Growth hormone disturbances in adolescents with type 1 (insulin-dependent) diabetes mellitus. Differentiating the GH signal

This Thesis provides evidence that raised plasma growth hormone (GH) levels play an intrinsic metabolic role in Type 1 diabetes. Physiological and functional aspects of GH pulsatility has been examined under standardized conditions. Diabetic subjects have prolonged GH clearance characteristics: Bolus GH half-life (t½) measurements and distribution volume (DV) are increased (mean±SEM t½13.6±1.1 vs control 8.9±0.54 mins, p<0.05; DV 6.1±0.4 vs control 3.54±0.32L, p< 0.005). Short-term euglycaemia, hyperglycaemia or hyperinsulinaemia do not influence GH decay. The time-mode of GH exposure critically extends GH half-life (60min exposure t½ 25.7 ± 2.1 mins; steady state (12h exposure) t½ 28.5±1.8 mins) describing an asymptote. The dynamics of GH secretion are also altered: Deconvolution analysis of adolescent plasma GH profiles confirm increased GH secretion rate (median (range) 1.88(0.56-3.81) vs. control 0.62 (0.32-1.92) mU/min, p<0.05) and altered dominant pulse periodicity (90min versus control 135min, p< 0.025). Exaggerated GH secretion persists despite overnight euglycaemic clamp. Pirenzepine (anticholinergic) reduces mean GH secretion (reduction of 63%, range 9.3-82.8%) suggesting the presence of an increased cholinergic tone exists in diabetic subjects; pirenzepine did not alter periodicity which remained shortened at 90minutes. During insulin-varying clamp and somatostatin suppression, trough plasma GH levels correlate with mean plasma insulin (r=0.52, p = 0.016); ambient glucose levels have no effect. The pulse signal was differentiated: GH pulsatility (3 pulses, mean peak 31.5 (range 26.5-36.9) mU/L) is primarily responsible for an oscillatory increase in insulin requirements occuring 135min after a GH pulse (r = 0.21,p