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Ghrelin levels fluctuate rapidly and dynamically with surges before meal times and postprandial troughs, and ghrelin increases appetite and food intake. Circulating ghrelin correlates negatively with body mass index (BMI), but obese individuals have a reduced postprandial decrease in ghrelin levels. Whether this reflects changes in secretion or clearance of ghrelin is uncertain. We therefore studied the pharmacokinetics of ghrelin in relation to anthropometric and biochemical measures. We also studied the effects of ghrelin on hormones and metabolites. In fasting humans, we used a constant infusion rate of ghrelin lasting 180 min at 5 pmol x kg body [wt.sup.1] x [min.sup.-1] in a randomized, double-blind, placebo-controlled crossover study. Serum ghrelin (s-ghrelin; total levels) was distributed and eliminated according to a two-compartment model, s-Ghrelin initial half-life was 24 [+ or -] 2 min and terminal half-life 146 [+ or -] 36 min, respectively. Mean residence time (MRT) of ghrelin was 93 [+ or -] 16 min. MRT correlated positively with both BMI (r = 0.51, P < 0.001) and high-density cholesterol (HDL) levels (r = 0.75, P < 0.001). Serum insulin levels remained constant during ghrelin infusion, whereas plasma glucose increased 0.3 [+ or -] 0.1 mmol/l (P < 0.01) and free fatty acid levels more than doubled (to 1.03 [+ or -] 0.08 mmol/l, P < 0.001), translating into a significant reduction of insulin sensitivity (P < 0.001). In conclusion, 1) we describe novel pharmacokinetics of ghrelin that are useful when tailoring ghrelin infusion rates in clinical experiments, 2) BMI and HDL correlate positively with MRT of infused ghrelin, and 3) supraphysiological ghrelin levels impair insulin sensitivity. mean residence time; insulin sensitivity doi: 10.1152/ajpendo.00682.2006

Fasting-related states of distress pose major health problems, and growth hormone (GH) plays a key role in this context. The present study was designed to assess the effects of GH on substrate metabolism and insulin sensitivity during short-term fasting. Six GH-deficient adults underwent 42.5 h of fasting on two occasions, with and without concomitant GH replacement. Palmitate and urea fluxes were measured with the steady-state isotope dilution technique after infusion of [9,10[-.sup.3]H]palmitate and [[sup.13]C]urea. During fasting with GH replacement, palmitate concentrations and fluxes increased by 50% [palmitate: 378 [+ or -] 42 (GH) vs. 244 [+ or -] 12 [micro]mol/1, P < 0.05; palmitate: 412 [+ or -] 58 (GH) vs. 276 [+ or -] 42 [micro]M, P = 0.05], and urea turnover and excretion decreased by 30-35% [urea rate of appearance: 336 [+ or -] 22 (GH) vs. 439 [+ or -] 43 [micro]mol * [kg.sup.-1] * [h.sup.-1], P < 0.01; urea excretion: 445 [+ or -] 43 (GH) vs. 602 [+ or -] 74 mmol/24 h, P < 0.05]. Insulin sensitivity (determined by a euglycemic hyperinsulinemic clamp) was significantly decreased [M value: 1.26 [+ or -] 0.06 (GH) vs. 2.07 [+ or -] 0.22 mg * [kg.sup.-1] * [min.sup.-1], P < 0.01] during fasting with GH replacement. In conclusion, continued GH replacement during fasting in GH-deficient adults decreases insulin sensitivity, increases lipid utilization, and conserves protein. fasting; growth hormone; substrate metabolism

At present, the circulating bioactivity of insulin-like growth factor I (IGF-I) is estimated by immunological measurements of IGF-I levels. However, immunoassays ignore the modifying effects of the IGF-binding proteins (IGFBPs) on the interaction between IGF-I and the IGF-I receptor (IGF-IR). Therefore, we developed an IGF-I kinase receptor activation assay (KIRA) based on cells transfected with the human IGF-IR gene. The bioassay was sensitive (detection limit 0.08 [micro]g/1), specific (cross-reactivity of insulin, insulin analogs, and proinsulin was kinase receptor activation assay; insulin-like growth factor I receptor

