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Original Studies |
Department of Medicine (D.R.C.), University of North Carolina, Chapel Hill, North Carolina 27599-7170; Celtrix Pharmaceuticals, Inc. (M.J.M., A.S., D.M.R.), San Jose, California; Northwest Kinetics (J.R.), Tacoma, Washington; and Joslin Diabetes Center and Beth Israel Deaconess Medical Center (A.C.M.), Boston, Massachusetts
Address correspondence and requests for reprints to: David R. Clemmons, M.D., Division of Endocrinology CB No. 7170, University of North Carolina, Chapel Hill, North Carolina 27599-7170. E-mail: endo{at}med unc.edu.
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Abstract |
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Twelve patients received recombinant human IGF-I plus IGFBP-3 (2 mg/kg·day) by continuous sc infusion for 2 weeks. Each subject served as his own control; and, during a paired 2-week period, each received a placebo infusion. The order of the treatments was randomized. Subjects were placed on a constant caloric intake but were allowed to adjust insulin doses to maintain appropriate levels of glycemic control. Subjects measured blood glucose four times per day at home and kept a log of their insulin use. Frequent sampling for glucose, insulin, and GH was conducted during four inpatient study periods, one at the beginning and one at the end of each 2-week study interval.
During IGF-I/IGFBP-3, insulin doses were reduced by 49%, and mean serum glucose was reduced by 23%. Free insulin levels obtained during frequent sampling in hospital fell 47% on IGF-I/IGFBP-3, compared with control, but showed no change with placebo. Concomitant glucose measurements did not differ in the two treatment groups. There was no change in body weight. Fructosamine levels decreased by 12%, but this was not significant (P < 0.1). Fasting triglyceride was unchanged, but cholesterol declined from 170 ± 24 to 149 ± 31 mg/dL (P < 0.05). IGFBP-2 (an IGF-I-dependent responsive variable) rose from 141 ± 56 to 251 ± 98 ng/mL (P < 0.01) on IGF-I/IGFBP-3. To analyze the mechanism by which IGF-I/IGFBP-3 might reduce insulin requirements, the change in serum GH was quantified. Mean GH levels were reduced by 72%, from 2.48 to 0.55 ng/mL (P < 0.001). An equal number (40%) of drug- and placebo-treated subjects had minor hypoglycemic episodes at home that required adjustment of insulin doses. No episode was classified as severe. In contrast to previous studies with free IGF-I, there were no cases of edema, headache, jaw pain, retinal edema, or Bell’s palsy. No subject withdrew because of drug complications. These findings indicate that IGF-I/IGFBP-3 is biologically active on carbohydrate metabolism, as measured by a decrease in insulin requirements in patients with type 1 diabetes. Further studies will be required to determine the long-term safety and efficacy of this combination in patients with insulin resistance and diabetes.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The molecular and physiological mechanisms by which IGF-I induces changes in carbohydrate metabolism and in insulin sensitivity have not been discerned. However, it has been shown that IGF-I infusions will acutely suppress glucagon and GH, two counter-regulatory hormones. Short-term infusion of IGF-I enhances lipid oxidation (16), and long-term administration results in reduction in body fat (11, 12), particularly intraabdominal fat. Each of these changes could contribute to the change in insulin sensitivity.
