Skip to main content
Molecular Medicine logoLink to Molecular Medicine
. 1996 Sep;2(5):533–540.

Nuclear magnetic resonance studies of glucose metabolism in non-insulin-dependent diabetes mellitus subjects.

R G Shulman 1
PMCID: PMC2230191  PMID: 8898370

Abstract

In this review, the results of a series of NMR experiments investigating glucose storage and synthesis in NIDDM patients and normal controls have been summarized. These have shown: 1. The deficit in nonoxidative glucose disposal in NIDDM subjects results from a defect in the muscle glycogen synthesis pathway. 2. Reduced activity of glucose transporter/hexokinase step in this pathway accounts for the reduced rate of glycogen synthesis in NIDDM patients. 3. This reduced activity of GT/Hk is a genetic defect present before the clinical onset of disease in prediabetic descendants of diabetic parents. 4. In muscle from normal, healthy subjects the rate of glycogen synthesis is controlled by the glucose transport/hexokinase activity step and not by the activity of the muscle glycogen synthase enzyme. 5. Hepatic gluconeogenesis is responsible for most hepatic glucose production during an overnight fast in both normal and NIDDM subjects, and increases in gluconeogenic flux are responsible for the increased rate of hepatic glucose production in NIDDM subjects. 6. In contrast to human muscle, where glycogenesis ceases at rest, in the liver gluconeogenesis and glycogenolysis are always active. Numerous previous studies were considered prior to embarking in each of these NMR experiments. In the original research articles we published, the earlier studies were discussed in terms of the relevant literature. Here, however, I have chosen to present the NMR data as simply as possible, in the hope of exposing the significance of these studies by disentangling the results from the complexities of NMR methodology.

