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Department of Endocrinology and Diabetes, St. Thomas’ Hospital, GKT School of Medicine (H.L.S., N.C.J., F.S.-M., R.H.J., P.H.S., A.M.U.), London, United Kingdom SE1 7EH; Department of Pediatrics, University of Cambridge, Addenbrooke’s Hospital (D.B.D.), Cambridge, United Kingdom CB2 2QQ; and Department of Diabetes and Endocrinology, Royal Surrey County Hospital (D.L.R.-J.), Guildford, Surrey, United Kingdom GU2 5XX
Address all correspondence and requests for reprints to: Dr. Helen Simpson, Department of Endocrinology and Diabetes, St. Thomas’ Hospital, GKT School of Medicine, London, United Kingdom SE1 7EH. E-mail: helen.simpson{at}kcl.ac.uk.
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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GH has insulin antagonistic effects with respect to glucose and lipid metabolism, as it increases hepatic glucose production, decreases peripheral glucose utilization (8, 9), and increases lipolysis (10). GH also has anabolic effects on protein metabolism by increasing protein synthesis (11). Conversely, IGF-I has a hypoglycemic action mediated by suppression of hepatic glucose production and stimulation of peripheral glucose uptake (12, 13, 14, 15). The effects of IGF-I on lipid metabolism are less conclusive. Several studies have demonstrated an increase in nonesterified fatty acids (NEFA) concentrations with IGF-I (14, 16), whereas others have demonstrated a reduction in NEFA (13, 15). IGF-I also has anabolic effects on protein metabolism. In the fasting state, IGF-I has been shown to decrease protein breakdown (16), but in the presence of amino acids during an amino acid clamp, IGF-I increases protein synthesis (17). In addition, two groups have reported that liver-specific IGF-I knockout mice with a 75% reduction in circulating IGF-I have decreased insulin sensitivity and increased GH secretion (18, 19), also suggesting a metabolic role for circulating IGF-I.
In vivo studies addressing the effect of IGF-I on glucose metabolism in type 1 diabetes have demonstrated improvements in insulin sensitivity as well as a reduction in overnight GH secretion (20, 21, 22, 23). More recently, an IGF-I/IGFBP-3 complex has been demonstrated to improve insulin sensitivity and decrease insulin requirements in type 1 diabetes (24). It remains unclear whether these effects of IGF-I are direct via stimulation of the type 1 IGF-I receptor or indirect by suppressing GH secretion. The aim of this study was to determine whether IGF-I has a direct effect on glucose, lipid, and protein metabolism independently of changes in GH secretion.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Seven patients with type 1 diabetes participated in the study (age, 32.6 ± 1.32 yr; duration of diabetes, 16.1 ± 2.92 yr; body mass index, 25.3 ± 0.92 kg/m2). All had stable metabolic control (mean hemoglobin A1c, 7.9 ± 0.67%), no evidence of microvascular complications and normal renal and hepatic function. Local ethical committee approval from Guys and St. Thomas’ National Health Service Trust, and written informed consent was obtained. Studies were conducted in accordance with the Declaration of Helsinki.
Experimental protocol (Fig. 1
)
Subjects were studied on three separate occasions in random order at least 1 wk apart. Before the study day subjects were asked to omit long-acting insulin for 36 h, taking short-acting insulin as an extra injection with a snack before bed. On the study day subjects attended the metabolic ward at 0700 h after a 10-h fast, were placed on bed rest, and remained supine for the duration of the study. Three indwelling venous cannulas were inserted, one in the right arm for venous sampling and 2 in the left arm for administering the iv infusions. An iv infusion of insulin (Actrapid Human Actrapid, Novo Nordisk, Copenhagen, Denmark) was infused at a maximal rate of 0.3 mU/kg·min for 2–3 h to achieve euglycemia. The metabolic protocol was started once euglycemia was achieved (time zero). The rate of insulin infusion was changed to a basal rate (0.2 mU/kg·min) for 300 min, after which a hyperinsulinemic (0.8 mU/kg·min) euglycemic (6 mmol/liter) clamp was performed for an additional 120 min.
