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Diabetes Care 26:1653-1654, 2003
© 2003 by the American Diabetes Association, Inc.

Letters: Comments and Responses
Letter

IGF-1 and Macrovascular Complications of Diabetes

Alternative interpretations of recently published data

Elena Conti, MD1, Dario Pitocco, MD2, Ettore Capoluongo, BSC, PHD3, Cecilia Zuppi, MD3, Giovanni Ghirlanda, MD2, Filippo Crea, MD, FESC, FACC1 and Felicita Andreotti, MD, PHD, FESC1

1 Department of Cardiology, Catholic University, Rome, Italy
2 Department of Diabetologia, Catholic University, Rome, Italy
3 Department of Hormonal Chemistry, Rome, Italy

The hypothesis of a detrimental role for IGF-1 and other growth factors in the development of vascular disease (1) has not been consistently supported by recent studies (2,3). New evidence suggests that cellular senescence (4) and impaired vascular endothelial proliferation, adhesion, and incorporation play a pivotal role in the development of macrovascular disease (5). Indeed, recent data on large numbers suggest that higher IGF-1 bioavailability may protect against the onset of ischemic heart disease (6,7) and glucose intolerance (8) and, in type 2 diabetic patients, may offer improved metabolic control and prevent vascular complications (9,10). Other potential beneficial actions of IGF-1 in cardiovascular physiology include increased nitric oxide synthesis and K+ channel opening (11,12), and this may explain the impaired small-vessel function associated with low IGF-1 levels in patients with cardiovascular syndrome X (12). By counteracting oxidized LDL-induced cytotoxicity and vascular smooth muscle cell apoptosis, IGF-1 may protect against plaque instability and rupture (2). In patients with acute myocardial infarction, markedly reduced IGF-1 values are associated with a worse outcome (13,14), and recent data suggest that intramyocardial (15,16) or vascular (17) gene delivery of growth factors can improve symptoms and exercise capacity in patients with coronary or peripheral vascular disease.

We were therefore surprised by two recent studies proposing IGF-1 as a mediator of harmful vascular effects (18,19). The authors found an inverse association between IGF binding protein (IGFBP)-1 and carotid intimal-medial thickness (r = -0.135, P = 0.041) (18), macrovascular disease (19), and hypertension (19) in patients with type 2 diabetes. IGFBP-1 is a minor component of the system of IGFBPs 1–6, first discovered in the 1990s, and regulated by a complex group of proteases and phosphatases (20). As IGFBP-1 is generally assumed to inhibit IGF-1 bioavailability (21), the authors conclude that IGF-1 exerted harmful vascular effect (18,19).

We propose two different interpretations of the above data, not necessarily exclusive. First, the reduced IGFBP-1 concentration observed in situations of vascular disease (18,19) could result from activation of a compensatory mechanism leading to higher IGF-1 bioavailability. This interpretation is confirmed by the finding in hypertensive patients of higher IGF-1 levels than in control subjects (22), and of a positive association among IGF-1, insulin sensitivity, and preserved vasodilator capacity (23,24). Indeed, in these patients, IGF-1 was the main independent predictor of both coronary reserve and insulin sensitivity (23). Second, alternatively or additionally, one should consider that the interaction between IGF-1 and its binding proteins is complex. An adequate serum amount of total IGFBP-1 is essential for IGF-1’s biological activity (8,25), independently of its phosphorilation status. Moreover, overexpression of IGFBP-1 attenuates IGF-1’s growth-promoting actions in vitro but enhances them in vivo (26). Thus, a threshold concentration of IGFBP-1 might enhance, rather than impair, IGF-1’s bioactivity through a partial agonism-like action.

Because IGFBPs have been characterized only recently and their physiology in humans is not completely understood, we think further studies are needed to better understand the true value of the IGF-1/IGFBP axis in promoting or protecting against vascular complications.

