J. Clin. Endocrinol. Metab. 2002 87: 1989-1995, doi: 10.1210/jc.87.5.1989  

Ron Rosenfeld, John Wass and David Dunger Kevin Yuen, Ken Ong, Sandra Husbands, Pierre Chatelain, Linda Fryklund, Peter Gluckman, Michael Ranke, David Cook,

  Adults

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

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The Effects of Short-Term Administration of Two LowDoses Versus the Standard GH Replacement Dose onInsulin Sensitivity and Fasting Glucose Levels in YoungHealthy Adults

KEVIN YUEN, KEN ONG, SANDRA HUSBANDS, PIERRE CHATELAIN, LINDA FRYKLUND,PETER GLUCKMAN, MICHAEL RANKE, DAVID COOK, RON ROSENFELD, JOHN WASS, AND

DAVID DUNGER

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 & Upjohn,Inc. Ltd. (P.C., L.F.), Stockholm SE-112 87, Sweden; University of Auckland (P.G.), Auckland, New Zealand; UniversityChildren’s Hospitals (M.R.), Tubingen, Germany D-72076; and Oregon Health Science University (D.C., R.R.), Portland,Oregon 97201

GH has both diabetogenic and insulin-like actions. Supra-physiological GH doses are known to reduce insulin sensitiv-ity (SI), but lower doses are less well studied. We thereforecompared the effects of two physiological GH doses (interme-diate, 0.0033 mg/kg�d; low, 0.0017 mg/kg�d) with the standardadult GH deficiency replacement dose (standard, 0.008 mg/kg�d) on SI, �-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 andintermediate GH doses, and 10 (5 males and 5 females, aged21–38 yr) received the low dose. Fasting blood samples werecollected daily (days 1–8). SI and �-cell function were calcu-lated using the Homeostasis model assessment.

All GH doses increased IGF-I and IGFBP-3 levels, with thestandard dose inducing the greatest rise (P < 0.001). At day 2vs. 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 SI (P � 0.01), whereas the inter-mediate dose increased SI (P < 0.005) and lowered fastinginsulin levels (P < 0.01). The low dose did not modify SI, butreduced fasting glucose levels (P < 0.0001) and increased�-cell function (P � 0.001). Males demonstrated higher IGF-Iand IGFBP-3 responsiveness to the standard dose than fe-males. Males also showed greater increase in SI and decreasein fasting glucose levels on both intermediate and low doses.

In conclusion, the metabolic effects of GH are dose- andgender-dependent. The standard adult GH deficiency replace-ment dose induced insulin resistance, whereas lower dosesimproved SI, especially in males. The low GH dose loweredfasting glucose levels and could represent the optimal dose tostimulate �-cell function without compromising SI in insulin-resistant GH-deficient adults. (J Clin Endocrinol Metab 87:1989–1995, 2002)

RECENT EVIDENCE HAS implicated the role of GH asan important regulator of metabolism (1, 2) and glu-

cose homeostasis (3, 4) in adults. Although several studieshave demonstrated that exogenously administered supra-physiological GH doses exert diabetogenic effects (5–7), ithas long been known that GH may also induce hypoglyce-mia, thus mimicking the action of insulin (8–10). Previousstudies examining the effects of GH insulin sensitivity (SI) innormal subjects have yielded contrasting results. Some in-vestigators have demonstrated acute insulin-like effects ofGH on carbohydrate metabolism (8, 9), whereas others havedemonstrated diabetogenic effects at the insulin receptor andpostreceptor sites (11, 12).

These contradictory results and conclusions raise the ques-tion as to whether GH doses lower than those used in pre-vious studies have distinct, independent effects on SI andblood glucose and plasma insulin levels. The present studywas therefore undertaken to analyze the early action of phys-iological to pharmacological doses of GH, administered over

7 d, on fasting glucose and insulin, SI, IGF-I, IGFBP-1, andIGFBP-3 levels in young healthy adults. Our physiologicalGH doses (intermediate dose, 0.0033 mg/kg�d; low dose,0.0017 mg/kg�d) represent the closest approximation to dailyphysiological GH production rates in adults; these decreasewith age (13–15) and are estimated as approximately 47 �g/liter�d (or approximately 0.003 mg/kg�d for an average 70-kgindividual) in middle-aged women and approximately 15�g/liter�d (or approximately 0.0011 mg/kg�d for an average70-kg individual) in men (16). We compared the effects ofthese physiological GH doses with the standard GH replace-ment dose (standard dose, 0.008 mg/kg�d) derived from thereported average GH dose used in the United Kingdom andEurope (17).