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Before the start of the metabolic protocol, two blood and breath samples were taken 15 min apart to determine background enrichment of plasma [2H2]glucose, [2H5]glycerol, and [13C]leucine and breath 13CO2. After 150 min, to allow tracers to reach isotopic equilibration, blood samples were taken at 150, 180, 210, 240, 270, 275, 280, 290, 300, 330, 360, 390, 395, 400, 410, and 420 min to measure the concentration and enrichment of glucose, glycerol, and leucine. Expired air was collected at the same time points using a GaSampler Breath Collection System (Quintron Instrument Co., Inc., Milwaukee, WI,) for the measurement of 13CO2 enrichment. Samples were taken every 20 min to measure GH and every 30 min to measure insulin, IGF-I, NEFA, and glucagon. The CO2 production rate was measured by indirect calorimetry using a computerized open-loop gas analyzer system (Horizon Beckman Instruments, Anaheim, CA).
Analytical methods
The plasma glucose concentration was measured immediately with a Clandon Scientific Glucose Analyzer (YSI, Inc., Yellow Springs, OH). Insulin was measured by a double antibody RIA as previously described, with an intraassay coefficient of variation (CV) of less than 9% and an interassay CV of less than 6% (26). GH was measured by a two-site immunoradiometric assay with intraassay CVs at analyte values of 0.3, 3.3, and 16.7 µg/liter of 3%, 1%, and 1.5%, respectively. The level of sensitivity of the assay was 0.06 µg/liter. Glucagon was measured using a double antibody RIA (Biogenesis Ltd., Poole, UK). The intraassay CVs at analyte values of 60, 90, and 220 pg/ml were 4.0%, 4.6%, and 4.0%, respectively. The plasma glycerol concentration was measured by a direct enzymatic colorimetric method (Randox Laboratories Ltd., Crumlin, UK; interassay CV, 3.7%), and NEFA was measured by an enzymatic colorimetric method (Wako Chemicals, Neuss, Germany; interassay CV, 3.6%) using a Cobas Fara II autoanalyzer (Roche, Welwyn Garden City, UK). Total IGF-I was measured by double-antibody RIA after acid/ethanol extraction using a commercially available reagent pack (Amersham Pharmacia Biotech, Arlington Heights, IL; interassay CV, <6%). The plasma leucine concentration was measured on an 
II+ automated amino acid analyzer (Amersham Pharmacia Biotech, Little Chalfont, UK; interassay CV, 5%).
Glucose, glycerol, and leucine enrichment was measured by gas chromatography-mass spectrometry using a Hewlett-Packard 5971A MSD (Agilent Technologies, Stockport, UK). Glucose enrichment was determined from deproteinized plasma using the methoxime-trimethlysilyl ether derivative (27). Glycerol was isolated from deproteinized plasma using ion exchange chromatography, and glycerol enrichment was determined using the Tris-trimethylsilyl derivative (28). Plasma -ketoisocaproate (-KIC) enrichment was used as a measure of intracellular leucine enrichment (29), using the O-tertiary-butyldimethylsilyl quinoxalinol derivative (30). Gas chromatography-mass spectrometry analysis used electron impact ionization with selected ion monitoring of the ions at mass/charge ratios of 319 and 321 for glucose, 205 and 208 for glycerol, and 259 and 260 for leucine. Expired 13CO2 enrichment was measured on a SIRA series II isotope ratio mass spectrometer (VG Isotech, Cheshire, UK) modified with a Roboprep G+ inlet system (Europa Scientific, Cheshire, UK).
Calculations
The enrichments of glucose, glycerol, and -KIC were expressed as the tracer/tracee ratio. The rates of appearance and disposal of glucose, glycerol, and leucine were calculated using both the Steele and Mari models for the nonsteady state modified for use with stable isotopes (31, 32, 33). The effective volume of distribution was assumed to be 143 ml/kg for glucose and leucine and 230 ml/kg for glycerol. The metabolic clearance rates (MCRs) for glucose and leucine were calculated by: MCR = isotope infusion rate/isotope concentration.
Leucine oxidation was calculated using the equation: oxidation = (ECO2 x RaCO2)/(EKIC x 0.8), where ECO2 is the enrichment of expired 13CO2, RaCO2 is the rate of total CO2 production (millimoles per minute), and EKIC is the enrichment of plasma -KIC. A factor of 0.8 was used to correct for CO2 retention and other losses. Nonoxidative leucine disposal (NOLD), a measure of whole body protein synthesis, was calculated by subtracting leucine oxidation from leucine uptake (Rd).
