1 Department of Endocrinology and Diabetology of the Adult, University Hospital of Bern, Inselspital, CH-3010 Bern, Switzerland; and Departments of 2 Medicine and 3 Chemical Pathology, King's College London, St. Thomas' Hospital Campus, London SE1 7EH, United Kingdom
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ABSTRACT |
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Abnormal lipid metabolism may be related
to the increased cardiovascular risk in type 1 diabetes. Secretion and
clearance rates of very low density lipoprotein (VLDL) apolipoprotein
B100 (apoB) determine plasma lipid concentrations. Type 1 diabetes is
characterized by increased growth hormone (GH) secretion and decreased
insulin-like growth factor (IGF) I concentrations. High-dose IGF-I
therapy improves the lipid profile in type 1 diabetes. This study
examined the effect of low-dose (40 µg · kg1 · day
1) IGF-I
therapy on VLDL apoB metabolism, VLDL composition, and the GH-IGF-I
axis during euglycemia in type 1 diabetes. Using a stable isotope
technique, VLDL apoB kinetics were estimated before and after 1 wk of
IGF-I therapy in 12 patients with type 1 diabetes in a double-blind,
placebo-controlled trial. Fasting plasma triglyceride
(P < 0.03), VLDL-triglyceride concentrations (P < 0.05), and the VLDL-triglyceride-to-VLDL apoB
ratio (P < 0.002) significantly decreased after IGF-I
therapy, whereas VLDL apoB kinetics were not significantly affected by
IGF-I therapy. IGF-I therapy resulted in a significant increase in
IGF-I and a significant reduction in GH concentrations. The mean
overnight insulin concentrations during euglycemia decreased by 25%
after IGF-I therapy. These results indicate that low-dose IGF-I therapy restores the GH-IGF-I axis in type 1 diabetes. IGF-I therapy changes fasting triglyceride concentrations and VLDL composition probably because of an increase in insulin sensitivity.
type 1 diabetes mellitus; insulin-like growth factor I; growth hormone secretion; very low density lipoprotein apolipoprotein B turnover study; stable isotope technique
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INTRODUCTION |
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TYPE 1 DIABETES MELLITUS is associated with an increased risk of atherosclerosis (31). Although type 1 diabetes appears to be an independent risk factor for cardiovascular disease, abnormalities in lipoprotein metabolism (17) and lipoprotein composition (26, 42) may contribute to the observed excess cardiovascular risk. Usually, the lipid profiles in well-controlled patients with type 1 diabetes mellitus are similar to those seen in matched, healthy control subjects (17). Poor diabetic control, however, is often associated with an increase in total cholesterol, triglycerides, and a decrease in high-density lipoprotein (HDL)-cholesterol (C; see Ref. 17).
Important determinants of the lipid profile are the secretion and clearance rates of the apolipoprotein 100 (apoB)-containing lipoproteins [very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL); see Ref. 36]. Because VLDL apoB is the precursor of IDL and LDL, plasma lipid concentrations are dependent on VLDL apoB metabolism (36). Hepatic overproduction of VLDL apoB has been demonstrated in type 2 diabetes mellitus and in several hyperlipidemic conditions associated with premature atherosclerosis (14, 15, 29, 30). VLDL apoB is constitutively expressed (20), and VLDL apoB secretion is essentially regulated by intrahepatic lipid substrate availability (triglycerides and cholesterol esters; see Ref. 40), whereas VLDL apoB clearance depends on a complex interaction between an enzyme (lipoprotein lipase) and receptors (LDL receptors; see Ref. 36). Insulin-like growth factor I (IGF-I) is known to promote lipid oxidation (25), which may lead to a decrease in hepatic lipid supply and consequently to a reduced VLDL apoB secretion. By increasing insulin sensitivity, IGF-I may increase lipoprotein lipase activity and therefore VLDL apoB clearance (46). In contrast, VLDL remnant clearance is unlikely to be influenced by IGF-I, since studies in rats suggest that IGF-I does not significantly affect hepatic expression of LDL receptor (3), although growth hormone (GH) has been shown to upregulate hepatic LDL receptors in humans (39).