Subjects and MethodsSubjects

In total, 14 young healthy nonobese adult volunteers participated inthe study. Eleven subjects (4 males and 7 females; age range, 21–38 yr)received two 7-d courses of the standard and intermediate GH doses.After the completion of administration of the 2 GH doses, the same 11subjects were invited to receive the low GH dose. Three subjects declined

Abbreviations: HOMA, Homeostasis model assessment; IGFBP, IGFbinding protein; SI, insulin sensitivity.

0013-7227/02/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 87(5):1989–1995Printed in U.S.A. Copyright © 2002 by The Endocrine Society

1989

and were replaced by three other volunteers (one subject subsequentlywithdrew for unrelated reasons). Thus, 10 subjects (5 males and 5 fe-males; age range, 21–38) successfully completed the low-dose phase ofthe study. The inclusion criteria were healthy subjects without anyprevious significant medical history and not taking any regular medi-cation. The study was approved by the local hospital Ethics Committee,and informed consent was obtained from all of the subjects.

GH administration

We chose two GH doses that approximated to the estimated dailyphysiological adult GH production rate (intermediate dose, 0.0033 mg/kg�d; low dose, 0.0017 mg/kg�d) and one dose that represented thestandard GH replacement dose used in GH-deficient adults (standarddose, 0.008 mg/kg�d) (12).

Subjects were instructed to self-administer GH by sc injection in thethigh, daily at 2200 h on 7 consecutive days for each dose. A 7-d washoutperiod separated the standard and intermediate dose phases. Duringthese two treatment phases, subjects used a Genotropin pen (PharmaciaLtd., Stockholm, Sweden). This injection device administers preset GHdoses adjustable in 0.133 mg (0.4 U) increments (clicks), and thereforethe calculated weight-dependent dose for each subject was rounded tothe nearest number of clicks. The low dose was administered using a0.3-ml syringe, thus allowing the individual weight-dependent doses tobe administered to the nearest 0.053 mg (i.e. minimal increments of 0.01ml from the syringe are equivalent to 0.053 mg of GH).

Blood samples and assays

During all three treatment phases, a venous blood sample was col-lected between 0800 and 1000 h after an overnight fast (day 1, or baseline)and on each morning following the evening GH injections (days 2–8).Blood glucose concentration was measured daily, and the remainingsample was spun down and stored at �20 C until assayed for insulin,GH, IGF-I, IGFBP-1, and IGFBP-3 levels.

Blood glucose concentration was measured on whole blood using aYSI, Inc. (Yellow Springs, OH) model 2300 stat plus analyser (Farnbor-ough, Hants, UK). The intra-assay coefficient of variation (CV) was 2.6%at 4.4 mmol/liter, and interassay CV were 8.8 and 3.1% at 4.4 mmol/literand 14.9 mmol/liter, respectively. Plasma insulin was measured usingthe Coat-A-Count RIA from Diagnostic Products (Llanberis, Gwynedd,UK) according to the manufacturer’s instructions. Intra-assays CV were3.5 and 3.2% and interassay CV were 7.2 and 4.9% at 50 and 200 mU/liter,respectively. Serum GH was measured by RIA (Endocrine Sciences,Inc.). Interassay CV was 12% at 19.2 mU/liter, and sensitivity was 0.17mU/liter. Serum IGF-I, IGFBP-3, and IGFBP-1 concentrations were de-termined by immunoradiometric assays using commercial kits (DSL,Tooting, London, UK) according to the manufacturer’s instructions. For

IGF-I, sensitivity was 0.080 ng/ml, intra-assay CV were 3.4 and 1.5% at9.4 and 263.6 ng/ml, respectively, and equivalent interassay CV were 8.2and 3.7%. For IGFBP-3, sensitivity was 0.5 ng/ml; intra-assay CV were3.9, 3.2, and 1.8% at 7.4, 27.5, and 82.7 ng/ml, respectively; and equiv-alent interassay CV were 0.6, 0.5, and 1.9%, respectively. For IGFBP-1,sensitivity was 0.33 ng/ml; intra-assay CV were 5.2, 4.6, and 2.7% at 5.2,50.2, and 144.6 ng/ml, respectively; and equivalent interassay CV were3.5, 6.0, and 3.6%, respectively.

