doi: 10.1161/01.CIR.0000074245.18499.68
(Circulation. 2003;107:e190.)
© 2003 American Heart Association, Inc.
Correspondence |
Unraveling Reaven’s Syndrome X: Serum Insulin-Like Growth Factor-I and Cardiovascular Disease
INSERM Unit 551, Hôpital Pitié-Salpetrière, Paris, France
Heart Lung Center Utrecht, Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands
Department of Endocrinology, University Medical Center Utrecht, Utrecht, the Netherlands
To the Editor:
Juul et al1 describe the interesting observation that low serum insulin-like growth factor-I (IGF-I) and high IGF-binding protein-3 (IGFBP-3) are associated with an increased occurrence of cardiovascular disease.
In line with their observation, we recently demonstrated that low plasma IGF-I levels were associated with postprandial dyslipidemia and insulin resistance. Postprandial dyslipidemia is an atherogenic risk factor, and this postprandial period is dominated by triglyceride-rich particles (TRPs) and high atherogenic TRP remnants, such as the remnant-like particle (RLP). Fasting and postprandial plasma RLP cholesterol (RLP-C) levels in heterozygous familial hypercholesterolemia have been reported by our group to be an additional factor in the atherogenic lipoprotein.2,3 The postprandial accumulation of RLP-C in adult growth hormone (GH)-deficient subjects is inversely associated with pretreatment plasma IGF-I levels; consequently, the lower the serum IGF-I level, the higher the postprandial RLP-C load.4 It is established that GH directly affects the expression of the hepatic low-density lipoprotein receptors and of key enzymes implicated in bile acid metabolism with effects on the intracellular cholesterol homeostasis in the liver; such homeostasis is linked to metabolism of TRPs. Consequently, the question arises whether the pituitary GH secretion capacity in the participants of the report by Juul et al1 may be impaired.
Additionally, knowledge about free IGF-I levels, and thus the biological active form, in the population studied by Juul et al is of major importance to more precisely understand their reported positive associations. Most circulating IGF-I is bound to IGFBP-3. Consequently, proteolysis of IGFBP-3 modulates the IGF bioavailability. In insulin-resistant subjects, the proteolysis of IGFBP-3 is increased, and this regulation mechanism for free exchangeable IGF-I in circulation keeps the IGF/intact IGFBP-3 ratio constant. A low total IGF level in insulin resistance may therefore have no biological consequences, and moreover, is influenced by glucose homeostasis.5 In line with these results, more details about glucose homeostasis from the participants in the report by Juul et al1 and a calculation of a IGF-1/IGFBP-3 ratio in relation to the occurrence of ischemic heart disease will be of additional interest.
The association that is found by Juul et al1 is an important observation that gives another opportunity to find new pathways that may unravel the anchor points of Reaven’s metabolic syndrome X.
References
1. Juul A, Scheike T, Davidsen M, et al. Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation. 2002; 106: 939–944.
2. de Sauvage Nolting PR, Twickler MB, Dallinga-Thie GM, et al. Elevated remnant-like particles in heterozygous familial hypercholesterolemia and response to statin therapy. Circulation. 2002; 106: 788–792.
3. Twickler TB, Dallinga-Thie GM, de Valk HW, et al. High dose of simvastatin normalizes postprandial remnant-like particle response in patients with heterozygous familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2000; 20: 2422–2427.
4. Twickler TB, Wilmink HW, Schreuder PC, et al. Growth hormone (GH) treatment decreases postprandial remnant-like particle cholesterol concentration and improves endothelial function in adult-onset GH deficiency. J Clin Endocrinol Metab. 2000; 85: 4683–4689.
5. Lassarre C, Duron F, Binoux M. Use of the ligand immunofunctional assay for human insulin-like growth factor ((IGF) binding protein-3 (IGFBP-3) to analyze IGFBP-3 proteolysis and IGF-I bioavailability in healthy adults, GH-deficient and acromegalic patients, and diabetics. J Clin Endocrinol Metab. 2001 86; 1942–1952.[Medline] [Order article via Infotrieve]
Third Department of Internal Medicine, General University Hospital Prague, Prague, Czech Republic, Jan.Malik@LF1.CUNI.CZ
To the Editor:
Juul et al1 have recently documented that low circulating insulin-like growth factor-I (IGF-I) and high IGF binding protein-3 (IGFBP-3) levels significantly increase the risk of ischemic heart disease. The prognostic impact of IGF-I and IGFBP-3 remained significant after correction for potential confounding factors, but the authors made no specific comments on any possible association between serum IGF-I and cholesterol. We have recently observed an increase of IGF-I after lipid-lowering therapy,2 which suggests that some relation between serum lipids and IGF-I might exist.
