glucose transport and glucose transporters in muscle and their metabolic regulation. Diabetes Care. 1990 Mar;13(3):228–243. doi: 10.2337/diacare.13.3.228. [DOI] [PubMed] [Google Scholar]
  32. Kong X., Manchester J., Salmons S., Lawrence J. C., Jr Glucose transporters in single skeletal muscle fibers. Relationship to hexokinase and regulation by contractile activity. J Biol Chem. 1994 Apr 29;269(17):12963–12967. [PubMed] [Google Scholar]
  33. Laakso M., Edelman S. V., Brechtel G., Baron A. D. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest. 1990 Jun;85(6):1844–1852. doi: 10.1172/JCI114644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Laakso M., Malkki M., Deeb S. S. Amino acid substitutions in hexokinase II among patients with NIDDM. Diabetes. 1995 Mar;44(3):330–334. doi: 10.2337/diab.44.3.330. [DOI] [PubMed] [Google Scholar]
  35. Lillioja S., Young A. A., Culter C. L., Ivy J. L., Abbott W. G., Zawadzki J. K., Yki-Järvinen H., Christin L., Secomb T. W., Bogardus C. Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man. J Clin Invest. 1987 Aug;80(2):415–424. doi: 10.1172/JCI113088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Mossberg K. A., Taegtmeyer H. Time course of skeletal muscle glucose uptake during euglycemic hyperinsulinemia in the anesthetized rabbit: a fluorine-18-2-deoxy-2-fluoro-D-glucose study. J Nucl Med. 1992 Aug;33(8):1523–1529. [PubMed] [Google Scholar]
  37. Nuutila P., Knuuti M. J., Mäki M., Laine H., Ruotsalainen U., Teräs M., Haaparanta M., Solin O., Yki-Järvinen H. Gender and insulin sensitivity in the heart and in skeletal muscles. Studies using positron emission tomography. Diabetes. 1995 Jan;44(1):31–36. doi: 10.2337/diab.44.1.31. [DOI] [PubMed] [Google Scholar]
  38. Nuutila P., Koivisto V. A., Knuuti J., Ruotsalainen U., Teräs M., Haaparanta M., Bergman J., Solin O., Voipio-Pulkki L. M., Wegelius U. Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo. J Clin Invest. 1992 Jun;89(6):1767–1774. doi: 10.1172/JCI115780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Nuutila P., Mäki M., Laine H., Knuuti M. J., Ruotsalainen U., Luotolahti M., Haaparanta M., Solin O., Jula A., Koivisto V. A. Insulin action on heart and skeletal muscle glucose uptake in essential hypertension. J Clin Invest. 1995 Aug;96(2):1003–1009. doi: 10.1172/JCI118085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Ohtake T., Yokoyama I., Watanabe T., Momose T., Serezawa T., Nishikawa J., Sasaki Y. Myocardial glucose metabolism in noninsulin-dependent diabetes mellitus patients evaluated by FDG-PET. J Nucl Med. 1995 Mar;36(3):456–463. [PubMed] [Google Scholar]
  41. Pedersen O., Bak J. F., Andersen P. H., Lund S., Moller D. E., Flier J. S., Kahn B. B. Evidence against altered expression of GLUT1 or GLUT4 in skeletal muscle of patients with obesity or NIDDM. Diabetes. 1990 Jul;39(7):865–870. doi: 10.2337/diab.39.7.865. [DOI] [PubMed] [Google Scholar]
  42. Pette D., Staron R. S. Cellular and molecular diversities of mammalian skeletal muscle fibers. Rev Physiol Biochem Pharmacol. 1990;116:1–76. doi: 10.1007/3540528806_3. [DOI] [PubMed] [Google Scholar]
  43. Phelps M. E., Huang S. C., Hoffman E. J., Selin C., Sokoloff L., Kuhl D. E. Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: validation of method. Ann Neurol. 1979 Nov;6(5):371–388. doi: 10.1002/ana.410060502. [DOI] [PubMed] [Google Scholar]
  44. Piper R. C., Hess L. J., James D. E. Differential sorting of two glucose transporters expressed in insulin-sensitive cells. Am J Physiol. 1991 Mar;260(3 Pt 1):C570–C580. doi: 10.1152/ajpcell.1991.260.3.C570. [DOI] [PubMed] [Google Scholar]