Statistical analyses
Data are expressed as the mean ± SEM. Statistical significance was evaluated using ANOVA with Bonferroni post hoc analysis using Stata (Stata Corp., Stata, TX). P < 0.05 was considered statistically significant.
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Results |
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There was no difference in the plasma insulin concentrations between any of the studies during either the basal insulin infusion (placebo, 13.3 ± 1.5; IGF-I, 16.7 ± 4.1; GH, 17.9 ± 3.3 mU/liter) or the hyperinsulinemic euglycemia clamp (placebo, 58.3 ± 3.9; IGF-I, 62.9 ± 7.0; GH, 69.2 ± 5.3 mU/liter; Fig. 2A). There was a predictable increase in insulin concentration (P < 0.005) during the hyperinsulinemic euglycemic clamp in all three studies. Glucagon concentrations were not different among the three studies during the basal insulin infusion (placebo, 82.8 ± 21.4; IGF-I, 80.8 ± 19.0; GH, 94.6 ± 6.4 pg/ml), or the hyperinsulinemic euglycemic clamp (placebo, 81.3 ± 18.2; IGF-I, 83.2 ± 18.6; GH, 73.6 ± 15.9 pg/ml; normal fasting glucagon, 50–150 pg/ml). GH levels increased in the rhGH study, peaking 60 min after the start of the infusion (GH, 31.6 ± 3.6 µg/liter; Fig. 2B). The GH concentration did not increase in either the placebo or rhIGF-I study. Baseline IGF-I concentrations were the same in the three studies (placebo, 116.0 ± 28.0; rhIGF-I, 111.7 ± 14.4; rhGH, 126.9 ± 11.4 ng/liter), at the lower end of the age-related normal ranges (IGF-I, 91.2–478.8 ng/liter). IGF-I levels increased in the rhIGF-I study, reaching a maximum 4 h after the rhIGF-I injection (IGF-I, 398.2 ± 34.9 ng/liter; P < 0.005). IGF-I concentrations did not change in either the placebo or the rhGH study (Fig. 2C).
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During the basal insulin infusion, glucose concentrations were lower in the rhIGF-I study (P < 0.05) compared with those in the placebo and rhGH studies (placebo, 7.08 ± 0.75; IGF-I, 6.37 ± 0.45; GH, 7.87 ± 0.82 mmol/liter; Fig 3A). There was no difference in glucose concentration among the three studies during the hyperinsulinemic euglycemic clamp. The glucose infusion rate required to maintain euglycemia was not different between the rhGH and placebo studies (Fig. 3B) at any time, but was higher in the rhIGF-I study compared with the placebo and rhGH studies during the basal insulin infusion (placebo, 0.2 ± 0.13; IGF-I, 1.04 ± 0.4; GH, 0.11 ± 0.1 mg/kg·min; P < 0.05) and the hyperinsulinemic clamp (placebo, 5.9 ± 1.5; IGF-I, 8.32 ± 0.93; GH, 6.0 ± 0.75 mg/kg·min; P < 0.005).
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). During the hyperinsulinemic clamp, the glucose Ra decreased in all three studies compared with that during the basal insulin infusion and remained lower in the IGF-I group (P < 0.05) compared with the placebo and rhGH groups (placebo, -0.14 ± 0.33; IGF-I, -0.8 ± 0.24; GH, 0.44 ± 0.2 mg/kg·min).
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). The glucose Rd was not different between the rhIGF-I and rhGH studies. During the hyperinsulinemic euglycemic clamp, the glucose Rd increased in all three studies compared with that during the basal insulin infusion (P < 0.005), remaining higher in the rhIGF-I study compared with the placebo and rhGH studies (P < 0.005; placebo, 6.23 ± 1.07; IGF-I, 8.47 ± 1.02; GH, 5.94 ± 0.78 mg/kg·min).
During the basal insulin infusion, the glucose MCR was higher in the rhIGF-I study compared with the placebo and GH studies (P < 0.005; placebo, 1.71 ± 0.16; IGF-I, 2.53 ± 0.33; GH, 2.05 ± 0.34 ml/kg·min; Fig. 4B). During the hyperinsulinemic euglycemic clamp. the glucose MCR increased in all three studies and was higher in the rhIGF-I study compared with both placebo and rhGH (P < 0.005; placebo, 5.40 ± 1.02; IGF-I, 8.32 ± 0.92; GH, 5.7 ± 0.93 ml/kg·min).
