Intracellular skeletal muscle glucose metabolism is differentially alteredby dexamethasone treatment of normoglycemic relatives of type 2 diabetic patients

Young first-degree relatives of type 2 diabetic patients are insulin-resist ant, with the insulin resistance mainly located in skeletal muscle due to d ecreased insulin-induced nonoxidative glucose metabolism and muscle glycoge n synthase activation. We investigated whether the mechanism differs for de xamethasone (dex)-induced insulin resistance in first-degree relatives of t ype 2 diabetics versus healthy control subjects by quantifying intracellula r glucose processing in muscle biopsies taken before and after 5 days of de x treatment (4 mg/d) in 20 normal glucose-tolerant relatives of type 2 diab etic patients and 20 matched controls (age, 29.4 +/- 1.7 v 29.4 +/- 1.6 yea rs; body mass index, 25.1 +/- 1.0 v 25.1 +/- 0.9 kg/m(2)). In addition, an intravenous glucose tolerance test (IVGTT) combined with continuous indirec t calorimetry was performed. Following 5 days of dex treatment, glucose tol erance deteriorated in both the relatives and the control subjects, Fasting dry-weight muscle glucose and fasting intracellular muscle glucose concent rations increased in response to dex only in the relatives (2.43 +/- 0.21 v 2.97 +/- 0.26 mmol/kg dry weight, P < .05; 0.28 +/- 0.07 v 0.45 +/- 0.08 m mol/L intracellular water, P < .05); no increases were observed in the cont rol subjects. Fasting dry-weight muscle lactate also increased post-dex onl y in the relatives (7.37 +/- 0.40 v 10.77 +/- 1.22 mmol/kg dry weight, P < .001). Both basal muscle glucose and lactate concentrations from the IVGTT study correlated with the 2-hour post-dex glucose value obtained during the OGTT study in the relatives (R = .76 and R = .74, respectively, both P < . 0001) but not in the control subjects. Basal intramuscular glycogen synthas e activity decreased approximately 25% in both the relatives and control su bjects post-dex; the decrement was significant (P < .01) only in control su bjects. Indirect calorimetry during the post-dex IVGTT demonstrated increas ed glucose oxidation (P < .03) and reduced lipid oxidation (P < .03) in the relatives only. We postulate that the insulin resistance induced by dex in first-degree relatives of type 2 diabetic patients is associated with a pr eferential channeling of glucose into the glycolytic pathway (increased glu cose oxidation and lactate production), probably associated with a preexist ing downregulation of the glycosen synthase pathway. Copyright(C) 1999 by W .B. Saunders Company.