The GH-IGF-I axis is disordered in type 1 diabetes, resulting in low levels of IGF-I and, consequently, decreased feedback in GH hypersecretion (2). The elevated GH concentrations, in particular at night, are thought to contribute to the reduced insulin sensitivity (16) and have been associated with diabetic microvascular complications (18). Exogenous IGF-I administration has been shown to decrease GH concentrations in adolescents (1, 4, 10, 44) and in adults (9) with type 1 diabetes and to improve insulin sensitivity (1, 4, 9, 10, 44). Furthermore, IGF-I treatment results in a decrease in fasting triglycerides, total cholesterol, and LDL-C concentrations in patients with type 1 diabetes (9). The mechanism, however, remains unknown.
Using a stable isotope technique, we aimed, therefore, to investigate overnight VLDL apoB kinetics during euglycemic conditions in 12 patients with type 1 diabetes before and after 1 wk of IGF-I treatment in a randomized, double-blind, placebo-controlled trial. In addition, VLDL composition, the overnight GH secretion profile, and insulin concentrations were assessed to determine the relationship between these variables and VLDL apoB metabolism.
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METHODS |
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Experimental subjects.
Twelve adult patients with type 1 diabetes mellitus participated in the
study. Their clinical and metabolic characteristics are summarized in
Table 1. All patients had stable
metabolic control and were on subcutaneous soluble and isophane
insulin. The patients were in good general health without
evidence of diabetic complications and had normal thyroid, renal, and
hepatic function. All of the patients had a C-peptide concentration of
<0.3 nmol/l, and the female patients were taking the combined oral
contraceptive pill. St. Thomas' Hospital Ethics Committee approved the
study, and all patients provided informed written consent. The effects of IGF-I therapy on glucose and protein metabolism in these
patients have been reported previously (7).
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Study protocol.
The study was randomized, double blind, and placebo controlled.
Patients were instructed in self-administration of IGF-I (Pharmacia & Upjohn, Milton-Keynes, UK) and were injected with 40 µg · kg1 · day
1
IGF-I/placebo subcutaneously at night (10:00 P.M.) for seven consecutive days.
Body composition. Body weight was measured on an electronic balance with subjects wearing light clothes and without shoes at the beginning of each study. Height was assessed by a stadiometer. Bioelectrical impedance analysis was measured in the erect position after voiding using a TBF-105 body fat analyzer (Tanita, Chicago, IL). Fat mass and lean body mass were calculated using a preprogrammed equation based on densitometric data in a healthy population (6).
Isolation and measurement of isotopic enrichment of VLDL apoB.
All EDTA-plasma samples were stored at 4°C and analyzed within
24 h of collection. A 2-ml aliquot of plasma was overlaid with 3 ml of sodium chloride density solution (1.006 kg/l) and
ultracentrifuged for 16 h at 147,000 g (Centrikon
T-2070 ultracentrifuge; Kontron Instruments, Zurich, Switzerland). The
supernatant containing VLDL was isolated by aspiration. ApoB was
precipitated by the tetramethylurea method, which is highly
specific (specificity 97%) for apoB (15). The precipitate
was delipidated by incubation with 3 ml ether-ethanol solution (1:3,
vol/vol) at 20°C for 12 h. After recentrifugation (2,000 revolutions/min, 30 min, 4°C), the supernatant was removed by
aspiration. The delipidated apoB precipitate was dried under
oxygen-free nitrogen (OFN; BOC, Guildford, UK) for 20 min at 25°C and
then hydrolyzed in 2 ml of 6 M hydrochloric acid. The samples were
heated for 24 h at 115°C to ensure complete hydrolysis and
reconstituted in 0.5 ml of 50% acetic acid. Amino acids were eluted by
cation-exchange chromatography [70 µm filter plastic columns
(Bioconnections, Leeds, UK) and H+ form cation-exchange
resin (Bio-Rad, Richmond, VA)] using 2 ml of 3 M ammonia. The eluted
amino acids were frozen (
70°C), lyophilized, and then stored at
20°C until derivatization. The samples were derivatized using 100 µl acetonitrile and 100 µl
N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide (Aldrich, Dorset, UK) to form the
bis(tert-butyldimethylsilyl) derivative. Excess reagent was
removed by blowing down under OFN, and the sample was reconstituted in
100 µl decane for gas chromatography-mass spectrometry. Isotopic
enrichment was determined by selected ion monitoring of fragments with
a mass-to-charge ratio (m/z) of 303 and 302 by
use of a gas chromatograph-mass spectrometer (VG Biotech TRIO-2; VG
Biotech) in the electron impact ionization mode. The quinoxalinol-tert-butyldimethylsilyl derivative of
-KIC
was prepared, and isotope enrichment was determined by selected ion
monitoring of fragments at m/z 259 and 260 (GC-MS
analysis; Hewlett Packard 5890A, Bracknell, UK). Analytical precision
of the method [coefficient of variation (CV)] has been shown to be
<8% for isotopic enrichment (E) of leucine and
-KIC
(15).