Glycerol and NEFA concentrations and glycerol Ra
Glycerol and NEFA concentrations were higher in the rhGH study (P < 0.005) during the basal insulin infusion than in the placebo and rhIGF-I studies (glycerol: placebo, 34.3 ± 5.6; IGF-I, 34.67 ± 5.4; GH, 61.66 ± 5.4 µmol/liter; Fig. 5A; NEFA: placebo, 0.35 ± 0.04; IGF-I, 0.31 ± 0.05; GH, 0.56 ± 0.09 mmol/liter; P < 0.005; Fig. 5B). There was no change in glycerol or NEFA concentration during the placebo or rhIGF-I studies. Glycerol and NEFA concentrations decreased in all three studies during the hyperinsulinemic euglycemic clamp (P < 0.005), but remained higher in the rhGH study (P < 0.05) compared with the placebo and rhIGF-I studies (glycerol: placebo, 13.04 ± 3.04; IGF-I, 10.12 ± 2.37; GH, 27.8 ± 5.0 µmol/liter; Fig. 5A; NEFA: placebo, 0.05 ± 0.01; IGF-I, 0.04 ± 0.007; GH, 0.12 ± 0.03 mmol/liter; Fig. 5B). The glycerol Ra was higher in the rhGH study (P < 0.005) during the basal insulin infusion compared with the rhIGF-I and placebo studies (placebo, 1.46 ± 0.12; IGF-I, 1.4 ± 0.14; GH, 2.54 ± 0.36 µmol/kg·min; Fig. 5C). The glycerol Ra was suppressed in all three studies during the hyperinsulinemic euglycemic clamp (P < 0.005), with no difference among the three studies (placebo, 0.62 ± 0.1; IGF-I, 0.7 ± 0.11; GH, 0.76 ± 0.12 µmol/kg·min).
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)The leucine concentration was lower in the rhIGF-I and rhGH studies compared with the placebo study during the basal insulin infusion (P < 0.05 and P < 0.005, respectively). The leucine concentration was reduced in all three studies during the hyperinsulinemic euglycemic clamp, remaining lower in the rhGH study compared with the placebo and rhIGF-I studies (P < 0.05). During both the basal insulin infusion and the hyperinsulinemic euglycemic clamp, leucine Ra was lower in the rhIGF-I study than in the placebo and rhGH studies (P < 0.05). The leucine oxidation rate was lower in the rhGH study during the basal insulin infusion compared with both placebo and rhIGF-I studies (P < 0.05). Leucine oxidation increased in all three studies during the hyperinsulinemic euglycemic clamp (P < 0.05 for all studies), with no differences among the three studies. During the basal insulin infusion, NOLD (a measure of protein synthesis) was lower in the rhIGF-I study compared with the placebo and rhGH studies (P < 0.05). During the hyperinsulinemic euglycemic clamp, NOLD was decreased in the GH study compared with that during the basal insulin infusion (P < 0.05). There was no difference among the three studies during the clamp. Leucine MCR was increased in the rhGH study compared with both placebo and rhIGF-I studies during the basal insulin infusion (P < 0.05). Leucine MCR increased during the hyperinsulinemic euglycemic clamp in the placebo and rhIGF-I studies (P < 0.05), with no difference in leucine MCR among the three studies during the clamp.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A single sc dose of 40 µg/kg rhIGF-I decreased hepatic glucose output during the basal insulin infusion and the hyperinsulinemic euglycemic clamp compared with the placebo study. As this study maintained concentrations of glucagon, and endogenous GH secretion was suppressed, changes in these hormones cannot explain this effect. It remains to be determined whether the direct effect of IGF-I is by cross-reactivity with the insulin receptor, whether hybrid IGF-I receptors are mediating this hepatic effect, or whether there are significant numbers of IGF-I receptors in the liver. One study has reported that human liver expresses few IGF-I receptors (34), but this study was performed in two obese adults, one of whom had type 2 diabetes, which may not give an accurate reflection of the true number of hepatic IGF-I receptors in humans. Some investigators have suggested that improvements in insulin sensitivity may be secondary to reductions in NEFA concentrations. However, in the rhIGF-I treatment study, there was no change in lipolysis or NEFA concentration. The increase in hepatic glucose output with rhGH confirms previous studies and demonstrates an insulin antagonistic effect in the presence of both basal and increased insulin concentrations (9).
