| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Paediatrics (T.S., R.A., R.M.W., K.C.Y., M.A.W., C.L.A., D.B.D.), University of Cambridge, Cambridge CB2 2QQ, United Kingdom; Diabetes Centre (C.F.), Northampton General Hospital National Health Service Trust, Northampton NN1 5BD, United Kingdom; and Department of Diabetes and Endocrinology (A.M.U.), Guy’s, King’s and Thomas’ School of Medicine, London SE1 7EH, United Kingdom
Address all correspondence and requests for reprints to: David B. Dunger, Department of Paediatrics, University of Cambridge, Box 116, Level 8, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom. E-mail: dbd25{at}cam.ac.uk.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
IGF-I has direct, insulin-like effects on hepatic glucose output and peripheral glucose uptake in subjects with type 1 diabetes (7). Restoration of circulating IGF-I levels to within the normal range by replacement therapy using recombinant human (rh)IGF-I might therefore be expected to improve insulin sensitivity and glycemic control in type 1 diabetes. Indeed, in randomized placebo-controlled studies, we showed significant reductions in short-term insulin requirements (8) and in glycosylated hemoglobin (HbA1c) in young subjects with type 1 diabetes receiving rhIGF-I (40 µg/kg·d sc for 6 months) (9). Similarly, a significant decrease in HbA1c and daily insulin dose was demonstrated in a multicenter trial of rhIGF-I at doses of 80, 120, or 140 µg/kg·d for 12 wk (10). Importantly, however, these higher IGF-I doses in the latter study (120 and 140 µg/kg·d) were associated with a dose-dependent increase in side effects, including edema, jaw pain, arthralgia, and early worsening of retinopathy.
The combination of rhIGF-I with rhIGFBP-3 (its natural carrier protein), in equimolar ratio to form a complex, may have therapeutic advantages whereby the delivery and efficacy of rhIGF-I can be achieved without the associated risks of toxicity. Preliminary data lends support to this hypothesis, in that therapy with rhIGF-I/IGFBP-3 complex was better tolerated, with few side effects, yet led to reduced insulin requirements and improved glycemic control in adult subjects with type 1 diabetes treated for 2 wk (11). However, in these studies, a very high dose of rhIGF-I/IGFBP-3 complex was used (2.0 mg/kg·d, equivalent to IGF-I 0.4 mg/kg·d). The present study was designed to find out whether lower doses of IGF-I/IGFBP-3 complex could achieve GH suppression and improve insulin sensitivity in adolescent and young adult patients with type 1 diabetes.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Inclusion criteria were: type 1 diabetes of at least 2 yr duration or C-peptide negative; age between 13–25 yr; puberty (Tanner) at least stage II; treatment with at least two insulin injections per day; and normal renal and liver function. Exclusion criteria were: obesity [i.e. body mass index (BMI) > 30 kg/m2]; untreated hypothyroidism; chronic illness; pregnancy; malignancy; or recurrent episodes of severe unexplained hypoglycemia.
Power calculations based on data from previous hyperinsulinemic clamp studies in subjects with type 1 diabetes (12) showed that a sample size of 16 subjects would allow us to detect a 20% difference in insulin sensitivity at a significance level of 95% and with 80% power. Forty-five consecutive subjects who fulfilled the criteria were approached at diabetes clinics at Addenbrooke’s Hospital and Northampton General Hospital. In total, 18 adolescents and young adults with type 1 diabetes participated in the study. Two subjects withdrew after the first overnight study visit because of inability to adhere to the protocol schedule. Data from one additional subject was omitted from analysis because euglycemia as defined in the study criteria was not achieved during the overnight study periods.
The study was approved by the Cambridge and Northampton Local Research Ethics Committees, and written informed consent was obtained from all subjects and/or from their parents. All overnight studies were performed in Cambridge in the Addenbrooke’s Clinical Research Centre, Wellcome Trust Clinical Research Facility.
