Time course and mechanisms of circulating progenitor cell reduction in the natural history of type 2 diabetes.
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.


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 >or=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 >or=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.
Department of Clinical and Experimental Medicine, University of Padova, Medical School, Padova, Italy. gianpaolofadini@hotmail.com
Gian Paolo
GP
Fadini
Elisa
E
Boscaro
Saula
S
de Kreutzenberg
Carlo
C
Agostini
Florian
F
Seeger
Stefanie
S
Dimmeler
Andreas
A
Zeiher
Antonio
A
Tiengo
Angelo
A
Avogaro
D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002452:Cell Count; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000473:pathology*; D003925:Diabetic Angiopathies / Q000453:epidemiology / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D018149:Glucose Intolerance / Q000453:epidemiology / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D018952:Antigens, CD34; D040301:Vascular Endothelial Growth Factor Receptor-2