Platelet Metabolism in Obesity and Diabetes-Associated Thrombosis

Diabetes mellitus (DM, both type 1 and 2) and other metabolic pathologies (e.g., obesity) are significant risk factors for cardiovascular disease, in part, because they increase thrombotic risk. Platelet hyperactivity, a sequela of DM, is an important contributor to this elevated risk; yet how these metabolic pathologies lead to platelet hyperactivity is poorly understood. Past research relied on semi-specific inhibitors and crude analytical tools, which yielded incomplete pictures of platelet bioenergetics. As the global prevalence of obesity and DM increases, therapeutics to control thrombosis are urgently needed. We hypothesize that metabolic plasticity of platelets contributes to their hyperglycemia-induced hyperactivity and dysfunction in obesity/DM. Our concept of platelet metabolic plasticity grows from our observations of platelet adaptability in utilizing different metabolites and how that affects platelet functions. We and others showed that megakaryocyte/platelet-specific deficiency in glucose transporters or in autophagy (a degradation pathway that recycles metabolites) leads to defective thrombosis. We have developed a comprehensive platelet metabolism analysis toolkit that includes state-of-the-art Stable Isotope Resolved Metabolomics (SIRM), Seahorse, mitochondrial membrane potential and total glycogen measurements. Our preliminary data show enormous metabolic plasticity in platelets during activation by thrombin, including enhanced anaerobic glycolysis/lactate fermentation (particularly fructose-1,6- bisphosphate depletion), glycogen consumption, the tricarboxylic acid (TCA) and pyruvate/malate cycles, and oxidative phosphorylation. Using our extraordinary tools to analyze both diabetic patient and rodent platelets, we will address our hypothesis in two aims: Aim 1, we will define hyperglycemia-induced metabolic plasticity in human and mouse platelets. Aim 2, we will delineate the effects of anti-diabetic drugs on platelet metabolism and functions. Our proposed experiments will uncover novel aspects of platelet biology and thus identify new therapeutic strategies to modulate platelet metabolism and reduce obesity/DMassociated thrombotic risk.