Journal of Clinical Endocrinology & Metabolism
, doi:10.1210/jc.2006-2699
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 7 2652-2658
Copyright © 2007 by The Endocrine Society
Effects of Combined Recombinant Insulin-Like Growth Factor (IGF)-I and IGF Binding Protein-3 in Type 2 Diabetic Patients on Glycemic Control and Distribution of IGF-I and IGF-II among Serum Binding Protein Complexes
D. R. Clemmons,
M. Sleevi,
G. Allan and
A. Sommer
Division of Endocrinology (D.R.C.), University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599; and Insmed, Incorporated (M.S., G.A., A.S.), Glen Allen, Virginia 23058-2400
Address all correspondence and requests for reprints to: David R. Clemmons, M.D., CB No. 7170, 8024 Burnett-Womack, Division of Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7170. E-mail: endo{at}med.unc.edu.
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Abstract
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Context: Administration of recombinant human IGF-I (rhIGF-I)/recombinant human IGF binding protein-3 (rhIGFBP-3) to patients with type 2 diabetes improves blood glucose and enhances insulin sensitivity. The changes in various components of the IGF system that occur in response to rhIGF-I/rhIGFBP-3 as well as the minimum effective dose have not been determined.
Objectives: The aim was to determine the dose of rhIGF-I/rh-IGFBP-3 necessary to achieve a significant decrease in glucose and to determine the changes that occur in the IGF-II and acid labile subunit in response to treatment.
Design: A total of 39 insulin-requiring type 2 diabetics were randomized to placebo or one of six groups that received different dosages of rhIGF-I/rhIGFBP-3. After 3 d in which insulin doses were adjusted to improve glucose control, a variable insulin dosage regimen was continued, and either placebo or one of six dosages (0.125–2.0 mg/kg·d) of rhIGF-I/rhIGFBP-3 was administered for 7 d. All subjects were hospitalized, and dietary intake as well as insulin dosage were controlled with instructions to treat to normal range targets.
Results: Fasting glucose was reduced in the groups that received either 1 (32 ± 5% reduction) or 2 mg/kg·d (40 ± 6% reduction) of the complex. Mean daily glucose (four determinations) was reduced by 26 ± 4% in the 1 mg/kg group and by 33 ± 5% in the 2 mg/kg group compared with 18 ± 4% in the placebo group. Total serum IGF-I increased between 2.0 ± 0.3- and 5.7 ± 1.3-fold by d 8. IGFBP-3 concentrations increased significantly only in the 2 mg/kg group. IGF-II concentrations declined to values that were between 27 ± 4% and 64 ± 7% below baseline. Acid labile subunit concentrations declined significantly in the three highest dose groups. The sum of the IGF-I + IGF-II concentrations was significantly increased at the two highest dosages. There were very few drug-associated adverse events reported in this study with the exception of hypoglycemia, which occurred in 15 subjects who had received rhIGF-I/rhIGFBP-3 treatment.
Conclusions: Administration of rhIGF-I/rhIGFBP-3 resulted in a redistribution of the amount of IGF-I and IGF-II that bound to IGFBP-3. Fasting and mean daily blood glucose were reduced significantly in the two highest dosage groups. The results suggest that both the total concentration of IGF-I as well as its distribution in blood may determine the extent to which insulin sensitivity is enhanced.
