Advertisement

Diabetologia

, Volume 36, Issue 10, pp 899–906 | Cite as

Involvement of non-esterified fatty acid oxidation in glucocorticoid-induced peripheral insulin resistance in vivo in rats

  • C. Guillaume-Gentil
  • F. Assimacopoulos-Jeannet
  • B. Jeanrenaud
Originals

Summary

The mechanism by which glucocorticoids induce insulin resistance was studied in normal rats administered for 2 days with corticosterone then tested by euglycaemic hyperinsulinaemic clamps. Corticosterone administration induced a slight hyperglycaemia, hyperinsulinaemia and increased non-esterified fatty acid levels. It impaired insulin-stimulated total glucose utilization (corticosterone 15.7±0.7; controls 24.6±0.8 mg·kg−1·min−1), as well as residual hepatic glucose production (corticosterone 4.9±1.0; controls 2.0±0.7 mg·kg−1·min−1). During the clamps, insulin did not decrease the elevated non-esterified fatty acid levels in corticosterone-administered rats (corticosterone 1.38±0.15, controls 0.22±0.04 mmol/l). Corticosterone administration decreased the in vivo insulin-stimulated glucose utilization index by individual muscles by 62±6%, and the de novo glycogen synthesis by 78±2% (n=8–9 muscles). GLUT4 protein and mRNA levels were either unchanged or slightly increased by corticosterone administration. Inhibition of lipid oxidation by etomoxir prevented corticosterone-induced muscle but not hepatic insulin resistance. In conclusion, glucocorticoid-induced muscle insulin resistance is due to excessive nonesterified fatty acid oxidation, possibly via increased glucose fatty-acid cycle ultimately inhibiting glucose transport, or via decreased glycogen synthesis, or by a direct effect on glucose transporter translocation or activity or both.