Calculations

The IGF-I/IGFBP-3 molar ratios were calculated by taking into ac-count the molecular weights of IGF-I (7.6 kDa) and IGFBP-3 (50 kDa).

The Homeostasis model assessment (HOMA), previously describedby Matthews and co-workers (18, 19), is a structural model of glucose/insulin interaction, with mathematical equations describing the func-tioning of the major effector organs. Assessment of the fasting glucoseand insulin concentrations in each subject allows the evaluation of thecombination of �-cell function and SI using the HOMA-CIGMA Calcu-lator Program (18). With such a method, high HOMA scores denote highSI. The HOMA method has been previously validated against indepen-dent measures of SI and �-cell function, including clamp-derived mea-sures (20–22).

Percentages of baseline values (day 1 value � 100%) were calculatedin each individual for SI, �-cell function, and all other hormone valuesto assess changes from baseline.

Statistical analyses

Statistical analyses were performed using SPSS for Windows (version10.0, SPSS, Inc. Chicago, IL). Data are expressed as means � se. Pairedt tests were used to test differences between baseline and treatmentvalues. Regression coefficients (B) with se values were used to describethe gradient of change in any measured parameter against time (in days).Each treatment phase was analyzed longitudinally using ANOVA; andbetween-dose effects were examined using analysis of covariance to takeinto account the longitudinal nature of the data from each treatmentphase in each subject, although the differences in subjects between eachtreatment dose excluded a formal within-subject analysis of GH doseeffects. The statistical tests were performed on the raw data, and theresults are demonstrated in the illustrations as percentages of baselinevalues (day 1 value � 100%). Pearson’s correlation coefficient was usedto calculate correlations. P values less than or equal to 0.05 definedstatistical significance.

TABLE 1. Characteristics of study subjects at start (d 1) of each 7-d GH dose administration

Actual GH dose administered (range)

Intended GH dose (mg/kg�d)

Low0.0017

Intermediate0.0033

Standard0.008

0.0015–0.002 0.0023–0.0044 0.0059–0.0093

No. of subjects 10 11 11Age (yr) 30.6 � 2.0 29.3 � 1.7 29.3 � 1.7Sex (female) 50% 63.7% 63.7%Weight (kg) 67.8 � 5.2 70.4 � 3.9 69.8 � 3.8Body mass index (kg/m2) 23.6 � 1.2 24.0 � 0.7 23.8 � 0.7Waist/hip ratio (cm) 0.79 � 0.03 0.8 � 0.03 0.8 � 0.03IGF-I (ng/ml) 345.1 � 33.6 234.3 � 15.6 244.3 � 18.4IGFBP-3 (ng/ml) 3388.9 � 181.1 4216.7 � 1017.4 4101.6 � 205.8IGF-I/IGFBP-3a 0.67 � 0.06 0.4 � 0.04 0.4 � 0.04IGFBP-1 (ng/ml) 51.6 � 9.7 48.7 � 10.0 57.1 � 9.3Fasting glucose (mmol/liter) 4.7 � 0.2 4.5 � 0.1 4.4 � 0.1Fasting insulin (mU/liter) 8.5 � 1.5 9.1 � 1.7 8.8 � 0.9Insulin sensitivity (HOMA-S) (%) 100.8 � 10.4 101.0 � 9.9 99.4 � 10.9�-cell function (HOMA-B) (%) 118.9 � 8.8 134.2 � 17.3 131.8 � 6.7

Mean � SEM, except for sex (%) and number of subjects.a IGF-I/IGFBP-3 molar ratio.

