Mitochondrial dysfunction and insulin resistance: an update

Abstract

Mitochondrial dysfunction has been implicated in the development of insulin resistance (IR); however, a large variety of association and intervention studies as well as genetic manipulations in rodents have reported contrasting results. Indeed, even 39 years after the first publication describing a relationship between IR and diminished mitochondrial function, it is still unclear whether a direct relationship exists, and more importantly if changes in mitochondrial capacity are a cause or consequence of IR. This review will take a journey through the past and summarise the debate about the occurrence of mitochondrial dysfunction and its possible role in causing decreased insulin action in obesity and type 2 diabetes. Evidence is presented from studies in various human populations, as well as rodents with genetic manipulations of pathways known to affect mitochondrial function and insulin action. Finally, we have discussed whether mitochondria are a potential target for the treatment of IR.

Keywords: insulin resistance; lipid accumulation; mitochondrial dynamics; mitochondrial function; mitophagy; oxidative stress.

Figure 1

Fatty acids and glucose enter the cell via various membrane transporters. Fatty acids can either be converted to ‘active’ (DAG and ceramide) and ‘inert’ (TAG) lipid species or be transported into the mitochondria for oxidation to acetyl-CoA. Similarly, glucose can be metabolised to acetyl-CoA in mitochondria. Acetyl-CoA entering the citric acid cycle produces reducing equivalents (NADH and FADH₂) that donate electrons for subsequent ATP generation in the electron transport chain. During electron transfer, superoxide (O₂·⁻) is generated, causing oxidative stress and potential induction of NRF2, and activation of antioxidant response elements to decrease oxidative stress levels.

Figure 2

Mitochondrial dysfunction includes a reduction in mitochondrial content and mitochondrial biogenesis, and/or a decrease in the expression of mitochondrial oxidative proteins, such as complexes of the electron transport chain (ETC), with all those changes likely leading to decreased substrate oxidation (A). A diminished electron flow through the ETC can subsequently cause electron leakage and superoxide generation, followed by oxidative stress and damage. In a healthy environment, mitochondria can respond to damage through mitophagy pathways (removal of damaged mitochondria, preventing cell death), or in the case of high cellular stress, with apoptosis (B), both aggravating the decrease in substrate utilisation, and all up leading to increased lipid accumulation (C). Active lipid intermediates, such as diacylglycerols (DAG) and ceramide (CER) then cause inhibition of the insulin signalling pathway.