[en] Insulin resistance may result from decreased muscle blood flow, impaired cellular glucose transport, or intracellular deficits of glucose metabolism. The mechanisms responsible for dexamethasone-induced insulin resistance were investigated in healthy human subjects. During a 2-h hyperinsulinemic clamp, dexamethasone decreased glucose uptake, oxidation, and nonoxidative glucose disposal during the first hour. During the second hour, glucose uptake was normalized by means of hyperglycemia; glucose oxidation, however, remained suppressed by dexamethasone. Dexamethasone also abolished the insulin-mediated increase in calf blood flow. When acipimox was administered during the clamps to correct glucocorticoid-induced inhibition of glucose oxidation, dexamethasone decreased whole body glucose uptake and nonoxidative glucose disposal in the same proportion as when no acipimox was administered. However, glucose oxidation and insulin-mediated calf blood flow were normalized after acipimox. During the second hour, exogenous glucose infusion was matched to that used in the control clamp and normalized whole body glucose uptake. However, hyperglycemia developed, indicating insulin resistance. It is concluded that dexamethasone 1) decreases glucose oxidation independently of glucose transport; this inhibition is reversed by acipimox; and 2) decreases whole body glucose uptake independently of increased lipolysis, decreased glucose oxidation, or an altered muscle blood flow.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Tappy, L.
Randin, D.
Vollenweider, P.
Vollenweider, L.
Paquot, Nicolas ; Centre Hospitalier Universitaire de Liège - CHU > Diabétologie,nutrition, maladies métaboliques
Scherrer, U.
Schneiter, P.
Nicod, P.
Jequier, E.
Language :
English
Title :
Mechanisms of dexamethasone-induced insulin resistance in healthy humans.
Publication date :
1994
Journal title :
Journal of Clinical Endocrinology and Metabolism
ISSN :
0021-972X
eISSN :
1945-7197
Publisher :
Endocrine Society, Chevy Chase, United States - Maryland
Klip A, Pâquet MR. 1990 Glucose transport and glucose transporters in muscle and their metabolic regulation. Diabetes Care. 13:228-243.
Gerich JE. 1993 Control of glycaemia. Bailliere Clin Endocrinol Metab. 7:551-586.
Laakso M, Edelman SV, Brechtel G, Baron AD. 1990 Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. J Clin Invest. 85:1844-1852.
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. 39:965-974.
McMahon M, Gerich J, Rizza R. 1988 Effects of glucocorticoids on carbohydrate metabolism. Diabetes Metab Rev. 4:17-30.
Nosadini R, Del Prato S, Tiengo A, et al. 1983 Insulin resistance in Cushing's syndrome. J Clin Endocrinol Metab. 57:529-536.
Baron AD, Wallace P, Brechtel G. 1987 In vivo regulation of non-insulin-mediated and insulin-mediated glucose uptake by cortisol. Diabetes. 36:1230-1237.
Carter-Su C, Okamoto K. 1985 Effect of glucocorticoids on hexose transport in rat adipocytes. J Biol Chem. 260:11091-11098.
Hallahan C, Young D, Munck A. 1973 Time course of early events in the action of glucocorticoids on rat thymus cells in vitro. J Biol Chem. 248:2922-2927.
Randle P, Garland P, Hales C, Newsholme E. 1963 The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1:785-789.
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.
Guillaume-Gentil C, Assimacopoulos-Jeannet F, Jeanrenaud B. 1993 Involvement of non-esterified fatty acid oxidation in glucocorticoid-induced peripheral insulin resistance in vivo in rats. Diabetologia. 36:899-906.
Scherrer U, Vollenweider P, Randin D, Jéquier E, Nicod P, Tappy L. 1993 Suppression of insulin induced sympathetic activation and vasodilation by dexamethasone in humans. Circulation. 88:388-394.
Tappy L, Owen O, Boden G. 1988 Effect of hyperinsulinemia on urea pool size and substrate oxidation rates. Diabetes. 37:1212-1217.
Jéquier E, Felber J. 1987 Indirect calorimetry. Bailliere Clin Endocrinol Metab. 1:911-935.
DeFronzo RA, Tobin JD, Andres R. 1979 Glucose clamp technique a method for quantifying insulin secretion and resistance. Am J Physiol. 237:E214-223.
Herbert V, Lau KS, Gottlieb CW, Bleicher SJ. 1965 Coated charcoal immunoassay of insulin. J Clin Endocrinol Metab. 25:1375-1384.
Hallman J, Farnebo LO, Hamberger B, Jonsson G. 1978 A sensitive method for determination of plasma catecholamines using liquid chromatography with electrochemical detection. Life Sci. 23:1049-1052.
Vollenweider P, Tappy L, Randin D, et al. 1993 Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J Clin Invest. 92:147-154.
DeBodo R, Steele R, Altszuler N, Dunn A, Bishop J. 1963 On the hormonal regulation of carbohydrate metabolism: studies with 14C-glucose. Recent Prog Horm Res. 19:445-488.
Serrano MAR, Curi R, Parry-Billings M, Williams JF, Newsholme EA. 1993 Effects of glucocorticoids on lymphocyte metabolism. Am J Physiol. 264:E24-E28.
Granner DK. 1985 Hormones of the adrenal gland. In: Martin Jr DW, Mayes PA, Rodwell VW, Granner DK, eds. Harper's review of biochemistry. Los Altos: Lange; 548-569.
Boden G, Jadali F, White J, et al. 1991 Effects of fat on insulin-stimulated carbohydrate metabolism in normal man. J Clin Invest. 88:960-966.
Fulcher GR, Walker M, Farrer M, Johnson AS, Alberti KGMM. 1993 Acipimox increases glucose disposal in normal man independent of changes in plasma nonesterified fatty acid concentration and whole-body lipid oxidation rate. Metabolism. 42:308-314.
Ekstrand A, Saloranta C, Ahonen J, Grönhagen-Riska C, Groop LC. 1992 Reversal of steroid-induced insulin resistance by a nicotinic-acid derivative in man. Metabolism. 41:692-697.
Hjemdahl P. 1993 Plasma catecholamines-analytical challenges and physiological limitations. Bailliere Clin Endocrinol Metab. 7:307-353.