Key words

Muscle glucocorticoids insulin resistance glucose transport glucose transporter glucose fatty-acid cycle lipid oxidation glycogen synthesis 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Nosadini R, Del Prato S, Tiengo A et al. (1983) Insulin resistance in Cushing's syndrome. J Clin Endocrinol Metab 57: 529–536PubMedGoogle Scholar
  2. 2.
    Rizza RA, Mandarino LJ, Gerich JE (1982) Cortisol-induced insulin resistance in man: impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor defect of insulin action. J Clin Endocrinol Metab 54: 131–138PubMedGoogle Scholar
  3. 3.
    Venkatesan N, Davidson MB, Hutchinson A (1987) Possible role for the glucose-fatty acid cycle in dexamethasone-induced insulin antagonism in rats. Metabolism 36: 883–891CrossRefPubMedGoogle Scholar
  4. 4.
    Block NE, Buse MG (1989) Effects of hypercortisolemia and diabetes on skeletal muscle insulin receptor function in vitro and in vivo. Am J Physiol 256: E39-E48PubMedGoogle Scholar
  5. 5.
    Riddick FA, Reisler DM, Kipnis DM (1962) The sugar transport system in striated muscle. Effect of growth hormone, hydrocortisone and alloxan diabetes. Diabetes 11: 171–178PubMedGoogle Scholar
  6. 6.
    Haber RS, Weinstein SP (1992) Role of glucose transporters in glucocorticoid-induced insulin resistance. GLUT 4 isoform in rat skeletal muscle is not decreased by dexamethasone. Diabetes 41: 728–735PubMedGoogle Scholar
  7. 7.
    Mueckler M (1990) Family of glucose-transporter genes. Implications for glucose homeostasis and diabetes. Diabetes 39: 6–11PubMedGoogle Scholar
  8. 8.
    James DE, Strube M, Mueckler M (1989) Molecular cloning and characterization of an insulin-regulatable glucose transporter. Nature 338: 83–87PubMedGoogle Scholar
  9. 9.
    Divertie GD, Jensen MD, Miles JM (1991) Stimulation of lipolysis in humans by physiological hypercortisolemia. Diabetes 40:1228–1232PubMedGoogle Scholar
  10. 10.
    Randle PJ, Hales CN, Garland PB, Newsholm EA (1963) The glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet I: 785–789Google Scholar
  11. 11.
    Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA (1983) Effect of fatty acids on glucose production and utilization in man. J Clin Invest 72: 1737–1747PubMedGoogle Scholar
  12. 12.
    Chambrier C, Picard S, Vidal H, Cohen R, Riou J-P, Beylot M (1990) Interactions of glucagon and free fatty acids with insulin in control of glucose metabolism. Metabolism 39: 976–984CrossRefPubMedGoogle Scholar
  13. 13.
    Boden G, Jadali F, White J et al. (1991) Effects of fat on insulin-stimulated carbohydrate metabolism in normal men. J Clin Invest 88: 960–966PubMedGoogle Scholar
  14. 14.
    Nuutila P, Koivisto VA, Knuuti J et al. (1992) Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo. J Clin Invest 89: 1767–1774PubMedGoogle Scholar
  15. 15.
    Vaag A, Skött P, Damsbo P, Gall M-A, Richter EA, Beck-Nielsen H (1991) Effect of the antilipolytic nicotinic acid analogue Acipimox on whole-body and skeletal muscle glucose metabolism in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 88: 1282–1290PubMedGoogle Scholar
  16. 16.
    Guillaume-Gentil C, Rohner-Jeanrenaud F, Abramo F, Bestetti GE, Rossi GL, Jeanrenaud B (1990) Abnormal regulation of the hypothalamo-pituitary-adrenal axis in the genetically obese fa/fa rat. Endocrinology 126: 1873–1879PubMedGoogle Scholar
  17. 17.
    Eistetter K, Wolf HPO (1986) Etomoxir. Drugs Future 12: 1034–1036Google Scholar
  18. 18.
    Reaven GM, Chang H, Hoffman BB (1988) Additive hypoglycemic effects of drugs that modify free-fatty acid metabolism by different mechanisms in rats with streptozocin-induced diabetes. Diabetes 37: 28–32PubMedGoogle Scholar
  19. 19.
    Martin C, Odeon M, Cohen R, Beylot M (1991) Mechanisms of the glucose lowering effect of carnitine palmitoyl transferase inhibitor in normal and diabetic rats. Metabolism 40: 420–427CrossRefPubMedGoogle Scholar
  20. 20.
    Beato M (1989) Gene regulation by steroid hormones. Cell 56: 335–344CrossRefPubMedGoogle Scholar
  21. 21.
    Simmons PS, Miles JM, Gerich JE, Haymond MW (1984) Increased proteolysis. An effect of increases in plasma cortisol within the physiologic range. J Clin Invest 73: 412–420PubMedGoogle Scholar
  22. 22.
    Terrettaz J, Jeanrenaud B (1983) In vivo hepatic and peripheral insulin resistance in genetically obese (fa/fa) rats. Endocrinology 112: 1346–1351PubMedGoogle Scholar
  23. 23.
