Changes in insulin sensitivity and glucose metabolism during therapy with recombinant human growth hormone in short children born small for gestational age show a negative correlation with baseline measurements.

Recombinant human growth hormone (rhGH) is an effective therapy for children with short stature born small for gestational age (SGA); however, insulin resistance can develop during treatment. This retrospective analysis assessed the effect of rhGH treatment (0.067 mg/kg/day) on glucose metabolism and insulin secretion in children with short stature born SGA, and measured whether baseline characteristics correlated with changes in insulin resistance or glucose sensitivity during treatment. Baseline glucose area under the concentration-time curve (AUC) was negatively correlated with the change in glucose AUC (p<0.001). Similar negative correlations were seen between baseline insulin AUC and the change in insulin AUC during treatment (p<0.001); and between baseline HOMA-IR (homeostatic model of insulin resistance) and the change in HOMA-IR during treatment (p<0.001). Small but significant changes, not thought to be clinically significant, were seen in indicators of insulin sensitivity during rhGH treatment. Glucose levels remained within the normal range during oral glucose tolerance testing.

Recombinant human growth hormone for children born small for gestational age: meta-analysis confirms the consistent dose-effect relationship on catch-up growth.

BACKGROUND: The optimal treatment regimen of recombinant human GH (r-hGH) for short children born small for gestational age (SGA) is still under discussion. METHODS: A meta-analysis was performed of existing clinical trials that investigated the treatment of r-hGH in short children diagnosed SGA or with intrauterine growth retardation to determine the relationship between the daily r-hGH dose (placebo/no treatment; 0.033 mg/kg/day; 0.067 mg/kg/day) and the effect on growth [change in height-SD score (SDS) for chronological age]. A mathematical model describing the dose-response relationship was produced, and growth response (gain in height-SDS) to 2 yr of r-hGH 0.033 mg/kg/day [somatropin (rDNA origin) for injection; Serono] was estimated and compared with the response to other r-hGH formulations. RESULTS: The relationship between r-hGH dose and 2-yr growth response was described by an equation. The equation yielded a mean difference in height- SDS gain of 0.48 (0.35) between r-hGH 0.033 and 0.067 mg/kg/day in favor of the higher dose. The height-SDS gain after 2 yr of Serono r-hGH formulation, 0.033 mg/kg/day was estimated as 1.2. Comparison of this estimate to the growth response to 2-yr treatment at 0.033 mg/kg/day of other r-hGH formulations (mean difference in height-SDS 0.05, lower limit of the 95% confidence interval=-0.15) confirmed that growth response to Serono r-hGH formulation 0.033 mg/kg/day is an inferred response estimated to be within the range of observed responses to a (non-Serono formulation) r-hGH dose of 0.033 mg/kg/day. CONCLUSION: There is a clear dose-response relationship for r-hGH in the treatment of short children born SGA and the analysis confirmed that treatment with Serono r-hGH formulation 0.033 mg/kg/day should provide a meaningful therapeutic response.

Insulin-induced phosphorylation of a 38 kDa DNA-binding protein in ventricular cardiomyocytes: possible implication of nuclear protein phosphatase activity.

Ventricular cardiomyocytes isolated from adult rat heart were used to analyze the effect of insulin on the phosphorylation of DNA-binding nuclear proteins and to elucidate the potential involvement of protein phosphatase-1 (PP-1) and PP-2A in this hormonal action. Cells were labelled with [33P]orthophosphate, stimulated with insulin (1.7 x 10(-7) M) and processed for the isolation of nuclei and extraction of DNA-binding proteins. Insulin was found to induce a rapid and constant increase in the serine/threonine phosphorylation of a 38 kDa DNA-binding protein, reaching 150% of control after 15 min and 180% after 150 min. Immunoprecipitation and Western blotting experiments revealed the presence of phosphorylated numatrin in the nuclear extract, however, insulin did not modify its phosphorylation state. Treatment of cardiomyocytes with okadaic acid (1 microM) resulted in a large increase (246 +/- 30%) in the phosphorylation of the 38 kDa protein. Using 32P-labelled phosphorylase as a substrate, we observed a significant inhibition of nuclear PP-1 activity to 38.5 +/- 7% (n = 3) of control after incubation of cardiomyocytes with insulin for 15 min. PP-2A, which corresponds to about 25% of total phosphatase activity, was also inhibited to the same extent. These data show the presence of an insulin-responsive 38 kDa DNA-binding phosphoprotein in the nucleus of cardiomyocytes, which is at least partly regulated by nuclear phosphatase activity. It is suggested that inhibition of nuclear PP-1 and PP-2A represents a possible mechanism of insulin signalling to the nucleus of target cells.

