The effects of GH replacement therapy on energy metabolism are still uncertain, and long-term benefits of increased muscle mass are thought to outweigh short-term negative metabolic effects. This study was designed to address this issue by examining both short-term (1 wk) and long-term (6 months) effects of a low-dose (9.6 micro g/kg body weight.d) GH replacement therapy or placebo on whole-body glucose and lipid metabolism (oral glucose tolerance test and euglycemic hyperinsulinemic clamp combined with indirect calorimetry and infusion of 3-[(3)H]glucose) and on muscle composition and muscle enzymes/metabolites, as determined from biopsies obtained at the end of the clamp in 19 GH-deficient adult subjects. GH therapy resulted in impaired insulin-stimulated glucose uptake at 1 wk (-52%; P = 0.008) and 6 months (-39%; P = 0.008), which correlated with deterioration of glucose tolerance (r = -0.481; P = 0.003). The decrease in glucose uptake was associated with an increase in lipid oxidation at 1 wk (60%; P = 0.008) and 6 months (60%; P = 0.008) and a concomitant decrease in glucose oxidation. The deterioration of glucose metabolism during GH therapy also correlated with the enhanced rate of lipid oxidation (r = -0.508; P = 0.0002). In addition, there was a shift toward more glycolytic type II fibers during GH therapy. In conclusion, replacement therapy with a low-dose GH in GH-deficient adult subjects is associated with a sustained deterioration of glucose metabolism as a consequence of the lipolytic effect of GH, resulting in enhanced oxidation of lipid substrates. Also, a shift toward more insulin-resistant type II X fibers is seen in muscle. Glucose metabolism should be carefully monitored during long-term GH replacement therapy.

To test the hypothesis that GH-induced insulin resistance is mediated by an increase in FFA levels we assessed insulin sensitivity after inhibiting the increase in FFA by a nicotine acid derivative, Acipimox, in nine GH-deficient adults receiving GH replacement therapy. The patients received in a double blind fashion either Acipimox (500 mg) or placebo before a 2-h euglycemic (plasma glucose, 5.5 +/- 0.2 mmol/liter) hyperinsulinemic (serum insulin, 28.7 +/- 6.3 mU/liter) clamp in combination with indirect calorimetry and infusion of [3-(3)H]glucose. Acipimox decreased fasting FFA by 88% (P = 0.012) and basal lipid oxidation by 39% (P = 0.015) compared with placebo. In addition, the insulin-stimulated lipid oxidation was 31% (P = 0.0077) lower during Acipimox than during placebo. Acipimox increased insulin-stimulated total glucose uptake by 36% (P = 0.021) compared with placebo, which mainly was due to a 47% (P = 0.015) increase in glucose oxidation. GH induced insulin resistance is partially prevented by inhibition of lipolysis by Acipimox.

Objective: Previous studies evaluating the lipolytic effect of GH have in general been performed in subjects on chronic GH therapy. In this study we assessed the lipolytic effect of GH in previously untreated patients and examined whether the negative effect of enhanced lipolysis on glucose metabolism could be counteracted by acute antilipolysis achieved with acipimox. Methods: Ten GH-deficient (GHD) adults participated in four experiments each, during which they received in a double-blind manner: placebo (A); GH (0.88^0.13 mg) (B); GH þ acipimox 250 mg b.i.d. (C); and acipimox b.i.d. (no GH) (D), where GH was given the night before a 2 h euglycemic, hyperinsulinemic clamp combined with infusion of [3-3 H]glucose and indirect calorimetry. Results: GH increased basal free fatty acid (FFA) levels by 74% (P ¼ 0.0051) and insulin levels by 93% (P ¼ 0.0051). This resulted in a non-significant decrease in insulin-stimulated glucose uptakes (16.61^8.03 vs 12.74^5.50 mmol/kg per min (S.D.), P ¼ 0.07 for A vs B). The rates of insulin-stimulated glucose uptake correlated negatively with the FFA concentrations (r ¼ 2 0.638, P , 0.0001). However, acipimox caused a significant improvement in insulin-stimulated glucose uptake in the GH-treated patients (17.35^5.65 vs 12.74^5.50 mmol/kg per min, P ¼ 0.012 for C vs B). The acipimox-induced enhancement of insulin-stimulated glucose uptake was mainly due to an enhanced rate of glucose oxidation (8.32^3.00 vs 5.88^2.39 mmol/kg per min, P ¼ 0.07 for C vs B). The enhanced rates of glucose oxidation induced by acipimox correlated negatively with the rate of lipid oxidation in GH-treated subjects both in basal (r ¼ 2 0.867, P ¼ 0.0093) and during insulinstimulated (r ¼ 2 0.927, P ¼ 0.0054) conditions. GH did not significantly impair non-oxidative glucose metabolism (6.86^5.22 vs 8.67^6.65 mmol/kg per min, P ¼ NS for B vs A). The fasting rate of endogenous glucose production was unaffected by GH and acipimox administration (10.99^1.98 vs 11.73^2.38 mmol/kg per min, P ¼ NS for B vs A and 11.55^2.7 vs 10.99^1.98 mmol/kg per min, P ¼ NS for C vs B). On the other hand, acipimox alone improved glucose uptake in the untreated GHD patients (24.14^8.74 vs 16.61^8.03 mmol/kg per min, P ¼ 0.0077 for D vs A) and this was again due to enhanced fasting (7.90^2.68 vs 5.16^2.28 mmol/kg per min, P ¼ 0.01 for D vs A) and insulin-stimulated (9.78^3.68 vs 7.95^2.64 mmol/kg per min, P ¼ 0.07 for D vs A) glucose oxidation. Conclusion: The study of acute administration of GH to previously untreated GHD patients provides compelling evidence that (i) GH-induced insulin resistance is mainly due to induction of lipolysis by GH; and (ii) inhibition of lipolysis can prevent the deterioration of insulin sensitivity. The question remains whether GH replacement therapy should, at least at the beginning of therapy, be combined with means to prevent an excessive stimulation of lipolysis by GH.

This study highlights the demographics of suffering, death, and end-of-life care in children with cancer at a government tertiary cancer center in India.

Background Increasing life expectancy for people with an intellectual disability (ID) is resulting in more persons with cancer and a greater need for end-of-life (EoL) care. There is a need for knowledge of health care utilisation over the last year of life to plan for resources that support a high quality of care for cancer patients with ID. Therefore, the aims of the study were to compare (1) health care utilisation during the last year of life among cancer patients with ID and cancer patients without ID and (2) the place of death in these two groups. Methods The populations were defined using national data from the period 2002-2015, one with ID (n = 15 319) and one matched 5:1 from the general population (n = 72 511). Cancer was identified in the Cause of Death Register, resulting in two study cohorts with 775 cancer patients with ID (ID cohort) and 2968 cancer patients from the general population (gPop cohort).