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

Abstract

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 >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.

Figure 1

Observed and adjusted variation of circulating CD34+ cells in patients grouped according to carbohydrate metabolism or diabetes (DM) duration, as appropriate. The mean value of patients with NGT was taken to represent the zero point. Bars indicate 95% CIs of means (observed values) and estimates (adjusted values). *Observed values significantly different versus NGT. †Adjusted values significantly different versus NGT. Model 1 (A) and model 2 (B) refers to the strategy used to control for confounders (see statistical analyses).

Figure 2

Potential mechanisms of CD34+ progenitor cell reduction. A: Circulating CD34+ cell counts in pooled patients with 0–19 years of disease duration, divided according to the use of drugs known to affect peripheral blood progenitor cells: statins, ACE inhibitors, angiotensin receptor blockers (ARBs), insulin, and all these medications together. B: Variation of plasma VEGF concentrations in pre-diabetic (IFG/IGT) and diabetic (DM) versus subjects with NGT. *Significant versus observed NGT values. C: A significant negative correlation was found between peripheral blood CD34+ cell count and the apoptotic rate of CD34+ cells. D: A significant direct correlation was found between peripheral blood and bone marrow CD34+ cell counts. ●, nondiabetic subjects; ○, diabetic patients; Ctrl, control.