Don´t give up on mitochondria as a target for the treatment of diabetes and its complications

Abstract

In this editorial, we discuss an article by Wang et al, focusing on the role of mitochondria in peripheral insulin resistance and insulin secretion. Despite numerous in vitro and pre-clinical studies supporting the involvement of mitochondrial dysfunction and oxidative stress in the pathogenesis of diabetes and its complications, efforts to target mitochondria for glycemic control in diabetes using mitochondria-targeted antioxidants have produced inconsistent results. The intricate functionality of mitochondria is summarized to underscore the challenges it poses as a therapeutic target. While mitochondria-targeted antioxidants have demonstrated improvement in mitochondrial function and oxidative stress in pre-clinical diabetes models, the results regarding glycemic control have been mixed, and no studies have evaluated their hypoglycemic effects in diabetic patients. Nonetheless, pre-clinical trials have shown promising outcomes in ameliorating diabetes-related complications. Here, we review some reasons why mitochondria-targeted antioxidants may not function effectively in the context of mitochondrial dysfunction. We also highlight several alternative approaches under development that may enhance the targeting of mitochondria for diabetes treatment.

Keywords: Diabetes mellitus; Insulin resistance; Mitochondrion; Mitochondrial dysfunction; MitoQ; MitoTEMPO; SkQ; Elamipretide; Mitochondria transplantation; Glycemic control

Core Tip: Mitochondrial dysfunction and oxidative stress are closely linked to the development of diabetes and its complications. This has motivated the targeting of antioxidants to the mitochondria for diabetes treatment, which has generated in pre-clinical trials some encouraging results in diabetic complications, but inconsistent results in glycemic control. Moreover, there are very few studies with these molecules and only in healthy patients, with no encouraging results. There are several challenges to overcome to make mitochondria an efficient pharmacological target against diabetes, but recent developments such as mitochondrial transplantation, bioactive small peptides, and atomistic simulations could help to achieve this goal.