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Introduction
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ADMINISTRATION OF IGF-I to normal volunteers, patients with severe insulin resistance, or with type 1 or 2 diabetes mellitus lowers blood glucose and improves insulin sensitivity (1, 2, 3, 4, 5, 6). IGF-I or the combination of IGF-I/IGF binding protein (IGFBP)-3 results in lower insulin requirements and improves mean daily glucose in type 1 diabetics (7, 8, 9, 10, 11). Administration of IGF-I or the combination of IGF-I/IGFBP-3 to type 2 diabetics results in lower fasting and mean daily glucose (2, 3, 4, 12, 13). In type 2 diabetics, this response could be demonstrated whether the subjects were receiving insulin or oral hypoglycemic agents, or both (2, 3). Although administration of the complex of IGF-I and IGFBP-3 (the principle serum IGFBP) might be expected to lead to attenuation of IGF-I actions, administration of this complex was efficacious in lowering mean daily glucose and insulin requirements in type 1 diabetics (7), and in lowering fasting blood glucose in patients with type 2 diabetes who were receiving insulin (12). The mechanism by which IGF-I administration acts to lower blood glucose has not been definitively established. Several studies have shown enhanced insulin action in the post-resorptive state (5, 13, 14). Because there are no IGF-I receptors present in mature hepatocytes or adipocytes, it has been proposed that this is due to the ability of IGF-I to sensitize skeletal muscle to insulin actions (5, 13, 15). Administration of IGF-I to type 1 diabetics results in inhibition of GH secretion (7, 8, 11, 14). Because this would reduce GH’s anti-insulin actions, it has been proposed as one of the mechanisms by which IGF-I functions (16, 17). A recent study in mice demonstrated that IGF-I inhibited renal gluconeogenesis, therefore, this could contribute to its glucose lowering effect (18). Whether the distribution of IGF-I among the various binding protein complexes in serum or whether changes in IGF-II contribute to these changes in insulin sensitivity is unknown. In a recent study, recombinant human IGF (rhIGF)-I/rhIGFBP-3 administration to type 2 diabetics resulted in a 34–38% decrease in fasting glucose. Despite administering an equimolar amount of both proteins, the ratio of IGF-I to IGFBP-3 increased from 0.25 to 1.04 (12). This study was undertaken to determine the dose of the IGF-I/IGFBP-3 complex necessary to achieve a glucose lowering response, to compare the maximum glucose lowering effect to subjects treated with intensive insulin therapy alone, and to determine the changes that occur in the components of the IGF system in response to IGF-I/IGFBP-3 administration.
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Patients and Methods
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This was an inpatient, double-blind, randomized, parallel group, placebo-controlled dose-ranging study. A total of 39 patients (18 males, 21 females) with type 2 diabetes mellitus, with an average duration of disease of 15.6 yr, were recruited into the study at a single site. All subjects provided written informed consent for a protocol that was approved by the local institutional review board. There were 37 subjects treated according to the protocol who had an average age of 56 ± 9 yr. Body mass index was 30.3 ± 5.5 kg/m2, and weight was 83.4 ± 15.4 kg. All subjects had fasting C-peptide values greater than 0.8 ng/ml (mean 2.2 ± 0.5 ng/ml). All subjects were being treated with insulin alone. The total daily insulin doses at study entry were comparable among the groups ranging from 65 ± 12 units/d in group 7 to 87 ± 16 in group 5. Mean fasting glucose was 245 mg/dl, and the values for the groups ranged from 221–266 mg/dl. Mean glycosylated (A1C) hemoglobin at study entry was 10.7%, and the values from the groups ranged from 9.5–11.6% (Table 1
). Comparisons of the baseline IGF-I, IGF-II, and IGFBP-3 values among the groups showed no significant differences. Subjects with clinically significant evidence of retinopathy, nephropathy, or neuropathy were excluded. Subjects who met the entry criteria were hospitalized and then randomized to one of seven treatment groups. They were placed on a weight-maintaining diet for a control, 3-d period. During each study day, glucose was measured four times daily at 700, 1200, 1800, and 2200 h. Meals were eaten at 0800, 1200, and 1800 h. Using these glucose measurements, a physician attempted to improve glucose control by insulin administration using humulin 70/30 or Novolin 70/30 (Novo Nordisk A/S, Bagsværd, Denmark). One of these was administered in the morning before breakfast and evening before dinner. The physician was also permitted to administer additional doses of humulin N, Novolin N, Humalin R, or Novolin R (Novo Nordisk A/S) at noon and bedtime if needed. Blood glucose measurement was performed using capillary glucose testing. Insulin dosage was adjusted to maintain optimal glycemic control targets of fasting glucose less than 126 mg/dl and postprandial glucoses less than 180 mg/dl while attempting to avoid hypoglycemia. Two of 39 subjects who were enrolled were omitted from the final data analysis because they received the incorrect dose of rhIGF-I/rhIGFBP-3 during the last 2 d of treatment.
