Uncoupling Proteins: Role in Insulin Resistance and Insulin Insufficiency

Abstract

Uncoupling proteins (UCPs) are modulators of mitochondrial metabolism that have been implicated in the development of both insulin resistance and insulin insufficiency, the two major pathophysiological events associated with type 2 diabetes. UCP2 mRNA is expressed in a wide range of tissues; however UCP2 protein expression is restricted to fewer tissues, including the endocrine pancreas, spleen, stomach, brain and the lung. To date, its role in the pathophysiology of diabetes has been most strongly associated with impaired glucose-stimulated insulin secretion from the beta-cell, particularly after its induction by free fatty acids. The physiological role of UCP2 remains controversial, but it may act as a downstream signal transducer of superoxide. UCP3 mRNA and protein are expressed in relatively few tissues, predominantly skeletal muscle, brown adipose tissue and heart. Increased expression of UCP3 in skeletal muscle is associated with protection from diet-induced insulin resistance in mice. In patients with type 2 diabetes UCP3 protein in muscle is reduced by 50% compared to healthy controls. The primary physiological role of the novel UCPs does not appear to be protection against positive energy balance and obesity; this is based largely on findings from studies of UCP2 and UCP3 knockout mice and from observed increases in UCP3 expression with fasting. The mechanism(s) of action of UCP2 and UCP3 are poorly understood. However, findings support roles for UCP2 and UCP3 as modifiers of fatty acid metabolism and in mitigating damage from reactive oxygen species.

Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels

“…When UCP2 expression decreases, insulin secretion is enhanced (Zhang et al 2001, Bordone et al 2006. Moreover, genetic studies have identified associations between polymorphisms in the human UCP2 promoter and type 2 diabetes as well as decreased insulin secretion (Chan & Harper 2006). Interestingly, the novel UCP2 inhibitor genipin also increases insulin secretion (Zhang et al 2006) and therefore UCP2 is envisaged as a novel drug target for the treatment of diabetes.…”

Mitochondrial uncoupling protein 2 in pancreatic β‐cells

“…Transcription of the Ucp2 gene is upregulated by transcription factors, such as PPARs (peroxisome proliferator-activated receptors), FOXA2 (forkhead box a2) and SREBP-1c (sterol regulatory-elementbinding protein-1c) [6,38], and downregulated by their antagonists, such as Sirt1 [39]. Reactive oxygen species may also upregulate UCP2 expression [40].…”

“…This reduction in protonmotive force will decrease oxidative phosphorylation, ATP/ADP ratio and GSIS. There has, therefore, been a great deal of interest in the possibility that endogenous uncoupling proteins in the β-cell might attenuate GSIS [4][5][6][7][8][9][10][11].…”

“…This reduction in protonmotive force will decrease oxidative phosphorylation, ATP/ADP ratio and GSIS. There has, therefore, been a great deal of interest in the possibility that endogenous uncoupling proteins in the β-cell might attenuate GSIS [4][5][6][7][8][9][10][11].Uncoupling protein 2 (UCP2), a member of the uncoupling protein family, is present in native β-cells [11]. Its concentration has been measured in a β-cell model, cultured insulinoma (INS-1E) cells, to be a modest 8 ng/mg mitochondrial protein [12].…”

Transcriptional Regulation of Insulin-degrading Enzyme Modulates Mitochondrial Amyloid β (Aβ) Peptide Catabolism and Functionality

“…and Parkinson diseases (1,2). The proteolytic system in mitochondria is crucial for the maintenance of protein turnover and integrity of the organelle.…”