Quantification of VLDL apoB and other analytes. Glucose concentrations were measured using the glucose oxidase method (glucose analyzer, YSI model 23AM; Yellow Springs Instruments). VLDL apoB concentration was determined using the Lowry method (13). Plasma total cholesterol and triglyceride concentrations were measured by an enzymatic method (Boehringer-Mannheim, Mannheim, Germany) using a Cobas Fara II analyzer (Roche, Welwyn Garden City, UK). HDL-C was separated by precipitation of apoB-containing lipoproteins with dextran sulfate/magnesium chloride and measured enzymatically. LDL-C was calculated according to the equation of Friedewald et al. (19). HbA1C was measured by anion exchange liquid chromatography (interassay CV 8%; Primus). GH was measured by an in-house double-antibody RIA with a detection limit of 0.3 mU/l. Intra-assay CV was 10, 4, and 5.4% at 1.7, 12.1 and 22.2 mU/l, respectively. Serum IGF-I concentrations were measured by a double-antibody RIA after an ethanol/hydrochloric acid extraction (intra-assay CV 6%; see Ref. 43). Plasma immunoreactive insulin concentration was determined by double-antibody RIA (interassay CV 6%; see Ref. 41). An immunoradiometric assay was used for the measurement of IGFBP-1 and IGFBP-3 [IRMA (Diagnostics Systems Laboratories); inter-assay CV for IGFBP-1 was 5%; interassay CV for IGFBP-3 was 1%]. Plasma FFA concentrations were measured enzymatically [FFA kit (Wako Chemicals); interassay CV 3.6%]. The apoE phenotype was determined by Western blotting after isoelectric focusing on a Pharmacia Phast system (Amersham-Pharmacia, Beaconsfield, UK; see Ref. 34).
Calculation of VLDL apoB secretion and clearance rates.
VLDL apoB enrichment with [13C]leucine and
[13C]KIC enrichment (precursor pool) was calculated using
the following formula (12): Et = [Rt R0/(1 + Rt
R0)] × 100, where
Rt is the 13C-to-12C
ratio at time t and R0 is the
13C-to-12C ratio at baseline before tracer
infusion. Fractional catabolic rate (FCR) and fractional secretion rate
(FSR) of VLDL were estimated by a multicompartmental model with an
intrahepatic delay function by use of SAMM II software (SAMM, Seattle,
WA). The precursor compartment for the incorporation of
[13C]leucine into the VLDL particles (forcing function)
was the steady-state tracer-to-tracee ratio of
-KIC. FSR of VLDL is
subject to an intrahepatic delay. The catabolic rate of VLDL apoB from
plasma is expressed as FCR. Throughout the study, the patients were in steady state, as shown by constant VLDL apoB concentrations (data not
shown). In this case, FSR equals FCR. The model parameters (intrahepatic delay and FCR) were estimated from the tracer-to-tracee ratio of VLDL apoB. A total of 13 time points over the 10-h tracer infusion was included in the mathematical analysis.
Statistical analyses.
Results are expressed as means ± SE. Skewed variables (plasma
total and VLDL-TG concentrations) were examined after log
transformation. Baseline characteristics between the placebo and the
IGF-I groups were compared using unpaired t-testing and,
where appropriate, 2-analysis. The responses of each
parameter (
values) in the placebo and the IGF-I groups were
analyzed for between-group comparison using unpaired
t-testing or, where appropriate, nonparametric testing
(kinetic data). For analysis of data from more than two time points,
ANOVA was performed. Analysis of GH secretion was performed using
Pulsar analysis (9) with nonparametric testing for
comparisons of variables. P values <0.05 were considered significant.