Study design
A randomized double-blind crossover study: subjects being randomly allocated to receive placebo or one of two study regimens (groups A and B).
There were no differences in demographic characteristics between groups A and B, and the mean baseline serum IGF-I levels were similar (Table 1
). Treatment regimens were as follows. Group A (n = 7) comprised: 1) rhIGF-I/IGFBP-3 complex (SomatoKine; Insmed Inc., Richmond, VA), 0.1 mg/kg (equivalent of rhIGF-I, 0.02 mg/kg); 2) rhIGF-I/IGFBP-3 complex, 0.4 mg/kg (rhIGF-I, 0.08 mg/kg); and 3) placebo, in random order. Group B (n = 8) comprised: 1) rhIGF-I/IGFBP-3 complex, 0.2 mg/kg (rhIGF-I, 0.04 mg/kg); 2) rhIGF-I/IGFBP-3 complex, 0.8 mg/kg (rhIGF-I, 0.16 mg/kg); and 3) placebo, in random order. In each patient in each group, the study medications were administered for 2 d on three occasions as outlined in Fig. 1. IGF-I and IGFBP-3 levels were assessed before and 24 h after the first injection of rhIGF-I/IGFBP-3, but the major assessment was undertaken immediately after the second injection at 1800 h on d 2.
|
|
Long- and intermediate-acting insulin was withdrawn and substituted with regular soluble insulin injections. The study medications were given as sc injections into the anterior aspect of the left thigh at 1800 h on d 1 and d 2. After the second injection, the subjects were admitted until 1400 h the next day. An iv insulin infusion was administered overnight (1800–0800 h) to achieve euglycemia. Glucose levels were maintained around 90 mg/dl (5 mmol/liter) throughout the night by adjusting the iv insulin infusion, based on 15 min blood glucose level measurements. The overnight steady-state period was defined as the period (0400–0800 h) during which blood glucose levels did not differ significantly from 90 mg/dl (5 mmol/liter) and during which there was no difference in blood glucose levels among the three study nights. Insulin sensitivity was assessed as insulin requirement for euglycemia during the steady-state period. A 4-h, two-step hyperinsulinemic euglycemic clamp was subsequently performed from 0800–1200 h. Between 0800–1000 h, a low-dose insulin infusion (insulin bolus, 2.8 mU/kg; infusion, 0.6 mU/kg·min) was given and euglycemia maintained by an infusion of 20% dextrose. Between 1000–1200 h, the insulin infusion rate was increased (insulin bolus, 7.0 mU/kg; infusion, 1.5 mU/kg·min) and the infusion of 20% glucose increased as necessary to maintain euglycemia. Blood glucose measurements were performed every 5 min.
Auxology
Height and weight were measured while the subjects stood in light clothing. Body fat mass and percentage of body fat were estimated using a bioelectrical impedance monitor (Biostat 1500, Isle of Man, UK).
