, Volume 37, Issue 3, pp 270–277 | Cite as

Effects of glycaemia on glucose transport in isolated skeletal muscle from patients with NIDDM: in vitro reversal of muscular insulin resistance

  • J. R. Zierath
  • D. Galuska
  • L. A. Nolte
  • A. Thörne
  • J. Smedegaard Kristensen
  • H. Wallberg-Henriksson


We investigated the influence of altered glucose levels on insulin-stimulated 3-0-methylglucose transport in isolated skeletal muscle obtained from NIDDM patients (n=13) and non-diabetic subjects (n=23). Whole body insulin sensitivity was 71% lower in the NIDDM patients compared to the non-diabetic subjects (p <0.05), whereas, insulin-mediated peripheral glucose utilization in the NIDDM patients under hyperglycaemic conditions was comparable to that of the non-diabetic subjects at euglycaemia. Following a 30-min in vitro exposure to 4 mmol/l glucose, insulin-stimulated 3-0-methylglucose transport (600 pmol/l insulin) was 40% lower in isolated skeletal muscle strips from the NIDDM patients when compared to muscle strips from the non-diabetic subjects. The impaired capacity for insulin-stimulated 3-0-methylglucose transport in the NIDDM skeletal muscle was normalized following prolonged (2 h) exposure to 4 mmol/l, but not to 8 mmol/l glucose. Insulin-stimulated 3-0-methylglucose transport in the NIDDM skeletal muscle exposed to 8 mmol/l glucose was similar to that of the non-diabetic muscle exposed to 5 mmol/l glucose, but was decreased by 43% (p <0.01) when compared to non-diabetic muscle exposed to 8 mmol/l glucose. Despite the impaired insulin-stimulated 3-0-methylglucose transport capacity demonstrated by skeletal muscle from the NIDDM patients, skeletal muscle glycogen content was similar to that of the non-diabetic subjects. Kinetic studies revel a Km for 3-0-methylglucose transport of 9.7 and 8.8 mmol/l glucose for basal and insulin-stimulated conditions, respectively. In conclusion, the impaired capacity for insulinstimulated glucose transport in skeletal muscle from patients with NIDDM appears to protect the cell from excessive glucose uptake under hyperglycaemic conditions. Furthermore, the in vitro normalization of the decreased insulin-stimulated glucose transport in NIDDM skeletal muscle following exposure to 4 mmol/l glucose suggests that glycaemia per se has a profound effect on the regulation of muscular glucose transport.

Key words

Glucose transport glucose kinetics human skeletal muscle insulin action insulin resistance 