Beginning on study d 1, study group 1 (n = 5) received a placebo injection at 2000 h in addition to insulin, and this was continued for 7 d. Group 2 (n = 5) received 0.125 mg/kg of rhIGF-I/rhIGFBP-3 sc daily, group 3 (n = 5) received 0.25 mg/kg, group 4 (n = 6) received 0.5 mg/kg, group 5 (n = 5) 0.5 mg/kg bid (0800 and 2000 h), group 6 (n = 5) 1.0 mg/kg, and group 7 (n = 6) 2.0 mg/kg. The last injection was administered on the evening of study d 7, except for group 5, which received the last injection on the morning of study d 8. Glucose values were measured by Glucometer (Bayer Corp., Tarrytown, NY). Dietary intake was 1.2-g protein, 32 kcal/kg. Food intake was monitored by weighing the amount of food not consumed and calculating any deficits. A dietician monitored compliance. Activity was monitored, and the subjects were not permitted to exceed more than 1 mile/d walking. Both investigators and subjects were blinded as to group designation. Subjects were monitored daily for the appearance of side effects. Fasting morning blood values were drawn daily at 0600 h. Adjustments in insulin dosage were made daily by medical personnel supervising the study in attempt to achieve the glycemic targets. Adjustments were made at more frequent intervals if it was thought to be necessary to avoid hypoglycemia. Fasting C-peptide was determined by immunochemiluminescence assay. Serum total IGF-I, IGF-II, IGFBP-3, and acid labile subunit (ALS) were determined using reagents supplied by Diagnostic Systems Laboratories (Webster, TX), and the assays were performed according to the manufacturer’s recommendations. C-peptide, cholesterol, triglycerides, and insulin measurements were performed in commercial laboratories. The results are presented as mean ± SE unless otherwise specified. The significance was determined using a paired Student’s t test with the Bonferroni correction for multiple comparisons. Significant changes were expressed as a value of P < 0.05.
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Results
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The results for insulin dosages, fasting glucoses, and mean daily glucoses were grouped into three study intervals. The first interval (d –2 through 0) was chosen to include the run in period before treatment. Day one was omitted because it included results obtained both before and after IGF-I treatment. Days two through four were pooled because they include the period in which IGF-I, IGF-II, and IGFBP-3 levels were changing rapidly. Days five through seven represent the period in which the three peptides had reached a new steady state. Subjects in all groups had increases in insulin dosage requirements during the first 3 d of the study, from a mean ± SE of 71 ± 14 U/d on d –2, to 84 ± 16 U/d for d 0 in an attempt to meet glucose targets. The increases for each group ranged from 7–16 U. Further increases in insulin dosage occurred during study d 1 or 2 in groups 1, 3, 5, and 6. When the insulin requirements from d 5–7 were examined, the total dosage was relatively stable, with no more than a 5-U/d reduction in groups 1–6 (Table 2). Group 7 (2 mg/kg) showed a progressive decrease in insulin dosage during d 5, 6, and 7, but the change in the mean value for d 5–7 was not significantly different when compared with baseline (e.g. d –2 to 0).
When the mean baseline fasting glucose (d –2 to 0) was compared with the mean for d 5–8, there was a 21 ± 4% decrease (P < 0.05) in the placebo-treated subjects (Fig. 1). All of the treatment groups also had significant decreases in each of the study periods compared with baseline that ranged from 21 ± 4% to 40 ± 6%. When the change in each group was compared with the change in the subjects who received placebo, the decrease was significantly greater for d 2–4 in group 6 (1 mg/kg), and d 2–4 and d 5–8 in group 7 (2 mg/kg). This group had near normalization of mean fasting glucose with decreases to 106 ± 9 and 104 ± 8 mg/dl during the two study intervals. When mean daily glucoses (4 determinations/d) were compared, similar results were obtained. The placebo group decreased from a mean (d –2 to 0) of 232 ± 30 to 193 ± 27 mg/dl during d 5–7 (Fig. 2). Groups 2–5 had decreases that varied between 11% and 20% but were not significantly different than the placebo. Group 6 had a 26 ± 4% decrease during d 5–7, which was significantly greater than placebo (P < 0.05). Group 7 decreased 33 ± 5%, which was significantly greater than placebo (P < 0.02). Of note, this group had a further 4% decrease in mean daily glucose during d 5–7 compared with d 2–4, even though its total daily insulin dose was decreased on d 6 and 7. There was no relationship between total daily insulin dose at study entry and the fasting or mean daily glucose responses to rhIGF-I/IGFBP-3. Similarly, when the hemoglobin A1C values at study entry were compared with the fasting or mean daily glucose response to the treatment, there was not a significant correlation.
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FIG. 1. Change in fasting blood glucose. Fasting blood glucose was compared for the three treatment periods. The first treatment period encompasses d –1 and 0, the second period d 2–4, and the third period d 5–8. The results are expressed as the mean ± 1 SD. When the degree of reduction for subjects in each group was compared with the change in the placebo treatment group, the differences that were significant (P < 0.05) are denoted with an asterisk (*).