Biochemical analyses
Blood glucose concentrations were measured using 25-µl whole-blood samples on a Y.S.I. model 2300 stat plus analyzer (YSI, Lynchford House, Farnborough, Hampshire, UK). The intraassay coefficient of variation (CV) at 74 mg/dl (4.1 mmol/liter) was 1.5%. The equivalent interassay CV at this glucose concentration was 2.8%, and was 1.7% at 254 mg/dl (14.1 mmol/liter). Plasma insulin concentrations were measured using an ELISA (Dako Ltd., Denmark House, Angel Drove, Ely, Cambridgeshire, UK) according to the manufacturer’s instructions. Intraassay imprecision (CV) was 4.3% at 14 mU/liter (82 pmol/liter), 3.0% at 67 mU/liter (402 pmol/liter), and 5.7% at 151 mU/liter (907 pmol/liter). Equivalent interassay imprecision was 4.3, 5.1, and 5.4%, respectively. GH concentrations were measured using an ELISA (DSL/Oxford Bio-Innovations, Upper Heyford, Oxon UK) according to the manufacturer’s instructions. The assay was calibrated to the WHO First International Standard (80/505). Intraassay imprecision (CV) was 9.7% at 0.7 ng/ml and 6.5% at 6.4 ng/ml. Equivalent interassay imprecision was 10.4 and 5.5%, respectively. Plasma IGF-I concentrations were measured in ethanolic extracts using an ELISA (DSL/Oxford Bio-Innovations) according to the manufacturer’s instructions. The sensitivity of this assay was 0.03 ng/ml. Interassay imprecision (CV) was 8.8% at 107 ng/ml and 9.4% at 262 ng/ml. Equivalent intraassay imprecision was 6.1 and 8.0%, respectively. Intraassay imprecision, including extraction, was 6.0% at 202 ng/ml. Plasma IGFBP-1 and IGFBP-3 levels were measured using an ELISA (DSL/Oxford Bio-Innovations) according to the manufacturer’s instructions. The sensitivity of IGFBP-1 assay was 0.25 ng/ml. Intraassay imprecision (CV) was 6.1% at 7.0 ng/ml and 5.3% at 48.4 ng/ml. Equivalent interassay imprecision was10.4 and 5.1%, respectively. The sensitivity of IGFBP-3 assay was 0.04 ng/ml. Intraassay imprecision (CV) was 4.9% at 5.2 ng/ml and 2.8% at 34.7 ng/ml. Equivalent interassay imprecision was 9.7 and 7.2%, respectively.
Calculations
BMI was defined as total body weight (kilograms) divided by square height (centimeters). Fat-free mass was calculated as total body mass subtracted by the amount of fat mass as determined by bioimpedance. A pulse detection program, Pulsar, was used to analyze 12-h (2000–0800 h) GH profiles. The program detects hormone pulses as deviations based on both height and duration from a smoothed detrended baseline, using the assay SD as a scale factor, and calculates mean GH level, basal GH level, peak amplitude (mean amplitude of all the discrete peaks) and frequency of peaks for each study period (13). Overnight steady-state insulin requirement for euglycemia was defined as mean insulin infusion rate (mU/kg fat-free body mass·min) during the steady-state period (0400–0800 h). M-values (defining insulin sensitivity) were calculated as mean glucose infusion rates (mg/kg fat-free body mass·min) during the steady-state periods of the hyperinsulinemic euglycemic clamp (step 1: 90–120 min; step 2: 210–240 min).
Statistical methods
All statistical analyses were performed on paired data, with the placebo period serving as the control for each subject. The between-dose effects were studied using analysis of covariance controlling for repeated assessments on the same individual. Post hoc analysis was made by paired t tests with Bonferroni correction for multiple comparisons. Distributions of the data were examined for normality by the Kolmogorov-Smirnov goodness-of-fit test. Logarithmic transformation was used when analyzing means of the variables that were not normally distributed (IGF-I, IGFBP-1, and free insulin levels). To explore the effect of the order of treatments on the results, we compared the effects of placebo according to whether the subject received placebo injections on his/her first (n = 5), second (n = 5), or third (n = 5) visit. We found similar mean overnight steady-state IGF-I, IGFBP-3, IGFBP-1, and free insulin levels, insulin requirements for euglycemia, as well as M-values in all groups (data not shown). All statistical analyses were performed using SPSS for Windows (version 11.0, SPSS Inc., Chicago, IL).
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
After the administration of rhIGF-I/IGFBP-3, mean serum levels of IGF-I increased significantly, with a dose-response effect (Fig. 2A). Overnight mean serum levels (±SEM) of IGF-I were 249 ± 48, 242 ± 57, 371 ± 55, and 460 ± 49 ng/ml on rhIGF-I/IGFBP-3 (0.1, 0.2, 0.4, and 0.8 mg/kg·d, respectively) vs. 150 ± 23 ng/ml on placebo (P < 0.001). Mean serum levels of IGFBP-3 were also increased (Fig. 2B). Overnight mean serum levels (±SEM) of IGFBP-3 were 4.45 ± 0.16, 4.45 ± 0.24, 4.91 ± 0.22, and 5.34 ± 0.30 µg/ml on rhIGF-I/IGFBP-3 (0.1, 0.2, 0.4, and 0.8 mg/kg·d, respectively) vs. 4.05 ± 0.17 µg/ml on placebo (P < 0.001).
