Variation in the UCP2-UCP3 Gene Cluster Predicts the Development of Type 2 Diabetes in Healthy Middle-Aged Men

Abstract

The impact of the UCP2 ؊866G>A and UCP3 ؊55C>T variants on prospective risk of type 2 diabetes was examined over 15 years in 2,936 healthy middle-aged men (mean age 56 years). Conversion to diabetes (n ‫؍‬ 169) was associated with higher BMI, blood pressure, cholesterol, triglycerides and C-reactive protein. T he rate of mitochondrial oxidative metabolism appears to be important in the development of type 2 diabetes with reduced expression of key genes in oxidative metabolism and mitochondrial function, not only in patients with type 2 diabetes (1) but also in subjects with pre-diabetes, even when glucose tolerance is normal (2). Fuel substrate oxidation, via the respiratory chain, leads to development of a proton gradient across the mitochondrial membrane, which can be dissipated to produce ATP. This gradient can also be dissipated without the production of ATP by uncoupled metabolism, with the release of energy as heat. Therefore, the rate of oxidative metabolism depends not only on ATP requirements but also the extent to which uncoupled fuel substrate oxidation is present (3).Uncoupling protein (UCP)2 and UCP3 are members of a mitochondrial carrier protein superfamily that can facilitate the exchange of substrates across the mitochondrial inner membrane. They show high (ϳ55%) amino acid homology with UCP1 (4), the first in the family to be identified, which occurs in brown adipose tissue. UCP1 plays an important role in nonshivering thermogenesis (5), dissipating the proton gradient by proton transfer across the mitochondrial membrane with the release of heat. The uncoupling of metabolism per se also causes an increase in glycolysis and GLUT4 synthesis and translocation, as well as increased breakdown of fatty acids. This leads to reduced blood glucose and fat mass and improved glucose tolerance (6). The UCP2 and UCP3 genes are located within 8 kb of each other on chromosome 11q13 (7), and the reported association of obesity and diabetes traits (8 -13) with variation in the UCP2-UCP3 gene cluster suggests the importance of this locus in determining risk of these disorders.A substantial role for UCP2 or UCP3 in thermogenesis in humans is unlikely because these proteins are not upregulated by cold, and it has been suggested that the main function of UCP2 is protection from damage caused by reactive oxygen species (ROS) or oxidative stress (14,15). The production of ROS depends, in part, on mitochondrial membrane potential, and reduction of this potential by uncoupling reduces ROS production. In pancreatic ␤-cells, uncoupling by UCP2 has a further effect on glucosestimulated insulin secretion. A reduction in insulin secretion is seen when UCP2 is overexpressed in isolated rat islet cells or human insulinoma cells, and glucose-stimulated insulin secretion is improved in the UCP2 knockout mouse (15). A common variant in the promoter (Ϫ866GϾA, rs659366) is associated with higher UCP2 mRNA levels and was associated with reduced insulin secretion or type 2 diabetes in Austrian (16), Italian (17), and Japanese samples...

Asociación de variantes en genes de las proteínas desacoplantes con diabetes mellitus tipo 2 en una población del nordeste colombiano

“…En ningún reporte revisado hasta la fecha, se ha estudiado de manera conjunta estos cinco polimorfismos que se encuentran en una región de menos de 35 kb en la posición 11q13, pero sí se han realizado estudios en los que se tienen en cuenta varios de ellos (12,47,48).…”

“…En un análisis de haplotipos con tres polimorfismos, el locus compuesto -1957G, -866G, D45 se encontraba con mayor frecuencia en individuos obesos comparados con delgados, sin diferencias significativas entre los grupos (47). En un estudio prospectivo, encontraron que el haplotipo -866A, -55T del gen UCP2 aumenta la probabilidad de sufrir diabetes mellitus tipo 2 después de 10 años, pero se pierde la significancia estadística para el análisis luego de 15 años (12). Por último, en una investigación reciente encontraron que el haplotipo -866G, D45, -55T, conformado por dos polimorfismos de UCP2 y uno de UCP3, respectivamente, se encuentra asociado a obesidad; sin embargo, esta asociación tampoco es significativa (48).…”

“…Además, en el último año, UCP1 y UCP3 se han asociado con la secreción de insulina estimulada por glucosa (5,9). Estos hallazgos son apoyados por la asociación de variantes en estos genes con las características fenotípicas mencionadas (11)(12)(13) variantes genéticas que otorgan susceptibilidad a almacenar energía que, en condiciones de escasez, son una ventaja adaptativa y, en condiciones de abundancia, se expresa en forma de enfermedad, en este caso particular como diabetes mellitus tipo 2 (14).…”

Genetic Variants in the UCP2-UCP3 Gene Cluster and Risk of Diabetes in the Women's Health Initiative Observational Study

“…Despite strong functional evidence for the UCP2 Ϫ866 G/A and UCP3 Ϫ55 C/T polymorphisms, previous association studies of both UCP2 and UCP3 gene variants have not been consistent. Several studies found that these functional variants exhibited significantly increased (8,9,13) or decreased (14 -16) type 2 diabetes risk, but others did not report any significant associations (10,17). Such discrepancies may be attributable to differences in study design (population based vs. hospital based), selection and ascertainment schemes, sample sizes, or statistical analysis strategies.…”

Interactions between uncoupling protein 2 gene polymorphisms, obesity and alcohol intake on liver function: a large meta-analysed population-based study

“…Polymorphisms within the UCP2 gene have been shown to be associated with various metabolic traits such as obesity (8,9) and type 2 diabetes (10,11). Although the effects of these polymorphisms on UCP2 function are still unclear, it could be hypothesised that the loss-of-function polymorphisms are likely to contribute to type 2 diabetes as a result of lower hepatic glucose uptake (12).…”