Articles |
From the Metabolism Unit, Departments of Surgery (H.O.), Clinical Chemistry (L.B.), and Medicine (B.A.), and the Molecular Nutrition Unit, Center for Nutrition and Toxicology, Novum, Karolinska Institute at Huddinge University Hospital, Huddinge, and the Department of Internal Medicine (A.G.J., E.L., S.L.), Uppsala University Hospital, Uppsala, Sweden.
Correspondence to Bo Angelin, MD, Department of Medicine, Huddinge University Hospital, S-141 86 Huddinge, Sweden.
| Abstract |
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Key Words: growth hormone insulin-like growth factorI lipoprotein
| Introduction |
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| Methods |
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Before and on the last day of treatment, fasting blood serum was obtained at 8 AM and analyzed for IGF-I, total cholesterol, HDL cholesterol (HDL-C), LDL-C, triglyceride, and Lp(a) concentrations.
Assays
Serum IGF-I was measured by using a radioimmunoassay after
acid-ethanol extraction and cryoprecipitation with des(1-3) IGF-I as
ligand.13 Total serum cholesterol and
triglycerides and blood glucose were determined by using
enzymatic techniques (Boehringer-Mannheim). HDL-C was
determined after the precipitation of apoB-containing lipoproteins with
phosphotungstic acid,14 and the concentration of LDL-C was
calculated according to the method of Friedewald et al.15
Duplicate determinations of serum Lp(a) concentration were performed in
all samples on one occasion by using a two-site immunoradiometric assay
(Pharmacia Diagnostics).4 The detection limit
of the assay is 12 mg/L. The intra-assay coefficients of variation were
3.4% and 2.5% at low (136 mg/L) and high (419 mg/L) standard
concentrations, respectively, and the interassay coefficient of
variation was 7.9% at the low and 6.5% at the high standard
concentration.
Statistics
Data are presented as mean±SEM or mean (range). The
significance of differences was assessed by Wilcoxon's test.
| Results |
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The effect of GH on lipoprotein levels (Table
) reflected
previous studies of short-term GH treatment.7 8 Thus, the
concentration of LDL-C fell (P<.01) in 9 of the 11
patients, whereas that of HDL-C remained stable. Serum
triglyceride levels increased in all subjects
(P<.005). After the treatment period with IGF-I, no
significant effects on LDL-C, HDL-C, or total triglycerides
were seen. In accordance with previous studies,7 8 GH
treatment increased serum Lp(a) levels in 9 of the 11 subjects
(P<.03). However, contrary to our hypothesis, treatment
with IGF-I reduced Lp(a) levels in 9 of the 11 subjects
(P<.04). Individual changes for all 11 subjects in Lp(a)
and LDL-C levels are shown in the Figure
.
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| Discussion |
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No significant changes in HDL-C, LDL-C, or
triglyceride levels were observed in the present study
during IGF-I administration. Furthermore, IGF-I treatment does not
influence the secretion of apoB or triglycerides in
cultured rat hepatocytes.22 It is therefore
more difficult to directly link the decrease in Lp(a) levels during
IGF-I administration (Table
), at least at the present doses, to an
effect on hepatic lipoprotein production. At any rate, our findings
underscore important differences between GH and IGF-I administration on
lipoprotein metabolism.
It must be emphasized that relatively low doses of IGF-I were used in this study on osteoporotic men, and IGF-I might have more drastic effects on lipoprotein levels at higher doses. This has been demonstrated by IGF-I treatment of subjects with type II diabetes, in which the administration of IGF-I interrupts the cycle of insulin resistance, hyperinsulinemia, and hyperglycemia, and results in improved lipid metabolism.23 Less is clear about the relationship between glucose homeostasis and Lp(a) in diabetic subjects,24 and it cannot be ruled out that the sensitivity in the response to IGF-I is different for Lp(a) and other lipoproteins. In rats, insulin secretion is reduced during IGF-I treatment25 ; clearly, the possible role of insulin as a regulator of Lp(a) levels needs to be further studied.
In the present experimental situation, in which relatively low doses of GH or IGF-I were administered, serum IGF-I levels were increased to approximately the same extent in both cases. Thus, as no significant changes in LDL-C levels were seen during IGF-I administration, this indirectly indicates that the previously demonstrated stimulatory effect of GH on hepatic LDL receptor expression10 may not be due to IGF-I. In contrast, during GH administration LDL-C decreased significantly, in agreement with an increased LDL receptor activity. These results disagree with previous studies that used cultured macrophages, in which the effect of IGF-I has been suggested as an explanation for the GH-induced stimulation of LDL receptor activity.26 In support of our present findings, however, we have found that IGF-I cannot substitute for GH to normalize the reduced hepatic LDL receptor activity resulting from hypophysectomy in the rat (M. Rudling, H. Olivecrona, G. Eggertsen, and B. Angelin, unpublished data, 1995). As LDL receptor activity appears to influence serum Lp(a) levels to only a minor extent, it is clear that the opposite effects of GH and IGF-I on this activity cannot explain the differing effects on Lp(a).
In conclusion, following low-dose treatment with IGF-I, serum Lp(a) levels were reduced, in contrast to the stimulatory effect observed in response to GH. The results do not support the contention that the effects of estrogen and GH on Lp(a) metabolism are mediated through IGF-I, but instead indicate that, analogously with their effects on glucose and free-fatty-acid homeostasis, IGF-I and GH have different effects on hepatic lipoprotein metabolism. Further studies on IGF-I at different dose levels are necessary to evaluate its potential therapeutic use in lipoprotein disorders. The present results, with a lowering of Lp(a), a lipoprotein that is implicated as a risk factor for cardiovascular disease, support the continued evaluation of IGF-I in the therapy of other metabolic disorders such as osteoporosis and diabetes.
| Acknowledgments |
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Received September 16, 1994; accepted April 11, 1995.
| References |
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