Bone Marrow Progenitor Cell Mobilization in Diabetes

Diabetes mellitus is associated with a significant reduction of circulating progenitor cells (CPCs). CPCs are defined by the surface expression of the stem cell antigen CD34 and or CD133. These cells include endothelial progenitor cells (EPCs), which are involved in cardiovascular homeostasis and repair. EPCs are characterized by the co-expression of endothelial antigen(s), such as KDR. A reduction of CPCs in metabolic patients is associated with an increased risk of future adverse cardiovascular outcomes, such as myocardial infarction, stroke, revascularization, etc. Therefore, ways to active stimulate an increase of CPC levels in diabetes are actively pursued. Indeed, there are several drugs that stimulate CPCs or EPCs, but it is not fully clear if they are active also in diabetic patients. The mechanisms that account for CPC reduction in diabetes include defective bone marrow mobilization, reduced survival and increased homing outside the bloodstream. Experimental animal studies and preliminary data in humans indicate that a bone marrow defect is causally related to the low CPC level in diabetes. Our previous data in rats indicate that diabetes reduces the bone marrow responsiveness to G-CSF in terms of c-kit+/Sca-1+ progenitor cell mobilization. There is also some experimental evidence in type 2 diabetic rats that a specific form of autonomic neuropathy impairs bone marrow mobilization of progenitor cells. In the present study, we aim at investigating bone marrow responsiveness to pharmacological mobilization of CPC in diabetic patients as compared to non-diabetic subjects. Diabetic subjects and control subjects will be administered with a single dose of granulocyte colony stimulating factor (G-CSF) and progenitor cells will be quantified before and 24 hours after G-CSF administration. Progenitor cells will be analyzed by flow cytometry on the basis of the expression of CD34, CD133 and KDR. Mean percentage variation of CPCs and EPCs will be compared in diabetic versus non diabetic patients to understand whether or not diabetes is associated with a significant defective mobilization of progenitor cells. As a secondary aim, diabetic patients will be divided in those with and without diabetic autonomic neuropathy (DAN) to understand if DAN modulates bone marrow responsiveness to G-CSF.