A major problem associated with administration of free IGF-I has been
the induction of side effects (17), particularly at doses 
80
µg/kg twice daily. Mild side effects, such as edema, jaw pain,
and headaches, occur in more than 80% of subjects, and serious side
effects, such as Bell’s palsy and retinal edema, in 10–15% of such
patients. Free IGF-I, administered sc, induces a 2.4-fold increase in
IGF binding protein (IGFBP)-2, suppresses IGFBP-3, and increases free
IGF-I levels (18, 19, 20). These changes that occur in the protein binding
of IGF-I in plasma are not physiologic and raise the question of
whether they may be related to the development of complications. In
contrast, when IGF-I was administered with IGFBP-3 to normal
volunteers at higher doses of IGF-I than were tolerated in previous
studies, side effects were not observed (21). Similarly, when the
combination of IGF-I/IGFBP-3 was administered to a group of 12 elderly,
osteoporotic women, status post hip fracture, for 2 months at a dose of
1 mg/kg·day, there were no side effects (22). These findings suggest
that IGFBP-3 is acting to limit the side effect profile, probably by
changing free IGF-I levels and the distribution of IGF-I among the
various binding proteins in serum. Although this regimen seems to limit
IGF-I-associated side effects, the question remains whether IGFBP-3
also will reduce the efficacy of IGF-I. Administration of IGF-I/IGFBP-3
to elderly, osteoporotic subjects with hip fractures improved bone
accretion (22). Similarly, infusion of the IGF-I/IGFBP-3 complex into
patients with severe burns stimulated protein synthesis (23). Infusion
of the IGF-I/IGFBP-3 complex into animals reveals that the anabolic and
osteotrophic effects of IGF-I can be retained, even if equimolar
concentrations of IGFBP-3 are infused simultaneously (24). Because the
presence of IGFBPs in plasma has been presumed to limit the
hypoglycemic response to IGF-I (25), the current studies were
undertaken to determine whether the known effects of IGF-I on
carbohydrate metabolism could be retained if it was administered with
IGFBP-3.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). Baseline IGF-I values ranged from
81–268 ng/mL, with a mean of 152 ng/mL. No subject had evidence of
significant diabetic retinopathy, as defined by the presence of
microaneurysms. All were screened for proteinuria, and all excreted
less than 50 µg/day protein. None had significant diabetic
neuropathy. Subjects with a history of any endocrinopathy or those who
were taking corticosteroids were excluded.
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During a 2-week lead-in phase, the subjects were evaluated thoroughly, by history and physical exam, to exclude other major medical problems. They were then placed on a constant food intake to match their home caloric intake. No attempt was made to improve dietary control, and the objective was to maintain a consistent caloric intake throughout the study. Subjects were also instructed in the use of a continuous sc infusion pump (CADD-1, Sims-Deltec, St. Paul, MN) and in obtaining glucoses 4 times per day by glucose reflective meter (Accu-check Advantage, Roche Molecular Biochemicals, Indianapolis, IN). The glucose values were down-loaded into a computerized recall system. Home blood glucose monitoring was timed to coincide with fasting in the morning, 30 min after lunch and dinner, and at bedtime. Meal times were standardized to occur at 0800, 1200, and 1800 h. No subject lost significant weight during this 2-week lead-in phase, and the degree of improvement in glucose control during this phase was modest (e.g. <5% reduction in mean daily glucose). All subjects provided written, informed consent, which was approved by the Institutional Review Board of each institution involved in the study.
Treatment phase
After the 2-week lead-in phase, subjects were randomized to one of two treatments, either IGF-I/IGFBP-3 at a dosage of 2 mg/kg·day (IGF-I and IGFBP-3 were prepared as a complex containing equimolar concentrations, i.e. 400 µg/kg of IGF-I and 1600 µg/kg IGFBP-3) or vehicle (saline) by continuous sc infusion. The order of treatment was randomized, and both the investigators and subjects were blinded as to what was being administered. The final analysis showed that seven subjects initially received placebo, and five received IGF-I/IGFBP-3. Subjects were hospitalized for 2 days before the start of the infusion. During this time, they received further instruction in diet and underwent frequent sampling (36 samples in 24 h) on day 2 for insulin and glucose. GH was measured every 30 min, from 2000 to 0800 h. At the beginning of day 3, the sc infusions were initiated; and, after 4 h, the subjects were discharged to home. Home glucose monitoring and insulin treatment continued during a 12-day outpatient treatment interval. During the home glucose monitoring interval, the subjects measured glucoses four times per day and maintained a log of insulin consumption. No attempt was made to alter the formulation of insulin that was being administered, and adjustments were made through daily phone contact to achieve reasonable glycemic control and to avoid hypoglycemia. At the completion of each treatment phase, the subjects were rehospitalized for 2 days and underwent the same testing protocol that was performed during the first 2 study days. They were discharged to a 2-week reequilibration period (wash-out) at home. During this time, the subjects were counseled by the dietitian and encouraged to continue the same dietary intake. They continued to monitor glucose levels and documented insulin consumption as before. After this 2-week interval, the subjects were rehospitalized and restudied in a manner identical to the first hospitalization. On the morning of the third hospital day, the subjects received a continuous, sc infusion of the paired treatment, with each subject serving as his or her own control. After the second 12-day outpatient study interval, the subjects were rehospitalized for 2 more days, during which time all of the previous measurements were repeated.