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FIG. 2. Change in mean daily glucose. The results for three treatment intervals are compared. The first interval encompasses d –1 and 0, the second interval d 2–4, and the third interval d 5–7. When the degree of reduction for each group is compared with the degree of reduction in group 1, the difference is significantly greater only for the treatment periods in groups 6 and 7 denoted with an asterisk (*) (P < 0.05).
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There were highly significant changes in the blood concentrations of analyses related to the IGF system. IGF-I concentrations increased in all groups, and the increase was proportionate to the total dose administered (Fig. 3). Total IGF-I peaked between d 3 and 5, and then declined slightly thereafter in most of the groups. All other groups showed significant increases that varied from 2.1- to 5.7-fold. There was no change in the placebo-treated group.
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FIG. 3. Change in IGF-I value. Daily IGF-I values (mean ± SD for each group) are shown. The mean daily values for all treatment groups except group 1 (placebo) are significantly (P < 0.05) increased for all days compared with baseline.
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The change in total IGF-I was accompanied by a proportionate reduction in IGF-II. Groups 2–7 had significant reductions in IGF-II, ranging from 26 ± 6% to 63 ± 8%, and the degree of change was proportionate to the degree of an increase in IGF-I (Fig. 4). During treatment there was no significant change in IGFBP-3 except in the highest dose group: 2.76 ± 0.45 to 4.04 ± 0.52 µg/ml (P < 0.05) (Fig. 5). When the ratio of IGF-I to IGFBP-3 was analyzed, the placebo group showed no change, but groups 2–7 had increases that varied between 1.6 and 4.9-fold (Fig. 6). The IGF-I to IGFBP-3 ratio in group 7 stabilized by d 4 at 1.1:1 and was maintained through d 8.
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FIG. 4. Change in IGF-II. The mean ± SD. IGF-II values for d 0, 1, 3, and 8 are shown. The degree of change in IGF-II is significant when the d-8 values are compared with the d-0 values for groups 2–7. The degree of decrease for groups 4–7 is significantly greater (P < 0.05) than for groups 2 and 3.
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FIG. 5. Change in IGFBP-3. The mean ± SD. IGFBP-3 values for each day are shown. The degree of change in IGFBP-3 is significantly increased only for group 7 on d 2–8 when compared with baseline (d 0).
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FIG. 6. Change in IGF-I to IGFBP-3 ratio. The mean daily values for the ratio of the IGF-I to IGFBP-3 are shown for all treatment groups. The degree of increase in the IGF-I to IGFBP-3 ratio is significant for treatment d 2–8 for all groups except group 1. The degree of change in the IGF-I to IGFBP-3 ratio was dose dependent because the values for groups 6 and 7 are significantly greater than those in groups 2–5.
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When the changes in IGF-I or IGF-II from the baseline period to the interval encompassing d 5–7 were compared with the changes in fasting glucose or mean daily glucose for these same intervals, there were significant correlations (Table 3). The best correlation was achieved when the change in IGF-I was compared with the change in glucose for groups 6 and 7. When the results from all treatment groups were analyzed, there was a modest but significant correlation.
When the ALS concentration that was measured at d 8 was compared with baseline, it did not change significantly in groups 1–4 (Table 4). However, groups 5–7 had significant decreases that varied from 19–24%. Because formation of the IGFBP-3/ALS complex is dependent upon the presence of either IGF-I or IGF-II, the change in the sum of the molar concentration of IGF-I and -II was analyzed. Groups 4 and 5 had minimal but significant increases in the sum of IGF-I and II between d 1 and 3, but these were not maintained at d 8. There was no significant change in the placebo group. When the d-8 values were compared with baseline (e.g. d 0 and 1), there were significant increases in the groups that received either 1 or 2 mg/kg (Table 5). Although this change was paralleled by an increase in IGFBP-3 in the 2-mg/kg group, the degree of increase in IGF-I + IGF-II (e.g. 80%) was greater than the increase in IGFBP-3 (e.g. 26%). Therefore, when the ratio of the IGF-I + IGF-II to IGFBP-3 was analyzed, the d-8 values were significantly increased in groups 6 and 7 (Table 6). This suggests that in these two groups, IGFBP-3 was saturated.
