Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1992 Apr;89(4):1069–1075. doi: 10.1172/JCI115686

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.

D L Rothman 1, R G Shulman 1, G I Shulman 1
PMCID: PMC442962  PMID: 1556176

Abstract

To assess the rate-limiting step in muscle glycogen synthesis in non-insulin-dependent diabetes mellitus (NIDDM), the concentration of glucose-6-phosphate (G6P) was measured by 31P nuclear magnetic resonance (NMR) during a hyperglycemic-hyperinsulinemic clamp. Six subjects with NIDDM and six age weight-matched controls were studied at similar steady-state plasma concentrations of insulin (approximately 450 pmol/liter) and glucose (11 mmol/liter). The concentration of G6P in the gastrocnemius muscle was measured by 31P NMR. Whole-body oxidative and nonoxidative glucose metabolism was determined by the insulin-glucose clamp technique in conjunction with indirect calorimetry. Nonoxidative glucose metabolism which under these conditions is a measure of muscle glycogen synthesis (1990. N. Engl. J. Med. 322:223-228), was 31 +/- 7 mumol/(kg body wt-min) in the normal subjects and 13 +/- 3 mumol/(kg body wt-min) in the NIDDM subjects (P less than 0.05). The concentration of G6P was higher (0.24 +/- 0.02 mmol/kg muscle) in the normal subjects than in the NIDDM subjects (0.17 +/- 0.02, P less than 0.01). Increasing insulin concentrations to insulin 8,500 pmol/liter in four NIDDM subjects restored the glucose uptake rate and G6P concentrations to normal levels. In conclusion, the lower concentration of G6P in the diabetic subjects despite a decreased rate of nonoxidative glucose metabolism is consistent with a defect in muscle glucose transport or phosphorylation reducing the rate of muscle glycogen synthesis.

