The Effects of TZD on Fat Metabolism and Insulin Sensitivity in GH-Replaced GHD Patients

In human subjects GH (Growth Hormone) acutely antagonises the effects of insulin on glucose uptake in skeletal muscle and increases the hepatic glucose production of humans. This has clinical implications for patients with active acromegaly, in whom the prevalence of glucose intolerance and overt diabetes mellitus is increased. It is also of significance in relation to GH replacement therapy in GH-deficient adults not least when considering that a substantial proportion of these patients are insulin resistant in the GH-untreated state. There is evidence to indicate that the acute insulin antagonistic effects may be balanced with time by the favourable effects of GH on body composition and physical fitness, but the data are ambiguous. The mechanism underlying these effects of GH are not fully characterised, but there is experimental evidence of a causal linked to the concomitant stimulation of lipolysis, since GH-induced insulin resistance is partly abrogated when lipolysis is pharmacologically suppressed. This is noteworthy since elevated levels of free fatty acids (FFA) are also implicated in the pathogenesis of insulin resistance in patients with the metabolic syndrome and type 2 diabetes mellitus. Thiazolidinediones (TZDs) are insulin sensitizers which function as highaffinity agonists for the nuclear peroxisome-proliferator-activated receptor (PPAR) gamma, which improve insulin sensitivity in T2DM. PPAR gamma is a nuclear receptor expressed mainly in adipocytes, which activates the transcription of genes involved in lipid and glucose metabolism. Administration of TZD in T2DM enhances insulin-stimulated glucose uptake via mechanisms including a lowering of circulating FFA and a redistribution of fat away from hepatocytes and myocytes and into peripheral adipocytes. To our knowledge, the impact of TZDs on GH-induced insulin resistance has not previously been reported. Experimental data in human subjects on this issue are of potential importance not only in relation to patients with abnormal GH status, but also regarding our understanding of the pathogenesis of insulin resistance in general and the complex actions of PPAR gamma activation in particular.