Platelet Bioenergetics Profiling Reveals Non-Mitochondrial Dysfunction as a Potential Biomarker of Diabetic Complications

Abstract

Diabetes is associated with systemic bioenergetic dysfunction that contributes to complications such as diabetic peripheral neuropathy (DPN). While mitochondrial impairment has been implicated, the role of non-mitochondrial pathways is less clearly defined. To address this gap, we optimized platelet-based extracellular flux assays as a minimally invasive platform to study human bioenergetics. A seeding density of 20 x 106 platelets per well provided reliable respiratory measurements, consistent with the presence of 5-8 mitochondria per platelet. Platelets from both type 2 diabetes (T2D) and DPN patients demonstrated a significant reduction in non-mitochondrial oxygen consumption rate (OCR) compared with controls. This finding suggests impairment of oxygen-consuming processes beyond the mitochondria, likely reflecting diminished activity of oxidoreductase enzymes such as NADPH oxidases, cyclooxygenases, and lipoxygenases, which regulate redox balance, inflammatory signaling, and vascular tone. In contrast, basal and ATP-linked OCR were only marginally reduced in T2D and not significantly altered in DPN, indicating that mitochondrial-linked dysfunction may be more subtle or heterogeneous in these patient populations. The consistent decrease in non-mitochondrial OCR across both T2D and DPN highlights its potential as an early and sensitive indicator of systemic bioenergetic dysregulation in diabetes. These findings demonstrate that platelets are a practical and repeatable resource for assessing bioenergetics in humans. Diabetes impairs both mitochondrial and non-mitochondrial respiration, with the latter showing the most robust alterations. Reduced non-mitochondrial OCR may contribute independently to the pathogenesis of DPN and holds promise as a biomarker for prognosis and therapeutic monitoring in diabetic complications.