Background. Most girls with Turner syndrome (TS) receive growth hormone (GH) treatment during childhood and adolescence, but controlled data on the effects on body composition and glucose metabolism are lacking. Objective. To study the effects of GH treatment on insulin sensitivity, glucose metabolism, bone turnover, and body composition. Methods. A randomized, placebo-controlled, crossover study was conducted with girls with TS. All girls with TS were treated with GH 0.1 IU/kg/d subcutaneously at bedtime or with placebo for 2 months and studied at the end of each period. Control subjects were studied once without treatment. Twelve girls with TS, aged 9.5 to 14.8 years (median: 12.9 years) and 16 age-matched control subjects (10.3-16.0 years; median: 12.1 years) were studied. Twenty-four-hour sampling of blood was performed; GH, insulin-like growth factor I (IGF-I), IGF binding proteins (IGFBPs), insulin, glucose, and lipolytic and gluconeogenic precursors were assayed, followed by an oral glucose tolerance test. Body composition was evaluated by dual-energy x-ray absorptiometry scanning and body mass index (BMI). Fasting bone markers were measured. Results. Height was reduced in TS as compared with control subjects. In the placebo situation, 24-hour integrated GH as well as IGF-I was significantly reduced in girls with TS compared with control subjects. Controlling for differences in lean body mass (LBM; or fat mass [FM]) and sexual development did not explain the difference in 24-hour integrated GH. Differences in sexual development, BMI, FM, insulin sensitivity, and IGFBP-3 could explain the difference in IGF-I between TS and control subjects. Carbohydrate metabolism in TS was comparable with control subjects. GH treatment induced insulin resistance, with increments in fasting glucose and insulin, as well as 24-hour insulin. Circulating levels of lipid and gluconeogenic substrates were comparable in TS and control subjects and unchanged in response to treatment. Bone markers increased in response to GH. Total FM was increased in girls with TS, accounted for by an increased FM in the arms and trunk, whereas LBM was decreased. Especially LBM in the legs was decreased. Overall, bone mineral content was diminished. Treatment with GH reduced FM in TS, especially in the arms and legs, and likewise increased total LBM, primarily in the trunk. Conclusion. This study documented evidence of impaired GH secretion and action, disproportionate body composition, but a normal carbohydrate metabolism in girls with TS. Short-term GH administration was associated with favorable changes in body composition but also with relative impairment of glucose tolerance and insulin sensitivity. We recommend that glucose metabolism be monitored carefully during long-term GH treatment in these patients. Pediatrics 2002;110:889-896; growth hormone treatment; glucose metabolism, insulin sensitivity, DXA scan, body composition, IGF-I, body mass index., Turner syndrome (TS) is an approved indication for growth hormone (GH) treatment in many countries. Numerous studies have documented the growth-promoting effect of GH treatment in these patients, and final [...]

Hansen, Troels Krarup, Jens MoLler, Klaus Thomsen, Erik Frandsen, Rolf Dall, Jens Otto Jorgensen, and Jens Sandahl Christiansen. Effects of growth hormone on renal tubular handling of sodium in healthy humans. Am J Physiol Endocrinol Metab 281: E1326-E1332, 2001.--To investigate the mechanisms behind the water- and sodium-retaining effects of growth hormone (GH), we studied the effect of GH on 1) water and sodium homeostasis, 2) the renin-angiotensin-aldosterone system (RAAS), and 3) lithium clearance ([C.sup.Li]) with and without concomitant prostaglandin (PG) synthesis inhibition with ibuprofen. GH administration for 6 days induced a significant increase in plasma renin, which was abolished by coadministration of ibuprofen (mU.[1.sup.-1].24 [h.sup-1]: control: 22.4 [+ or -] 4.3; GH: 37.7 [+ or -] 8.8; ibuprofen: 15.2 [+ or -] 3.0; GH + ibuprofen: 19.7 [+ or -] 2.5; ANOVA: P < 0.01). Comparable increments in extracellular volume were seen after 6-day treatment with GH alone and in combination with ibuprofen [liters: control, 19.57 [+ or -] 0.92; GH, 20.80 [+ or -] 1.00 (ANOVA: P < 0.0005); ibuprofen, 19.38 [+ or -] 0.90; GH + ibuprofen, 21.63 [+ or -] 1.37 (ANOVA: P < 0.0005)]. Treatment with GH increased [C.sub.Li] and changed the tubular handling of sodium and water. The absolute distal sodium reabsorption was increased, and this was only partially counterbalanced by decreased reabsorption in the proximal tubules. The data demonstrate that GH-induced activation of the RAAS can be blocked by concomitant PG synthesis inhibition and that the tubular effects of GH include increased distal nephron sodium and water reabsorption. sodium metabolism; renin-angiotensin-aldosterone system; lithium clearance; ibuprofen Received 13 February 2001; accepted in final form 3 August 2001