Platelet biomarkers of thrombotic risk in type 2 diabetes

Abstract

Platelet hyperreactivity contributes to the increased cardiovascular risk in type 2 diabetes mellitus (T2DM), yet its molecular basis is incompletely defined. The platelet endoplasmic reticulum (ER) is central to calcium storage, lipid synthesis and protein folding. In other cell types, ER stress disrupts calcium homeostasis, and platelets in T2DM exhibit elevated cytosolic calcium, suggesting ER dysfunction may drive platelet hyperreactivity.

This thesis examined how metabolic perturbations remodel the platelet proteome and alter function. Platelets from patients with T2DM and cardiovascular disease, together with platelets and bone marrow megakaryocytes from diabetic mouse models, were analysed. SEC61B, a subunit of the ER-resident SEC61 translocon, was significantly increased in platelets from hyperglycaemic humans and mice. Functional studies demonstrated that SEC61 acts as a calcium leak channel in platelets and is dysregulated in hyperglycaemia. Pharmacological inhibition of SEC61 in diabetic mice reduced platelet calcium mobilisation, aggregation and thrombus formation, identifying SEC61 as a potential antiplatelet target.

Given interest in fasting as a strategy to improve metabolic health, platelet proteomics and function were also assessed in healthy volunteers undergoing prolonged supervised fasting. Fasting altered the platelet proteome, enriching pathways involved in fatty acid β-oxidation and enhancing activation via protease-activated receptor-4 signalling.

Megakaryocyte ER proteins were further examined in diabetic mice, and ER protein 57 (ERp57) was increased in hyperglycaemia. Platelet-specific ERp57 knockout induced compensatory ER stress pathway enrichment and reduced platelet von Willebrand factor.

ER-resident proteins, particularly SEC61 and ERp57, are regulators of platelet activation and may be potential therapeutic targets to reduce thrombotic risk in T2DM.