1990 J Clin Endocrinol Metab, May 2002, 87(5):1989–1995 Yuen et al. • Low vs. Standard GH Replacement Dose

ResultsCharacteristics of study subjects

Table 1 presents the baseline characteristics (day 1) for thethree GH dose groups. There were no differences with regardto age, height, weight, body mass index, and waist-to-hipratio between groups at baseline. No significant changes inbody size or body composition were seen during treatmentwith any of the GH doses.

IGF-I and IGFBP levels

IGF-I levels increased on all three GH doses. The standarddose induced the steepest rise in IGF-I levels (B � 12.5 �2.0ng/ml�d; P � 0.001), whereas the intermediate dose (B �6.2 � 1.4 ng/ml�d; P � 0.001) and the low dose (B � 8.8 �4.2 ng/ml�d; P � 0.04) induced significant but lesser increases(Fig. 1).

The standard GH dose induced the steepest rise inIGFBP-3 levels (B � 123.6 � 24.1 ng/ml�d; P � 0.001).IGFBP-3 levels increased to a lesser extent on the interme-diate (B � 35.7 � 18.4 ng/ml�d; P � 0.056) and low (B �40.2 � 14.9 ng/ml�d, P � 0.009) doses (Fig. 1). The rise inIGFBP-3 levels (day 8 vs. baseline) was significantly greateron the standard dose than on the intermediate (P � 0.008) orlow (P � 0.03) doses.

The IGF-I/IGFBP-3 molar ratio increased by a similar per-

centage of baseline on all three GH doses (day 2 vs. baselinestandard dose, P � 0.004; intermediate dose, P � 0.01; lowdose, P � 0.002), and these elevations persisted from day 2to day 8 (Fig. 1).

A significant reduction in IGFBP-1 was seen on the stan-dard GH dose (day 2 vs. baseline, P � 0.05), and IGFBP-1levels remained low up to day 8. However the intermediateand low doses did not produce any significant changes inIGFBP-1 levels (day 8 vs. baseline, intermediate dose, P � 0.8;low dose; P � 0.5) (Fig. 1).

Insulin and glucose metabolism

The standard GH dose lowered SI (day 8 vs. baseline, P �0.04), with a small increase in fasting insulin levels (day 8 vs.baseline, P � 0.04). However, there were no changes in fast-ing glucose levels (B � 0.01 � 0.015 mmol/liter�d; P � 0.4)or �-cell function (B � 1.77 � 1.31%/d; P � 0.2) (Fig. 2).

Conversely, the intermediate GH dose increased SI (B �3.0 � 1.0%/d; P � 0.005), and reduced fasting insulin levels(B � �0.25 � 0.1 mU/liter�d; P � 0.009). Again, fastingglucose levels (B � 0.02 � 0.02 mmol/liter�d; P � 0.3) and�-cell function (B � �1.53 � 1.25%/d; P � 0.2) were un-changed (Fig. 2).

The low GH dose produced a steady decline in fastingglucose levels (B � 0.08 � 0.2 mmol/liter; P � 0.0001); com-

FIG. 1. Percentage of baseline IGF-I, IGFBP-3, IGF-I/IGFBP-3 ratio and IGFBP-1 levels on GH administration with standard dose (0.008mg/kg�d), � and bold solid line; intermediate dose (0.0033 mg/kg�d), f and dotted line; and low dose (0.0017 mg/kg�d), F and dashed line.

Yuen et al. • Low vs. Standard GH Replacement Dose J Clin Endocrinol Metab, May 2002, 87(5):1989–1995 1991

pared with baseline, fasting glucose levels were 12% loweron day 8 (P � 0.03). This GH dose also produced a rise in�-cell function (B � 6.31 � 1.82%/d; P � 0.001), althoughfasting insulin levels (B � 0.07 � 0.1 mU/liter�d; P � 0.5) andSI (B � �0.17 � 0.89%/d; P � 0.8) were unchanged (Fig. 2).

Table 2 shows a summary of the biochemical responses forthe three GH doses.

Between-dose effects

Analysis of covariance using the whole dataset demon-strated that increasing GH dose was associated with a sig-nificant linear reduction in SI (B � �112.6 � 32.8%/d; P �0.0007) and increase in fasting insulin levels (B � 10.06 � 2.82mU/liter; P � 0.001). The final percentage change in SI (day8 minus day 1) was inversely related to the final percentagechange in IGF-I levels (r � �0.39; P � 0.03), but not with thechanges in IGFBP-3 or IGFBP-1 levels.