Full text

PDF
1069

Selected References

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

  1. Bogardus C., Lillioja S., Stone K., Mott D. Correlation between muscle glycogen synthase activity and in vivo insulin action in man. J Clin Invest. 1984 Apr;73(4):1185–1190. doi: 10.1172/JCI111304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chance B., Eleff S., Leigh J. S., Jr, Sokolow D., Sapega A. Mitochondrial regulation of phosphocreatine/inorganic phosphate ratios in exercising human muscle: a gated 31P NMR study. Proc Natl Acad Sci U S A. 1981 Nov;78(11):6714–6718. doi: 10.1073/pnas.78.11.6714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ciaraldi T. P., Kolterman O. G., Scarlett J. A., Kao M., Olefsky J. M. Role of glucose transport in the postreceptor defect of non-insulin-dependent diabetes mellitus. Diabetes. 1982 Nov;31(11):1016–1022. doi: 10.2337/diacare.31.11.1016. [DOI] [PubMed] [Google Scholar]
  4. DANFORTH W. H. GLYCOGEN SYNTHETASE ACTIVITY IN SKELETAL MUSCLE. INTERCONVERSION OF TWO FORMS AND CONTROL OF GLYCOGEN SYNTHESIS. J Biol Chem. 1965 Feb;240:588–593. [PubMed] [Google Scholar]
  5. DeFronzo R. A., Ferrannini E., Hendler R., Wahren J., Felig P. Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange. Proc Natl Acad Sci U S A. 1978 Oct;75(10):5173–5177. doi: 10.1073/pnas.75.10.5173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. DeFronzo R. A., Jacot E., Jequier E., Maeder E., Wahren J., Felber J. P. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes. 1981 Dec;30(12):1000–1007. doi: 10.2337/diab.30.12.1000. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Eriksson J., Franssila-Kallunki A., Ekstrand A., Saloranta C., Widén E., Schalin C., Groop L. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med. 1989 Aug 10;321(6):337–343. doi: 10.1056/NEJM198908103210601. [DOI] [PubMed] [Google Scholar]
  9. Felber J. P., Golay A., Felley C., Jéquier E. Regulation of glucose storage in obesity and diabetes: metabolic aspects. Diabetes Metab Rev. 1988 Nov;4(7):691–700. doi: 10.1002/dmr.5610040706. [DOI] [PubMed] [Google Scholar]
  10. Foley J. E., Thuillez P., Lillioja S., Zawadzki J., Bogardus C. Insulin sensitivity in adipocytes from subjects with varying degrees of glucose tolerance. Am J Physiol. 1986 Sep;251(3 Pt 1):E306–E310. doi: 10.1152/ajpendo.1986.251.3.E306. [DOI] [PubMed] [Google Scholar]
  11. Freymond D., Bogardus C., Okubo M., Stone K., Mott D. Impaired insulin-stimulated muscle glycogen synthase activation in vivo in man is related to low fasting glycogen synthase phosphatase activity. J Clin Invest. 1988 Nov;82(5):1503–1509. doi: 10.1172/JCI113758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Guinovart J. J., Salavert A., Massagué J., Ciudad C. J., Salsas E., Itarte E. Glycogen synthase: a new activity ratio assay expressing a high sensitivity to the phosphorylation state. FEBS Lett. 1979 Oct 15;106(2):284–288. doi: 10.1016/0014-5793(79)80515-3. [DOI] [PubMed] [Google Scholar]
  13. Harris R. C., Hultman E., Nordesjö L. O. Glycogen, glycolytic intermediates and high-energy phosphates determined in biopsy samples of musculus quadriceps femoris of man at rest. Methods and variance of values. Scand J Clin Lab Invest. 1974 Apr;33(2):109–120. [PubMed] [Google Scholar]
  14. James D. E., Strube M., Mueckler M. Molecular cloning and characterization of an insulin-regulatable glucose transporter. Nature. 1989 Mar 2;338(6210):83–87. doi: 10.1038/338083a0. [DOI] [PubMed] [Google Scholar]
  15. Kashiwagi A., Verso M. A., Andrews J., Vasquez B., Reaven G., Foley J. E. In vitro insulin resistance of human adipocytes isolated from subjects with noninsulin-dependent diabetes mellitus. J Clin Invest. 1983 Oct;72(4):1246–1254. doi: 10.1172/JCI111080. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kashiwagi A., Verso M. A., Andrews J., Vasquez B., Reaven G., Foley J. E. In vitro insulin resistance of human adipocytes isolated from subjects with noninsulin-dependent diabetes mellitus. J Clin Invest. 1983 Oct;72(4):1246–1254. doi: 10.1172/JCI111080. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. Lawson J. W., Veech R. L. Effects of pH and free Mg2+ on the Keq of the creatine kinase reaction and other phosphate hydrolyses and phosphate transfer reactions. J Biol Chem. 1979 Jul 25;254(14):6528–6537. [PubMed] [Google Scholar]
  20. Lillioja S., Mott D. M., Howard B. V., Bennett P. H., Yki-Järvinen H., Freymond D., Nyomba B. L., Zurlo F., Swinburn B., Bogardus C. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. N Engl J Med. 1988 May 12;318(19):1217–1225. doi: 10.1056/NEJM198805123181901. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Maehlum S., Høstmark A. T., Hermansen L. Synthesis of muscle glycogen during recovery after prolonged severe exercise in diabetic and non-diabetic subjects. Scand J Clin Lab Invest. 1977 Jun;37(4):309–316. doi: 10.3109/00365517709092634. [DOI] [PubMed] [Google Scholar]
  23. Mandarino L. J., Wright K. S., Verity L. S., Nichols J., Bell J. M., Kolterman O. G., Beck-Nielsen H. Effects of insulin infusion on human skeletal muscle pyruvate dehydrogenase, phosphofructokinase, and glycogen synthase. Evidence for their role in oxidative and nonoxidative glucose metabolism. J Clin Invest. 1987 Sep;80(3):655–663. doi: 10.1172/JCI113118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Petroff O. A., Prichard J. W., Behar K. L., Alger J. R., den Hollander J. A., Shulman R. G. Cerebral intracellular pH by 31P nuclear magnetic resonance spectroscopy. Neurology. 1985 Jun;35(6):781–788. doi: 10.1212/wnl.35.6.781. [DOI] [PubMed] [Google Scholar]
  26. Piras R., Staneloni R. In vivo regulation of rat muscle glycogen synthetase activity. Biochemistry. 1969 May;8(5):2153–2160. doi: 10.1021/bi00833a056. [DOI] [PubMed] [Google Scholar]
  27. Roch-Norlund A. E., Bergström J., Hultman E. Muscle glycogen and glycogen synthetase in normal subjects and in patients with diabetes mellitus. Effect of intravenous glucose and insulin administration. Scand J Clin Lab Invest. 1972 Sep;30(1):77–84. doi: 10.3109/00365517209081094. [DOI] [PubMed] [Google Scholar]
  28. Rosselin G., Assan R., Yalow R. S., Berson S. A. Separation of antibody-bound and unbound peptide hormones labelled with iodine-131 by talcum powder and precipitated silica. Nature. 1966 Oct 22;212(5060):355–357. doi: 10.1038/212355a0. [DOI] [PubMed] [Google Scholar]
  29. Rossetti L., Giaccari A. Relative contribution of glycogen synthesis and glycolysis to insulin-mediated glucose uptake. A dose-response euglycemic clamp study in normal and diabetic rats. J Clin Invest. 1990 Jun;85(6):1785–1792. doi: 10.1172/JCI114636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rossetti L., Smith D., Shulman G. I., Papachristou D., DeFronzo R. A. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest. 1987 May;79(5):1510–1515. doi: 10.1172/JCI112981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. 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]
  32. Taylor D. J., Styles P., Matthews P. M., Arnold D. A., Gadian D. G., Bore P., Radda G. K. Energetics of human muscle: exercise-induced ATP depletion. Magn Reson Med. 1986 Feb;3(1):44–54. doi: 10.1002/mrm.1910030107. [DOI] [PubMed] [Google Scholar]
  33. Thiebaud D., Jacot E., DeFronzo R. A., Maeder E., Jequier E., Felber J. P. The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man. Diabetes. 1982 Nov;31(11):957–963. doi: 10.2337/diacare.31.11.957. [DOI] [PubMed] [Google Scholar]
  34. Yki-Järvinen H., Helve E., Koivisto V. A. Hyperglycemia decreases glucose uptake in type I diabetes. Diabetes. 1987 Aug;36(8):892–896. doi: 10.2337/diab.36.8.892. [DOI] [PubMed] [Google Scholar]
  35. Yki-Järvinen H., Mott D., Young A. A., Stone K., Bogardus C. Regulation of glycogen synthase and phosphorylase activities by glucose and insulin in human skeletal muscle. J Clin Invest. 1987 Jul;80(1):95–100. doi: 10.1172/JCI113069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Yki-Järvinen H., Sahlin K., Ren J. M., Koivisto V. A. Localization of rate-limiting defect for glucose disposal in skeletal muscle of insulin-resistant type I diabetic patients. Diabetes. 1990 Feb;39(2):157–167. doi: 10.2337/diab.39.2.157. [DOI] [PubMed] [Google Scholar]
  37. Young A. A., Bogardus C., Stone K., Mott D. M. Insulin response of components of whole-body and muscle carbohydrate metabolism in humans. Am J Physiol. 1988 Feb;254(2 Pt 1):E231–E236. doi: 10.1152/ajpendo.1988.254.2.E231. [DOI] [PubMed] [Google Scholar]

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

RESOURCES