    Ferré P, Leturque A, Burnol AF, Pénicaud 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: 103–110PubMedGoogle Scholar
  24. 24.
    James DE, Jenkins AB, Kraegen EW (1985) Heterogeneity of insulin action in individual muscles in vivo: euglycaemic clamp studies in rats. Am J Physiol 248: E567-E574PubMedGoogle Scholar
  25. 25.
    Chan TM, Exton JH (1976) A rapid method for the determination of glycogen content and radioactivity in small quantities of tissue or isolated hepatocytes. Anal Biochem 71: 96–105CrossRefPubMedGoogle Scholar
  26. 26.
    Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159CrossRefPubMedGoogle Scholar
  27. 27.
    Le Marchand-Brustel Y, Olichon-Berthe C, Gremeaux T, Tanti JF, Rochet N, van Obberghen E (1990) Glucose transporters in insulin sensitive tissues of lean and obese mice. Effects of the thermogenic agent BRL 26830A*. Endocrinology 127: 2687–2695PubMedGoogle Scholar
  28. 28.
    Klip A, Ramlal T, Young DA, Holloszy JO (1987) Insulin-induced translocation of glucose transporters in rat hindlimb muscles. FEBS Lett 224: 224–230CrossRefPubMedGoogle Scholar
  29. 29.
    Haspel HC, Birnbaum MJ, Wilk EW, Rosen OM (1985) Biosynthetic precursors and in vitro translation products of human hepatocarcinoma cells, human fibroblasts and murine preadipocytes. J Biol Chem 260: 7219–7225PubMedGoogle Scholar
  30. 30.
    Herbert V, Lau KS, Gottlieb CW, Bleicher SJ (1965) Coated charcoal immunoassay of insulin. J Clin Endocrinol 25: 1375–1384Google Scholar
  31. 31.
    Gwosdow-Cohen A, Chen CL, Besch EL (1982) Radioimmunoassay (RIA) of serum corticosterone in rats. Proc Soc Exptl Biol Med 170: 29–34Google Scholar
  32. 32.
    Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254CrossRefPubMedGoogle Scholar
  33. 33.
    Labarca C, Paigen K (1980) A simple, rapid and sensitive DNA assay procedure. Anal Biochem 102: 344–352CrossRefPubMedGoogle Scholar
  34. 34.
    Cusin I, Terrettaz J, Rohner-Jeanrenaud F, Jeanrenaud B (1990) Metabolic consequences of hyperinsulinaemia imposed on normal rats on glucose handling by white adipose tissue, muscles and liver. Biochem J 267: 99–103PubMedGoogle Scholar
  35. 35.
    Garvey WT, Huecksteadt TP, Monzon R, Marshall S (1989) Dexamethasone regulates the glucose transport system in primary cultured adipocytes: different mechanisms of insulin resistance after acute and chronic exposure. Endocrinology 124: 2063–2073PubMedGoogle Scholar
  36. 36.
    Carter-Su C, Okamoto K (1987) Effect of insulin and glucocorticoids on glucose transporters in rat adipocytes. Am J Physiol 252: E441-E453PubMedGoogle Scholar
  37. 37.
    Pedersen O, Bak JF, Andersen PH et al. (1990) Evidence against altered expression of GLUT 1 or GLUT 4 in skeletal muscle of patients with obesity or NIDDM. Diabetes 39: 865–870PubMedGoogle Scholar
  38. 38.
    Wake SA, Sowden JA, Storlien LH et al. (1991) Effects of exercise training and dietary manipulation on insulin-regulatable glucose-transporter mRNA in rat muscle. Diabetes 40: 275–279PubMedGoogle Scholar
  39. 39.
    Koranyi L, James D, Mueckler M, Permutt MA (1990) Glucose transporter levels in spontaneously obese (db/db) insulin-resistant mice. J Clin Invest 85: 962–967PubMedGoogle Scholar
  40. 40.
    Kahn BB, Rossetti L, Lodish HF, Charron MJ (1991) Decreased in vivo glucose uptake but normal expression of GLUT 1 and GLUT 4 in skeletal muscle of diabetic rats. J Clin Invest 87: 2197–2206PubMedGoogle Scholar
  41. 41.
    Zarjevski N, Doyle P, Jeanrenaud B (1992) Muscle insulin resistance may not be a primary etiological factor in the genetically obese fa/fa rat. Endocrinology 130: 1564–1570CrossRefPubMedGoogle Scholar
  42. 42.
    Davidson MB, Garvey D (1993) Studies on mechanisms of hepatic insulin resistance in cafeteria-fed rats. Am J Physiol 264: E18-E23PubMedGoogle Scholar
  43. 43.
    Rennie MJ, Holloszy JO (1977) Inhibition of glucose uptake and glycogenolysis by availability of oleate in well-oxygenated perfused skeletal muscle. Biochem J 168: 161–170PubMedGoogle Scholar
  44. 44.
    Danforth WH (1965) Glycogen synthetase activity in skeletal muscle. Interconversion of two forms and control of glycogen synthesis. J Biol Chem 240: 588–593PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • C. Guillaume-Gentil
    • 1
  • F. Assimacopoulos-Jeannet
    • 1
  • B. Jeanrenaud
    • 1
  1. 1.Laboratoires de Recherches Métaboliques Faculty and Department of MedicineUniversity of GenevaGeneva 4Switzerland

Personalised recommendations