Targeting Mitochondria in Diabetes

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.

Keywords: blood cells; diabetes therapy; exercise; insulin resistance; liver; mitochondria; respiration; respiratory capacity; skeletal muscle; type 2 diabetes.

Figure 1

Cellular mechanisms underlying exercise as lifestyle intervention in T2D. Exercise increases insulin sensitivity in T2D by affecting energy metabolism through induction of mitochormesis, stimulation of mitochondrial turnover and biogenesis, increase in Ca²⁺ concentration, AMP/ATP and NAD⁺/NADH ratios and increase in respiration: ROUTINE, LEAK, OXPHOS and ET capacity. Symbol: ↑ = increase.

Figure 2

Potential mitochondria targeting agents that might improve insulin sensitivity through modulation of mitochondrial function. They are grouped based on the strategy of their pharmacological actions, which implies potential molecular mechanisms: NBMs (NAD+ boosting molecules), mitochondrial membrane properties modulators, STACs (Sirt1-activating compounds), OXPHOS modulators, AMPK activators, PPAR agonists, antioxidants (ROS scavenger), MCP (mitochondrial pyruvate carrier) inhibitors, CI (respiratory complex I) inhibitors, mPTP (mitochondrial permeability transition pore) inhibitors, CoQ10 (coenzyme Q10) analogues, mitochondrial-associated ER membranes (MAM) modulators and novel drugs to be designed. Symbols: ? = unknown drug—to be designed; ↑ = increase.

Figure 3

Mitochondria as an effector target of main diabetogenic factors such as obesity, aging and sedentary habits, which all cause a decrease of respiratory capacity, while the lifestyle and pharmacological interventions cause an increase of respiratory capacity and improvement of metabolic health.