We have therefore compared circulating IGF-I and IGFBP-3 levels in 27 otherwise healthy subjects with severe isolated hypercholesterolemia (total cholesterol 8.59±0.72 mmol/L, age 52±11 years [mean±SD]) and in 31 age- and sex-matched healthy controls (total cholesterol 5.63±0.58 mmol/L). IGF-I and IGFBP-3 levels were determined by radioimmunoassay (Immunotech); for each subject, we also calculated IGF-I/IGFBP-3 ratio, an indirect indicator of biologically active free IGF-I. These values are expressed as medians [25th, 75th percentiles]; inter-group comparisons were performed by Mann-Whitney U test. Hypercholesterolemic subjects had lower IGF-I levels (median: 181 [25th, 75th percentile: 132, 223] versus 240 [187, 286] µg/L, P=0.001), higher IGFBP-3 levels (4.8 [4.2, 5.3] versus 3.6 [3.3, 4.0] mg/L, P<10-5), and a lower IGF-I/IGFBP-3 ratio (35.2 [31.1, 42.9] versus 62.4 [50.7, 74.5], P<10-7) than controls. Together with our earlier observations,2 these data suggest a possible link between circulating IGF-I and lipids.
The intriguing work by Juul et al1 documents that the association of IGF-I and its binding proteins with atherosclerosis is clinically relevant. Our results further extend their observations, suggesting that serum cholesterol, a risk factor of atherosclerosis, may be directly involved in this relationship. Therefore, some association between IGF-I and lipids might also exist in the study of Juul et al,1 and perhaps the authors have some additional data to further clarify this issue.
References
1. Juul A, Scheike T, Davidsen M, et al. Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation. 2002; 106: 939–944.
2. Malik J, Melenovsky V, Krsek M, et al. Atorvastatin but not fenofibrate increases insulin-like growth factor-I levels. J Am Coll Cardiol. 2002; 39 (suppl B): 155B. Abstract.
Institute of Cardiology, Catholic University Medical School, Rome, Italy, e_conti02@hotmail.com
To the Editor:
We read with satisfaction the article by Juul et al,1 which showed in a nested case-control study that individuals with low circulating insulin-like growth factor (IGF)-I and high IGF-binding protein (BP)-3 levels have a significantly increased risk of myocardial infarction (MI) and cardiovascular death during a 15-year follow-up, independent of traditional risk factors. Although the accompanying editorial2 found the results "contrary to the beliefs of many," increasing clinical and experimental evidence not quoted by Juul et al supports the contention that reduced IGF-I represents a new risk factor for ischemic heart disease, closely linked to glucose intolerance and type 2 diabetes.
Indeed, we recently found markedly reduced serum IGF-I levels in patients with acute MI compared with healthy controls, preceding the rise in markers of myocardial necrosis; notably, among patients with MI, IGF-I concentrations were significantly lower in those with adverse events compared with those with an uneventful course.3 Furthermore, the absence of a 192-bp allele in the promoter of the IGF-I gene on chromosome 12 has been associated with reduced circulating IGF-I, an increased risk for type 2 diabetes and MI, and an especially high risk of MI (odds ratio 3.4, 95% confidence interval 1.1 to 11.3) among patients with type 2 diabetes.4 Finally, in a recent large population study, serum IGF-I concentrations were predictive of 2-hour glucose levels at an oral glucose tolerance test.5 These clinical findings are fully supported by experimental data showing that IGF-I is an insulin-sensitizing agent, increases NO synthesis and K+ channel activity, is antiapoptotic, has vasodilator properties on large and small coronary vessels,3–5 and therefore has a widespread cardioprotective potential.
The debate on the causes of low IGF-I serum concentrations is still at its beginning: The finding that healthy centenarians have high IGF-I and low IGFBP-3 levels should encourage us to keep on searching.6
References
1. Juul A, Scheike T, Davidsen M, et al. Low serum insulin-like growth factor-1 is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation. 2002; 106: 939–944.
2. Frystyk J, Ledet T, Møller N, et al. Cardiovascular disease and insulin-like growth factor I. Circulation. 2002; 106: 893–895.
3. Conti E, Andreotti F, Sciahbasi A, et al. Markedly reduced insulin-like growth factor-1 in the acute phase of myocardial infarction. J Am Coll Cardiol. 2001; 38: 26–32.
4. Vaessen N, Heutink P, Janssen JA, et al. A polymorphism in the gene for IGF-1: functional properties and risk for type 2 diabetes and myocardial infarction. Diabetes. 2001; 50: 637–642.
