The role of uncoupling proteins in diabetes mellitus

Abstract

Uncoupling proteins (UCPs) are anion carriers expressed in the mitochondrial inner membrane that uncouple oxygen consumption by the respiratory chain from ATP synthesis. The physiological functions of UCPs have long been debated since the new UCPs (UCP2 to 5) were discovered, and the role of UCPs in the pathogeneses of diabetes mellitus is one of the hottest topics. UCPs are thought to be activated by superoxide and then decrease mitochondrial free radicals generation; this may provide a protective effect on diabetes mellitus that is under the oxidative stress conditions. UCP1 is considered to be a candidate gene for diabetes because of its role in thermogenesis and energy expenditure. UCP2 is expressed in several tissues and acts in the negative regulation of insulin secretion by β-cells and in fatty acid metabolism. UCP3 plays a role in fatty acid metabolism and energy homeostasis and modulates insulin sensitivity. Several gene polymorphisms of UCP1, UCP2, and UCP3 were reported to be associated with diabetes. The progress in the role of UCP1, UCP2, and UCP3 on diabetes mellitus is summarized in this review.

Figure 1

The mechanisms of ROS and DM development. Hyperglycemia may activate ROS generation through the mitochondrial and nonmitochondrial origins: NADPH oxidase, xanthine oxidase, uncoupled eNOS, lipoxygenase, cyclooxygenase, cytochrome P450 enzymes, and other hemoproteins. ROS can further cause β-cell damages and the development of DM and related complications.

Figure 2

“Antioxidative activity” of UCP. High transmembrane proton gradient and membrane potential of mitochondria will induce ROS production and thus oxidative damage; these ROSs may activate UCPs and therefore cause a “mild uncoupling” and (as a negative feedback) will prevent further superoxide production and decrease oxidative damage. ΔpH: transmembrane proton gradient; ΔΨm: mitochondrial membrane potential.

Figure 3

The role of UCPs on the development of DM and/or complications. UCPs may affect the development of DM through 4 aspects: decrease mitochondrial membrane potential, increase energy expenditure especially through glucose and lipid metabolisms, downregulate ROS generation, and gene polymorphisms. The green arrows represent pathways activation, the dotted green arrow means that this pathway needs to be further proved, and the red inhibition arrows represent the inhibition effect.