Non-Traditional Pathways for Platelet Pathophysiology in Diabetes: Implications for Future Therapeutic Targets

Abstract

Cardiovascular complications remain the leading cause of morbidity and mortality in individuals with diabetes, driven by interlinked metabolic, inflammatory, and thrombotic changes. Hyperglycaemia, insulin resistance/deficiency, dyslipidaemia, and associated oxidative stress have been linked to abnormal platelet function leading to hyperactivity, and thus increasing vascular thrombotic risk. However, emerging evidence suggests platelets also contribute to low-grade inflammation and additionally possess the ability to interact with circulating immune cells, further driving vascular thrombo-inflammatory pathways. This narrative review highlights the role of platelets in inflammatory and immune processes beyond typical thrombotic effects and the impact these mechanisms have on cardiovascular disease in diabetes. We discuss pathways for platelet-induced inflammation and how platelet reprogramming in diabetes contributes to the high cardiovascular risk that characterises this population. Fully understanding the mechanistic pathways for platelet-induced vascular pathology will allow for the development of more effective management strategies that deal with the causes rather than the consequences of platelet function abnormalities in diabetes.

Keywords: diabetes; platelets; thrombo-inflammation.

Figure 1

Factors contributing to endothelial dysunfction, elevated vascular inflammation, platelet activation driving the development of atheroma and intravascular thrombus. Abbreviations; FFA: Free Fatty Acids, ROS: Reactive Oxygen Species, NF-kB: nuclear factor kappa-light-chain-enhacer of activated B cells, PKC: protein kinase C, AGEs: Advanced Glycation End Products, ox-LDL: oxidised-low density lipoprotein.

Figure 2

Factors present in diabetes that drive unopposed platelet activation, increased platelet activation and release of inflammatory cytokines, increased platelet aggregation and also elevated platelet inflammatory responses. Abbreviations; NO: nitric oxide, ROS: reactive oxygen species, AGEs: Advanced Glycation End Products, PKC: protein kinase C, TLR: Toll-like receptor, NLRP3: NOD-like receptor protein 3, IL-1β: interleukin-1β.