Gender differences

The IGF-I response to the standard GH dose was higher inmales (B � 21.9 � 3.1 ng/ml�d; P � 0.001) than females (B �

7.3 � 2.2 ng/ml�d; P � 0.002), but the intermediate and lowdoses increased IGF-I levels similarly in both genders. Sim-ilarly, males showed a greater IGFBP-3 response to the stan-dard dose (B � 171.2 � 28.1 ng/ml�d; P � 0.001) than females(B � 96.4 � 33.9 ng/ml�d; P � 0.006), but there were nogender differences in the effects of the physiological doses onIGFBP-3 levels.

TABLE 2. Summary of the biochemical responses for the threeGH doses

GH dose (mg/kg/d)

Low0.0017

Intermediate0.0033

Standard0.008

IGF-I 1c 1a 1a

IGFBP-3 1b 1 1a

IGF-I/IGFBP-3 molar ratio 1c 1c 1b

IGFBP-1 – – 2c

Fasting glucose 2a – –Fasting insulin – 2b 1c

SI – 1a 2c

�-cell function 1b – –

1, Increase; –, unchanged; and 2, decrease.a P � 0.001, b P � 0.01, and c P � 0.05.

FIG. 2. Effects of standard (0.008 mg/kg�d), intermediate (0.0033 mg/kg�d), and low (0.0017 mg/kg�d) GH dose on percentage of baseline fastingglucose, fasting insulin, and SI from d 1–8.

1992 J Clin Endocrinol Metab, May 2002, 87(5):1989–1995 Yuen et al. • Low vs. Standard GH Replacement Dose

In males, the physiological GH doses significantly de-creased fasting glucose levels (low dose, B � �0.11 � 0.03mmol/liter�d, P � 0.001; intermediate dose, B � �0.04 � 0.02mmol/liter�d, P � 0.03) and increased SI (low dose, B �1.92 � 0.9%/d, P � 0.04; intermediate dose, B � 4.6 �1.6%/d, P � 0.007). In females, the low and the intermediatedoses decreased fasting glucose (B � �0.06 � 0.03 mmol/liter�d; P � 0.05) and insulin (B � �0.31 � 0.14 mU/liter�d;P � 0.05) levels, respectively.

Discussion

This study addressed the alterations in levels of IGF-I,IGFBP-1, IGFBP-3, and insulin and glucose homeostasis dur-ing a 7-d daily administration of recombinant GH in younghealthy adults. All three GH doses increased IGF-I andIGFBP-3 levels, and only the standard dose reduced IGFBP-1levels. Interestingly, GH effects on SI varied between thedoses. Although the standard adult GH deficiency replace-ment dose lowered SI, the intermediate GH dose increasedSI with a concomitant reduction in fasting insulin levels, andon the low-dose fasting glucose levels decreased and �-cellfunction increased.

Circulating IGF-I is mostly bound to IGFBP-3 and acidlabile subunit, and this ternary complex has a plasma half-lifeof approximately 15 h (23). The stimulatory effects of GH onIGF-I and IGFBP-3 levels in healthy adults have been pre-viously demonstrated (24) with two higher GH doses thanthose used in our study. Our highest GH dose (standarddose, 0.008 mg/kg�d) induced the greatest rise in IGF-I andIGFBP-3 levels, whereas our two lower physiological GHdoses (intermediate, 0.0033 mg/kg�d; and low, 0.0017 mg/kg�d) appeared to have similar stimulatory effects on IGF-Iand IGFBP-3 levels. Ghigo et al. (25) demonstrated a cleardose-response effect of GH on IGF-I and IGFBP-3 levels;however, in that study the minimum doses that were effec-tive in inducing IGF-I and IGFBP-3 levels were 0.0025 and0.005 mg/kg�d, respectively, which are higher than our lowdose (0.0017 mg/kg�d). The lack of dose-response effect be-tween our lower GH doses possibly suggests a thresholdeffect in the induction of IGF-I and IGFBP-3.