|
Administration of rhIGF-I/IGFBP-3 was followed by dose-dependent reductions, ranging from 3–61% compared with placebo, in overnight (2000–0800 h) mean GH levels (P < 0.001) (Fig. 3). Pulsar analysis demonstrated reductions in both mean GH peak amplitude (P = 0.003) and mean calculated baseline GH concentration (P = 0.005) (Table 2). No significant changes were found in GH pulse frequencies (data not shown).
|
|
During the overnight euglycemic steady-state period, mean blood glucose levels were similar after the administration of rhIGF-I/IGFBP-3 and placebo (Table 3). The rate of insulin infusion required for maintenance of euglycemia during this period was significantly and dose-dependently reduced after rhIGF-I/IGFBP-3 (P < 0.001) (Fig. 4 and Table 3). Accordingly, serum free insulin levels during the overnight steady-state period tended to be lower after rhIGF-I/IGFBP-3 (Table 3), although the difference was not statistically significant (P = 0.1). Steady-state mean serum IGFBP-1 levels were increased after rhIGF-I/IGFBP-3 (P < 0.001) (Table 3).
|
|
Insulin sensitivity
During hyperinsulinemic euglycemic clamp studies, mean blood glucose levels and plasma free insulin concentrations during the steady-state periods were similar after administration of rhIGF-I/IGFBP-3 and placebo (Table 4). rhIGF-I/IGFBP-3 was associated with increased insulin sensitivity as defined by M-values (step 1, P = 0.006; step 2, P = 0.04) (Fig. 5); however, in post hoc analysis for step 1, only rhIGF-I/IGFBP-3 (0.8 mg/kg·d) was significantly different from placebo (P = 0.005); and for step 2, only rhIGF-I/IGFBP-3 (0.4 mg/kg·d) was significantly different from placebo (P = 0.04) (Fig. 5).
|
|
Sex differences
There were no differences between sexes in baseline characteristics and in the effect of rhIGF-I/IGFBP-3 on endpoint parameters (data not shown).
Adverse events
The study medication was well tolerated. Three patients reported a total of four episodes of mild to moderate headache, lasting from 3–12 h. One episode followed injection of placebo, one episode was reported during rhIGF-I/IGFBP-3 (0.2 mg/kg·d), and two episodes during rhIGF-I/IGFBP-3 (0.4 mg/kg·d), respectively. One episode of injection site redness, swelling, and pain was noticed after rhIGF-I/IGFBP-3 (0.8 mg/kg·d).
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Low circulating levels of IGF-I have consistently been reported in adolescents with type 1 diabetes (14, 15). Accordingly, baseline serum IGF-I levels in our subjects were low, with mean levels in both groups falling below –2 SD for this age group (16, 17). Serum IGF-I level peaks at 8 h after a sc injection of rhIGF-I/IGFBP-3 complex (Insmed Inc., unpublished data); and in circulation, it forms a ternary complex with acid labile subunit. The half-life of the ternary complex is approximately 15 h (18). In our subjects, mean serum IGF-I levels, 24 h after the first injection, were twice as high as the baseline levels, and the second injection resulted in a further 20% increase in mean serum IGF-I levels during the overnight steady-state (0400–0800 h). The overall magnitude of increase of serum IGF-I after rhIGF-I/BP-3 is comparable with that noticed after rhIGF-I alone. Cheetham et al. (8) reported increases of mean serum IGF-I levels in adolescents with type 1 diabetes of 74% during the 18 h after rhIGF-I (40 µg/kg sc) compared with placebo; this corresponds to an increase from 137 to 242 ng/ml (77%) after an equivalent dose of rhIGF-I/IGFBP-3 (0.2 mg/kg) in our subjects. The overnight serum IGF-I levels after the highest dose of rhIGF-I/IGFBP-3 (0.8 mg/kg·d) were increased 3-fold compared with baseline levels; however, even these levels are lower than +2 SD for healthy nondiabetic subjects of a similar age (16, 17).