5. Sandhu MS, Heald AH, Gibson JM, et al. Circulating concentrations of insulin-like growth factor-1 and development of glucose intolerance: a prospective observational study. Lancet. 2002; 359: 1740–1745.[CrossRef][Medline] [Order article via Infotrieve]
6. Paolisso G, Ammendola S, Del Buono A, et al. Serum levels of insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 in healthy centenarians: relationship with plasma leptin and lipid concentrations, insulin action, and cognitive function. J Clin Endocrinol Metab. 1997; 82: 2204–2209.
Response
Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark
Department of Biostatistics, Panum Institute, Copenhagen, Denmark
Centre for Preventive Medicine, Medical Department M, Glostrup County Hospital, University of Copenhagen, Copenhagen, Denmark
Malik et al suggest that the relationship between insulin-like growth factor-I (IGF-I) and atherosclerosis could be explained by changes in cholesterol. They say that patients with severe isolated hypercholesterolemia have lower IGF-I and higher IGF-binding protein-3 (IGFBP-3) compared with normocholesterolemic subjects. Twickler and coworkers comment that low pretreatment IGF-I levels in adult growth hormone (GH) deficient subjects were inversely associated with postprandial remnant-like particles, which is reported to be an atherogenic risk factor. In our study,1 we found that the cardiovascular risk attributed to IGF-I was significantly diminished when we adjusted for lipids. Although IGF-I remained a significant risk factor after adjustment for lipids, part of the association between IGF-I and risk of cardiovascular disease may be accounted for by lipids. We have no information on the pulsatile 24-hour GH secretion in our subjects, but others have found that GH, and not IGF-I, was significantly inversely associated with cholesterol and triglyceride levels in healthy subjects.2 Thus, we cannot exclude the possibility that IGF-I serves as a proxy for the pulsatile GH secretion. On the other hand, systemic IGF-I treatment in patients with type 1 diabetes results in a lowering of the GH secretion and an increased insulin sensitivity concomitant with a lowering of fasting triglyceride and very low-density lipoprotein-triglyceride concentrations.3
Böger and coworkers previously demonstrated that the GH-induced increase in IGF-I was associated with increased urinary excretion of markers of nitric oxide (NO) production (cGMP) in GH deficient adults. Thus, IGF-I may be involved in NO-mediated vasodilation. Another study found that IGF-I correlated positively with blood pressure-corrected aortic distensibility in healthy normotensive adults,4 and several authors have shown that intraarterial infusion of IGF-I in healthy controls increased forearm blood flow, which was blocked by an inhibitor of nitric oxide synthase. Thus, IGF-I may stimulate endothelial NO formation, thereby decreasing peripheral arterial resistance which could also explain, at least in part, our findings of an association between low IGF-I and increased risk of cardiovascular disease.
Insulin resistance is likely to be a major player in the association between IGF-I and cardiovascular risk, as pointed out by Twickler et al in their comment. Clearly, IGF-I improves insulin resistance, and low IGF-I was in fact shown to predict the occurrence of abnormal glucose tolerance testing in a prospective follow-up study of 615 healthy subjects.5
Much controversy exists regarding IGF-I levels in patients with heart disease. The strength of our study is the fact that IGF-I was determined many years before signs or symptoms of cardiovascular disease were evident. Clearly, the recent study by Vaessen et al,6 in which genetic polymorphisms in the promotor region of the IGF-I gene were studied and found to be associated with risk of myocardial infarction, are in strong support of our findings.
References
1. Juul A, Scheike T, Davidsen M, et al. Low serum insulin-like growth factor-1 is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation. 2002; 106: 939–944.
2. Vahl N, Klausen I, Christiansen JS, et al. Growth hormone (GH) status is an independent determinant of serum levels of cholesterol and triglycerides in healthy adults. Clin Endocrinol (Oxford). 1999; 51: 309–316.[CrossRef][Medline] [Order article via Infotrieve]
3. Christ ER, Carroll PV, Albany E, et al. Effect of IGF-I therapy on VLDL apolipoprotein B100 metabolism in type 1 diabetes mellitus. Am J Physiol Endocrinol Metab. 2002; 282: E1154–E1162.
4. Hopkins KD, Lehmann ED, Gosling RG, et al. Biochemical correlates of aortic distensibility in vivo in normal subjects. Clin Sci (Colch.). 1993; 84: 593–597.[Medline] [Order article via Infotrieve]
5. Sandhu MS, Heald AH, Gibson JM, et al. Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study. Lancet. 2002; 359: 1740–1745.[CrossRef][Medline] [Order article via Infotrieve]
6. Vaessen N, Heutink P, Janssen JA, et al. A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction. Diabetes. 2001; 50: 637–642.
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