457 Clinical Science (2002) 102, 457–464 (Printed in Great Britain) Glucose flux is normalized by compensatory hyperinsulinaemia in growth hormone-induced insulin resistance in healthy subjects, while skeletal muscle protein synthesis remains unchanged Jonas NYGREN*, Anders THORELL*, Kerstin BRISMAR†, Pia ESSE  N‡, Jan WERNERMAN‡, Margaret A. MCNURLAN§, Peter J. GARLICK§ and Olle LJUNGQVIST* *Centre for Gastrointestinal Disease, Ersta Hospital, Karolinska Institute, 116 91 Stockholm, Sweden, †Department of Endocrinology, Karolinska Hospital, Karolinska Institute, 171 76 Stockholm, Sweden, ‡Department of Anaesthesia, Huddinge University Hospital, Karolinska Institute, 141 86 Stockholm, Sweden, and §Department of Surgery, State University of New York, Stony Brook, NY 11794, U.S.A. A B S T R A C T The aim of this present investigation was to study the relationship between the reduction in insulin sensitivity accompanying 5 days of treatment with growth hormone (GH; 0.05 mg  24 h - 1  kg - 1 ) and intracellular substrate oxidation rates in six healthy subjects, while maintaining glucose flux by a constant glucose infusion and adjusting insulin infusion rates to achieve normoglycaemia (feedback clamp). Protein synthesis rates in skeletal muscle (flooding dose of L-[ 2 H 5 ]phenylalanine) were determined under these conditions. We also compared changes in insulin sensitivity after GH treatment with simultaneous changes in energy requirements, protein synthesis rates, nitrogen balance, 3-methylhistidine excretion in urine, body composition and the hormonal milieu. After GH treatment, 70 % more insulin was required to maintain normoglycaemia (P  0.01). The ratio between glucose infusion rate and serum insulin levels decreased by 34 % at the two levels of glucose infusion tested (P  0.05). Basal levels of C-peptide, insulin-like growth factor (IGF)-I and IGF-binding protein-3 increased almost 2-fold, while levels of glucose, insulin, glucagon, GH and IGF-binding protein-1 remained unchanged. Non-esterified fatty acid levels decreased (P  0.05). In addition, 24 h urinary nitrogen excretion decreased by 26 % (P  0.01) after GH treatment, while skeletal muscle protein synthesis and 3-methylhistidine excretion in urine remained unchanged. Energy expenditure increased by 5 % (P  0.05) after treatment, whereas fat and carbohydrate oxidation were unaltered. In conclusion, when glucose flux was normalized by compensatory hyper- insulinaemia under conditions of GH-induced insulin resistance, intracellular rates of oxidation of glucose and fat remained unchanged. The nitrogen retention accompanying GH treatment seems to be due largely to improved nitrogen balance in non-muscle tissue. Key words: glucose clamp technique, glucose metabolism, growth hormone, insulin resistance, protein metabolism. Abbreviations: GH, growth hormone ; IGF, insulin-like growth factor ; IGFBP, IGF-binding protein ; MI ratio, mean level of glucose infusionmean serum insulin level ; NEFA, non-esterified fatty acids. Correspondence : Dr Jonas Nygren, Centre for Gastrointestinal Disease, Ersta Hospital, Box 4622, 116 91 Stockholm, Sweden (e-mail jonas.nygrenersta.se).  2002 The Biochemical Society and the Medical Research Society