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. 1997 May 1;99(9):2219–2224. doi: 10.1172/JCI119395

Mechanism of impaired insulin-stimulated muscle glucose metabolism in subjects with insulin-dependent diabetes mellitus.

G W Cline 1, I Magnusson 1, D L Rothman 1, K F Petersen 1, D Laurent 1, G I Shulman 1
PMCID: PMC508052  PMID: 9151794

Abstract

To determine the mechanism of impaired insulin-stimulated muscle glycogen metabolism in patients with poorly controlled insulin-dependent diabetes mellitus (IDDM), we used 13C-NMR spectroscopy to monitor the peak intensity of the C1 resonance of the glucosyl units in muscle glycogen during a 6-h hyperglycemic-hyperinsulinemic clamp using [1-(13)C]glucose-enriched infusate followed by nonenriched glucose. Under similar steady state (t = 3-6 h) plasma glucose (approximately 9.0 mM) and insulin concentrations (approximately 400 pM), nonoxidative glucose metabolism was significantly less in the IDDM subjects compared with age-weight-matched control subjects (37+/-6 vs. 73+/-11 micromol/kg of body wt per minute, P < 0.05), which could be attributed to an approximately 45% reduction in the net rate of muscle glycogen synthesis in the IDDM subjects compared with the control subjects (108+/-16 vs. 195+/-6 micromol/liter of muscle per minute, P < 0.001). Muscle glycogen turnover in the IDDM subjects was significantly less than that of the controls (16+/-4 vs. 33+/-5%, P < 0.05), indicating that a marked reduction in flux through glycogen synthase was responsible for the reduced rate of net glycogen synthesis in the IDDM subjects. 31P-NMR spectroscopy was used to determine the intramuscular concentration of glucose-6-phosphate (G-6-P) under the same hyperglycemic-hyperinsulinemic conditions. Basal G-6-P concentration was similar between the two groups (approximately 0.10 mmol/kg of muscle) but the increment in G-6-P concentration in response to the glucose-insulin infusion was approximately 50% less in the IDDM subjects compared with the control subjects (0.07+/-0.02 vs. 0.13+/-0.02 mmol/kg of muscle, P < 0.05). When nonoxidative glucose metabolic rates in the control subjects were matched to the IDDM subjects, the increment in the G-6-P concentration (0.06+/-0.02 mmol/kg of muscle) was no different than that in the IDDM subjects. Together, these data indicate that defective glucose transport/phosphorylation is the major factor responsible for the lower rate of muscle glycogen synthesis in the poorly controlled insulin-dependent diabetic subjects.

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Selected References

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  1. Baron A. D., Zhu J. S., Zhu J. H., Weldon H., Maianu L., Garvey W. T. Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle. Implications for glucose toxicity. J Clin Invest. 1995 Dec;96(6):2792–2801. doi: 10.1172/JCI118349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bloch G., Chase J. R., Avison M. J., Shulman R. G. In vivo 31P NMR measurement of glucose-6-phosphate in the rat muscle after exercise. Magn Reson Med. 1993 Sep;30(3):347–350. doi: 10.1002/mrm.1910300311. [DOI] [PubMed] [Google Scholar]
  3. Cline G. W., Rothman D. L., Magnusson I., Katz L. D., Shulman G. I. 13C-nuclear magnetic resonance spectroscopy studies of hepatic glucose metabolism in normal subjects and subjects with insulin-dependent diabetes mellitus. J Clin Invest. 1994 Dec;94(6):2369–2376. doi: 10.1172/JCI117602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cohn S. H., Vartsky D., Yasumura S., Sawitsky A., Zanzi I., Vaswani A., Ellis K. J. Compartmental body composition based on total-body nitrogen, potassium, and calcium. Am J Physiol. 1980 Dec;239(6):E524–E530. doi: 10.1152/ajpendo.1980.239.6.E524. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. 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]
  7. Marshall S., Bacote V., Traxinger R. R. Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance. J Biol Chem. 1991 Mar 15;266(8):4706–4712. [PubMed] [Google Scholar]
  8. Revers R. R., Kolterman O. G., Scarlett J. A., Gray R. S., Olefsky J. M. Lack of in vivo insulin resistance in controlled insulin-dependent, type I, diabetic patients. J Clin Endocrinol Metab. 1984 Feb;58(2):353–358. doi: 10.1210/jcem-58-2-353. [DOI] [PubMed] [Google Scholar]
  9. Rossetti L., Giaccari A., DeFronzo R. A. Glucose toxicity. Diabetes Care. 1990 Jun;13(6):610–630. doi: 10.2337/diacare.13.6.610. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. 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]
  13. 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]
  14. Taylor R., Price T. B., Rothman D. L., Shulman R. G., Shulman G. I. Validation of 13C NMR measurement of human skeletal muscle glycogen by direct biochemical assay of needle biopsy samples. Magn Reson Med. 1992 Sep;27(1):13–20. doi: 10.1002/mrm.1910270103. [DOI] [PubMed] [Google Scholar]
  15. 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]

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