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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

Address all correspondence and requests for reprints to: Professor David B. Dunger, University Department of Paediatrics, Level 8, Box 116, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom. E-mail: dbd25{at}cam.ac.uk.

High-dose GH administration is commonly associated with impaired insulin sensitivity (S_I) in humans. Paradoxically we have shown that low-dose GH (1.7 µg/kg·d) administration enhances ß-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 = 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 amplitude decreased (P < 0.01) after 14 d. In subjects treated with placebo first (group B, n = 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 = 12) showed that 14-d GH treatment decreased overnight plasma insulin levels (P < 0.02) and hepatic glucose appearance (P < 0.05) and increased S_I (P < 0.01). Of note, the GH-induced changes in S_I positively correlated with the changes in free IGF-I (r = 0.72, P < 0.01).

In conclusion, low-dose GH administration enhanced S_I and suppressed endogenous peak GH release, and we hypothesize that these effects are the direct result of increased serum levels of free IGF-I.

K.Y. is supported by a research grant from Pfizer Ltd., and J.F. is supported by a grant from the Danish Health Research Council.

Abbreviations: CV, Coefficient of variation; endoRa, glucose appearance; HOMA, homeostasis model assessment; IGFBP, IGF binding protein; NEFA, nonesterified fatty acid; Rd, glucose disappearance; S_I, insulin sensitivity.

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