Potential Role of Mitochondria as Modulators of Blood Platelet Activation and Reactivity in Diabetes and Effect of Metformin on Blood Platelet Bioenergetics and Platelet Activation

Abstract

Blood platelet dysfunctions are strongly involved in the development of the micro- and macrovascular complications in diabetes mellitus (DM). However, the molecular causes of abnormal platelet activation in DM remain unclear. Experimental data suggests that platelet mitochondria can regulate the prothrombotic phenotype of platelets, and changes in these organelles may influence platelet activation and modify platelet responses to stimulation. The present study evaluates the impact of DM on mitochondrial respiratory parameters and blood platelet activation/reactivity in a rat model of experimental diabetes following 1, 2.5 and 5 months of streptozotocin (STZ)-induced diabetes. Moreover, a mild inhibition of the mitochondrial respiratory chain with the use of metformin under in vitro and in vivo conditions was tested as a method to reduce platelet activation and reactivity. The platelets were studied with a combination of flow cytometry and advanced respirometry. Our results indicate that prolonged exposure of blood platelets to high concentrations of glucose, as in diabetes, can result in elevated blood platelet mitochondrial respiration; this may be an effect of cell adaptation to the high availability of energy substrates. However, as these alterations occur later than the changes in platelet activation/reactivity, they may not constitute the major reason for abnormal platelet functioning in DM. Moreover, metformin was not able to inhibit platelet activation and reactivity under in vitro conditions despite causing a decrease in mitochondrial respiration. This indicates that the beneficial effect of metformin on the coagulation system observed in vivo can be related to other mechanisms than via the inhibition of platelet activation.

High Dose of Metformin Decreases Susceptibility to Occlusive Arterial Thrombosis in Type-2 Diabetic Mice

“…5). T2D mice show higher baseline platelet mitochondrial respiration (23), consistent with hyperglycemia-induced increase in glucose metabolism (24). There were no differences with Metformin treatment in any of the parameters we interrogated in T2D treated mice compared to controls (Fig.…”

High Dose of Metformin Decreases Susceptibility to Occlusive Arterial Thrombosis Uniquely in Type-2 Diabetic Mice

“…Accumulating studies establish a role for mitochondrial dysfunction in platelets in T2D [23] . Therefore, we decided to measured platelet mitochondrial bioenergetics in our model.…”

Platelet mitochondria: the mighty few

“…Specific mechanisms leading to increased platelet reactivity have not fully been elucidated, but include increased platelet receptor density, increased Ca 2+ signaling and hyperreactivity to platelet agonists [79–81]. Recent work linked platelet mitochondrial impairment to the dysregulation in platelet function observed in diabetes [82 ▪▪ ,83]. Mitochondrial stress tests, which calculate mitochondrial efficiency in various metabolic processes, have shown that resting platelets from diabetic patients have lower maximal respiration compared with nondiabetic patients [25,82 ▪▪ ,83].…”

“…Recent work linked platelet mitochondrial impairment to the dysregulation in platelet function observed in diabetes [82 ▪▪ ,83]. Mitochondrial stress tests, which calculate mitochondrial efficiency in various metabolic processes, have shown that resting platelets from diabetic patients have lower maximal respiration compared with nondiabetic patients [25,82 ▪▪ ,83]. Activation of diabetic platelets with thrombin further accentuated differences in maximal respiration, while also demonstrating a decrease in basal oxygen rate consumption (OCR) and ATP production [82 ▪▪ ].…”