Non-insulin-dependent diabetes mellitus


Krebs-Henseleit bicarbonate buffer


bovine serum albumin


analysis of variance


insulin regulated glucose transporter


  1. 1.
    Reaven GM, Olefsky JM (1978) The role of insulin resistance in the pathogenesis of diabetes mellitus. Adv Metab Res 9: 313–331Google Scholar
  2. 2.
    DeFronzo RA, Bonadonna RC, Ferrannini E (1992) Pathogenesis of NIDDM. A balanced overview. Diabetes Care 15: 318–368Google Scholar
  3. 3.
    Dohm GL, Tapscott EB, Pories WJ et al. (1988) An in vitro human muscle preparation suitable for metabolic studies. J Clin Invest 82: 486–494Google Scholar
  4. 4.
    Andréasson K, Galuska D, Thörne A, Sonnenfeld T, Wallberg-Henriksson H (1991) Decreased insulin-stimulated 3-0-methylglucose transport in in vitro incubated muscle strips from type II diabetic subjects. Acta Physiol Scand 142: 255–260Google Scholar
  5. 5.
    De Fronzo RA, Gunnarsson R, Björkman O, Olsson M, Wahren J (1985) Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest 76: 149–155Google Scholar
  6. 6.
    Rossetti L, Giaccari A, DeFronzo RA (1990) Glucose toxicity. Diabetes Care 13: 610–630Google Scholar
  7. 7.
    Sasson S, Edelson D, Cerasi E (1987) In vitro autoregulation of glucose utilization in rat soleus muscles. Diabetes 36: 1041–1046Google Scholar
  8. 8.
    Richter EA, Hansen BF, Hansen SA (1988) Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake. Biochem J 252: 733–737Google Scholar
  9. 9.
    Sasson S, Cerasi E (1986) Substrate regulation of the glucose transport system in rat skeletal muscle. J Biol Chem 261: 16827–16833Google Scholar
  10. 10.
    Yki-Järvinen H, Helve E, Koivisto VA (1987) Hyperglycemia decreases glucose uptake in type I diabetes. Diabetes 36: 892–896Google Scholar
  11. 11.
    Unger RH, Grundy S (1985) Hyperglycemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes. Diabetologia 28: 119–121Google Scholar
  12. 12.
    Kahn BB, Schulman GI, DeFronzo RA, Cushman SW, Rossetti L (1991) 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 87: 561–570Google Scholar
  13. 13.
    Scarlett JA, Kolterman OG, Ciaraldi TP, Kao M, Olefsky JM (1983) Insulin treatment reverses the postreceptor defect in adipocyte 3-0-methylglucose transport in type II diabetes mellitus. J Clin Endocrinol Metab 56: 1195–1201Google Scholar
  14. 14.
    Foley JE, Kashiwagi A, Verso MA, Reaven G, Andrews J (1983) Improvement in in vitro insulin action after one month of insulin therapy in obese noninsulin-dependent diabetics. J Clin Invest 72: 1901–1909Google Scholar
  15. 15.
    Hollund E, Pedersen O, Sorensen NS (1987) Adipocyte insulin binding and action in moderately obese NIDDM patients after dietary control of plasma glucose: reversal of post-binding abnormalities. Diabetes Care 10: 306–312Google Scholar
  16. 16.
    Zierath JR, Galuska D, Engström Å et al. (1992) Human islet amyloid polypeptide at pharmacological levels inhibits insulin and phorbol ester-stimulated glucose transport in in vitro incubated human muscle strips. Diabetologia 35: 26–31Google Scholar
  17. 17.
    Bergman RN, Ider YZ, Bowden CR, Cobelli C (1979) Quantitative estimation of insulin sensitivity. Am J Physiol 236: E667-E677Google Scholar
  18. 18.
    DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237: E214-E223Google Scholar
  19. 19.
    Henriksson KG (1979) Semi-open muscle biopsy technique. Acta Neurol Scand 59: 317–323Google Scholar
  20. 20.
    Vinten J (1978) Cytochlasin B inhibition and temperature dependence of 3-0-methylglucose transport in fat cells. Biochim Biophy Acta 511: 259–273Google Scholar
  21. 21.
    Wallberg-Henriksson H, Nie Z, Henriksson J (1987) Reversibility of decreased insulin-stimulated glucose transport capacity in diabetic muscle with in vitro incubation: insulin is not required. J Biol Chem 262: 7665–7671Google Scholar
  22. 22.
    Lowery, OH, Passonneau JV (1972) A flexible system of enzymatic analysis. Academic Press, New YorkGoogle Scholar
  23. 23.
    Bourey RE, Koranyi L, James DE, Mueckler M, Permutt MA (1990) Effects of altered glucose homeostasis on glucose transporter expression in skeletal muscle of the rat. J Clin Invest 86: 542–547Google Scholar
  24. 24.