Acute and chronic effects of troglitazone (CS-045) on isolated rat ventricular cardiomyocytes.

Freshly isolated and primary cultured adult rat cardiomyocytes were used to elucidate the mechanism of action of the new oral antidiabetic agent (+/-)-5-[4-(6-hydroxy-2, 5, 7, 8-tetramethyl-chroman-2-yl-methoxy)benzyl]-2,4-thiazolidinedione (troglitazone) on the heart. Interaction with protein kinase C (PKC) and regulation of glucose transport were evaluated as possible sites of drug action. Acute treatment (30 min) of cardiomyocytes with troglitazone did not affect the phorbolester-induced membrane association of PKC-delta and PKC-epsilon, which represent the major isoforms present in these cells. However, under these conditions the phorbolester-mediated increase in membrane associated PKC activity was inhibited by 43 +/- 4% (n = 4) without affecting the basal distribution of PKC activity. In contrast to these findings, troglitazone had no acute effect on basal or insulin-stimulated glucose transport in freshly isolated cardiomyocytes; even after 120 min treatment an unaltered release of lactate was determine in the presence of the drug. After 20 h in serum-free culture troglitazone induced a dose-dependent increase in 2-deoxyglucose uptake reaching a 40-fold stimulation at 5 mumol/l. This was paralleled by a dose-dependent increase of glucose transporter-1 (GLUT1) and GLUT4 protein expression to 320 +/- 80 and 156 +/- 15% of control, respectively. In addition, chronic exposure to troglitazone increased the GLUT4 abundance in a plasma membrane fraction about twofold. These data show that troglitazone exerts multiple effects on cardiomyocytes involving inhibition of PKC and regulation of glucose transporter expression and distribution. We suggest that an increased glucose supply may be beneficial for the diabetic heart and that modulation of PKC-activity could be relevant for improving insulin action in muscle tissue.

Direct stimulation of myocardial glucose transport and glucose transporter-1 (GLUT1) and GLUT4 protein expression by the sulfonylurea glimepiride.

Freshly isolated and primary cultured cardiac myocytes from adult rats were used to elucidate acute and chronic effects of the sulfonylurea drug glimepiride on basal and insulin-stimulated glucose transport and on expression of the transporter isoforms glucose transporter-1 (GLUT1) and GLUT4. A 30-min incubation with glimepiride (100 microM) was unable to modify the initial rates of 3-O-methylglucose transport in freshly isolated cardiocytes, both in the absence or presence of insulin (10(-7) M). Cells were then kept in serum-free culture for 20 h in the presence of glimepiride (10 microM) and a physiological insulin dose. Under these conditions, the sulfonylurea induced an increase in 2-deoxyglucose uptake to 186% of control. This drug effect was dose dependent and could also be demonstrated in the absence of insulin during the culture period. The acute action of insulin on glucose transport was additive to the effect of glimepiride, and the insulin responsiveness of glucose transport remained unaltered in sulfonylurea-treated cultures. Western blot analysis of crude membrane fractions obtained from cultured cardiocytes showed that glimepiride increased the expression of both GLUT1 and GLUT4 to 164% +/- 21% and 148% +/- 5% of control, respectively. We concluded that glimepiride increases cardiac glucose uptake by an insulin-independent pathway, probably involving an increased protein expression of GLUT1 and GLUT4. The increased expression of GLUT4 may have a therapeutic impact on the treatment of insulin-resistant states.