  45. Postic C., Leturque A., Printz R. L., Maulard P., Loizeau M., Granner D. K., Girard J. Development and regulation of glucose transporter and hexokinase expression in rat. Am J Physiol. 1994 Apr;266(4 Pt 1):E548–E559. doi: 10.1152/ajpendo.1994.266.4.E548. [DOI] [PubMed] [Google Scholar]
  46. Reivich M., Alavi A., Wolf A., Fowler J., Russell J., Arnett C., MacGregor R. R., Shiue C. Y., Atkins H., Anand A. Glucose metabolic rate kinetic model parameter determination in humans: the lumped constants and rate constants for [18F]fluorodeoxyglucose and [11C]deoxyglucose. J Cereb Blood Flow Metab. 1985 Jun;5(2):179–192. doi: 10.1038/jcbfm.1985.24. [DOI] [PubMed] [Google Scholar]
  47. Rodnick K. J., Slot J. W., Studelska D. R., Hanpeter D. E., Robinson L. J., Geuze H. J., James D. E. Immunocytochemical and biochemical studies of GLUT4 in rat skeletal muscle. J Biol Chem. 1992 Mar 25;267(9):6278–6285. [PubMed] [Google Scholar]
  48. Rothman D. L., Shulman R. G., Shulman G. I. 31P nuclear magnetic resonance measurements of muscle glucose-6-phosphate. Evidence for reduced insulin-dependent muscle glucose transport or phosphorylation activity in non-insulin-dependent diabetes mellitus. J Clin Invest. 1992 Apr;89(4):1069–1075. doi: 10.1172/JCI115686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Selberg O., Burchert W., vd Hoff J., Meyer G. J., Hundeshagen H., Radoch E., Balks H. J., Müller M. J. Insulin resistance in liver cirrhosis. Positron-emission tomography scan analysis of skeletal muscle glucose metabolism. J Clin Invest. 1993 May;91(5):1897–1902. doi: 10.1172/JCI116407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Sherman W. M., Katz A. L., Cutler C. L., Withers R. T., Ivy J. L. Glucose transport: locus of muscle insulin resistance in obese Zucker rats. Am J Physiol. 1988 Sep;255(3 Pt 1):E374–E382. doi: 10.1152/ajpendo.1988.255.3.E374. [DOI] [PubMed] [Google Scholar]
  51. Shulman G. I., Rothman D. L., Jue T., Stein P., DeFronzo R. A., Shulman R. G. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med. 1990 Jan 25;322(4):223–228. doi: 10.1056/NEJM199001253220403. [DOI] [PubMed] [Google Scholar]
  52. Simoneau J. A., Colberg S. R., Thaete F. L., Kelley D. E. Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women. FASEB J. 1995 Feb;9(2):273–278. [PubMed] [Google Scholar]
  53. Sokoloff L., Reivich M., Kennedy C., Des Rosiers M. H., Patlak C. S., Pettigrew K. D., Sakurada O., Shinohara M. The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem. 1977 May;28(5):897–916. doi: 10.1111/j.1471-4159.1977.tb10649.x. [DOI] [PubMed] [Google Scholar]
  54. Vidal-Puig A., Printz R. L., Stratton I. M., Granner D. K., Moller D. E. Analysis of the hexokinase II gene in subjects with insulin resistance and NIDDM and detection of a Gln142-->His substitution. Diabetes. 1995 Mar;44(3):340–346. doi: 10.2337/diab.44.3.340. [DOI] [PubMed] [Google Scholar]
  55. Voipio-Pulkki L. M., Nuutila P., Knuuti M. J., Ruotsalainen U., Haaparanta M., Teräs M., Wegelius U., Koivisto V. A. Heart and skeletal muscle glucose disposal in type 2 diabetic patients as determined by positron emission tomography. J Nucl Med. 1993 Dec;34(12):2064–2067. [PubMed] [Google Scholar]
  56. Ziel F. H., Venkatesan N., Davidson M. B. Glucose transport is rate limiting for skeletal muscle glucose metabolism in normal and STZ-induced diabetic rats. Diabetes. 1988 Jul;37(7):885–890. doi: 10.2337/diab.37.7.885. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES