In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats (original) (raw)

Abstract

To test the hypothesis that increased flux through the hexosamine biosynthetic pathway can induce insulin resistance in skeletal muscle in vivo, we monitored glucose uptake, glycolysis, and glycogen synthesis during insulin clamp studies in 6-h fasted conscious rats in the presence of a sustained (7-h) increase in glucosamine (GlcN) availability. Euglycemic (approximately 7 mM) insulin (approximately 2,500 pM) clamps with saline or GlcN infusions were performed in control (CON; plasma glucose [PG] = 7.4 +/- 0.2 mM), diabetic (D; PG = 19.7 +/- 1.1), and phlorizin-treated (3-wk) diabetic rats (D + PHL; PG = 7.6 +/- 0.9). 7-h euglycemic hyperinsulinemia with saline did not significantly decrease Rd (360-420 min = 39.2 +/- 3.6 vs. 60-120 min = 42.2 +/- 3.7 mg/kg.min; P = NS). GlcN infusion raised plasma GlcN concentrations to approximately 1.2 mM and increased muscle and liver UDP-GlcNAc levels by 4-5-fold in all groups. GlcN markedly decreased Rd in CON (360-420 min = 30.4 +/- 1.3 vs. 60-120 min = 44.1 +/- 3.5 mg/kg.min; P < 0.01) and D + PHL (360-420 min = 29.4 +/- 2.5 vs. 60-120 min = 43.8 +/- 2.9 mg/kg.min; P < 0.01), but not in D (5-7 h = 21.5 +/- 0.8 vs. 0-2 h = 24.3 +/- 1.1 mg/kg.min; P = NS). Thus, increased GlcN availability induces severe skeletal muscle insulin resistance in normoglycemic but not in chronically hyperglycemic rats. The lack of additive effects of GlcN and chronic hyperglycemia (experimental diabetes) provides support for the hypothesis that increased flux through the GlcN pathway in skeletal muscle may play an important role in glucose-induced insulin resistance in vivo.

132

Images in this article

Selected References

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

  1. Anumula K. R., Taylor P. B. Quantitative determination of phenyl isothiocyanate-derivatized amino sugars and amino sugar alcohols by high-performance liquid chromatography. Anal Biochem. 1991 Aug 15;197(1):113–120. doi: 10.1016/0003-2697(91)90365-z. [DOI] [PubMed] [Google Scholar]
  2. Balkan B., Dunning B. E. Glucosamine inhibits glucokinase in vitro and produces a glucose-specific impairment of in vivo insulin secretion in rats. Diabetes. 1994 Oct;43(10):1173–1179. doi: 10.2337/diab.43.10.1173. [DOI] [PubMed] [Google Scholar]
  3. Barzilai N., Rossetti L. Role of glucokinase and glucose-6-phosphatase in the acute and chronic regulation of hepatic glucose fluxes by insulin. J Biol Chem. 1993 Nov 25;268(33):25019–25025. [PubMed] [Google Scholar]
  4. Bonner-Weir S., Trent D. F., Weir G. C. Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release. J Clin Invest. 1983 Jun;71(6):1544–1553. doi: 10.1172/JCI110910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Crook E. D., Daniels M. C., Smith T. M., McClain D. A. Regulation of insulin-stimulated glycogen synthase activity by overexpression of glutamine: fructose-6-phosphate amidotransferase in rat-1 fibroblasts. Diabetes. 1993 Sep;42(9):1289–1296. doi: 10.2337/diab.42.9.1289. [DOI] [PubMed] [Google Scholar]
  6. Daniels M. C., Kansal P., Smith T. M., Paterson A. J., Kudlow J. E., McClain D. A. Glucose regulation of transforming growth factor-alpha expression is mediated by products of the hexosamine biosynthesis pathway. Mol Endocrinol. 1993 Aug;7(8):1041–1048. doi: 10.1210/mend.7.8.8232303. [DOI] [PubMed] [Google Scholar]
  7. Davidson A. L., Arion W. J. Factors underlying significant underestimations of glucokinase activity in crude liver extracts: physiological implications of higher cellular activity. Arch Biochem Biophys. 1987 Feb 15;253(1):156–167. doi: 10.1016/0003-9861(87)90648-5. [DOI] [PubMed] [Google Scholar]
  8. DeFronzo R. A., Hendler R., Simonson D. Insulin resistance is a prominent feature of insulin-dependent diabetes. Diabetes. 1982 Sep;31(9):795–801. doi: 10.2337/diab.31.9.795. [DOI] [PubMed] [Google Scholar]
  9. DeFronzo R., Deibert D., Hendler R., Felig P., Soman V. Insulin sensitivity and insulin binding to monocytes in maturity-onset diabetes. J Clin Invest. 1979 May;63(5):939–946. doi: 10.1172/JCI109394. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  10. Dimitrakoudis D., Ramlal T., Rastogi S., Vranic M., Klip A. Glycaemia regulates the glucose transporter number in the plasma membrane of rat skeletal muscle. Biochem J. 1992 Jun 1;284(Pt 2):341–348. doi: 10.1042/bj2840341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Garvey W. T., Olefsky J. M., Marshall S. Insulin receptor down-regulation is linked to an insulin-induced postreceptor defect in the glucose transport system in rat adipocytes. J Clin Invest. 1985 Jul;76(1):22–30. doi: 10.1172/JCI111950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Garvey W. T., Olefsky J. M., Matthaei S., Marshall S. Glucose and insulin co-regulate the glucose transport system in primary cultured adipocytes. A new mechanism of insulin resistance. J Biol Chem. 1987 Jan 5;262(1):189–197. [PubMed] [Google Scholar]
  13. Giaccari A., Rossetti L. Isocratic high-performance liquid chromatographic determination of the concentration and specific radioactivity of phosphoenolpyruvate and uridine diphosphate glucose in tissue extracts. J Chromatogr. 1989 Dec 29;497:69–78. doi: 10.1016/0378-4347(89)80006-4. [DOI] [PubMed] [Google Scholar]
  14. Giaccari A., Rossetti L. Predominant role of gluconeogenesis in the hepatic glycogen repletion of diabetic rats. J Clin Invest. 1992 Jan;89(1):36–45. doi: 10.1172/JCI115583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hager S. R., Jochen A. L., Kalkhoff R. K. Insulin resistance in normal rats infused with glucose for 72 h. Am J Physiol. 1991 Mar;260(3 Pt 1):E353–E362. doi: 10.1152/ajpendo.1991.260.3.E353. [DOI] [PubMed] [Google Scholar]
  16. Hansen B. F., Hansen S. A., Ploug T., Bak J. F., Richter E. A. Effects of glucose and insulin on development of impaired insulin action in muscle. Am J Physiol. 1992 Apr;262(4 Pt 1):E440–E446. doi: 10.1152/ajpendo.1992.262.4.E440. [DOI] [PubMed] [Google Scholar]
  17. Hostetler K. Y., Landau B. R. Estimation of the pentose cycle contribution to glucose metabolism in tissue in vivo. Biochemistry. 1967 Oct;6(10):2961–2964. doi: 10.1021/bi00862a001. [DOI] [PubMed] [Google Scholar]
  18. Kahn B. B., Rossetti L., Lodish H. F., Charron M. J. Decreased in vivo glucose uptake but normal expression of GLUT1 and GLUT4 in skeletal muscle of diabetic rats. J Clin Invest. 1991 Jun;87(6):2197–2206. doi: 10.1172/JCI115254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kahn B. B., Shulman G. I., DeFronzo R. A., Cushman S. W., Rossetti L. Normalization of blood glucose in diabetic rats with phlorizin treatment reverses insulin-resistant glucose transport in adipose cells without restoring glucose transporter gene expression. J Clin Invest. 1991 Feb;87(2):561–570. doi: 10.1172/JCI115031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Karlander S., Roovete A., Vranić M., Efendić S. Glucose and fructose 6-phosphate cycle in humans. Am J Physiol. 1986 Nov;251(5 Pt 1):E530–E536. doi: 10.1152/ajpendo.1986.251.5.E530. [DOI] [PubMed] [Google Scholar]