IGF-I has insulin-independent stimulatory effects on glucose metabolism that are predominantly mediated through type 1 IGF receptor (19). Interestingly, IGF-I increases glucose disposal; yet in normal subjects, it also directly suppresses insulin secretion (20). Enhanced insulin sensitivity after administration of rhIGF-I has been demonstrated in both nondiabetic subjects (21) and those with type 1 diabetes (22).
Multiple regression analysis of our data demonstrates that those subjects with the lowest baseline IGF-I levels had the greatest reductions in insulin requirements, suggesting that the effects of rhIGF-I/IGFBP-3 complex on insulin sensitivity were associated with recovery of physiological levels of circulating IGF-I rather than with exposure of tissues to excessive amounts of bioactive IGF-I. However, changes in GH levels may also be important.
We also found significant reductions in both overnight baseline GH concentrations and GH pulse amplitudes after rhIGF-I/IGFBP-3 complex treatment, as a result of normalization of circulating IGF-I levels and reduction of negative feedback drive on pituitary GH hypersecretion. Overnight serum GH secretion in adolescence is strongly dependent on the stage of puberty, with the highest values of both baseline concentrations and peak amplitudes occurring at puberty stages 2–3 in girls and at stages 4–5 in boys. In adolescents with type 1 diabetes, both overnight baseline GH levels and GH pulse amplitudes are increased compared with nondiabetic subjects at the same pubertal stage (3). Normative data for characteristics of GH secretion from large population-based studies in the age range that we studied (13–25 yr) do not exist. The majority of our subjects were young adults, and the mean overnight GH levels after the highest doses of rhIGF-I/IGFBP-3 were similar to those reported for nondiabetic subjects of this age (3).
Augmented circulating IGF-I levels and reduced GH secretion after rhIGF-I/IGFBP-3 were associated with reductions in overnight insulin requirements for euglycemia. A large amount of data has been accumulated on the deleterious effects of GH on glucose metabolism and insulin action. In nondiabetic subjects, physiological levels of endogenously secreted GH antagonize the action of insulin both in hepatic and peripheral tissues, and excess GH secretion leads to impaired glucose tolerance and insulin resistance, demonstrated by impaired suppression of hepatic glucose production and decreased glucose uptake in peripheral tissue (23). These effects of GH on glucose metabolism are either direct or mediated by promotion of lipolysis and increase in circulating free fatty acids (24). The increase in early morning insulin requirements correlates with increased GH pulsatility (25). Accordingly, GH hypersecretion has been implicated as the cause of dawn phenomenon (26) as well as of the overall poor metabolic control in type 1 diabetes (27). Thus, it might be anticipated that suppression of GH secretion using rhIGF-I improves glucose metabolism in type 1 diabetes. Indeed, in subjects with type 1 diabetes, administration of either rhIGF-I (12, 28, 29); a long-acting somatostatin analog, octreotide (30); or a anticholinergic agent, pirenzepine (31) result in suppression of overnight GH secretion with parallel reductions in insulin requirements. Therefore, the effects of rhIGF-I/IGFBP-3 on insulin requirements are likely to be partially explained by suppression of GH hypersecretion. Administration of a specific GH antagonist, B2036-PEG (pegvisomant), results in reduced overnight insulin requirements in young adults with type 1 diabetes, although insulin sensitivity was not improved (32). GH antagonists suppress serum IGF-I levels; therefore, long-term treatment in adolescence might lead to reduction in statural growth. However, GH antagonists could be a therapeutic option in adult subjects with type 1 diabetes.
