Skip to main content
SpringerLink
Log in

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

  • Originals
  • Published:
Diabetologia Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Nosadini R, Del Prato S, Tiengo A et al. (1983) Insulin resistance in Cushing's syndrome. J Clin Endocrinol Metab 57: 529–536

    CAS  PubMed  Google Scholar 

  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: 131–138

    CAS  PubMed  Google Scholar 

  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: 883–891

    Article  CAS  PubMed  Google Scholar 

  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-E48

    CAS  PubMed  Google Scholar 

  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: 171–178

    PubMed  Google Scholar 

  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: 728–735

    CAS  PubMed  Google Scholar 

  7. Mueckler M (1990) Family of glucose-transporter genes. Implications for glucose homeostasis and diabetes. Diabetes 39: 6–11

    CAS  PubMed  Google Scholar 

  8. James DE, Strube M, Mueckler M (1989) Molecular cloning and characterization of an insulin-regulatable glucose transporter. Nature 338: 83–87

    CAS  PubMed  Google Scholar 

  9. Divertie GD, Jensen MD, Miles JM (1991) Stimulation of lipolysis in humans by physiological hypercortisolemia. Diabetes 40:1228–1232

    CAS  PubMed  Google Scholar 

  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: 785–789

    Google Scholar 

  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: 1737–1747

    CAS  PubMed  Google Scholar 

  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: 976–984

    Article  CAS  PubMed  Google Scholar 

  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: 960–966

    CAS  PubMed  Google Scholar 

  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: 1767–1774

    CAS  PubMed  Google Scholar 

  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: 1282–1290

    CAS  PubMed  Google Scholar 

  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: 1873–1879

    CAS  PubMed  Google Scholar 

  17. Eistetter K, Wolf HPO (1986) Etomoxir. Drugs Future 12: 1034–1036

    Google Scholar 

  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: 28–32

    CAS  PubMed  Google Scholar 

  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: 420–427

    Article  CAS  PubMed  Google Scholar 

  20. Beato M (1989) Gene regulation by steroid hormones. Cell 56: 335–344

    Article  CAS  PubMed  Google Scholar 

  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: 412–420

    CAS  PubMed  Google Scholar 

  22. Terrettaz J, Jeanrenaud B (1983) In vivo hepatic and peripheral insulin resistance in genetically obese (fa/fa) rats. Endocrinology 112: 1346–1351

    CAS  PubMed  Google Scholar 

  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: 103–110

    PubMed  Google Scholar 

  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-E574

    CAS  PubMed  Google Scholar 

  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: 96–105

    Article  CAS  PubMed  Google Scholar 

  26. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159

    Article  CAS  PubMed  Google Scholar 

  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: 2687–2695

    PubMed  Google Scholar 

  28. Klip A, Ramlal T, Young DA, Holloszy JO (1987) Insulin-induced translocation of glucose transporters in rat hindlimb muscles. FEBS Lett 224: 224–230

    Article  CAS  PubMed  Google Scholar 

  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: 7219–7225

    CAS  PubMed  Google Scholar 

  30. Herbert V, Lau KS, Gottlieb CW, Bleicher SJ (1965) Coated charcoal immunoassay of insulin. J Clin Endocrinol 25: 1375–1384

    CAS  Google Scholar 

  31. Gwosdow-Cohen A, Chen CL, Besch EL (1982) Radioimmunoassay (RIA) of serum corticosterone in rats. Proc Soc Exptl Biol Med 170: 29–34

    CAS  Google Scholar 

  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: 248–254

    Article  CAS  PubMed  Google Scholar 

  33. Labarca C, Paigen K (1980) A simple, rapid and sensitive DNA assay procedure. Anal Biochem 102: 344–352

    Article  CAS  PubMed  Google Scholar 

  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: 99–103

    CAS  PubMed  Google Scholar 

  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: 2063–2073

    CAS  PubMed  Google Scholar 

  36. Carter-Su C, Okamoto K (1987) Effect of insulin and glucocorticoids on glucose transporters in rat adipocytes. Am J Physiol 252: E441-E453

    CAS  PubMed  Google Scholar 

  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: 865–870

    CAS  PubMed  Google Scholar 

  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: 275–279

    CAS  PubMed  Google Scholar 

  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: 962–967

    CAS  PubMed  Google Scholar 

  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: 2197–2206

    CAS  PubMed  Google Scholar 

  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: 1564–1570

    Article  CAS  PubMed  Google Scholar 

  42. Davidson MB, Garvey D (1993) Studies on mechanisms of hepatic insulin resistance in cafeteria-fed rats. Am J Physiol 264: E18-E23

    CAS  PubMed  Google Scholar 

  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: 161–170

    CAS  PubMed  Google Scholar 

  44. Danforth WH (1965) Glycogen synthetase activity in skeletal muscle. Interconversion of two forms and control of glycogen synthesis. J Biol Chem 240: 588–593

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratoires de Recherches Métaboliques Faculty and Department of Medicine, University of Geneva, 64, Avenue de la Roseraie, CH-1211, Geneva 4, Switzerland

    C. Guillaume-Gentil, F. Assimacopoulos-Jeannet & B. Jeanrenaud

Authors
  1. C. Guillaume-Gentil
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Assimacopoulos-Jeannet
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. Jeanrenaud
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guillaume-Gentil, C., Assimacopoulos-Jeannet, F. & Jeanrenaud, B. Involvement of non-esterified fatty acid oxidation in glucocorticoid-induced peripheral insulin resistance in vivo in rats. Diabetologia 36, 899–906 (1993). https://doi.org/10.1007/BF02374470

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02374470

Key words

Search

Navigation