Diabetes mellitus impairs circulating proangiogenic granulocytes.

Aims/hypothesis: Cardiovascular risk in diabetes is at least in part attributable to defective angiogenesis. Since diabetes negatively affects blood cells involved in angiogenesis, we herein evaluated whether diabetes impairs proangiogenic granulocytes (PAGs).

Methods: We characterised and quantified PAGs as CD49d granulocytes in peripheral blood of participants with type 2 or type 1 diabetes and in non-diabetic control participants. We evaluated PAG antigenic profile and assessed in vitro functional properties of CD49d granulocytes using 2D and 3D angiogenesis assays. We also quantified PAGs before and after glucose control with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin. In parallel, we measured Ly6GCD49d PAGs in streptozotocin-induced type 1-like diabetic mice vs non-diabetic control mice.

Results: PAGs were composed of eosinophils (>80%) and neutrophils (<20%). Within both populations, CD49d identified CXCR4/VEGFR1 cells. CD49d granulocytes supported in vitro angiogenesis by endothelial cells significantly more than CD49d control granulocytes, and physically interacted with endothelial cells. Granulocytes from type 2 diabetic participants had a profoundly impaired capacity to stimulate endothelial cell tubule formation compared with those from non-diabetic control participants. CD49d PAGs were reduced by 30-40% and were functionally impaired in diabetic vs control individuals. PAG levels inversely correlated with plasma glucose (r = -0.25; p = 0.025) and significantly increased 1.8-times after glucose control with dapagliflozin, which reduced HbA by 1.0% (11 mmol/mol). Levels of Ly6GCD49d PAGs were also significantly reduced also in type 1 diabetic mice vs control mice.

Conclusions/interpretation: We illustrate a significant impairment of PAGs in diabetes and provide evidence for a direct role of hyperglycaemia. These findings add mechanistic information to explain the defective angiogenesis in diabetes. Graphical abstract.