No consistent changes were seen with IGFBP-1 levels; onlythe standard dose induced a significant reduction in IGFBP-1levels. This observation could be explained by the effects ofthe standard dose on fasting insulin levels; as this dose in-creased circulating insulin levels, this induced a reduction inIGFBP-1 levels in a reciprocal manner.

We also analyzed a single fasting GH level on each dayduring each treatment phase in each subject (data not shown)and found that GH levels were unchanged, even after theadministration of the standard GH dose. However, this is notsurprising because the timing of blood samples taken for GHanalysis was at least 10 h post GH injection.

For the standard GH dose (0.008 mg/kg�d), although fast-ing glucose levels were unchanged, the rise in insulin levelsand the corresponding deterioration in SI indicates that con-ventional GH replacement doses may have anti-insulin ac-tions per se independent of endogenous GH levels. Indeed,Fowelin et al. (6) demonstrated a temporary reduction in SIin a group of GH-deficient adults after 6 wk, with partial

restoration of pretreatment SI after 26 wk of GH therapy.However, the GH dose used in that study was almost 3-foldhigher than our standard dose, and the partial improvementin SI may be secondary to increased lean body mass anddecreased body fat associated with prolonged GH therapy.In vivo studies have shown that GH administration producesa rapid reduction of forearm muscle uptake of glucose within10 min (26), and this GH-induced insulin resistance may bedue to alterations in insulin receptor function and post-receptor coupling (11).

Previous trials in GH-deficient adults have used GH dosesbased on body weight or body surface area, adopted fromexperience in GH-deficient children, and have not taken intoaccount the possibility of individual responsiveness to GH(27). A number of these trials have reported an increasedincidence of side effects, particularly in older patients (28).Therefore, there has been a move toward lower GH replace-ment doses in adults that do not compromise their subjectiveand objective improvements in sense of well-being and en-ergy (29–31). The use of low GH replacement doses in GH-deficient adults is also advocated to minimize the risk of GHover-replacement, subsequent side effects (29, 32), and thedevelopment of insulin resistance (33). GH therapy thereforeshould be commenced on a low starting dose (34), indepen-dent of body weight or body surface area, which mimicsnormal physiological GH production.

GH-induced insulin resistance has been demonstrated inchildren treated with daily supraphysiological GH dosesusing indirect measures of SI in both short- and long-termstudies (35, 36). Paradoxically, Press et al. (37) reported thatwhen GH-deficient children were treated with alternate-dayGH therapy, fasting hypoglycemia occurred 36–60 h aftereach injection. Serum GH levels peaked at 3–6 h after eachinjection and returned to baseline by 24 h (38), whereascirculating IGF-I levels peaked 19 h post injection, and thenfell slowly with a half-life of approximately 20 h (39). Thus,on the second or third day post injection, raised IGF-I levelswere not accompanied by elevated GH levels, and the ob-served fasting hypoglycemia could be due to insulin-likemetabolic effects of IGF-I unbalanced by any GH-inducedinsulin antagonism.

On daily intermediate dose GH administration, we ob-served an increase in SI without hypoglycemic episodes,possibly because adults are relatively more insulin resistantthan GH-deficient children (35). Low-dose IGF-I therapy hasbeen shown to improve SI in vitro and in vivo in normalsubjects and also in patients with type 1 diabetes (40), andtherefore mild improvement IGF-I bioavailability generatedby the intermediate dose could explain the improvement inSI. Adamson et al. (41) demonstrated inhibitory effects of GHon splanchnic glucose production, and this could also ex-plain the improved SI seen with the intermediate dose.

More surprising was the effect of the low (0.0017 mg/kg�d)GH dose on reducing fasting glucose levels and increasing�-cell function, without altering fasting insulin levels. Theseparadoxical data may reflect the limitations of the HOMAmethod of assessing �-cell function. A possible explanationis that there may be an increase in insulin-stimulated glucosedisposal causing the lowering of fasting glucose levels thatwere seen; and this sustained insulin release must suggest

Yuen et al. • Low vs. Standard GH Replacement Dose J Clin Endocrinol Metab, May 2002, 87(5):1989–1995 1993

alterations in �-cell response to ambient blood glucose con-centrations. It is also possible that this dose lowers glucoselevels by inhibition of splanchnic glucose production (41), orby direct �-cell stimulation. Direct insulinotrophic effects onthe �-cell and increased insulin secretion have been demon-strated after GH therapy (1, 2), but the doses used in thosestudies were relatively high. Indeed, high-dose GH admin-istration in dogs resulted in a large initial rise in insulinsecretion but was associated with the early development ofinsulin resistance (42).