Glucose Rd and MCR were increased by rhIGF-I at basal insulin levels, demonstrating a direct effect of IGF-I on peripheral glucose disposal. In the rhGH treatment study, the increase in glucose Rd may be due to GH having an initial insulin-like action. An in vitro study has described an increase in GLUT4 transporters with acute GH treatment (35). However, in the current study there was no increase in glucose MCR with rhGH. There was a trend for the glucose concentration to be higher in the GH treatment study during the basal insulin infusion, which may explain the higher glucose Rd, as glucose disposal is concentration dependent (36). During the hyperinsulinemic euglycemic clamp, there was an increase in glucose disposal and MCR in all three studies, as would be expected in response to an increase in insulin concentration. This was greater with rhIGF-I treatment, demonstrating that the effect of rhIGF-I and insulin to increase glucose disposal is additive.
Although the mean basal insulin concentrations were higher than nondiabetic fasting levels (0–12 mU/liter) during the basal insulin infusion, this is probably not of physiological significance, as subjects with type 1 diabetes are more insulin resistant with respect to glucose, lipid, and protein. This may be because the liver is exposed to less insulin than is normal in type 1 diabetes due to the relatively low levels of portal insulin, resulting in less suppression of hepatic glucose production. A higher than usual peripheral insulin concentration is therefore required to achieve euglycemia by increasing glucose disposal.
The IGF-I concentrations achieved in the rhIGF-I study were at the upper end of the normal age-related range, suggesting that physiological, rather than pharmacological, concentrations had been achieved. Although free IGF-I concentrations were not measured, the use of an sc injection would have allowed IGF-I to equilibrate with the binding proteins. A similar dose of rhIGF-I has been shown to result in free IGF-I being less than 10% of the total IGF-I concentration (37). The lack of any effect of GH on IGF-I concentration may reflect hepatic GH resistance, which has been demonstrated in type 1 diabetes (38, 39), and a relatively short observation period.
Although during this study the exogenous glucose infused included [2H2]glucose, we obtained negative values for hepatic glucose output during the hyperinsulinemic euglycemic clamp. There was no change in the tracer/tracee ratio throughout the study, suggesting that the negative Ra was not due to dilution of the tracer during the high rates of exogenous glucose infusion. This suggests that glucose Ra was significantly underestimated by the Steele model, as has been reported by others (40, 41). This results in a negative value for endogenous glucose Ra when the large amount of dextrose infused during the hyperinsulinemic euglycemic clamp is subtracted from the total glucose Ra in the calculations of endogenous glucose production. The two-compartment Mari model was proposed to overcome this underestimation of endogenous Ra (33). However, in the current study the negative glucose Ra remained even when applying this model.
Although basal insulin concentrations were higher than the normal fasting range, there was no significant suppression of lipolysis in the basal state, suggesting that subjects with type 1 diabetes are insulin resistant with respect to lipolysis (2). The lack of any effect of rhIGF-I on lipolysis as measured by glycerol Ra in this study is perhaps not surprising, because it has been demonstrated that adipocytes have low numbers of IGF-I receptors (42). However, Boulware et al. (13) reported that rhIGF-I treatment of healthy subjects results in a decrease in lipolysis. That study used an iv infusion of rhIGF-I at much larger doses than the current study and would have resulted in high free IGF-I concentrations, probably cross-reacting with the insulin receptor, thus inhibiting lipolysis. In contrast, Hussain et al. (14) reported an increase in NEFA concentrations with rhIGF-I treatment, suggesting an increase in lipolysis. However, there was also a reduction in insulin concentrations as a result of the IGF-I infusion, which would increase NEFA concentrations.
It is well documented that GH is a major lipolytic hormone. The results from this study are in agreement with those of other studies and demonstrate that GH has a lipolytic action at basal insulin concentrations, overcome by modest hyperinsulinemia. Although glycerol and NEFA concentrations remained higher in the GH treatment group during the hyperinsulinemic euglycemic clamp, there was no difference in glycerol Ra, an index of the rate of lipolysis, among the three groups at this time, suggesting that there was a reduction in the clearance of glycerol and NEFA after rhGH.