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RESULTS |
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Patients. The clinical and metabolic characteristics were similar in the placebo and IGF-I groups. All subjects did not experience any side effects during the study period except subject 9 (randomized to placebo), who had a hypoglycemic episode the day after study 1. Total body weight and body composition did not change significantly during the study.
Mean overnight glucose concentrations were similar in both groups on both occasions (IGF-I group 5.4 ± 0.1 vs. 5.6 ± 0.1 mmol/l, pre- vs. posttreatment, ANOVA P = 0.49; placebo group 6.3 ± 0.3 vs. 6.5 ± 0.2 mmol/l, pre- vs. posttreatment, ANOVA P = 0.25). In the IGF-I group, one patient was heterozygous for apoE2 and one for apoE4. In the placebo group, two patients were heterozygous for apoE2 and two for apoE4. The remaining patients presented the phenotype apoE3/E3 (Table 1).IGF-I and insulin concentrations. Pretreatment serum IGF-I concentrations were similar in the two groups. IGF-I therapy led to a significant rise in circulating IGF-I within the normal range, whereas there were no changes in the placebo group (IGF-I group 28.2 ± 2.4 vs. 42.7 ± 3.8 nmol/l, pre- vs. posttreatment; placebo group 34.2 ± 4.0 vs. 29.3 ± 3.2 nmol/l, pre- vs. posttreatment, P < 0.03).
Pretreatment overnight insulin concentrations during euglycemia were not significantly different between the IGF-I and placebo groups. IGF-I therapy resulted in a 25% decrease in mean overnight insulin concentrations, whereas no significant change was observed in the placebo group (IGF-I group 35.6 ± 6.7 vs. 27.0 ± 7.0 mU/l, pre- vs. posttreatment; placebo group 29.9 ± 4.6 vs. 29.4 ± 3.1 mU/l, pre- vs. posttreatment, P < 0.05).Lipid profile.
There were no statistically significant differences in fasting plasma
lipid profiles between the two groups before treatment. IGF-I therapy
significantly decreased total plasma triglyceride concentrations
(P < 0.03), VLDL-TG concentrations (P < 0.05), and VLDL-TG-to-VLDL-apoB ratios (P < 0.002),
whereas no significant changes were observed after placebo treatment.
The reduction in nonesterified free fatty acid (NEFA) concentrations
after IGF-I therapy did not reach statistical significance
(P = 0.09; Tables 2 and
3).
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Kinetic characteristic of VLDL apoB metabolism.
As shown in Figs. 1 and
2, apoB kinetics were in steady state,
since VLDL apoB concentrations did not show a significant change at the
selected time points throughout the study. Precursor pool enrichment as
measured by -[13C]KIC remained constant throughout the
study periods (Fig. 1, A and B). Because of
technical problems (insufficient enrichment of VLDL apoB), we were not
able to include turnover data of subjects 4 (placebo group)
and 12 (IGF-I group). The calculated values of all the
kinetic measurements were not statistically different between the
groups before treatment. After IGF-I or placebo therapy, VLDL apoB pool
size, FCR, VLDL apoB secretion, and clearance rate did not change
significantly in either group (Figs. 1 and 2 and Table
4).
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Overnight GH secretion.
Mean overnight GH concentrations were significantly decreased after
IGF-I therapy, whereas no change was observed after placebo (IGF-I
group 23.6 ± 3.8 vs. 10.5 ± 1.3 mU/l pre- vs.
posttreatment; placebo group 13.5 ± 1.8 vs. 14.3 ± 1.6 mU/l
pre- vs. posttreatment, P < 0.007). With the use of
pulsar analysis, this reduction was attributable to a reduction in GH
peak amplitude (IGF-I group 31.7 ± 6.3 vs. 21.5 ± 7.2 mU/l,
pre- vs. posttreatment; placebo group 23.0 ± 3.9 vs. 30.4 ± 5.2 mU/l, pre- vs. posttreatment, P < 0.02) and peak
length (IGF-I group 1.5 ± 0.3 vs. 1.3 ± 0.2 h, pre-
vs. posttreatment, placebo group 1.3 ± 0.1 vs. 1.7 ± 0.2 h, pre- vs. posttreatment, P < 0.03). No
change was observed in either the frequency of peaks or the length of
intervals between peaks in either group. Total area under the GH curve
was significantly decreased by IGF-I, whereas no significant changes
were observed in the placebo group (IGF-I group 131.6 ± 46.5 vs.
