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01-10-2007 | Article

Glucose tolerance is negatively associated with circulating progenitor cell levels

Authors: G. P. Fadini, L. Pucci, R. Vanacore, I. Baesso, G. Penno, A. Balbarini, R. Di Stefano, R. Miccoli, S. de Kreutzenberg, A. Coracina, A. Tiengo, C. Agostini, S. Del Prato, A. Avogaro

Published in: Diabetologia | Issue 10/2007

Abstract

Aims/hypothesis

Circulating progenitor cells participate in cardiovascular homeostasis. Depletion of the pool of endothelial progenitor cells (EPCs) is associated with increased cardiovascular risk. Furthermore, EPCs are reduced in the presence of classical risk factors for atherosclerotic disease, including diabetes mellitus. This study was designed to evaluate progenitor cell levels in volunteers with different degrees of glucose tolerance.

Methods

Cardiovascular parameters and the levels of circulating CD34⁺ and CD34⁺ kinase insert domain receptor (KDR)⁺ cells were determined in 219 middle-aged individuals with no pre-diagnosed alterations in carbohydrate metabolism. Glucose tolerance was determined by fasting and 2 h post-challenge glucose levels, with IFG and IGT considered as pre-diabetic states.

Results

CD34⁺ and CD34⁺KDR⁺ cells were significantly reduced in individuals who were found to have diabetes mellitus, and were negatively correlated with both fasting and post-challenge glucose in the whole population. While only CD34⁺ cells, but not CD34⁺KDR⁺ cells, were significantly reduced in pre-diabetic individuals, post-challenge glucose was an independent determinant of the levels of both CD34⁺ and CD34⁺KDR⁺ cells.

Conclusions/interpretation

Glucose tolerance was negatively associated with progenitor cell levels in middle-aged healthy individuals. Depletion of endothelial progenitors with increasing fasting and post-meal glucose may be one cause of the high incidence of cardiovascular damage in individuals with pre-diabetes.

Almdal T, Scharling H, Jensen J, Vestergaard H (2004) The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. Arch Intern Med 164:1422–1426PubMedCrossRef

UKPDS Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853CrossRef

Caballero AE (2005) Metabolic and vascular abnormalities in subjects at risk for type 2 diabetes: the early start of a dangerous situation. Arch Med Res 36:241–249PubMedCrossRef

Eschwege E, Richard J, Thibult N et al (1985) Coronary heart disease mortality in relation with diabetes, blood glucose and plasma insulin levels. The Paris Prospective Study, ten years later. Horm Metab Res Suppl 15:41–46PubMed

DECODE Study Group and the European Diabetes Epidemiology Group (2001) Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med 161:397–405CrossRef

Hu F, Stampfer M, Haffner S, Solomon C, Willett W, Manson J (2002) Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care 25:1129–1134PubMedCrossRef

Lawes C, Parag V, Bennett D et al (2004) Blood glucose and risk of cardiovascular disease in the Asia Pacific region. Diabetes Care 27:2836–2842PubMedCrossRef

Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A (1999) Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care 22:920–924PubMedCrossRef

Chiasson J, Josse R, Gomis R et al (2003) Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA 290:486–494PubMedCrossRef

10.

Ceriello A (2005) Postprandial hyperglycemia and diabetes complications: is it time to treat? Diabetes 54:1–7PubMedCrossRef

11.

Yudkin J (2001) Post-load hyperglycaemia—an inappropriate therapeutic target. Lancet 359:166–167CrossRef

12.

Asahara T, Murohara T, Sullivan A et al (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967PubMedCrossRef

13.

Takahashi T, Kalka C, Masuda H et al (1999) Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 5:434–438PubMedCrossRef

14.

Iwakura A, Luedemann C, Shastry S et al (2003) Estrogen-mediated, endothelial nitric oxide synthase-dependent mobilization of bone marrow-derived endothelial progenitor cells contributes to reendothelialization after arterial injury. Circulation 108:3115–3121PubMedCrossRef

15.

Fadini GP, de Kreutzenberg SV, Coracina A et al (2006) Circulating CD34+ cells, metabolic syndrome, and cardiovascular risk. Eur Heart J 27:2247–2255PubMedCrossRef

16.

Vasa M, Fichtlscherer S, Aicher A et al (2001) Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 89:E1–E7PubMed

17.

Shantsila E, Watson T, Lip GY (2007) Endothelial progenitor cells in cardiovascular disorders. J Am Coll Cardiol 49:741–752PubMedCrossRef

18.

Rosenzweig A (2005) Circulating endothelial progenitors—cells as biomarkers. N Engl J Med 353:1055–1057PubMedCrossRef

19.

Fadini GP, Miorin M, Facco M et al (2005) Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus. J Am Coll Cardiol 45:1449–1457PubMedCrossRef

20.

Fadini GP, Sartore S, Albiero M et al (2006) Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler Thromb Vasc Biol 26:2140–2146PubMedCrossRef

21.

Fadini GP, Sartore S, Schiavon M et al (2006) Diabetes impairs progenitor cell mobilisation after hindlimb ischaemia–reperfusion injury in rats. Diabetologia 49:3075–3084PubMedCrossRef

22.

Jiao C, Fricker S, Schatteman G (2006) The chemokine (C–X–C motif) receptor 4 inhibitor AMD3100 accelerates blood flow restoration in diabetic mice. Diabetologia 49:2786–2789PubMedCrossRef

23.