Full text

PDF
533

Images in this article

Selected References

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

  1. Bogardus C., Lillioja S., Howard B. V., Reaven G., Mott D. Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects. J Clin Invest. 1984 Oct;74(4):1238–1246. doi: 10.1172/JCI111533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. David M., Petit W. A., Laughlin M. R., Shulman R. G., King J. E., Barrett E. J. Simultaneous synthesis and degradation of rat liver glycogen. An in vivo nuclear magnetic resonance spectroscopic study. J Clin Invest. 1990 Aug;86(2):612–617. doi: 10.1172/JCI114752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. DeFronzo R. A., Ferrannini E., Simonson D. C. Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism. 1989 Apr;38(4):387–395. doi: 10.1016/0026-0495(89)90129-7. [DOI] [PubMed] [Google Scholar]
  4. Douen A. G., Ramlal T., Rastogi S., Bilan P. J., Cartee G. D., Vranic M., Holloszy J. O., Klip A. Exercise induces recruitment of the "insulin-responsive glucose transporter". Evidence for distinct intracellular insulin- and exercise-recruitable transporter pools in skeletal muscle. J Biol Chem. 1990 Aug 15;265(23):13427–13430. [PubMed] [Google Scholar]
  5. Gruetter R., Prolla T. A., Shulman R. G. 13C NMR visibility of rabbit muscle glycogen in vivo. Magn Reson Med. 1991 Aug;20(2):327–332. doi: 10.1002/mrm.1910200216. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Jue T., Rothman D. L., Tavitian B. A., Shulman R. G. Natural-abundance 13C NMR study of glycogen repletion in human liver and muscle. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1439–1442. doi: 10.1073/pnas.86.5.1439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kacser H., Burns J. A. The control of flux. Symp Soc Exp Biol. 1973;27:65–104. [PubMed] [Google Scholar]
  9. 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]
  10. Magnusson I., Rothman D. L., Jucker B., Cline G. W., Shulman R. G., Shulman G. I. Liver glycogen turnover in fed and fasted humans. Am J Physiol. 1994 May;266(5 Pt 1):E796–E803. doi: 10.1152/ajpendo.1994.266.5.E796. [DOI] [PubMed] [Google Scholar]
  11. Magnusson I., Rothman D. L., Katz L. D., Shulman R. G., Shulman G. I. Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. J Clin Invest. 1992 Oct;90(4):1323–1327. doi: 10.1172/JCI115997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Piras R., Rothman L. B., Cabib E. Regulation of muscle glycogen synthetase by metabolites. Differential effects on the I and D forms. Biochemistry. 1968 Jan;7(1):56–66. doi: 10.1021/bi00841a009. [DOI] [PubMed] [Google Scholar]
  13. Price T. B., Perseghin G., Duleba A., Chen W., Chase J., Rothman D. L., Shulman R. G., Shulman G. I. NMR studies of muscle glycogen synthesis in insulin-resistant offspring of parents with non-insulin-dependent diabetes mellitus immediately after glycogen-depleting exercise. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5329–5334. doi: 10.1073/pnas.93.11.5329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Price T. B., Rothman D. L., Taylor R., Avison M. J., Shulman G. I., Shulman R. G. Human muscle glycogen resynthesis after exercise: insulin-dependent and -independent phases. J Appl Physiol (1985) 1994 Jan;76(1):104–111. doi: 10.1152/jappl.1994.76.1.104. [DOI] [PubMed] [Google Scholar]
  15. Richter E. A., Garetto L. P., Goodman M. N., Ruderman N. B. Enhanced muscle glucose metabolism after exercise: modulation by local factors. Am J Physiol. 1984 Jun;246(6 Pt 1):E476–E482. doi: 10.1152/ajpendo.1984.246.6.E476. [DOI] [PubMed] [Google Scholar]
  16. Roach P. J., Larner J. Rabbit skeletal muscle glycogen synthase. II. Enzyme phosphorylation state and effector concentrations as interacting control parameters. J Biol Chem. 1976 Apr 10;251(7):1920–1925. [PubMed] [Google Scholar]
  17. Rothman D. L., Magnusson I., Cline G., Gerard D., Kahn C. R., Shulman R. G., Shulman G. I. Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):983–987. doi: 10.1073/pnas.92.4.983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Rothman D. L., Magnusson I., Katz L. D., Shulman R. G., Shulman G. I. Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR. Science. 1991 Oct 25;254(5031):573–576. doi: 10.1126/science.1948033. [DOI] [PubMed] [Google Scholar]
  19. Rothman D. L., Magnusson I., Katz L. D., Shulman R. G., Shulman G. I. Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR. Science. 1991 Oct 25;254(5031):573–576. doi: 10.1126/science.1948033. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. 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]
  22. Shulman R. G., Bloch G., Rothman D. L. In vivo regulation of muscle glycogen synthase and the control of glycogen synthesis. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8535–8542. doi: 10.1073/pnas.92.19.8535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Shulman R. G., Rothman D. L. Enzymatic phosphorylation of muscle glycogen synthase: a mechanism for maintenance of metabolic homeostasis. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7491–7495. doi: 10.1073/pnas.93.15.7491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Shulman R. G., Rothman D. L., Price T. B. Nuclear magnetic resonance studies of muscle and applications to exercise and diabetes. Diabetes. 1996 Jan;45 (Suppl 1):S93–S98. doi: 10.2337/diab.45.1.s93. [DOI] [PubMed] [Google Scholar]
  25. Sillerud L. O., Shulman R. G. Structure and metabolism of mammalian liver glycogen monitored by carbon-13 nuclear magnetic resonance. Biochemistry. 1983 Mar 1;22(5):1087–1094. doi: 10.1021/bi00274a015. [DOI] [PubMed] [Google Scholar]
  26. Wallberg-Henriksson H., Constable S. H., Young D. A., Holloszy J. O. Glucose transport into rat skeletal muscle: interaction between exercise and insulin. J Appl Physiol (1985) 1988 Aug;65(2):909–913. doi: 10.1152/jappl.1988.65.2.909. [DOI] [PubMed] [Google Scholar]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ

RESOURCES