However, GH-independent effects of IGF-I and IGFBP-3 on insulin sensitivity cannot be ruled out. Crowne et al. (33) showed reductions in overnight insulin requirements in type 1 diabetes after rhIGF-I vs. placebo, despite identical GH profiles achieved by administration of somatostatin and exogenous GH pulses. Furthermore, O’Connell and Clemmons (34) demonstrated improvement in insulin sensitivity in patients with acromegaly receiving GH antagonist plus rhIGF-I/IGFBP-3 compared with GH antagonist alone (34). Direct, insulin-like effects of IGF-I on hepatic glucose output and glucose uptake in skeletal muscle (7) might be mediated through activation of hybrid insulin/IGF-I receptors that have high affinity for IGF-I (35).
Despite large reductions in insulin requirements, we observed only a nonsignificant tendency toward lower circulating insulin concentrations. This may be explained by decreased metabolic clearance of insulin. In young subjects with type 1 diabetes, insulin clearance is directly correlated with overnight GH concentrations (36) but is also altered after rhIGF-I administration (C.L.A., unpublished observations).
Dose-response characteristics of the effect of rhIGF-I/IGFBP-3 on insulin sensitivity, measured during hyperinsulinemic clamp conditions, differed somewhat from those of the overnight studies, in that no effect on M-values was noticed after the lower doses of rhIGF-I/IGFBP-3 (0.1 or 0.2 mg/kg); whereas the higher doses (0.4 or 0.8 mg/kg) resulted in mean increases in M-values of 63 and 19% in steps 1 and 2 of the clamp, respectively. This is in accordance with an earlier study, where rhIGF-I at the dose of 0.04 mg/kg (equivalent to rhIGF-I/IGFBP-3, 0.2 mg/kg) did not improve peripheral glucose disposal, yet insulin requirements were reduced (12). This may be related to the level of overnight GH suppression achieved. We found strong inverse correlations between M-values and overnight GH peak amplitudes in our subjects. The lower doses of rhIGF-I/IGFBP-3 failed to suppress overnight GH peak amplitudes, which might explain why they did not improve insulin sensitivity even though overnight IGF-I levels were increased.
In contrast to sustained increases of circulating IGF-I after rhIGF-I/IGFBP-3 complex, we found only modest elevations in overnight serum IGFBP-3 levels, despite equimolar ratio of rhIGF-I and rhIGFBP-3 in the injections. There may be several explanations for this finding. First, rhIGFBP-3 is a large molecule (molecular mass, 28.7 kDa), and it is possible that, after an injection, a fraction of rhIGFBP-3 was retained in sc tissue and only slowly absorbed to circulation. Second, proteolysis of IGFBP-3 may have been enhanced, resulting in IGFBP-3 fragments that were not detected by our assay method. IGFBP-3 proteolysis has been reported to be increased in children with newly diagnosed type 1 diabetes (37). Our preliminary analysis demonstrates dose-dependent enhancement of IGFBP-3 proteolysis after administration of IGF-I/IGFBP-3 (38). It has been suggested that proteolyzed fragments have lower affinity to IGF-I and therefore may result in more availability of IGF-I for tissue receptors, therefore enhancing IGF-I bioactivity at tissue level (39). Nevertheless, the half-life of circulating IGF-I clearly was extended, compared with administration of rhIGF-I alone: the levels of IGF-I and IGFBP-3 remained stable overnight and were associated with sustained suppression of GH secretion, suggesting that a substantial fraction of rhIGF-I was bound by intact IGFBP-3 overnight. The highest doses of rhIGF-I/IGFBP-3 resulted in increased steady-state IGFBP-1 levels. This probably reflects the substantially reduced insulin infusion rates and, accordingly, reduced serum free insulin levels. An inverse relationship has previously been demonstrated between serum free insulin levels and hepatic IGFBP-1 production in both nondiabetic subjects and subjects with type 1 diabetes (6, 40). We have earlier shown that administration of rhIGF-I results in enhanced IGF-I bioactivity despite an increase in serum IGFBP-1 (41).