    James DE, Studelska DR, Rodnick KJ (1992) Glucose transporter gene expression in muscle. In: Devlin JT, Horton ES, Vranic M (eds) Diabetes mellitus and exercise. Smith-Gordon, London, pp 45–54Google Scholar
  25. 25.
    Ramlal T, Rastogi S, Vranic M, Klip A (1989) Decrease in glucose transporter number in skeletal muscle of mildly diabetic (streptozotocin-treated) rats. Endocrinology 125: 890–897Google Scholar
  26. 26.
    Handberg A, Vaag A, Damsbo P, Beck-Nielsen H, Vinten J (1990) Expression of insulin-regulatable glucose transporters in skeletal muscle from type 2 (non-insulin-dependent) diabetic patients. Diabetologia 33: 625–627Google Scholar
  27. 27.
    Pedersen O, Bak JF, Andersen PH et al. (1990) Evidence against altered expression of GLUT1 or GLUT4 in skeletal muscle of patients with obesity or NIDDM. Diabetes 39: 865–870Google Scholar
  28. 28.
    Garvey WT, Maianu L, Hancock JA, Golichowski AM, Baron A (1992) Gene expression of GLUT4 in skeletal muscle from insulin-resistant patients with obesity, IGT, GDM, and NIDDM. Diabetes 41: 465–475Google Scholar
  29. 29.
    Vogt B, Mühlbacher C, Carrascosa J et al. (1992) Subcellular distribution of GLUT 4 in the skeletal muscle of lean type 2 (non-insulin-dependent) diabetic patients in the basal state. Diabetologia 35: 456–463Google Scholar
  30. 30.
    Vaag A, Damsbo P, Hother-Nielsen O, Beck-Nielsen H (1992) Hyperglycaemia compensates for the defect in insulin-mediated glucose metabolism and in the activation of glycogen synthase in the skeletal muscle of patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 35: 80–88Google Scholar
  31. 31.
    Revers RR, Fink R, Griffin J, Olefsky JM, Kolterman OG (1984) Influence of hyperglycemia on insulin's in vivo effects in type II diabetes. J Clin Invest 73: 664–672Google Scholar
  32. 32.
    Kelley DE, Mandarino LJ (1990) Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in noninsulin-dependent diabetes mellitus. J Clin Invest 86: 1999–2007Google Scholar
  33. 33.
    Gottesman I, Mandarino L, Verdonk C, Rizza R, Gerich J (1982) Insulin increases the maximum velocity for glucose uptake without altering the Michaelis constant in man. Evidence that insulin increases glucose uptake merely by providing additional transport sites. J Clin Invest 70: 1310–1314Google Scholar
  34. 34.
    Laakso M, Edelman SV, Olefsky JM, Brechtel G, Wallace P, Baron AD (1990) Kinetics of in vivo muscle insulin-mediated glucose uptake in human obesity. Diabetes 39: 965–974Google Scholar
  35. 35.
    Edelman SV, Laakso M, Wallace P, Brechtel G, Olefsky JM, Baron AD (1990) Kinetics of insulin-mediated and non-insulin-mediated glucose uptake in humans. Diabetes 39: 955–964Google Scholar
  36. 36.
    Fink RI, Wallace P, Brechtel G, Olefsky JM (1992) Evidence that glucose transport is rate-limiting for in vivo glucose uptake. Metabolism 41: 897–902Google Scholar
  37. 37.
    Laakso M, Edelman SV, Brechtel G, Baron AD (1992) Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM. Diabetes 41: 1076–1083Google Scholar
  38. 38.
    Boström M, Nie Z, Goertz G, Henriksson J, Wallberg-Henriksson H (1989) Indirect effect of catecholamines on development of insulin resistance in skeletal muscle from diabetic rats. Diabetes 38: 906–910Google Scholar
  39. 39.
    Laakso M, Edelman SV, Brechtel G, Baron A (1992) Effects of epinephrine on insulin-mediated glucose uptake in whole body and leg muscle in humans: role of blood flow. Am J Physiol 263: E199-E204Google Scholar
  40. 40.
    Nesher R, Karl I, Kipnis DM (1985) Dissociation of effects of insulin and contraction on glucose transport in rat epitrochlearis muscle. Am J Physiol 249: C226-C232Google Scholar
  41. 41.
    Karl IE, Gavin JR III, Levy J (1990) Effect of insulin on glucose utilization in epitrochlearis muscle of rats with streptozotocin-induced NIDDM. Diabetes 39: 1106–1115Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • J. R. Zierath
    • 1
  • D. Galuska
    • 1
  • L. A. Nolte
    • 1
  • A. Thörne
    • 2
  • J. Smedegaard Kristensen
    • 3
  • H. Wallberg-Henriksson
    • 1
  1. 1.Department of Clinical Physiology, Karolinska HospitalKarolinska InstituteStockholmSweden
  2. 2.Department of SurgeryHuddinge HospitalStockholmSweden
  3. 3.Department of Diabetes ResearchNovo Research InstituteBagsvaerdDenmark

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