Metabolic Effects of Growth Hormone Replacement Therapy in Adults - with Special Reference to Insulin Sensitivity

Sammanfattning: A risk for premature atherosclerosis and increased cardiovascular mortality has been reported in adult patients suffering from growth hormone deficiency (GHD) and receiving conventional hormone substitution without growth hormone (GH) replacement. GHD patients are resistant to insulin, which is a potential risk factor for cardiovascular mortality. Insulin resistance can develop from an unfavourable body composition, which entails increased fat mass and decreased lean body mass due to loss of the stimulating effect of GH on lipolysis and protein synthesis. GH replacement therapy reverses these untoward changes in body composition, but it apparently does not fully restore sensitivity to insulin. The aim of the research underlying this thesis was to examine the role of free fatty acids (FFAs) in GH-induced insulin resistance in adults with GHD. To accomplish that objective, a euglycaemic hyperinsulinaemic clamp and indirect calorimetry techniques were used to study the effect of GH on insulin sensitivity. Impaired insulin-stimulated glucose metabolism was detected after six months of GH therapy, and this negative effect was correlated with enhanced lipolysis and lipid oxidation (paper 1). In two follow-up studies, the GH-induced resistance to insulin could be prevented by using the antilipolytic agent acipimox to inhibit the increase in lipolysis; acipimox was administered during both acute and chronic treatment with GH. Obviously, it was possible that other hormones, such as cortisol could have been involved in the observed effect. However, a confounding influence of cortisol replacement therapy was ruled out by results showing that insulin sensitivity did not differ, regardless of whether cortisol was given before or after the clamp. Our findings supported the theories that stimulation of lipolysis by GH is the main cause of GH-induced insulin resistance, and that co-administration of an antilipolytic agent can block the rise in FFA levels during GH replacement therapy and thereby partially prevents the accompanying deterioration in glucose metabolism.