Triglycerides decreased in all treatment groups, but there was no effect of the drug compared with placebo on this parameter (Table 7). Cholesterol was significantly decreased in groups 1, 4, 5, 6, and 7 compared with baseline (P < 0.05). When the degree of change in the d-8 value was compared with the screening value, the degree of decrease was significantly greater in groups 6 and 7 compared with placebo. Fasting C-peptide decreased in treatment groups 1, 2, 4, 6, and 7 from baseline to d 8, but there was no significant difference in the degree of change in these groups compared with placebo.
Adverse events that are known to be related to IGF-I administration were minimal with the exception of hypoglycemia. Headache was present in two subjects in group 6, one subject in group 2, and one subject in group 4. Arthralgias occurred only in one subject in group 3. Paresthesias occurred in one subject in group 6 and one subject in group 7. Injection site erythema occurred in one subject in group 6. There was no significant change in heart rate. No subjects reported salivary gland pain or peripheral edema. There was a total of 31 treatment-emergent hypoglycemic events. Group 7 had the highest incidence of hypoglycemia (e.g. five of six subjects). There was a total of 12 hypoglycemic events in that group, but none was associated with any serious untoward complications.
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Discussion
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The results show that two highest dosages, i.e. 1.0 and 2.0 mg/kg of rhIGF-I/rhIGFBP-3, lowered fasting and mean daily blood glucose to a greater extent than increased insulin doses plus placebo. The magnitude of reduction in glucose with the 2-mg/kg dose was near the potential maximum because mean daily and fasting glucose were 122 and 104 mg/dl, respectively. The incidence of hypoglycemia in this group indicates that a further increase in dosage would have likely increased the frequency or severity of this problem. Therefore, this dose was associated with the best response, and a dose of 1 mg/kg was required to see a threshold effect.
Compared with the prior studies in which rhIGF-I or the rhIGF-I/rhIGFBP-3 complex has been administered to type 2 diabetics, there was a similar degree improvement in glycemic control (2, 3, 4, 12, 13, 19). A prior study using rhIGF-I/rhIGFBP-3 showed fasting glucose was decreased 34–38%, which is comparable to the responses in groups 6 and 7 (12). However, because this study included placebo-treated subjects who received more intensive insulin therapy, the difference between rhIGF-I/rhIGFBP-3 and placebo treatments can be more reliably predicted due to the effect of rhIGF-I/rhIGFBP-3. Exactly how this would compare with subjects who are self-administering these medications in a nonhospitalized setting remains to be determined. In a prior study, subjects who were taking insulin and were treated as outpatients with rhIGF-I alone had significant improvement in fasting and mean daily glucose, as well as hemoglobin A1C that was sustained for 12 wk (19). The data in this study and previous studies with the rhIGF-I/rhIGFBP-3 complex suggest that a similar degree of glycemic improvement can be achieved. Therefore, it appears that dosages in the 1.0 and 2.0 mg/kg range are likely to be effective in improving glucose over longer study periods.
The improvement in glucose metabolism was associated with a significant reduction in fasting triglycerides, but there was no difference between placebo and drug-treated subjects. In contrast, cholesterol was decreased to a greater extent in the subjects who received the 1.0 or 2.0 mg/kg dose, and this change is likely due to the drug. A decrease in cholesterol has been noted previously when IGF-I/IGFBP-3 was administered to type 1 diabetics (11).
Typical adverse events that have been noted after administration of rhIGF-I or rhIGF-I/rhIGFBP-3 include arthralgias, headaches, paresthesias, facial edema, peripheral edema, pseudotumor cerebri, and Bell’s palsy (2, 3, 4, 12, 13, 19). In this 1-wk study, they were either infrequent or not observed. Because only a small number of subjects developed any of these complications, it is not possible to determine if they were dose related. Headache was noted in four subjects, but its distribution among treatment groups did not show a relation to dose. The lower incidence of these side effects compared with prior studies in which IGF-I was administered alone could be due to administering the combination of rhIGF-I/rhIGFBP-3 or simply due to a short study duration, e.g. 7 d of treatment. The only clear-cut dose-related side effect was hypoglycemia, with five of six subjects who received the highest dose having at least one hypoglycemic reaction. Therefore, the administration of rhIGF-I/rhIGFBP-3 plus insulin will require careful titration of the insulin dosage after the maximum insulin sensitizing effect of this complex has been achieved.
