Changes in Free Rather Than Total Insulin-Like Growth Factor-I Enhance Insulin Sensitivity and Suppress Endogenous Peak Growth Hormone (GH) Release following Short-Term Low-Dose GH Administration in Young Healthy Adults

0021-972X/04/$15.00/0 Printed in U.S.A. The Journal of Clinical Endocrinology & Metabolism 89(8):3956 –3964 Copyright © 2004 by The Endocrine Society doi: 10.1210/jc.2004-0300 Changes in Free Rather Than Total Insulin-Like Growth Factor-I Enhance Insulin Sensitivity and Suppress Endogenous Peak Growth Hormone (GH) Release following Short-Term Low-Dose GH Administration in Young Healthy Adults Department of Paediatrics (K.Y., D.D.), University of Cambridge, Cambridge CB2 2QQ, United Kingdom; Medical Research Laboratories (J.F.), Aarhus University Hospital, Aarhus, Denmark DK-8000; Department of Diabetes and Endocrinology (M.U.), Guy’s King’s and St. Thomas’ School of Medicine, King’s College, London SE1 7EH, United Kingdom; and Pfizer Health AB (L.F.), Stockholm SE-11287, Sweden High-dose GH administration is commonly associated with impaired insulin sensitivity (SI) in humans. Paradoxically we have shown that low-dose GH (1.7 ␮g/kg䡠d) administration enhances ␤-cell function in young healthy adults. In the present double-blind, placebo-controlled, cross-over study, we explored the physiological effects of this low GH dose on glucose metabolism in 12 young healthy adults (seven males, 19 –29 yr). At pretreatment and after each 14-d treatment block, overnight metabolic profiles were assessed followed by a hyperinsulinemic euglycemic clamp, whereas fasting blood samples were collected weekly. In subjects treated with GH first (group A, n ⴝ 6), GH treatment increased total IGF-I (P < 0.05) and IGF binding protein-3 (P < 0.01) after 7 d, but these levels subsequently returned to pretreatment levels after 14 d. In contrast, free IGF-I increased (P < 0.05), and overnight GH pulse peak am- T HE INSULIN ANTAGONISTIC actions of GH are well described in conditions of GH excess such as acromegaly (1), after GH administration in GH-deficient adults (2, 3), and in healthy adults (4, 5). Whereas most studies demonstrating these effects used supraphysiological GH doses (4 – 6), there is also evidence that short-term GH administration exerts temporary acute insulin-like effects (7–9) by inhibiting endogenous glucose production (8, 10, 11). We recently demonstrated that 7-d low-dose GH (1.7 ␮g/ kg䡠d) administration, a dose much lower than those used in previous studies and closely resembling the daily physiological GH production rate in adults (12), enhanced ␤-cell function and decreased fasting blood glucose levels without modifying insulin sensitivity (SI) in young healthy adults (9). In that study, SI was estimated using the homeostasis model assessment (HOMA) (13), which is derived from fasting glucose and fasting insulin levels. Fasting glucose levels are Abbreviations: CV, Coefficient of variation; endoRa, glucose appearance; HOMA, homeostasis model assessment; IGFBP, IGF binding protein; NEFA, nonesterified fatty acid; Rd, glucose disappearance; SI, insulin sensitivity. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community. plitude decreased (P < 0.01) after 14 d. In subjects treated with placebo first (group B, n ⴝ 6), all biochemical parameters were unchanged after placebo treatment, whereas the changes in free and total IGF-I were similar to those of group A after GH treatment. Combined clamp data from both groups A and B (n ⴝ 12) showed that 14-d GH treatment decreased overnight plasma insulin levels (P < 0.02) and hepatic glucose appearance (P < 0.05) and increased SI (P < 0.01). Of note, the GHinduced changes in SI positively correlated with the changes in free IGF-I (r ⴝ 0.72, P < 0.01). In conclusion, low-dose GH administration enhanced SI and suppressed endogenous peak GH release, and we hypothesize that these effects are the direct result of increased serum levels of free IGF-I. (J Clin Endocrinol Metab 89: 3956 –3964, 2004) largely determined by basal hepatic glucose production (14, 15); thus, the HOMA may provide a better estimate of hepatic rather than peripheral SI. However, the HOMA methodology for assessing SI may be too imprecise for studies of small sample sizes. The present study was therefore undertaken to analyze the effects of 14-d GH administration, using an identical low GH dose (1.7 ␮g/kg䡠d), on SI using the gold standard hyperinsulinemic euglycemic clamp technique as well as ␤-cell function, circulating levels of IGF-I, and IGF binding protein (IGFBP)-1 and -3 in young healthy adults. Additionally, the effects of the low GH dose on hepatic and peripheral SI, and their relationship to whole-body SI, and overnight metabolic profiles were also examined. Subjects and Methods Subjects Twelve healthy nondiabetic subjects (seven males, age range 19 –29 yr, body mass index [mean ⫾ se] 22.9 ⫾ 3.8 kg/m2) participated in the study. Body weight was stable for at least 3 months before participation and during the 5-wk study period. The subjects had a mean waist circumference of 81.4 ⫾ 7.6 cm, total fat mass of 12.9 ⫾ 7.0 kg, and total lean body mass of 57.8 ⫾ 10.1 kg. Ethical permission for the study was granted by the Cambridge Local Research Ethics Committee, and each subject gave written informed consent before participation. The subjects 3956 KEVIN YUEN, JAN FRYSTYK, MARGOT UMPLEBY, LINDA FRYKLUND, AND DAVID DUNGER Yuen et al. • Low-Dose GH and Insulin Sensitivity J Clin Endocrinol Metab, August 2004, 89(8):3956 –3964 3957 were asked to maintain their normal physical activity and diet for at least 3 d before the investigations, and all subjects were free from any illnesses at the time of the investigations. Anthropometric assessment Height, weight, waist circumference, body fat mass, and fat-free mass were measured at each visit. Total body fat mass and fat-free mass were obtained using a bioelectrical impedence monitor (Bodystat 1500, Isle of Man, UK). Study design Fasting blood samples After a 10- to 12-h fast, blood samples were collected at 0800 h the following morning at each visit (visits 1– 6) for the analysis of glucose, insulin, C-peptide, IGF-I, IGFBP-3, IGFBP-1, and NEFA concentrations. Fasting blood glucose was analyzed immediately, and the remaining samples were placed on ice and centrifuged on-site in a cooled centrifuge. Aliquoted samples were then stored at ⫺80 C within 4 h until assayed. Hyperinsulinemic euglycemic clamp At 0500 h, the basilic vein in the antecubital fossa of one arm was cannulated, and a primed continuous infusion of [6,6 2H2] glucose (170 Randomization On completion of the overnight visit at study entry, the subjects were randomized into two groups: group A to receive GH followed by placebo treatment (GH-placebo) and group B to receive placebo followed by GH treatment (placebo-GH) for 14 d separated by a 7-d wash-out period (Fig. 1). The subjects self-injected 1.7 ␮g/kg䡠d GH (Genotropin; Pharmacia Ltd., Milton Keynes, UK) or placebo sc at 2200 h with a 0.3-ml insulin syringe, thus allowing the GH and placebo doses t (...truncated)