IGF-I reduced leucine concentration, protein breakdown, and protein synthesis with no change in leucine MCR, suggesting that the reduction in the leucine concentration was due to a decrease in leucine appearance from protein breakdown rather than an increase in leucine clearance. The reduced protein synthesis may be due to the reduced amino acid availability as amino acids are an important stimulus for protein synthesis. IGF-I, therefore, seems to potentiate the effects of insulin to inhibit protein breakdown even at a low dose, suggesting that common intracellular signaling mechanisms had been activated. The effect of rhGH to increase leucine oxidation is well recognized. The increase in leucine clearance provides a mechanism for the decrease in the leucine concentration and suggests that rhGH increased transporter-mediated leucine uptake. This is supported by in vitro and in vivo data showing that GH increases amino acid uptake (11, 43). Treatment with rhGH for 1 wk has been shown to increase protein synthesis (44). However, the single dose of rhGH used in the current study was insufficient to stimulate such an increase in protein synthesis.
An unexpected finding was the increase in leucine oxidation in all three studies during the hyperinsulinemic clamp compared with the basal insulin infusion. This is unlikely to be due to the exogenous infusion of dextrose, as it has been reported that neither the rate of exogenous glucose infusion nor the glucose concentration affects leucine flux (45). Most previous studies have demonstrated a decrease in leucine oxidation with increasing doses of insulin (3, 46). An investigation of the dose-response effect of insulin on protein metabolism in type 1 diabetes has shown insulin resistance with respect to protein metabolism, with insulin concentrations higher than 80 mU/liter (higher than those reached in the current study) required to inhibit leucine oxidation. However, this does not explain the increase in leucine oxidation. There is evidence to suggest that there is a reciprocal relationship between NEFA concentrations and leucine oxidation rate. Tessari et al. (47) demonstrated an increase in leucine oxidation when lipolysis was suppressed with nicotinamide in fasting dogs. Others have demonstrated that an infusion of lipid and heparin can result in a decrease in leucine oxidation (48, 49). This suggests that NEFAs are an important substrate for oxidation, and in the absence of appropriate concentrations of NEFAs, other metabolic substrates, such as amino acids, are oxidized in their place. In the current study lipolysis was suppressed during the hyperinsulinemic euglycemic clamp, resulting in very low NEFA concentrations, possibly explaining amino acid oxidation being increased as a source of metabolic substrate. In addition, the GH concentration was low during the hyperinsulinemic euglycemic clamp, removing the effect of GH on sparing protein oxidation (50).
It is well recognized that subjects with type 1 diabetes have an abnormal IGF-I/GH axis, with low portal insulin levels leading to low circulating IGF-I-reduced negative feedback of GH and increased circulating GH levels. It has been shown that restoring rhIGF-I to physiological levels can reduce GH secretion, and this provides a mechanism for improvements in glucose homeostasis. In this study, however, we demonstrated that rhIGF-I also has a significant direct effect on glucose homeostasis, decreasing glucose Ra and increasing glucose Rd and MCR. In addition, rhIGF-I decreased protein breakdown. This suggests that circulating IGF-I may act in concert with insulin to control glucose and protein metabolism, and provides more evidence to support the use of rhIGF-I as an adjunct to insulin therapy in type 1 diabetes.
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Acknowledgments |
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Footnotes |
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Abbreviations: CV, Coefficient of variation; -KIC, -ketoisocaproate; MCR, metabolic clearance rate; NEFA, nonesterified fatty acids; NOLD, nonoxidative leucine disposal; Ra, production rate; Rd, rate of uptake; rh, recombinant human.
Received July 22, 2003.
Accepted October 7, 2003.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, Placebo study; 
, IGF-I study; 
, GH study.
, placebo study; 
, IGF-I study; •, GH study. Glucose Ra: *, P < 0.05, IGF-I vs. P; ¶, P < 0.005, GH vs. P basal steady state; ##, P < 0.05, IGF-I vs. P and GH clamp steady state. Glucose Rd: 
, P < 0.005, P vs. IGF-I and GH basal steady state; ##, P < 0.005, IGF-I vs. P and GH clamp steady state. Glucose MCR: #, P < 0.005, IGF-I vs. P and GH basal steady state; ##, P < 0.005, IGF-I vs. P and GH clamp steady state.
, P < 0.005, GH vs. P and IGF-I basal steady state,