Quantification of Mitochondrial Oxidative Phosphorylation in Metabolic Disease: Application to Type 2 Diabetes

Int J Mol Sci. 2019 Oct 24;20(21):5271. doi: 10.3390/ijms20215271.

Abstract

Type 2 diabetes (T2D) is a growing health concern with nearly 400 million affected worldwide as of 2014. T2D presents with hyperglycemia and insulin resistance resulting in increased risk for blindness, renal failure, nerve damage, and premature death. Skeletal muscle is a major site for insulin resistance and is responsible for up to 80% of glucose uptake during euglycemic hyperglycemic clamps. Glucose uptake in skeletal muscle is driven by mitochondrial oxidative phosphorylation and for this reason mitochondrial dysfunction has been implicated in T2D. In this review we integrate mitochondrial function with physiologic function to present a broader understanding of mitochondrial functional status in T2D utilizing studies from both human and rodent models. Quantification of mitochondrial function is explained both in vitro and in vivo highlighting the use of proper controls and the complications imposed by obesity and sedentary lifestyle. This review suggests that skeletal muscle mitochondria are not necessarily dysfunctional but limited oxygen supply to working muscle creates this misperception. Finally, we propose changes in experimental design to address this question unequivocally. If mitochondrial function is not impaired it suggests that therapeutic interventions and drug development must move away from the organelle and toward the cardiovascular system.

Keywords: ATP free energy; aerobic capacity; exercise; insulin resistance; metabolic disease; muscle performance; oxygen delivery; phosphate potential.

Publication types

  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology*
  • Electron Transport Chain Complex Proteins / metabolism
  • Exercise
  • Humans
  • Insulin Resistance
  • Mitochondria / metabolism*
  • Muscle, Skeletal / metabolism
  • Oxidative Phosphorylation

Substances

  • Electron Transport Chain Complex Proteins