In addition to those measurements listed previously, each subject had a total serum cholesterol, fructosamine, body weight, triglycerides, and hemoglobin A1c at the beginning and end of each 2-week treatment interval. Safety studies were conducted with a complete serum chemistry analysis, including liver and renal function tests, as well as uric acid and serum phosphorous determinations. Laboratory measurements of glycosylated hemoglobin and fructosamine (normal range, 190–270 mmol/L) were determined using standard methods. Insulin and C peptide were determined, by double-antibody RIAs, by Quest Diagnostics, Inc., San Juan Capistrano, CA. Total serum IGF-I levels were determined by Quest Diagnostics, Inc., using the Nichols assay kit. IGFBP-2 values were determined by RIA, as previously described (25A ). GH values were determined by a sensitive immunochemiluminescence assay by Quest Diagnostics, Inc., with a detection limit of 20 pg/mL.
Statistics
All data are expressed as the mean ± SD. The significance of the effects of IGF-I/IGFBP-3 on the various outcome parameters was determined using the paired Student’s t test with a Bonferroni correction for multiple comparisons using SAS Institute, Inc. (Cary, NC). Significant changes were expressed as a value of P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). Analysis of the time of day of
glucose reduction revealed no reproducible pattern of the decrease. All
subjects reported some reduction in insulin dosage (range, 38–61%).
No subject reported significant reduction in food intake, and weights
were constant during this phase of the study. Frequent insulin and
glucose measurements that were obtained during the inpatient study
intervals confirmed these findings. Measurement of free insulin
confirmed reduced insulin dosage, because after 2 weeks of treatment,
mean serum free insulin decreased from 37.5 ± 16.9 to 20.1
± 9.0 µU/mL (47% decrease, P < 0.01), whereas mean
blood glucose did not change [216 ± 88 to 204 ± 76
(P, not significant, N.S.)] (Figs. 2 and 3).
In contrast, after placebo treatment, the mean free insulin
concentrations were unchanged at 40.1 ± 14.0, compared with
38.2 ± 14.1 µU/mL, after 2 weeks (P, N.S.), and mean
glucose values were 202 ± 61 before and 207 ± 81 mg/dL
during treatment (P, N.S.).
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). In addition, the frequency of GH
peaks greater than 3 ng/mL was reduced from a mean of 4.2 to 1.7 in the
IGF-I/IGFBP-3 treatment group. These findings indicate that sufficient
IGF-I was available to significantly suppress endogenous GH secretion.
Total IGF-I values rose from a mean of 167 ± 65 to 625 ±
186 ng/mL after 1 week and declined to 493 ± 143 ng/mL
(P < 0.001) after 2 weeks of IGF-I/IGFBP-3. There was
no change in total IGF-I levels during the placebo phase (Fig. 5). Neither hemoglobin
A1c nor fructosamine changed significantly during
either treatment; however, fructosamine values trended downward even
after only 2 weeks (Table 2). Analysis of
total triglycerides and cholesterol revealed a significant reduction in
total cholesterol, from 170 ± 24 to 149 ± 31 mg/dL
(P < 0.05), during IGF-I/IGFBP-3 administration. In
contrast, tri-glycerides, which have been reported to decrease 40%
when IGF-I alone is given to subjects with type 2 diabetes, were not
reduced significantly. Because IGFBP-2 has been shown to be very
responsive to IGF-I, we determined the IGFBP-2 response to
IGF-I/IGFBP-3. After 2 weeks of IGF-I/IGFBP-3, the mean IGFBP-2 rose
from 141 ± 56 to 251 ± 98 ng/mL (P <
0.01), whereas it remained unchanged on placebo [148 ± 50,
compared with 143 ± 46 ng/mL (P, N.S.)] (Fig. 6).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Administration of IGF-I alone has been shown to result in improved glycemic control and a 3.4-fold improvement in insulin sensitivity in patients with type 2 diabetes (6). A larger study (i.e. 204 patients), in which IGF-I was used as monotherapy (40 µg/kg BID), showed a 1.7% reduction in hemoglobin A1c compared with placebo (11). This degree of improvement also was demonstrated in a study in which IGF-I was administered with insulin to subjects with type 2 diabetes. Quattrin et al. were able to demonstrate a 28% reduction in insulin dosage with no significant deterioration in glycemic control during a 4-week trial in patients with type 1 diabetes using 80 µg/kg·day of free IGF-I (13). Because our study also showed a significant reduction in total daily insulin dose and mean glucose, this suggests that the administration of this binding protein with IGF-I did not result in a loss of efficacy.