In prior studies, one of the most consistent responses has been the ability of IGF-I or IGF-I/ IGFBP-3 to reduce fasting glucose (2, 5, 11, 12, 13). The molecular mechanism that accounts for this effect of IGF-I has not been determined. Prior studies suggest that IGF-I suppresses hepatic glucose output (13, 20, 21). However, because there are no IGF-I receptors in hepatocytes, it has been proposed that this effect is indirectly mediated through suppression of GH (7, 8, 14, 16), which acts directly on hepatocytes to antagonize the effects of insulin (22). A recent study in mice showed that IGF-I had its major effect by inhibiting renal gluconeogenesis (18). Because several recent reports have suggested that renal gluconeogenesis contributes significantly to overnight glucose production (23, 24) and because there are abundant IGF-I receptors in kidney (25), it is possible that IGF-I acts to lower fasting glucose by suppressing renal gluconeogenesis in humans. Therefore, because studies have also shown that IGF-I can enhance insulin action in muscle postprandially, it is likely that IGF-I is functioning by all three mechanisms to lower blood glucose.
The changes that occurred in the various proteins in the IGF-I axis are informative. There was a dose-dependent increase in the ratio of IGF-I to IGFBP-3 and a decrease in IGF-II. The decrease in IGF-II is most likely due to the replacement of endogenous IGF-II that is bound to IGFBP-3 by recombinant IGF-I. Whether this substitution is required to achieve improvement in glucose use is unclear. It is also possible that both IGF-I and IGF-II are acting to facilitate insulin action and that it is the sum of the actions of both proteins, not just IGF-I alone, that contributes to improvement in glucose metabolism (26).
When the ratio of the sum of IGF-I plus IGF-II to IGFBP-3 was analyzed, groups 4–7 had ratios that exceeded 1:1. Although free IGF-I was not measured in this study, it can be concluded from the prior study (in which there was an 8-fold increase) that there was a significant increase in free IGF-I when either the 1.0 or 2.0 mg/kg dose was given. Free IGF-I suppresses GH secretion (27). Because ALS synthesis is directly stimulated by GH, these higher free IGF-I concentrations would be predicted to suppress GH, leading to lower serum ALS (28). Saukkonen et al. (17) have published that the degree of GH suppression that can be achieved with the IGF-I/IGFBP-3 combination is dose dependent and that 0.8 mg/kg of complex resulted in significant GH suppression. Therefore, it is likely that our doses of 1 and 2 mg/kg resulted in a reduction in GH leading to decreased ALS.
The reduction in ALS places limits on the ability to increase IGFBP-3 concentrations that are needed to maintain high levels of IGF binding capacity. In a prior study in which IGF-I was administered at very high concentrations, e.g. 100 µg/kg·h by infusion, there was a significant reduction in IGFPB-3 and ALS (28). In this study, despite administering equimolar concentrations of IGFBP-3 with IGF-I, the maximal increase in IGFBP-3 that could be attained was 33%, whereas the sum of IGF-I and IGF-II increased 80% in these subjects. This suggests that the decrease in ALS limits the degree of increase in IGFBP-3. The degree of increase could also be limited by IGFBP-3 proteolysis, which is known to be increased in diabetic plasma (29). The net result of these changes would be that free IGF-I levels would increase relative to the increase in total IGF-I, thus limiting the ability of IGFBP-3 to control the rate of efflux of IGF-I from the circulation.
In summary, rhIGF-I/rhIGFBP-3 significantly lowered blood glucose in type 2 diabetics who were receiving intensive insulin treatment. The doses that were effective were those that resulted in a major increase in IGF-I and a major decrease in IGF-II. Suppression of ALS and increased IGFBP-3 proteolysis in diabetes place an upper limit on how much rhIGF-I/ rhIGFBP-3 can be safely administered. The findings show that when IGF-I is administered exogenously, the components of the 150-kDa complex undergo re-equilibration and that steady-state levels of total IGF-I are modulated by factors that influence the abundance of IGFBP-3, such as ALS, IGFBP-3 proteolysis, and GH. This re-equilibration places restrictions on the maximal levels of the ternary complex that can be achieved.
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Acknowledgments
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We thank Ms. Laura Lindsey for her help in preparing the manuscript.
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Footnotes
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Disclosure Information: M.S., G.A., and A.S. are employed by and have equity interest in Insmed, Inc. D.R.C. has equity interest in Insmed, Inc.
First Published Online April 10, 2007
Abbreviations: A1C, Glycosylated; ALS, acid labile subunit; IGFBP, IGF binding protein; rh, recombinant human.
Received December 6, 2006.
Accepted April 4, 2007.
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Abstract
Introduction
