Time Course and Mechanisms of Circulating Progenitor Cell Reduction in the Natural History of Type 2 Diabetes

• Published in: Diabetes care Vol. 33; no. 5; pp. 1097 - 1102
• Main Authors: Fadini, Gian Paolo, Boscaro, Elisa, de Kreutzenberg, Saula, Agostini, Carlo, Seeger, Florian, Dimmeler, Stefanie, Zeiher, Andreas, Tiengo, Antonio, Avogaro, Angelo
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.05.2010
• Subjects: Adult; Aged; Antigens, CD34; Antigens, CD34 - metabolism; Apoptosis; Biological and medical sciences; blood; Bone marrow; Bone Marrow Cells; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Carbohydrate metabolism; Cardiovascular diseases; Cell Count; Cell research; Cholesterol; Cross-Sectional Studies; cytology; Dextrose; Diabetes; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 2 - epidemiology; Diabetes Mellitus, Type 2 - pathology; Diabetes. Impaired glucose tolerance; Diabetic Angiopathies; Diabetic Angiopathies - epidemiology; Diabetic Angiopathies - pathology; Disease Progression; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; epidemiology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; fasting; Female; Flow cytometry; Glucose; Glucose Intolerance; Glucose Intolerance - epidemiology; Glucose Intolerance - pathology; Glucose metabolism; glucose tolerance; Hematopoietic Stem Cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Homeostasis; Humans; Hyperglycemia; Male; Medical sciences; Metabolic diseases; Metabolic disorders; metabolism; Middle Aged; Miscellaneous; natural history; noninsulin-dependent diabetes mellitus; Original Research; pathology; Physiological aspects; Public health. Hygiene; Public health. Hygiene-occupational medicine; Risk Factors; stem cells; Studies; Type 2 diabetes; Variables; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Endocrinopathy; Type 2 diabetes; Human; Nutrition; Pathophysiology; Pathogenesis; Natural history of the disease; Stem cell; Metabolic diseases; Mechanism; Reduction; Temporal study; Evolution; Endocrinology
• ISSN: 0149-5992; 1935-5548; 1935-5548
• DOI: 10.2337/dc09-1999

OBJECTIVE: Reduction of bone marrow-derived circulating progenitor cells has been proposed as a novel mechanism of cardiovascular disease in type 2 diabetes. The present study was designed to describe the extent and potential mechanisms of progenitor cell reduction during the natural history of type 2 diabetes. RESEARCH DESIGN AND METHODS: We identified 425 individuals, divided into seven categories according to carbohydrate metabolism status (normal glucose tolerance [NGT], impaired fasting glucose, impaired glucose tolerance [IGT], and newly diagnosed type 2 diabetes) and diabetes duration (0-9, 10-19, and ≥20 years). These categories were examined as ideally describing the natural history of type 2 diabetes development and progression. We measured CD34+ and CD34+KDR+ progenitor cells by flow cytometry. We also evaluated progenitor cells in 20 coupled bone marrow and peripheral blood samples and examined progenitor cell apoptosis in 34 subjects. RESULTS: In comparison to NGT, CD34+ cells were significantly reduced in IGT and had a first nadir in newly diagnosed type 2 diabetes and a second nadir after 20 years of diabetes. Statistical adjustment for possible confounders confirmed that CD34+ cell counts are deeply reduced at time of diagnosis, that they partially recover during the subsequent 0-19 years, and that they dip again after ≥20 years. A similar, but less consistent, trend was detected for CD34+KDR+ cells. Peripheral blood CD34+ cells were directly correlated with bone marrow CD34+ cells and inversely correlated with CD34+ cell apoptosis. CONCLUSIONS: Circulating progenitor cell reduction marks the clinical onset of type 2 diabetes. Both defective mobilization and increased apoptosis may account for this phenomenon. While a partial recovery occurs during subsequent years, bone marrow reserve seems exhausted in the long term.