Previous studies using the combination of IGF-I/IGFBP-3 have shown that it preserves muscle protein and bone mineral content in oophorectomized rats (24). Osteoporotic females with hip fractures have responded with a 1.5% decrease in bone mineral density, as compared with an 6.3% loss in age-matched hip fracture subjects who received placebo (22). Similarly, catabolic patients with severe burns responded to the IGF-I/IGFBP-3 complex with a significant improvement in net protein balance (23). These results suggest that the combination of IGF-I/IGFBP-3 does not attenuate the anabolic effects of IGF-I if the two are administered in equimolar concentrations. Taken together, these findings suggest that when IGF-I is administered with IGFBP-3, the material that is bound to the ternary complex in blood equilibrates with other binding proteins within the vascular space and with extravascular tissues so that IGF-I receptors are exposed to a greater concentration of IGF-I over an extended period of time (26). The exact mechanism by which this occurs is undefined, but the biologic activity of IGF-I clearly can be preserved. That this maintenance of a strong anabolic effect is caused by a change in the distribution and clearance of IGF-I and not by direct additive effects of IGFBP-3 acting at the cellular level is suggested by the observation that infusion of an anti-IGF-I antibody with IGF-I to experimental animals results in potentiation of IGF-I’s anabolic effects (27).
Although the growth-promoting effects of IGF-I might have been predicted to be preserved based on these animal studies, IGFBP-3 has been proposed previously to be an inhibitor of the glucose-lowering actions of IGF-I. Indeed, some in vitro studies have shown that IGFBP-3 will inhibit IGF-I-stimulated glucose transport (28). However, in contrast to IGFBP-1, no in vivo study has shown an attenuation of glucose tolerance to occur after IGFBP-3 infusion or overexpression (29, 30).
The mechanism(s) by which IGF-I induces its effects on carbohydrate metabolism is unknown. Previous studies with IGF-I in type 2 diabetics have shown that it lowers triglycerides by as much as 40% in patients with diabetes (5). In one study, IGF-I infusion decreased free fatty acid (FFA) levels, suggesting that the reduction in triglycerides and FFA might enhance insulin sensitivity by facilitating glucose use and decreasing the competitive effect of FFA on the cellular uptake of glucose (31). However, in the current study in type 1 diabetics, there was no change in the triglycerides when IGFBP-3 was administered with IGF-I, suggesting that changes in triglyceride metabolism were probably not responsible for the short-term changes that were observed.
IGF-I administration to normal humans and to diabetic animals has been associated with glucagon suppression, which could alter insulin sensitivity (32, 33). Similarly, IGF-I administration to type 1 diabetics has been shown to suppress GH secretion (33, 34), and several studies have hypothesized that suppression of GH significantly improves insulin sensitivity (12, 13, 14, 15, 33, 34, 35). In keeping with that finding, in this study, we found a 77% reduction in overnight GH secretion, suggesting that eliminating the counterregulatory effect of GH on gluconeogenesis and hepatic glucose output may have been an important determinant of the change in insulin requirements. GH also may act to directly antagonize insulin action in the liver; thus, IGF-I/IGFBP-3 administration, by lowering GH levels (which are elevated in some patients with type 1 diabetes), restores more normal physiology.
Because this was a short-term study and there was no reduction in body weight, this suggests that body fat did not change significantly during the 2-week period. Therefore, it is unlikely that changes in visceral fat contributed to the change in insulin sensitivity. Another possible mechanism by which an IGF-I could induce changes in insulin requirements is through insulin/IGF-I hybrid receptors, which have been shown to be increased in skeletal muscle in type 2 diabetics (36). The peak total IGF-I levels achieved in this study (e.g. 540 ng/mL) remain primarily protein bound; and therefore, it is difficult to extrapolate that high-enough free IGF-I levels were achieved to directly stimulate the insulin receptor. However, the IGF-I/insulin receptor signaling pathways use many of the same components. It is also possible that alteration in stimulation of IGF-I signaling results in downstream enhancement of insulin receptor-mediated signaling, particularly in skeletal muscle, where IGF-I receptors are abundant.
A major concern in previous studies with IGF-I has been toxicity. Those
studies have demonstrated that severe edema, arthralgias,
temporomandibular joint pain, and headaches are extremely common
(i.e. 25–80%) in patients receiving 40 µg/kg sc
BID of free IGF-I (11, 12, 17). Other more unusual (but nevertheless
severe) side effects include Bell’s palsy and optic nerve edema
(4–8% of patients). None of these side effects were noted in this
study, in spite of the fact that total IGF-I levels were comparable
with peak levels that have induced side effects in previous studies (6, 15). This suggests that, in the short-term studies, IGF-I/IGFBP-3 is
safe. Longer studies must be undertaken in order to determine whether
patients remain free of these side effects for periods of 2 months, as
they did when IGF-I/IGFBP-3 was administered to elderly female subjects
with osteoporosis. Similarly, longer studies will be required to
conclude that there is no progression of diabetic retinopathy.
