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In many countries, treatment of childhood-onset GH deficiency (GHD) with GH ceases when linear growth is complete. Peak bone mass occurs several years after the completion of linear growth. Given that GH has important anabolic actions on bone, discontinuation of GH therapy at the completion of linear growth may have adverse consequences for the attainment of peak bone mass in adolescent GHD patients. In this United Kingdom multicenter study, 24 adolescents (13 males, mean age 17.0 +/- 1.4 yr, SD) with severe GHD were randomized to discontinue or continue GH (0.35 IU/kg x wk) at the completion of linear growth. Whole body bone mineral content (BMC) and lumbar spine bone mineral density were assessed by dual-energy x-ray absorptiometry at baseline and then at 6-month intervals for 1 yr. Markers of bone remodeling (serum bone-specific alkaline phosphatase and urinary deoxypyridinoline) were measured at the same time points. In patients who continued GH (GH+), median BMC increased by 3.8% (interquartile range, 2.6, 5.9, P < 0.001) at 6 months; and by 6.0% (3.7-9.1, P < 0.001) at 12 months. In patients who discontinued GH (GH-) median BMC was unchanged at 6 and 12 months (+1.9%, -0.4-4.2, P = 0.9; and +2.4%, 0.4-4.9, P = 0.5, respectively, median, interquartile range). The differences in median change in BMC between the two groups at 6 and 12 months was marginally significant (P = 0.085 and 0.074, respectively). Mean lumbar spine bone mineral density increased by 4.7 (95% confidence interval, 1.0, 8.2) at 12 months in patients continuing GH (P = 0.01), but the mean change was not statistically significant change in patients who discontinued GH [+2.7% (95% confidence interval, -0.8, +6.2)]. These preliminary data suggest that, in adolescent patients with severe GHD, discontinuation of GH at completion of growth may limit the attainment of peak bone mass in this patient group. This may predispose to clinically significant osteopenia in later adult life.

Type 1 diabetes is associated with abnormalities of the growth hormone (GH)-IGF-I axis. Such abnormalities include decreased circulating levels of IGF-I. We studied the effects of IGF-I therapy (40 microg x kg(-1) x day(-1)) on protein and glucose metabolism in adults with type 1 diabetes in a randomized placebo-controlled trial. A total of 12 subjects participated, and each subject was studied at baseline and after 7 days of treatment, both in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp. Protein and glucose metabolism were assessed using infusions of [1-13C]leucine and [6-6-2H2]glucose. IGF-I administration resulted in a 51% rise in circulating IGF-I levels (P < 0.005) and a 56% decrease in the mean overnight GH concentration (P < 0.05). After IGF-I treatment, a decrease in the overnight insulin requirement (0.26+/-0.07 vs. 0.17+/-0.06 U/kg, P < 0.05) and an increase in the glucose infusion requirement were observed during the hyperinsulinemic clamp (approximately 67%, P < 0.05). Basal glucose kinetics were unchanged, but an increase in insulin-stimulated peripheral glucose disposal was observed after IGF-I therapy (37+/-6 vs. 52+/-10 micromol x kg(-1) x min(-1), P < 0.05). IGF-I administration increased the basal metabolic clearance rate for leucine (approximately 28%, P < 0.05) and resulted in a net increase in leucine balance, both in the basal state and during the hyperinsulinemic amino acid clamp (-0.17+/-0.03 vs. -0.10+/-0.02, P < 0.01, and 0.25+/-0.08 vs. 0.40+/-0.06, P < 0.05, respectively). No changes in these variables were recorded in the subjects after administration of placebo. These findings demonstrated that IGF-I replacement resulted in significant alterations in glucose and protein metabolism in the basal and insulin-stimulated states. These effects were associated with increased insulin sensitivity, and they underline the major role of IGF-I in protein and glucose metabolism in type 1 diabetes.

Patients with type 1 diabetes are at increased risk of cardiovascular disease, which may be related to abnormal lipid metabolism. Secretion and clearance of VLDL apolipoprotein B100 (apoB) are important determinants of plasma lipid concentrations and are known to be influenced by hormones, including insulin and growth hormone.This study examined overnight VLDL apoB metabolism and VLDL composition in six lean patients with type 1 diabetes during euglycaemia (controlled by a varying insulin infusion) and in six age-, sex- and BMI-matched control subjects.VLDL apoB kinetics were determined using a primed constant 1-13C leucine infusion, and VLDL apoB enrichment was measured by gas-chromatography mass-spectrometry. Fasting lipid profile, IGF-I, IGFBP-3, overnight GH profiles and free insulin concentrations were also assessed.Fasting concentrations of triglycerides (TG), total cholesterol (TC), HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C) were similar in both groups. The VLDL apoB secretion and metabolic clearance rates were not significantly different between the two groups, but the VLDL-TGNLDL apoB and the VLDL-CNLDL apoB ratios were significantly increased in those with diabetes (P0.02 and P0.03, respectively). Total IGF-I concentrations were similar between the two groups; however, the GH area under the curve and free insulin concentrations were increased in patients with type 1 diabetes (GH: diabetes: 94.8 +/- 15.1 vs. controls: 45.6 +/- 10-6, mU/L/h, P0.04; free insulin: diabetes: 78.4 +/- 5.0 vs. controls: 28.3 +/- 3.26, pmol/l, P0.001). IGFBP-3 concentrations were lower in diabetic patients (diabetes: 2,454.2 +/- 68.7 vs. controls: 3,219.4 +/- 76.4, ng/ml, P0.001). In the control group overnight GH secretion correlated negatively with fasting TC (P0.01) and LDL-C (P0.03) concentrations, whereas free insulin concentrations correlated positively with fasting TG concentrations (P0.009). No significant correlations were found in the patients with diabetes.This study suggests that in euglycaemic conditions patients with type 1 diabetes mellitus have normal VLDL apoB kinetics but altered VLDL composition. The altered VLDL composition may be associated with accelerated atherogenesis. We speculate that the disrupted hormonal balance and, in particular, the increased GH secretion might be responsible for the compositional changes of VLDL particles in type 1 diabetes mellitus.