  21. Kolterman O. G., Gray R. S., Griffin J., Burstein P., Insel J., Scarlett J. A., Olefsky J. M. Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus. J Clin Invest. 1981 Oct;68(4):957–969. doi: 10.1172/JCI110350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Marshall S., Bacote V., Traxinger R. R. Complete inhibition of glucose-induced desensitization of the glucose transport system by inhibitors of mRNA synthesis. Evidence for rapid turnover of glutamine:fructose-6-phosphate amidotransferase. J Biol Chem. 1991 Jun 5;266(16):10155–10161. [PubMed] [Google Scholar]
  23. 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]
  24. Marshall S., Garvey W. T., Traxinger R. R. New insights into the metabolic regulation of insulin action and insulin resistance: role of glucose and amino acids. FASEB J. 1991 Dec;5(15):3031–3036. doi: 10.1096/fasebj.5.15.1743436. [DOI] [PubMed] [Google Scholar]
  25. Richter E. A., Hansen B. F., Hansen S. A. Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake. Biochem J. 1988 Jun 15;252(3):733–737. doi: 10.1042/bj2520733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rizza R. A., Mandarino L. J., Gerich J. E. Mechanism and significance of insulin resistance in non-insulin-dependent diabetes mellitus. Diabetes. 1981 Dec;30(12):990–995. doi: 10.2337/diab.30.12.990. [DOI] [PubMed] [Google Scholar]
  27. Robinson K. A., Sens D. A., Buse M. G. Pre-exposure to glucosamine induces insulin resistance of glucose transport and glycogen synthesis in isolated rat skeletal muscles. Study of mechanisms in muscle and in rat-1 fibroblasts overexpressing the human insulin receptor. Diabetes. 1993 Sep;42(9):1333–1346. doi: 10.2337/diab.42.9.1333. [DOI] [PubMed] [Google Scholar]
  28. Rossetti L., Giaccari A., Barzilai N., Howard K., Sebel G., Hu M. Mechanism by which hyperglycemia inhibits hepatic glucose production in conscious rats. Implications for the pathophysiology of fasting hyperglycemia in diabetes. J Clin Invest. 1993 Sep;92(3):1126–1134. doi: 10.1172/JCI116681. [DOI] [PMC free article] [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., Hu M. Skeletal muscle glycogenolysis is more sensitive to insulin than is glucose transport/phosphorylation. Relation to the insulin-mediated inhibition of hepatic glucose production. J Clin Invest. 1993 Dec;92(6):2963–2974. doi: 10.1172/JCI116919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rossetti L., Lauglin M. R. Correction of chronic hyperglycemia with vanadate, but not with phlorizin, normalizes in vivo glycogen repletion and in vitro glycogen synthase activity in diabetic skeletal muscle. J Clin Invest. 1989 Sep;84(3):892–899. doi: 10.1172/JCI114250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 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]
  33. Sivitz W. I., DeSautel S. L., Kayano T., Bell G. I., Pessin J. E. Regulation of glucose transporter messenger RNA levels in rat adipose tissue by insulin. Mol Endocrinol. 1990 Apr;4(4):583–588. doi: 10.1210/mend-4-4-583. [DOI] [PubMed] [Google Scholar]
  34. Thomas J. A., Schlender K. K., Larner J. A rapid filter paper assay for UDPglucose-glycogen glucosyltransferase, including an improved biosynthesis of UDP-14C-glucose. Anal Biochem. 1968 Oct 24;25(1):486–499. doi: 10.1016/0003-2697(68)90127-9. [DOI] [PubMed] [Google Scholar]
  35. Traxinger R. R., Marshall S. Coordinated regulation of glutamine:fructose-6-phosphate amidotransferase activity by insulin, glucose, and glutamine. Role of hexosamine biosynthesis in enzyme regulation. J Biol Chem. 1991 Jun 5;266(16):10148–10154. [PubMed] [Google Scholar]
  36. Traxinger R. R., Marshall S. Insulin regulation of pyruvate kinase activity in isolated adipocytes. Crucial role of glucose and the hexosamine biosynthesis pathway in the expression of insulin action. J Biol Chem. 1992 May 15;267(14):9718–9723. [PubMed] [Google Scholar]
  37. Traxinger R. R., Marshall S. Role of amino acids in modulating glucose-induced desensitization of the glucose transport system. J Biol Chem. 1989 Dec 15;264(35):20910–20916. [PubMed] [Google Scholar]
  38. Unger R. H., Grundy S. Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes. Diabetologia. 1985 Mar;28(3):119–121. doi: 10.1007/BF00273856. [DOI] [PubMed] [Google Scholar]
  39. Vuorinen-Markkola H., Koivisto V. A., Yki-Jarvinen H. Mechanisms of hyperglycemia-induced insulin resistance in whole body and skeletal muscle of type I diabetic patients. Diabetes. 1992 May;41(5):571–580. doi: 10.2337/diab.41.5.571. [DOI] [PubMed] [Google Scholar]
  40. 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]
  41. Yki-Järvinen H., Koivisto V. A. Natural course of insulin resistance in type I diabetes. N Engl J Med. 1986 Jul 24;315(4):224–230. doi: 10.1056/NEJM198607243150404. [DOI] [PubMed] [Google Scholar]