The findings also suggest that side effects induced by IGF-I are not a continuum of biologic response. In this study, we noted a significant biologic response, but no significant side effects were present. This strongly suggests that the side effect profile noted previously with free IGF-I administration probably is attributable to transient increases in free IGF-I that are much greater than those that occur when it is administered by continuous sc infusion with IGFBP-3, wherein both proteins form a stable ternary complex with the acid labile subunit. The pharmacodynamics of IGF-I when administered with IGFBP-3 were not analyzed. However, we did note a 1.8-fold increase in IGFBP-2 that was substantially less than the 3.2-fold increase noted previously with administration of free IGF-I (6). This suggests that relatively more IGF-I would be bound to IGFBP-3 and less to IGFBP-2 in our patients, compared with patients receiving free IGF-I. Because IGFBP-2 does not form the ternary complex and crosses the intact capillary barrier, this suggests that, in patients who are receiving free IGF-I, more of the peptide may enter the extravascular compartment in the period of time immediately after IGF-I administration. Therefore, improvement in the side effect profile may be closely related to a reduction in the rate at which IGF-I enters the extravascular compartment. It will be interesting, in future studies, to determine whether side effects are more closely related to the temporal pattern of changes in free IGF-I, a time-dependent change in the rate of equilibration with the extracellular space, or to changes in the type of binding protein that binds to IGF-I. Direct measurements of these pharmacokinetic parameters need to be undertaken to determine which of these parameters bear the closest relationship to side-effect development.
In summary, the results of this study show clearly that IGF-I can be administered with IGFBP-3 and retain biological activity for carbohydrate metabolism, as reflected by a decrease in requirements for exogenous insulin. The combination was safe for 14 days, and many of the short-term side effects that have been noted with free IGF-I did not occur. This suggests that longer-term studies can be safely undertaken to determine the efficacy of IGF-I/IGFBP-3 in improving glycemic control in diabetes and to determine the mechanism by which IGF-I enhances insulin sensitivity in these patients.
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Acknowledgments |
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Footnotes |
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Received October 26, 1999.
Revised December 17, 1999.
Accepted December 31, 1999.
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References |
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B. Andersson, G. Johannsson, G. Holm, B.-A. Bengtsson, A. Sashegyi, I. Pavo, T. Mason, and P. W. Anderson Raloxifene Does Not Affect Insulin Sensitivity or Glycemic Control in Postmenopausal Women with Type 2 Diabetes Mellitus: A Randomized Clinical Trial J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 122 - 128. [Abstract] [Full Text] [PDF]
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K. L. Knudtson, M. Boes, A. Sandra, B. L. Dake, B. A. Booth, and R. S. Bar Distribution of Chimeric IGF Binding Protein (IGFBP)-3 and IGFBP-4 in the Rat Heart: Importance of C-Terminal Basic Region Endocrinology, September 1, 2001; 142(9): 3749 - 3755. [Abstract] [Full Text] [PDF]
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K. Sjogren, K. Wallenius, J.-L. Liu, M. Bohlooly-Y, G. Pacini, L. Svensson, J. Tornell, O. G.P. Isaksson, B. Ahren, J.-O. Jansson, et al. Liver-Derived IGF-I is of Importance for Normal Carbohydrate and Lipid Metabolism Diabetes, July 1, 2001; 50(7): 1539 - 1545. [Abstract] [Full Text] [PDF]
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 V. ROELFSEMA and R. G. CLARK The Growth Hormone and Insulin-Like Growth Factor Axis: Its Manipulation for the Benefit of Growth Disorders in Renal Failure J. Am. Soc. Nephrol., June 1, 2001; 12(6): 1297 - 1306. [Abstract] [Full Text]
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S. Yakar, J.-L. Liu, A. M. Fernandez, Y. Wu, A. V. Schally, J. Frystyk, S. D. Chernausek, W. Mejia, and D. Le Roith Liver-Specific igf-1 Gene Deletion Leads to Muscle Insulin Insensitivity Diabetes, May 1, 2001; 50(5): 1110 - 1118. [Abstract] [Full Text]
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