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In vivo insulin resistance in individual peripheral tissues of the high fat fed rat: assessment by euglycaemic clamp plus deoxyglucose administration


We have examined peripheral insulin action in conscious rats chronically fed high fat (60% calories as fat) or high carbohydrate (lab chow) diets using the euglycaemic clamp plus 3 H-2-deoxyglucose technique. A response parameter of individual tissue glucose metabolic rate (the glucose metabolic index, based on tissue deoxyglucose phosphorylation) was used to assess diet effects in eight skeletal muscle types, heart, lung and white and brown adipose tissue. Comparing high fat with high carbohydrate fed rats, basal glucose metabolism was only mildly reduced in skeletal muscle (only diaphragm was significant,p<0.05), but was more substantially reduced in other tissues (e.g. white adipose tissue 61% and heart 33%). No evidence of basal hyperinsulinaemia was found. In contrast, widespread insulin resistance was found during the hyperinsulinaemic clamp (150 mU/l) in high fat fed animals; mean whole body net glucose utilization was 34% lower (p<0.01), and the glucose metabolic index was lower in skeletal muscle (14 to 56%,p< 0.05 in 6 out of 8 muscles), white adipose (27%,p<0.05) and brown adipose tissue (76%,p<0.01). The glucose metabolic index was also lower at maximal insulin levels in muscle and fat, suggesting the major effect of a high fat diet was a loss of insulin responsiveness. White adipose tissue differed from muscle in that incremental responses (maximal insulin minus basal) were not reduced by high fat feeding. The heart showed an effect opposite to other tissues, with an increase in insulin-stimulated glucose metabolism in high fat versus chow fed rats. We conclude that high fat feeding, without a major increase in body weight or basal hyperinsulinaemia, causes widespread but varying degrees of in vivo insulin resistance in peripheral tissues, with major effects in principally oxidative skeletal muscle.


  1. 1.

    Sweeney JH (1927) Dietary factors that influence the dextrose tolerance test. Arch Intern Med 40: 818–30

    CAS  Google Scholar 

  2. 2.

    Himsworth HP (1934) Dietetic factors influencing the glucose tolerance and the activity of insulin. J Physiol 81: 29–48

    CAS  PubMed  Google Scholar 

  3. 3.

    Christophe I, Mayer Z (1959) Influence of diet on utilization of glucose and incorporation of acetate 1–14 C into liver fatty acids and cholesterol in rats. Am J Physiol 197: 55–9

    PubMed  CAS  Google Scholar 

  4. 4.

    Zaragoza-Hermans N, Felber JP (1972) Studies of the metabolic effects induced in the rat by a high fat diet. II. Disposal of orally administered (14C)glucose. Horm Metab Res 4: 25–30

    PubMed  CAS  Google Scholar 

  5. 5.

    Lavau M, Susini C (1975) U-14C-Glucose metabolism in vivo in rats rendered obese by a high fat diet. J Lipid Res 16: 134–42

    PubMed  CAS  Google Scholar 

  6. 6.

    Bringolf M, Zaragoza N, Rivier D, Felber J-P (1972) Studies on the metabolic effects induced in the rat by a high-fat diet: Inhibition of pyruvate metabolism in diaphragm in vitro and its relation to the oxidation of fatty acids. Eur J Biochem 26: 360–7

    PubMed  CAS  Article  Google Scholar 

  7. 7.

    Susini C, Lavau M (1978) In-vitro and in-vivo responsiveness of muscle and adipose tissue to insulin in rats rendered obese by a high-fat diet. Diabetes 27: 114–20

    PubMed  CAS  Google Scholar 

  8. 8.

    Grundleger ML, Thenen SW (1982) Decreased insulin binding, glucose transport, and glucose metabolism in soleus muscle of rats fed a high fat diet. Diabetes 31: 232–7

    PubMed  CAS  Google Scholar 

  9. 9.

    Rattigan S, Filsell OH, Reppucci D, Patten GS, Clark MG (1983) Impaired basal and epinephrine-stimulated glucose uptake by hearts from rats fed high-fat diets. Nutr Rep Int 28: 603–12

    CAS  Google Scholar 

  10. 10.

    Olefsky JM (1978) The effects of dietary carbohydrate content on insulin binding and glucose metabolism in isolated rat adipocytes. Endocrinology 103: 2253–63

    Article  Google Scholar 

  11. 11.

    Salans LB, Foley JE, Wardzala LJ, Cushman SW (1981) Effects of dietary composition on glucose metabolism in rat adipose cells. Am J Physiol 240: E175–83

    PubMed  CAS  Google Scholar 

  12. 12.

    Hissin PJ, Karnieli E, Simpson IA, Salans LB, Cushman SW (1982) A possible mechanism of insulin resistance in the rat adipose cell with high-fat/low-carbohydrate feeding. Depletion of intracellular glucose transport systems. Diabetes 31: 589–92

    PubMed  CAS  Google Scholar 

  13. 13.

    Bjorntorp P, Sjostrom L (1978) Carbohydrate metabolism in man. Speculations and some quantitative considerations. Metabolism 2 (Suppl 2): 1853–63

    Google Scholar 

  14. 14.

    Kraegen EW, James DE, Jenkins AB, Chisholm DJ (1985) Doseresponse curves for in vivo insulin sensitivity in individual tissues in rats. Am J Physiol 248: E353–62

    PubMed  CAS  Google Scholar 

  15. 15.

    Defronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP (1981) The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterisation. Diabetes 30: 1000–7

    PubMed  CAS  Google Scholar 

  16. 16.

    James DE, Jenkins AB, Kraegen EW (1985) Heterogeneity of insulin action in individual muscles in vivo: euglycaemic clamp studies in the rat. Am J Physiol 249: E567-E574

    Google Scholar 

  17. 17.

    Kraegen EW, James DE, Bennett SP, Chisholm DJ (1983) In vivo insulin sensitivity in the rat determined by euglycaemic clamp. Am J Physiol 245: E1-E7

    PubMed  CAS  Google Scholar 

  18. 18.

    Ferre P, Leterque A, Bumol A-F, Penicaud L, Girard J (1985) A method to quantify glucose utilization in vivo in skeletal muscle and white adipose tissue of the anaesthetized rat. Biochem J 228: 103–110

    PubMed  CAS  Google Scholar 

  19. 19.

    Ariano MA, Armstrong RG, Edgerton VR (1973) Hindlimb muscle fibre populations of five mammals. J Histochem Cytochem 21: 51–5

    PubMed  CAS  Google Scholar 

  20. 20.

    James DE, Burleigh KM, Chisholm DJ, Kraegen EW (1985) In vivo dose response curves of insulin action in heart: anomalous effects at high insulin doses. J Mol Cell Cardiol 17: 981–985

    PubMed  CAS  Google Scholar 

  21. 21.

    York DA (1979) The characteristics of genetically obese mutants. In: Festing MFW (ed) Animal models of obesity. Macmillan, London, Basingstoke, pp 39–64

    Google Scholar 

  22. 22.

    Zaragoza N, Felber JP (1970) Studies on the metabolic effects induced in the rat by a high fat diet. I Carbohydrate metabolism in vivo. Horm Metab Res 2: 323–9

    PubMed  CAS  Article  Google Scholar 

  23. 23.

    Lawson N, Jennings RJ, Pollard AD, Sturton RG, Ralph SJ, Marsden CA, Fears R, Brindley DN (1981) Effects of chronic modification of dietary fat and carbohydrate in rats. The activities of some enzymes of hepatic glycerolipid synthesis and the effects of corticotropin injection. Biochem J 200: 265–73

    PubMed  CAS  Google Scholar 

  24. 24.

    Lavau M, Fried SK, Susini C, Freychet P (1979) Mechanism of insulin resistance in adipocytes of rats fed a high-fat diet. J Lipid Res 20: 8–16

    PubMed  CAS  Google Scholar 

  25. 25.

    Rhoades RA (1974) Net uptake of glucose, glycerol and fatty acids by the isolated perfused rat lung. Am J Physiol 226: 144–9

    PubMed  CAS  Google Scholar 

  26. 26.

    Salans LB, Dougherty JW (1971) Effect of insulin of glucose metabolism by adipose cells of different size. J Clin Invest 50: 1399–408

    PubMed  CAS  Google Scholar 

  27. 27.

    Bernstein RS, Marshall MC, Carney AL (1977) Effects of dietary composition on adipose tissue hexokinase-II and glucose utilization in normal and streptozotocin-diabetic rats. Diabetes 26: 770–9

    PubMed  CAS  Google Scholar 

  28. 28.

    Liang C-S, Doherty JU, Faillace R, Maekawa K, Arnold S, Gavras H, Hood WB Jr (1982) Insulin infusion in conscious dogs. Effects on systemic and coronary hemodynamics, regional blood flows and plasma catecholamines. J Clin Invest 69: 1321–36

    PubMed  CAS  Google Scholar 

  29. 29.

    Cooney GJ, Newsholme EA (1984) Does brown adipose tissue have a metabolic role in the rat? TIBS 25: 303–5

    Google Scholar 

  30. 30.

    James DE, Kraegen EW, Chisholm DJ (1985) Effects of exercise training on in vivo insulin action in individual tissues of the rat. J Clin Invest 76: 657–666

    PubMed  CAS  Google Scholar 

  31. 31.

    Friche RF, Longmore WJ (1979) Effects of insulin and diabetes on 2-deoxy-D-glucose uptake by the isolated perfused rat lung. J Biol Chem 254: 5092–98

    Google Scholar 

  32. 32.

    Hom FG, Goodner CJ, Berrie MA (1984) A 2-3 H deoxyglucose method for comparing rates of glucose metabolism and insulin responses among rat tissues in vivo. Validation of the model and the absence of an insulin effect on brain. Diabetes 33: 141–52

    PubMed  CAS  Google Scholar 

  33. 33.

    Strubbe JH, Steffens AB (1975) Rapid insulin release after ingestion of a meal in the unanaesthetized rat. Am J Physiol 229: 1019–22

    PubMed  CAS  Google Scholar 

  34. 34.

    Lillioja S, Bogardus C, Mott DM, Kennedy AL, Knowler WC, Howard BV (1985) Relationship between insulin-mediated glucose disposal and lipid metabolism in man. J Clin Invest 75: 1106–1115

    PubMed  CAS  Article  Google Scholar 

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Correspondence to E. W. Kraegen.

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Kraegen, E.W., James, D.E., Storlien, L.H. et al. In vivo insulin resistance in individual peripheral tissues of the high fat fed rat: assessment by euglycaemic clamp plus deoxyglucose administration. Diabetologia 29, 192–198 (1986).

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Key words

  • Diet
  • insulin action
  • muscle
  • glucose metabolism