Footnotes

Address correspondence to Elena Conti, MD, Institute of Cardiology, Catholic University, Via Todi 60, 00181 Rome. E-mail: e_conti02{at}hotmail.com.

References

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  2. Frystyk J, Ledet T, Moller N, Flyvbjerg A, Orskov H: Cardiovascular disease and insulin-like growth factor 1. Circulation 106:893–895, 2002[Free Full Text]
  3. Janssen JA, Lamberts SWJ: The role of IGF-1 in the development of cardiovascular disease in type 2 diabetes mellitus: is prevention possible? Eur J Endocrinol 146:467–477, 2002[Abstract]
  4. Erusalimsky JD, Fenton M: Further in vivo evidence that cellular senescence is implicated in vascular pathophysiology (Letters). Circulation 106:e144, 2002[Free Full Text]
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  7. Conti E, Crea F, Andreotti F: IGF-1 and risk of ischemic heart disease. Circulation. In press
  8. Sandhu MS, Heald AH, Gibson JM, Cruickshank JK, Dunger DB, Wareham NJ: Circulating concentrations of insulin-like growth factor-1 and development of glucose intolerance: a prospective observational study. Lancet 359:1740–1745, 2002[Medline]
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  13. Conti E, Andreotti F, Sciahbasi A, Riccardi P, Marra G, Menini E, Ghirlanda G, Maseri A: Markedly reduced insulin-like growth factor-1 in the acute phase of myocardial infarction. J Am Coll Cardiol 38:26–32, 2001[Abstract/Free Full Text]
  14. Friberg L, Werner S, Eggertsen G, Ahnve S: Growth hormone and insulin-like growth factor-1 in acute myocardial infarction. Eur Heart J 21:1547–1554, 2000[Abstract/Free Full Text]
  15. Stewart DJ, on behalf of the REVASC Study Investigators: A phase 2, randomized, multicenter, 26-week study to assess the efficacy and safety of BIOBYPASS (AdGVVEGF121,10) delivered through minimally invasive surgery versus maximum medical treatment in patients with severe angina, advanced coronary artery disease, and no options for revascularization (Abstract). Circulation 106:2986, 2002[Free Full Text]
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  17. Vale PR, Isner JM, Rosenfield K: Therapeutic angiogenesis in critical limb and myocardial ischemia. J Interv Cardiol 14:511–528, 2001[Medline]
  18. Leinonen ES, Salonen JT, Salonen RM, Koistinen RA, Leinonen PJ, Sarna SS, Taskinen MR: Reduced IGFBP-1 is associated with thickening of the carotid wall in type 2 diabetes. Diabetes Care 25:1807–1812, 2002[Abstract/Free Full Text]
  19. Heald AH, Siddals KW, Fraser W, Taylor W, Kaushal K, Morris J, Young RJ, White A, Gibson JM: Low circulating levels of insulin-like growth factor binding protein-1 (IGFBP-1) are closely associated with the presence of macrovascular disease and hypertension in type 2 diabetes. Diabetes 51:2629–2636, 2002[Abstract/Free Full Text]
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  23. Galderisi M, Caso P, Cicala S, De Simone L, Barbieri M, Vitale G, de Divitiis O, Paolisso G: Positive association between circulating free insulin-like growth factor-1 levels and coronary flow reserve in arterial systemic hypertension. Am J Hypertens 15:766–772, 2002[Medline]
  24. Laviades C, Gil MJ, Monreal I, Gonzalez A, Diez J: Tissue availability of insulin-like growth factor I is inversely related to insulin resistance in essential hypertension: effects of angiotensin converting enzyme inhibition. J Hypertens 16:863–870, 1998[Medline]
  25. Shinobe M, Sanaka T, Nihei H, Nobuhiro S: IGF-1/IGFBP-1 as an index for discrimination between responder and nonresponder to recombinant human growth hormone in malnourished uremic patients on hemodialysis. Nephron 77:29–36, 1997[Medline]
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