Hyperglycemia enhances arsenic-induced platelet and megakaryocyte activation

J Transl Med. 2017 Mar 6;15(1):55. doi: 10.1186/s12967-017-1148-1.


Objective: Low to moderate inorganic arsenic (iAs) exposure is independently associated with cardiovascular disease (CVD), particularly for patients with diabetes mellitus (DM). The mechanism of increased CVD risk from iAs exposure in DM has not been adequately characterized. We evaluated whether increasing concentrations of glucose enhance the effects of iAs on platelet and megakaryocyte activity, key steps in atherothrombosis.

Methods: Healthy donor whole blood was prepared in a standard fashion and incubated with sodium arsenite in a range from 0 to 10 µM. iAs-induced platelet activation was assessed by platelet receptor CD62P (P-selectin) expression and monocyte-platelet and leukocyte-platelet aggregation (MPA and LPA, respectively) in the presence of increasing sodium arsenite and glucose concentrations. Megakaryocyte (Meg-01) cell adhesion and gene expression was assessed after incubation with or without iAs and increasing concentrations of D-glucose.

Results: Platelet activity markers increased significantly with 10 vs. 0 µM iAs (P < 0.05 for all) and with higher D-glucose concentrations. Platelet activity increased significantly following co incubation of 1 and 5 µM iAs concentrations with hyperglycemic D-glucose (P < 0.01 for both) but not after incubation with euglycemic D-glucose. Megakaryocyte adhesion was more pronounced after co incubation with iAs and hyperglycemic than euglycemic D-glucose, while gene expression increased significantly to iAs only after co incubation with hyperglycemic D-glucose.

Conclusion: We demonstrate that glucose concentrations common in DM potentiate the effect of inorganic arsenic exposure on markers of platelet and megakaryocyte activity. Our results support recent observational cohort data that DM enhances the vasculotoxic effects of arsenic exposure, and suggest that activation of the platelet-megakaryocyte hemostatic axis is a pathway through which inorganic arsenic confers atherothrombotic risk, particularly for patients with DM.

Keywords: Atherothrombosis; Diabetes mellitus; Environmental exposures; Inorganic arsenic; Megakaryocyte adhesion; Platelet activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Arsenic / pharmacology*
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism*
  • Blood Platelets / pathology
  • Cell Adhesion / drug effects
  • Flow Cytometry
  • Gene Expression Regulation / drug effects
  • Humans
  • Hyperglycemia / pathology*
  • Megakaryocytes / drug effects
  • Megakaryocytes / metabolism*
  • Megakaryocytes / pathology
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • P-Selectin / metabolism
  • Platelet Activation / drug effects*
  • Thrombin / pharmacology


  • NF-kappa B
  • P-Selectin
  • Thrombin
  • Arsenic