67.3 ± 25.8 mU · l1 · h
1 pre- vs.
posttreatment; placebo group 82.4 ± 11.9 vs. 91.1 ± 15.4 mU · l
1 · h
1 pre- vs.
posttreatment, P < 0.04).
IGFBP. Before treatment, IGFBP-1 and IGFBP-3 concentrations were similar in the IGF-I-treated and placebo groups. Mean IGFBP-1 concentrations increased 1.5-fold after IGF-I therapy (IGF-I group 82.1 ± 10.1 vs. 124.9 ± 15.8 ng/ml pre- vs. posttreatment; placebo group 71.5 ± 13.7 vs. 87.5 ± 13.0 ng/ml pre- vs. posttreatment, ANOVA P < 0.001). IGFBP-3 concentrations did not change significantly in either group (IGF-I group 2,311.4 ± 196.0 vs. 2,541 ± 168.8 ng/ml pre- vs. posttreatment; placebo group 2,611.6 ± 273.9 vs. 2,694.3 ± 239.9 ng/ml pre- vs. posttreatment, ANOVA P = 0.12).
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DISCUSSION |
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This study demonstrates that low-dose IGF-I therapy in adult patients with type 1 diabetes significantly decreases fasting triglyceride and VLDL-TG concentrations without affecting VLDL apoB kinetics. After IGF-I, overnight GH secretion and mean overnight insulin concentrations decreased, whereas IGFBP-I concentrations significantly increased.
Decreased fasting triglyceride concentrations after IGF-I therapy are consistent with findings in patients with type 2 (47) and type 1 diabetes mellitus (9). Increasing evidence suggests that triglyceride concentrations may be a significant risk factor for cardiovascular disease (24) and that lowering triglycerides (32, 38) can reduce this risk. These clinical findings are supported by the fact that triglyceride-rich lipoproteins (i.e., VLDL and IDL) have been identified in human atherosclerotic plaques, and these particles are associated with progression of coronary lesions (45). Increased triglyceride concentrations are associated with decreased insulin sensitivity (42). A decrease in insulin concentrations for a similar glycemic control (euglycemia) measured in the current study suggests an increase in insulin sensitivity. Therefore, it is likely that the IGF-I-induced improvement in insulin sensitivity has led to the reduction of triglyceride and VLDL-TG concentrations. In contrast to previous studies, total cholesterol and LDL-C did not change significantly after IGF-I therapy in this study (9, 47). This may be because only 40% of the previous dose of IGF-I was administered in this study. Alternatively, the small sample size did not have enough statistical power to detect statistically significant differences in fasting cholesterol concentrations.
It has been shown previously (26) that, even in well-controlled diabetic patients, fasting VLDL composition is altered with an increase in lipid content (in particular triglycerides) within the VLDL fraction compared with matched control subjects. Elevated VLDL-TG concentrations have been associated with a parallel increase in small dense LDL, a subfraction of LDL particles that are known to be particularly atherogenic (26, 36, 42). In this study after IGF-I therapy, VLDL-TG concentration decreased, as did the VLDL-TG-to-VLDL-apoB ratio. This may indicate a reversal of the impaired VLDL composition and may be associated with improvements in the LDL subfraction profile (26, 36, 42). A possible explanation of the findings of this study is that the decrease in GH secretion leads to a reduction in peripheral lipolysis and a decrease in NEFA flux to the liver (6). The reduced hepatic NEFA content, in turn, may result in decreased lipid esterification and lower incorporation of triglycerides into VLDL particles (40). This hypothesis is supported by the tendency for a reduction in NEFA concentrations with IGF-I therapy seen here. In addition, administration of GH to healthy subjects in a dose mimicking the increased GH secretion in type 1 diabetes results in a compositional change of VLDL particles with an increase in triglyceride content (35), supporting our hypothesis.
The finding of unchanged VLDL apoB kinetics despite a decrease in fasting triglyceride concentrations is intriguing. It may be related to the small number of patients included in this study. A mean reduction in VLDL apoB secretion of 33% after IGF-I therapy, although not significant statistically, may support this hypothesis. Alternatively, it is well known that the VLDL fraction is heterogeneous, consisting of triglyceride-rich (large VLDL) and cholesterol-rich (small VLDL) subfractions that are independently secreted by the liver (36). Insulin is known to act primarily on the triglyceride-rich VLDL subfraction (36). The observed increase in insulin sensitivity may, therefore, primarily affect the kinetics of triglyceride-rich VLDL subfractions, which were not assessed separately in this study.