Schatteman GC, Hanlon HD, Jiao C, Dodds SG, Christy BA (2000) Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice. J Clin Invest 106:571–578PubMedCrossRef

24.

Dupont W, Plummer W (1990) Power and sample size calculations: a review and computer program. Control Clin Trials 11:116–128PubMedCrossRef

25.

Akhter J (1997) The American Diabetes Association’s clinical practice recommendations and the developing world. Diabetes Care 20:1044–1045PubMed

26.

Fadini GP, Sartore S, Agostini C, Avogaro A (2007) Significance of endothelial progenitor cells in subjects with diabetes mellitus. Diabetes Care 30:1305–1313PubMedCrossRef

27.

Rustemeyer P, Wittkowski W, Jurk K, Koller A (2006) Optimized flow cytometric analysis of endothelial progenitor cells in peripheral blood. J Immunoassay Immunochem 27:77–88PubMedCrossRef

28.

Fadini GP, Coracina A, Baesso I et al (2006) Peripheral blood CD34+KDR+ endothelial progenitor cells are determinants of subclinical atherosclerosis in a middle-aged general population. Stroke 37:2277–2282PubMedCrossRef

29.

Werner N, Kosiol S, Schiegl T et al (2005) Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 353:999–1007PubMedCrossRef

30.

Schmidt-Lucke C, Rossig L, Fichtlscherer S et al (2005) Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation 111:2981–2987PubMedCrossRef

31.

Botta R, Gao E, Stassi G et al (2004) Heart infarct in NOD-SCID mice: therapeutic vasculogenesis by transplantation of human CD34+ cells and low dose CD34+KDR+ cells. FASEB J 18:1392–1394PubMed

32.

Madeddu P, Emanueli C, Pelosi E et al (2004) Transplantation of low dose CD34+KDR+ cells promotes vascular and muscular regeneration in ischemic limbs. FASEB J 18:1737–1739PubMed

33.

Kunz GA, Liang G, Cuculoski F et al (2006) Circulating endothelial progenitor cells predict coronary artery disease severity. Am Heart J 152:190–195PubMedCrossRef

34.

Fadini GP, Sartore S, Agostini C, Avogaro A (2007) Endothelial progenitor cells and the natural history of atherosclerosis. DOI: 10.1016/j.atherosclerosis.2007.03.046 (in press)

35.

Tepper OM, Galiano RD, Capla JM et al (2002) Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 106:2781–2786PubMedCrossRef

36.

Meigs J, Nathan D, D’Agostino R Sr, Wilson P, Study FO (2002) Fasting and postchallenge glycemia and cardiovascular disease risk: the Framingham Offspring Study. Diabetes Care 25:1845–1850PubMedCrossRef

37.

Bonora E (2002) Postprandial peaks as a risk factor for cardiovascular disease: epidemiological perspectives. Int J Clin Pract Suppl 129:5–11PubMed

38.

Muntner P, Wildman R, Reynolds K, Desalvo K, Chen J, Fonseca V (2005) Relationship between HbA1c level and peripheral arterial disease. Diabetes Care 28:1981–1987PubMedCrossRef

39.

Marchetti V, Menghini R, Rizza S et al (2006) Benfotiamine counteracts glucose toxicity effects on endothelial progenitor cell differentiation via Akt/FoxO signaling. Diabetes 55:2231–2237PubMedCrossRef

40.

Krankel N, Adams V, Linke A et al (2005) Hyperglycemia reduces survival and impairs function of circulating blood-derived progenitor cells. Arterioscler Thromb Vasc Biol 25:698–703PubMedCrossRef

41.

Humpert PM, Neuwirth R, Battista MJ et al (2005) SDF-1 genotype influences insulin-dependent mobilization of adult progenitor cells in type 2 diabetes. Diabetes Care 28:934–936PubMedCrossRef

42.

Ceriello A (2004) Impaired glucose tolerance and cardiovascular disease: the possible role of post-prandial hyperglycemia. Am Heart J 147:803–807PubMedCrossRef

43.

Cavalot F, Petrelli A, Traversa M et al (2006) Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the San Luigi Gonzaga Diabetes Study. J Clin Endocrinol Metab 91:813–819PubMedCrossRef

44.

Ceriello A, Taboga C, Tonutti L et al (2002) Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment. Circulation 106:1211–1218PubMedCrossRef

45.

Yeh E, Zhang S, Wu H, Korbling M, Willerson J, Estrov Z (2003) Transdifferentiation of human peripheral blood CD34+-enriched cell population into cardiomyocytes, endothelial cells, and smooth muscle cells in vivo. Circulation 108:2070–2073PubMedCrossRef

46.

Madeddu P (2005) Therapeutic angiogenesis and vasculogenesis for tissue regeneration. Exp Physiol 90:315–326PubMedCrossRef

47.

Hirschi KK, Goodell MA (2002) Hematopoietic, vascular and cardiac fates of bone marrow-derived stem cells. Gene Ther 9:648–652PubMedCrossRef

Title: Glucose tolerance is negatively associated with circulating progenitor cell levels
Authors: G. P. Fadini
L. Pucci
R. Vanacore
I. Baesso
G. Penno
A. Balbarini
R. Di Stefano
R. Miccoli
S. de Kreutzenberg
A. Coracina
A. Tiengo
C. Agostini
S. Del Prato
A. Avogaro
Publication date: 01-10-2007
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 10/2007
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-007-0732-y

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