No systemic adverse events were noticed in this study, apart from headache, which occurred as frequently with rhIGF-I/IGFBP-3 as with placebo. Tolerability to rhIGF-I/IGFBP-3 needs to be addressed in longer-term studies, however, because therapy with rhIGF-I alone has earlier been associated with a relatively high frequency of mild or moderate adverse effects, including peripheral edema, headache, arthralgias, jaw tenderness, postural hypotension, and optic nerve swelling (10). However, all of these adverse events were dose-related and occurred only at doses in excess of 80 µg/kg·d rhIGF-I. Administration of large doses of rhIGF-I exceeds the binding capacity of the available circulating BPs and results in exposure of tissue to high levels of free and bioavailable IGF-I (42). Combining rhIGF-I with rhIGFBP-3 may avoid this problem by providing substrate for naturally abundant acid labile subunit, and by forming stable ternary complexes within the circulation, an approach which was confirmed by the study of Clemmons et al. (11) showing no toxicity in diabetic subjects given rhIGF-I/IGFBP-3 in a dose of 2 mg/kg·d for 2 wk. Our study demonstrates that the desired effects on insulin sensitivity can be obtained using doses significantly lower than those in earlier studies, suggesting that rhIGF-I/IGFBP-3 may be advantageous as an adjunct of insulin therapy in type 1 diabetes. However, larger controlled clinical trials are necessary to address the long-term efficacy and tolerability of such therapy.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Abbreviations: BMI, Body mass index; BP, binding protein; CV, coefficient of variation; HbA1c, glycosylated hemoglobin; rh, recombinant human.
Received February 10, 2004.
Accepted May 26, 2004.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  C. E. Higham, S. Rowles, D. Russell-Jones, A. M. Umpleby, and P. J. Trainer Pegvisomant Improves Insulin Sensitivity and Reduces Overnight Free Fatty Acid Concentrations in Patients with Acromegaly J. Clin. Endocrinol. Metab., July 1, 2009; 94(7): 2459 - 2463. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Robertson, Y. Lu, K. De Jesus, B. Li, Q. Su, P. K. Lund, and J.-L. Liu A general and islet cell-enriched overexpression of IGF-I results in normal islet cell growth, hypoglycemia, and significant resistance to experimental diabetes Am J Physiol Endocrinol Metab, May 1, 2008; 294(5): E928 - E938. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U Berg, T Gustafsson, C J Sundberg, L Kaijser, C Carlsson-Skwirut, and P Bang Interstitial IGF-I in exercising skeletal muscle in women Eur. J. Endocrinol., October 1, 2007; 157(4): 427 - 435. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. McDonald, R. M Williams, F. M Regan, R. K Semple, and D. B Dunger IGF-I treatment of insulin resistance Eur. J. Endocrinol., August 1, 2007; 157(suppl_1): S51 - S56. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Clemmons, M. Sleevi, G. Allan, and A. Sommer 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 J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2652 - 2658. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ekstrom, J. Salemyr, I. Zachrisson, C. Carlsson-Skwirut, E. Ortqvist, and P. Bang Normalization of the IGF-IGFBP Axis by Sustained Nightly Insulinization in Type 1 Diabetes Diabetes Care, June 1, 2007; 30(6): 1357 - 1363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A M Zandbergen, S. W J Lamberts, J. A M J L Janssen, and A. H Bootsma Short-term administration of an angiotensin-receptor antagonist in patients with impaired fasting glucose improves insulin sensitivity and increases free IGF-I. Eur. J. Endocrinol., August 1, 2006; 155(2): 293 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Saukkonen, F. Shojaee-Moradie, R. M. Williams, R. Amin, K. C. Yuen, A. Watts, C. L. Acerini, A. M. Umpleby, and D. B. Dunger Effects of Recombinant Human IGF-I/IGF-Binding Protein-3 Complex on Glucose and Glycerol Metabolism in Type 1 Diabetes. Diabetes, August 1, 2006; 55(8): 2365 - 2370. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
