Editors' ChoiceDiabetes

It’s reticulated: Diabetes, atherosclerosis, and reticulated platelets

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Science Translational Medicine  14 Jun 2017:
Vol. 9, Issue 394, eaan5224
DOI: 10.1126/scitranslmed.aan5224


New research describes regulatory pathways for reticulated thrombocytosis in a mouse model of diabetes.

Worldwide, 8% of adults have diabetes, which is associated with a doubled risk of heart attack and stroke. Immature platelets are reticulated and more reactive than mature platelets. These reactive, reticulated platelets have been characterized in conditions including cardiovascular disease, sepsis, platelet disorders, and diabetes. In a recent paper, Kraakman et al. investigated immature reticulated platelets and the pathways involved in their regulation using a mouse model of diabetes.

Diabetes was induced in C57BL/6 mice with streptozotocin, which is toxic to insulin-producing pancreatic beta cells. These mice had increased reticulated platelets, platelet-leukocyte aggregates, and leukocyte activation and proliferation. These changes resolved with normalization of blood glucose using an oral hypoglycemic agent. A liver macrophage, called Kupffer cell, population is increased in diabetic mice, and a greater proportion of these cells produce the proinflammatory cytokine interleukin 6 (IL-6). IL-6 production is regulated via binding of the receptor for advanced glycation endproducts (RAGE) to neutrophil-derived S100 calcium-binding proteins A8/A9 (S100A8/A9) ligand. IL-6 increases thrombopoietin, which then increases reticulated platelets via interaction with platelet progenitor cells. Chemical depletion of Kupffer cells, genetic knockout of IL-6 or RAGE, neutrophil depletion, and S100A8/A9 deletion or blockade reduced reticulated platelets in mice with diabetes. In diabetic Apoe–/– mice, which are prone to atherosclerosis, blockade of S100A8/A9 decreased aortic plaque size and macrophage density. Diet-induced obese mice and mice with an obese phenotype due to genetic background (ob/ob) had more IL-6 production by Kupffer cells and more reticulated platelets than lean mice.

The authors next assessed some of these parameters in a cohort of people with type 2 diabetes (DM2, n = 10), who also had peripheral vascular disease and were preparing to undergo lower extremity revascularization procedures. The comparison cohort (n = 14) was “healthy controls” who did not have any cardiovascular disease. However, both cases and controls were taking aspirin, an antiplatelet agent, for at least 7 days. People with DM2, peripheral vascular disease, and taking aspirin had increased reticulated platelets, monocyte-platelet aggregates, and more S100A8/A9 than controls taking aspirin. A reported positive correlation between hemoglobin A1C and reticulated platelets included the 14 controls, who presumably had normal A1C.

This study intrigues with the questions it raises. S100A8/A9 ligand binds toll-like receptor 4 (TLR4), in addition to RAGE. Given the importance of TLR4 signaling in innate immune response to infection, how does S100A8/A9 blockade impact infection risk? Could dual glycemic control and S100A8/A9 blockade further diminish atherosclerotic plaques? The impact of S100A8/A9 blockade in ob/ob mice was not reported, which is an important comparison to assess this pathway in metabolic syndromes. Does S100A8/A9 blockade normalize reticulated platelets and IL-6 production in obesity and metabolic syndromes? Additionally, the impact that aspirin therapy had on platelet populations is unclear, as is the degree to which concomitant peripheral arterial disease in the DM2 group impacted the differences in cases and controls attributed to DM2 by the authors. Nonetheless, this research describes interesting pathways involved in regulation of reticulated platelets.

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