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The Effects of Short-Term Administration of Two Low Doses Versus the Standard GH Replacement Dose on Insulin Sensitivity and Fasting Glucose Levels in Young Healthy Adults

University Department of Pediatrics (K.Y., K.O., D.D.), Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom; Department of Endocrinology (S.H., J.W.), Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom; Pharmacia \|[amp ]\| Upjohn, Inc. Ltd. (P.C., L.F.), Stockholm SE-112 87, Sweden; University of Auckland (P.G.), Auckland, New Zealand; University Children’s Hospitals (M.R.), Tubingen, Germany D-72076; and Oregon Health Science University (D.C., R.R.), Portland, Oregon 97201

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

Abstract

GH has both diabetogenic and insulin-like actions. Supraphysiological GH doses are known to reduce insulin sensitivity (S_I), but lower doses are less well studied. We therefore compared the effects of two physiological GH doses (intermediate, 0.0033 mg/kg·d; low, 0.0017 mg/kg·d) with the standard adult GH deficiency replacement dose (standard, 0.008 mg/kg·d) on S_I, ß-cell function, IGF-I, and IGF binding proteins (IGFBPs)-1 and -3 in healthy adults.

Eleven healthy nonobese volunteers (4 males and 7 females, aged 21–38 yr) received 7 daily injections of the standard and intermediate GH doses, and 10 (5 males and 5 females, aged 21–38 yr) received the low dose. Fasting blood samples were collected daily (days 1–8). S_I and ß-cell function were calculated using the Homeostasis model assessment.

All GH doses increased IGF-I and IGFBP-3 levels, with the standard dose inducing the greatest rise (P < 0.001). At day 2 vs. baseline, all three doses increased the IGF-I/IGFBP-3 ratio, but only the standard dose lowered IGFBP-1 levels (P = 0.03). The standard dose reduced S_I (P = 0.01), whereas the intermediate dose increased S_I (P < 0.005) and lowered fasting insulin levels (P < 0.01). The low dose did not modify S_I, but reduced fasting glucose levels (P < 0.0001) and increased ß-cell function (P = 0.001). Males demonstrated higher IGF-I and IGFBP-3 responsiveness to the standard dose than females. Males also showed greater increase in S_I and decrease in fasting glucose levels on both intermediate and low doses.

In conclusion, the metabolic effects of GH are dose- and gender-dependent. The standard adult GH deficiency replacement dose induced insulin resistance, whereas lower doses improved S_I, especially in males. The low GH dose lowered fasting glucose levels and could represent the optimal dose to stimulate ß-cell function without compromising S_I in insulin-resistant GH-deficient adults.

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