Alpha-ketoglutarate supplementation reduces inflammation and thrombosis in type 2 diabetes by suppressing leukocyte and platelet activation

The interplay between platelets and leukocytes contributes to the pathogenesis of inflammation, thrombosis, and cardiovascular diseases (CVDs) in type 2 diabetes (T2D). Our recent studies described alpha-ketoglutarate (alpha KG), a Krebs cycle intermediate metabolite as an inhibitor to platelets and leukocytes activation by suppressing phosphorylated-Akt (pAkt) through augmentation of prolyl hydroxylase-2 (PHD2). Dietary supplementation with a pharmacological concentration of aKG significantly inhibited lung inflammation in mice with either SARS-CoV-2 infection or exposed to hypoxia treatment. We therefore investigated if aKG supplementation could suppress hyperactivation of these blood cells and reduce thromboinflammatory complications in T2D. Our study describes that dietary supplementation with aKG (8 mg/100 g body wt. daily) for 7 days significantly reduced the activation of platelets and leukocytes (neutrophils and monocytes), and accumulation of IL1 beta, TNF alpha, and IL6 in peripheral blood of T2D mice. aKG also reduced the infiltration of platelets and leukocytes, and accumulation of inflammatory cytokines in lungs by suppressing pAkt and pP65 signaling. In a cross-sectional investigation, our study also described the elevated platelet-leukocyte aggregates and pro-inflammatory cytokines in circulation of T2D patients. T2D platelets and leukocytes showed an increased aggregation and thrombus formation in vitro. Interestingly, a pre-incubation of T2D blood samples with octyl aKG significantly suppressed the activation of these blood cells and ameliorated aggregate/thrombus formation in vitro. Thus, suggesting a potential therapeutic role of aKG against inflammation, thrombosis, and CVDs in T2D.