Hwu et al. (43) recently found a small but significant im-provement in SI after 12 months of GH replacement in GH-deficient adults. The subjects in that study were almost iden-tical in age (mean age, 29.5 yr) and body mass index (mean,22.8 kg/m2) to our volunteers and were not insulin resistantbefore the commencement of GH therapy. However, themean GH dose used (0.011 mg/kg�d) was higher than ourstandard dose (0.008 mg/kg�d). The metabolic effect of aphysiological GH bolus in the postabsorptive state was stud-ied by Moller et al. (44), who demonstrated stimulation oflipolysis after a lag time of 2–3 h. Plasma glucose, seruminsulin, and C-peptide levels remained unchanged, with sub-tle reductions in muscular glucose uptake and oxidation,reflecting substrate competition between glucose and fattyacids. By contrast, prolonged exposure to supraphysiologicalGH levels induces both hepatic and peripheral (muscular)insulin resistance, increased lipid oxidation, compensatoryhyperinsulinemia (33), and subsequent �-cell exhaustion (2).Thus, from the work by Hwu et al. (43), Rosenfalck et al. (33),and Moller et al. (44), GH dose, timing and duration of GHadministration, age, baseline body composition, and baselineSI all appear to be important factors in determining the met-abolic manifestations after GH replacement therapy.

Our study also confirmed gender differences in the stim-ulatory effects between GH doses on fasting glucose andinsulin levels, SI, IGF-I, and IGFBP-3 levels. Indeed, Ho et al.(13) previously reported that both spontaneous and stimu-lated GH levels are higher in females, and Ghigo et al. (25)and Dall et al. (45) demonstrated gender differences in GH-stimulated IGF-I response to low and supraphysiologicaldoses. The reasons for this discrepancy are unclear, and apossible confounding factor may be due to the interactionsbetween female sex steroids and GH action in the peripheraltissues (46). Another possibility is the effect of androgens inenhancing GH action, as demonstrated by Erfurth et al. (47),and in this context one can speculate that the inhibitoryinfluence of estrogen on GH action in females might be partlydue to its indirect, testosterone-lowering effect. These ob-servations in our normal adult cohort support the idea thathypopituitary female patients require higher maintenanceGH doses than males for a given biochemical response(48, 49).

In conclusion, this study underlines the role of gender andthe differences in the effects of physiological vs. standard GHreplacement doses. Although supraphysiological doses inGH-deficient adults predispose normal adults to insulin re-sistance, short-term intermediate dose GH (0.0033 mg/kg�d)therapy unexpectedly improved SI, possibly due to increasedIGF-I bioavailability, direct splanchnic glucose inhibition,and/or peripheral insulin sensitization. The low (0.0017 mg/

kg�d) dose reduced glucose levels and increased in �-cellfunction, and could therefore be the optimal dose in stimu-lating �-cell function without necessarily compromising SI.The study was conducted over 7 d, and it remains to be seenwhether longer-term intermediate (0.0033 mg/kg�d) and low(0.0017 mg/kg�d) GH dose administration is able to sustainthe benefits on insulin action and �-cell function and pro-mote as well favorable changes in body composition, lipidparameters, and bone density. Also, whether these beneficialmetabolic effects can be extrapolated to pathophysiologicalconditions associated with insulin resistance, such as obesity,adult GH deficiency, and type 2 diabetes mellitus, meritsfurther study.

Acknowledgments

We are grateful to Pharmacia & Upjohn, Inc. Ltd. for providing theGH used in this study and for supporting the costs of the hormoneassays.

Received September 25, 2001. Accepted January 17, 2002.Address all correspondence and requests for reprints to: Prof. David

B. Dunger, University Department of Pediatrics, Level 8, Box 116, Ad-denbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom. E-mail:dbd25@cam.ac.uk.

This work was also supported by funds from Pharmacia & Upjohn,Inc., Ltd. (to K.Y.).

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