Type 2 diabetes was associated with significantly higher levels of reticulated platelets compared to healthy controls (11.1% vs 6.6%), correlating with hemoglobin A1c and plasma S100A8/A9 levels.
Observational (n=24)
Does inhibiting S100A8/A9 signaling or lowering blood glucose reduce reticulated thrombocytosis and atherogenesis in diabetic models?
This study identifies a novel mechanism where hyperglycemia-induced, neutrophil-derived S100A8/A9 promotes reticulated thrombocytosis and atherogenesis via Kupffer cell IL-6 production, offering new therapeutic targets for cardiovascular risk in diabetes.
Absolute Event Rate: 11.1% vs 6.6%
p-value: p=0.0102
Platelets play a critical role in atherogenesis and thrombosis-mediated myocardial ischemia, processes that are accelerated in diabetes. Whether hyperglycemia promotes platelet production and whether enhanced platelet production contributes to enhanced atherothrombosis remains unknown. Here we found that in response to hyperglycemia, neutrophil-derived S100 calcium-binding proteins A8/A9 (S100A8/A9) interact with the receptor for advanced glycation end products (RAGE) on hepatic Kupffer cells, resulting in increased production of IL-6, a pleiotropic cytokine that is implicated in inflammatory thrombocytosis. IL-6 acts on hepatocytes to enhance the production of thrombopoietin, which in turn interacts with its cognate receptor c-MPL on megakaryocytes and bone marrow progenitor cells to promote their expansion and proliferation, resulting in reticulated thrombocytosis. Lowering blood glucose using a sodium-glucose cotransporter 2 inhibitor (dapagliflozin), depleting neutrophils or Kupffer cells, or inhibiting S100A8/A9 binding to RAGE (using paquinimod), all reduced diabetes-induced thrombocytosis. Inhibiting S100A8/A9 also decreased atherogenesis in diabetic mice. Finally, we found that patients with type 2 diabetes have reticulated thrombocytosis that correlates with glycated hemoglobin as well as increased plasma S100A8/A9 levels. These studies provide insights into the mechanisms that regulate platelet production and may aid in the development of strategies to improve on current antiplatelet therapies and to reduce cardiovascular disease risk in diabetes.
Kraakman et al. (Sun,) conducted a observational in Type 2 diabetes (n=24). Type 2 diabetes vs. Healthy controls was evaluated on Reticulated platelets (%) (p=0.0102). Type 2 diabetes was associated with significantly higher levels of reticulated platelets compared to healthy controls (11.1% vs 6.6%), correlating with hemoglobin A1c and plasma S100A8/A9 levels.