Targeting Mitochondria in Diabetes.

Nina Krako Jakovljevic,Marija Macesic,Katarina Lalic,Aleksandra Jotic,Tanja Milicic,Kasja Pavlovic,Milica Stoiljkovic,Jelena Stanarcic Gajovic,Nebojsa M Lalic,Ljiljana Lukic

doi:10.3390/ijms22126642

Nina Krako Jakovljevic, Marija Macesic + Show 8 more

Open Access

https://doi.org/10.3390/ijms22126642

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Abstract

Type 2 diabetes (T2D), one of the most prevalent noncommunicable diseases, is often preceded by insulin resistance (IR), which underlies the inability of tissues to respond to insulin and leads to disturbed metabolic homeostasis. Mitochondria, as a central player in the cellular energy metabolism, are involved in the mechanisms of IR and T2D. Mitochondrial function is affected by insulin resistance in different tissues, among which skeletal muscle and liver have the highest impact on whole-body glucose homeostasis. This review focuses on human studies that assess mitochondrial function in liver, muscle and blood cells in the context of T2D. Furthermore, different interventions targeting mitochondria in IR and T2D are listed, with a selection of studies using respirometry as a measure of mitochondrial function, for better data comparison. Altogether, mitochondrial respiratory capacity appears to be a metabolic indicator since it decreases as the disease progresses but increases after lifestyle (exercise) and pharmacological interventions, together with the improvement in metabolic health. Finally, novel therapeutics developed to target mitochondria have potential for a more integrative therapeutic approach, treating both causative and secondary defects of diabetes.

Highlights

Diabetes is a chronic metabolic disease caused by insufficient insulin production and secretion and, in case of type 2 diabetes (T2D), the inability of tissues to adequately respond to insulin
This review aims to give an overview of the latest studies done in human subjects with Type 2 diabetes (T2D) that investigate mitochondria in skeletal muscle, liver and blood cells as a potential target for diabetes therapy
Among all insulin-sensitive tissues, we decided to focus on the role of mitochondria in skeletal muscle and liver, since insulin resistance and mitochondrial dysfunction in these tissues have the biggest impact on the disruption of whole-body energy homeostasis

Summary

Introduction

Diabetes is a chronic metabolic disease caused by insufficient insulin production and secretion and, in case of type 2 diabetes (T2D), the inability of tissues to adequately respond to insulin. Among all insulin-sensitive tissues, we decided to focus on the role of mitochondria in skeletal muscle and liver (as major sites for glucose disposal and production), since insulin resistance and mitochondrial dysfunction in these tissues have the biggest impact on the disruption of whole-body energy homeostasis Along with these tissues commonly studied in diabetes, we include in this review studies done on blood cells, as we want to point out the potential of respirometric analysis of these samples in drug screening and surrogate marker validation. Liver adiposity and mitochondrial function in hepatocytes play an important role in the development of insulin resistance and fatty liver disease in patients with diabetes

Blood Cells

Exercise

Pharmacological Therapy

Novel Therapeutic Approaches That Target Mitochondria

Findings

Conclusions and Perspectives