Insulin-like growth factor-I (IGF-I) has both insulin-like and anabolic actions but unlike insulin, IGF-I circulates bound to a number of specific binding proteins that regulate its availability and activity. Patients with type 1 diabetes mellitus have low levels of circulating IGF-I despite increased growth hormone (GH) secretion, and are a group that may benefit from rhIGF-I therapy. Understanding the relationship between IGF-I and its binding proteins is necessary to appreciate the actions of exogenously administered rhIGF-I. Therefore, we examined the effects of 19 days' subcutaneous administration of rhIGF-I (50 micrograms/kg BID) on the levels of IGF-I, IGF-II and the IGF-binding proteins (IGFBPs), as well as the daily dose of insulin necessary to maintain glycaemic control in patients with type 1 diabetes mellitus.This was an open study, and the patients were studied initially while resident (days 1-5) in the hospital and thereafter (days 6-24) as outpatients. Serum was collected at baseline and at intervals throughout the study for the measurement of total IGF-I, IGF-II, IGFBP-1, -2, -3, free insulin and growth hormone (GH). Daily insulin doses and glucometer readings were recorded throughout the study. The changes in each of these variables were examined. The subjects were six adults (35.3 +/- 4.0 years, mean +/- SE), with type 1 diabetes, and all had reasonable glycaemic control (HbA1c 7.2 +/- 0.5%).rhIGF-I administration increased circulating total IGF-I over two-fold (15.3 +/- 1.9 vs. 33.7 +/- 5.4 nmol/l, mean +/- SEM, P0.01, day 1 vs. day 20) and decreased plasma IGF-II concentration (85.0 +/- 4.7 vs. 50.6 +/- 4.7 nmol/l, P0.01, day 1 vs. day 20). The dose of insulin required for adequate glycaemic control decreased significantly during rhIGF-I therapy (46 +/- 7 vs. 31 +/- 8 U/day, P0.05, day -1 vs. day 19), as did the fasting free insulin concentration (8.4 +/- 1.5 vs. 5.0 +/- 0.8 mU/l, P0.05, baseline vs. day 5). IGFBP-2 concentration increased (388 +/- 115 vs. 758 +/- 219 micrograms/l, P0.05, day 1 vs. day 20), but IGFBP-1 and IGFBP-3 were unchanged during rhIGF-I treatment. Mean nocturnal GH concentration decreased (12.7 +/- 3.3 vs. 3.8 +/- 0.9 mU/l, P = 0.05) after 4 days' rhIGF-I therapy.Twice daily rhIGF-I therapy in adults with type 1 diabetes resulted in an increase in circulating IGF-I with a reciprocal decrease in IGF-II, and a marked elevation of IGFBP-2 concentration. The levels of IGFBP-1 and -3 were not dramatically changed despite a reduction in the concentration of serum free insulin, and a large decrease in the requirement for insulin. The mechanisms behind these changes remains unclear but alterations in circulating levels of of IGFBPs may alter IGF-I bioactivity. If rhIGF-I is to have an application in the management of adults with type 1 diabetes, further work is necessary to determine the metabolic consequences of the alterations seen in the IGFs and their binding proteins following rhIGF-I administration.

Cushing's syndrome is characterized by central obesity and muscle wasting. As GH is anabolic, it may be able to counteract the loss of body protein. To evaluate the potential therapeutic use of GH preoperatively, eight patients with Cushing's syndrome received sc injections of recombinant human GH (0.07 U/kg.day) for 7 days. Whole body leucine and glucose turnover were measured after an infusion of [1-13C]leucine and [6,6-2H2]glucose before (day 0) and after 2 and 7 days of GH treatment. Compared with the value on day 0, there was a significant increase on days 2 and 7 in insulin (P0.005 and P0.001), C peptide (P0.01 and P0.005), insulin-like growth factor I (P0.001), and glucose concentrations (P0.01 and P0.005) and a decrease in the leucine concentration (P0.005). There was no significant change in glucose production rate, glucose MCR, leucine production rate (a measure of protein degradation), or nonoxidative leucine disappearance rate (a measure of protein synthesis). The leucine MCR was increased after 7 days (P0.05), and the clearance of leucine into protein (nonoxidative leucine disappearance rate/leucine concentration) was increased (P0.05) after 2 and 7 days of GH treatment. This is consistent with GH stimulating the availability of amino acid transporters. GH may, therefore, have a therapeutic role in the preoperative treatment of Cushing's syndrome.