In patients with adult GH deficiency, GH replacement therapy has been demonstrated to increase whole VLDL apoB turnover (11). The current study, however, suggests that VLDL apoB metabolism is unchanged after IGF-I therapy despite a reduction in GH secretion. A possible explanation for this effect includes the fact that insulin is a powerful regulator of VLDL apoB metabolism, and, if euglycemia is maintained, it outweighs any possible effects of GH. Alternatively, hepatic GH resistance may occur, as has been suggested, especially in adolescents with type 1 diabetes (1, 4, 10, 44). GH is the principal regulator of hepatic synthesis of IGFBP-3 (6). Unchanged IGFBP-3 concentrations after IGF-I therapy despite a decrease in GH secretion are consistent with previous results (28, 44) and support the hypothesis of GH resistance. Possible mechanisms include insufficient portal insulinization, leading to decreased hepatic expression of GH receptors (23) and/or to insufficient synthesis of IGF-I (5).
Reduced IGFBP-1 concentrations are associated with an increased prevalence of cardiovascular disease in patients with type 2 diabetes (21) and in an elderly nondiabetic population (28). The increase in IGFBP-1 concentrations in the current study may, therefore, indicate a beneficial effect on the cardiovascular risk profile in type 1 diabetes mellitus. Our findings are consistent with results in some (4), but not in all, of the previous studies (8, 44). Interestingly, the 2.5-5 times lower dose of IGF-I administered in the current study increased IGFBP-1 concentrations to a very similar degree compared with the previous results (4). This is most likely because of the concomitant insulin treatment. In the current study, euglycemia was achieved by intravenous insulin, whereas in the previous studies subcutaneous intermediate and soluble insulin was used, leading to a less tight glycemic control (4, 8).
This study has its limitations. First, it was designed to investigate VLDL composition, VLDL apoB metabolism, and hormone profiles during euglycemia, acutely induced by insulin. It is conceivable that long-term metabolic control influences these variables and should therefore be addressed in further studies. Second, apoE polymorphisms have been shown to influence apoB metabolism (37). The patients in the placebo and the IGF-I groups were not ideally matched for the apoE phenotype; hence, we cannot exclude that this may have influenced our findings. However, differences in VLDL apoB kinetics have been shown only in apoE2 homozygous patients (37), not included in the current study. It is therefore unlikely that the present results were confounded by the differences in apoE phenotype.
In conclusion, the current results indicate that low-dose IGF-I therapy
(40 µg · kg1 · day
1) is
well tolerated and restores the disordered GH-IGF-I axis in type 1 diabetes. IGF-I therapy does not significantly influence VLDL apoB
kinetics but changes fasting triglyceride concentrations and the
composition of VLDL particles probably because of an increase in
insulin sensitivity. The decreased triglyceride content within the VLDL
particles leading to a reduction in atherogenic small dense LDL
particles and an increase in IGFBP-1 concentrations may favorably
influence the macrovascular risk profile in type 1 diabetes. In
addition, by reducing GH secretion, IGF-I may have a beneficial effect
on microvascular complications. Further long-term studies are required
to investigate a possible role of low-dose IGF-I therapy in the
management of patients with type 1 diabetes mellitus.
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ACKNOWLEDGEMENTS |
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We thank Dr. R. Jones, St. Thomas' Hospital, London, and R. W. James, Geneva, for reviewing the manuscript.
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FOOTNOTES |
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E. R. Christ was supported by a grant from the Swiss National Foundation and the Walther and Margarethe Lichtenstein Foundation (Basel, Switzerland). P. V. Carroll was supported by the Special Trustees of St. Thomas' Hospital. The study was supported by a grant from the Juvenile Diabetes Foundation.
Address for reprint requests and other correspondence: E. Christ, Dept. of Endocrinology and Diabetology of the Adult, Inselspital, CH-3010 Bern, Switzerland (E-mail: Emanuel.Christ{at}insel.ch).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published January 2, 2002;10.1152/ajpendo.00470.2001
Received 18 October 2001; accepted in final form 17 December 2001.
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