The role of uncoupling protein 2 (UCP2) on the development of type 2 diabetes mellitus and its chronic complications

Abstract

SUMMARYIt is well established that genetic factors play an important role in the development of type 2 diabetes mellitus (DM2) and its chronic complications, and that genetically susceptible subjects can develop the disease after being exposed to environmental risk factors. Therefore, great efforts have been made to identify genes associated with DM2. Uncoupling protein 2 (UCP2) is expressed in several tissues, and acts in the protection against oxidative stress; in the negative regulation of insulin secretion by beta cells, and in fatty acid metabolism. All these mechanisms are associated with DM2 pathogenesis and its chronic complications. Therefore, UCP2 is a candidate gene for the development of these disorders. Indeed, several studies have reported that three common polymorphisms in UCP2 gene are possibly associated with DM2 and/or obesity. Only a few studies investigated these polymorphisms in relation to chronic complications of diabetes, with inconclusive results. Arq Bras Endocrinol Metab. 2011;55(4):239-48 Keywords UCP2; type 2 diabetes mellitus; diabetic retinopathy; diabetic nephropathy; DNA polymorphisms; haplotype SUMÁRIO Está bem estabelecido que fatores genéticos têm papel importante no desenvolvimento do diabetes melito tipo 2 (DM2) bem como de suas complicações crônicas e que indivíduos geneticamente suscetíveis podem desenvolver essa doença após exposição a fatores de risco ambientais. Assim, grandes esforços têm sido feitos para a identificação de genes associados ao DM2. A proteína desacopladora 2 (UCP2) é expressa em diversos tecidos e atua na proteção contra o estresse oxidativo, na regulação negativa da secreção de insulina pelas células-beta e no metabolismo dos ácidos graxos, mecanismos associados tanto à patogênese do DM2 como a suas complicações crônicas. Portanto, o gene UCP2 é um gene candidato para o desenvolvimento dessas doenças. De fato, diversos estudos têm relatado que três polimorfismos comuns no gene UCP2 estão possivelmente associados ao DM2 e/ou à obesidade. Apenas poucos estudos investigaram esses polimorfismos em relação às complicações crônicas do diabetes, obtendo resultados pouco conclusivos. Arq Bras Endocrinol Metab. 2011;55(4):239-48 Descritores UCP2; diabetes mellitus tipo 2; retinopatia diabética; nefropatia diabética; polimorfismos de DNA; haplótipo

Downregulation of uncoupling protein-2 by genipin exacerbates diabetes-induced kidney proximal tubular cells apoptosis

“…It has been demonstrated that ''mild uncoupling'' of the mitochondrial respiratory chain due to UCP2 activity allows a more rapid flux of electrons through the mitochondrial inner membrane, reducing membrane potential and decreasing ROS production. 28 Hence, UCP2 may play a protective role in the pathogenesis of DM and its complications. Chuang et al 29 show that upregulation of mitochondrial UCP2 expression decreased ROS overproduction, leading to amelioration of apoptotic neuronal cell death in the hippocampus following status epilepticus.…”

Mitochondrial oxidative metabolism and uncoupling proteins in the failing heart

“…Moreover, upregulation of UCP2, which has been detected in type 2 diabetes mellitus, may be linked to the proteosome system dysfunction [63,307]. Physiological role and regulation of UCP3 and UCP2, which is particularly highly expressed in the pancreatic b-cells in type 2 diabetes mellitus, have been discussed in the several recent reviews [308][309][310][311].…”

UCP2 I/D Modulated Change in BMI During a Lifestyle Modification Intervention Study in Japanese Subjects

“…The UCP gene family is comprised of five homologous genes (UCP1 to UCP5) that encode for mitochondrial protein carriers, which promote net translocation of protons from the inter-membrane space, across the inner mitochondrial membrane to the mitochondrial matrix. This dissipates the potential energy available for the conversion of ADP to ATP and decreases ATP production (Souza et al, 2011). These genes have been shown to be involved in energy expenditure, and glucose and lipid oxidation (Dulloo and Samec, 2000;Souza et al, 2011), all of which contribute to the regulation of body weight.…”

“…This dissipates the potential energy available for the conversion of ADP to ATP and decreases ATP production (Souza et al, 2011). These genes have been shown to be involved in energy expenditure, and glucose and lipid oxidation (Dulloo and Samec, 2000;Souza et al, 2011), all of which contribute to the regulation of body weight.…”

“…mediated by certain events that cause calorie depletion (Souza et al, 2011). In this regard, it was reported that UCP2 and UCP3 expressions were increased 2-to 2.5-fold by calorie restriction in human adipose and skeletal muscle (Millet et al, 1997).…”