diabetes mellitus ( dm ) is a chronic metabolic disease which is characterized by hyperglycemia , absolute or relative deficiencies in insulin secretion , and/or insulin action . the new classification proposed by the american diabetes association in 1997 was based on the pathogenesis of the disease and comprises four categories : type 1 dm ( dm1 ) , type 2 dm ( dm2 ) , other types , and gestational diabetes .
dm1 is mostly due to genetic disorders and an autoimmune disease resulting in the selective destruction of -cells in the pancreas that leads to insulin loss .
dm2 , also called noninsulin - dependent diabetes mellitus ( niddm ) , is characterized by insulin resistance with significant metabolic dysfunction including obesity , impaired insulin function and secretion , and increased endogenous glucose output .
although the two types of diabetes have distinct etiologies , they lead to similar diabetic complications , and both of them are related to oxidative stress status .
it is demonstrated that activation of oxidative stress pathways plays a key role in the development of not only the late complications ( such as cardiovascular disease , nephropathy , retinopathy , and amputations ) in dm1 and dm2 , but also in the early stage such as insulin resistance .
there are many sources of reactive oxygen species ( ros ) production in diabetes including mitochondrial and nonmitochondrial origins : nadph oxidase , xanthine oxidase , uncoupled enos , lipoxygenase , cyclooxygenase , cytochrome p450 enzymes , and other hemoproteins , and mitochondrion is thought to be the main source of ros generation site in dm . the mechanisms about ros and dm development were shown in figure 1 .
the uncoupling proteins ( ucps ) are a family of mitochondrial transport proteins located in the inner mitochondrial membrane .
these anion - carrier proteins transport protons ( h ) to the mitochondrial matrix and in turn dissipate the proton motive force as heat and uncouple the substrate oxidation from the production of atp .
ucp1 is mainly expressed in brown adipose tissue ( bat ) , which is responsible for thermogenesis in newborns .
ucp2 is widely distributed in several tissues including the spleen , kidney , immune system , pancreas , and central nervous system , whereas ucp3 is mainly restricted to the skeletal muscle , and ucp4 and ucp5/bmcp1 are mainly expressed in the brain . besides the nonshivering thermogenesis function of ucp1 , functions of the other ucps are still unclear .
ucp2 is reported to be involved in glucose and lipid metabolism   to control immune cell activation by modulating mapk pathways and the production of mitochondrial ros , and a neuroprotective role is also suggested based on the regulation of mitochondria membrane potential , production of ros , preservation of calcium homeostasis , modulation of neuronal activity , and eventually inhibition of cellular damage .
ucp3 is suggested to be involved in mediating energy expenditure via uncoupling , especially in fatty acid metabolism , and it seems to protect mitochondria against lipid - induced oxidative stress , which makes this protein a potential player in the development of dm2 .
fewer studies focused on the physiologic roles of ucp4 and ucp5 , and the protection against oxidative stress and mitochondrial dysfunction are also reported .
although the physiological functions of ucps are still not been completely elucidated , their abilities of reducing mitochondrial ros formation are widely accepted .
that is , high membrane potential of mitochondria will induce ros production and thus oxidative damage ; these ros may activate ucps and therefore cause a  mild uncoupling  and ( as a negative feedback ) will prevent further superoxide production and decrease oxidative damage ( figure 2 ) .
this  antioxidative activity  of ucps makes it logical to search any benefit on dm through counteracting the oxidative stress appeared in dm and the complications . on the other hand , it is also found that ucp2 is a negative regulator of insulin secretion ; the superoxide - mediated activation of ucp2 causes pancreatic -cell dysfunction .
the vast majority of diabetes are type 1 or type 2 ( dm2 represents at least 80 percent and dm1 accounts for about 510 percent ) , and increasing numbers of studies focused on the roles of ucps on dm or the complications .
we will review the progress in the relations between ucps ( ucp1 , ucp2 , and ucp3 ) and dm1 and/or dm2 in the following .
the relationship between ucp1 and dm has already been reported long before the other ucps were discovered in 1997 .
studies revealed that ucp1 mrna and protein concentrations in bat were regulated by insulin [ 12 , 13 ] .
as ucp1 has been proved to decrease membrane potential , downregulate ros generation , and increase energy expenditure , so ucp1 gene is regarded as a candidate gene for obesity , dm2 , or related traits .
the role of ucp1 in the development of obesity and dm2 has been reviewed in 2010 and 2012 [ 14 , 15 ] ; the authors focused on the polymorphisms 3826a / g , 1766a / g , and 112a / c in the promoter region , ala64thr in exon 2 , and met299leu in exon 5 of ucp1 gene and pointed out that they are possibly associated with obesity , lipid / lipoprotein - related disease , and/or dm2 .
the 3826a / g polymorphism of ucp1 was further reported to be associated with diabetic retinopathy ( dr ) in dm1 group and the ucp1 gene expression was increased in human retina ; while the same polymorphism of ucp1 ( 3826a / g ) was not found the association with dm2 with european ancestry in another study , although a significant association between the ucp2 ala55val and ucp3 55c / t polymorphisms and increased susceptibility for dm2 were detected in asians in the same study .
the 3826a / g polymorphism influenced ucp1 gene expression : g allele carriers had higher ucp1 cdna and protein concentrations than a / a carriers . and more interestingly , g allele carriers exhibited increased mnsod2 expression , which suggested that this allele could be a marker of oxidative stress .
as oxidative stress is related to dr , so this deleterious polymorphism in ucp1 gene is suggested to be a risk factor for dr ( multivariate analysis confirmed that the g / g genotype was an independent risk factor for dr ) .
ucp1 had been thought to be expressed only in rodents and human infants for a long time ; however , ucp1 protein and/or its mrna expression were detected in human white adipose tissue , skeletal muscle , longitudinal smooth muscle layers , retinal cells , and islet cells recently [ 18 , 19 ] , although the physiological functions of ucp1 in these tissues and organs are not established as well as in bat . in 2013 ,
the adult human neck brown fat is further reported with the anatomical localization , gene expression profiling , and functional characterization .
the imbalance between energy intake and expenditure is the underlying cause of obesity and dm .
bat consumes fuel for thermogenesis through tissue - specific ucp1 ; it was once thought that bat had a functional role in rodents and human infants only , but it has been recently shown that in response to mild cold exposure adult human bat consumes more glucose per gram than any other tissues .
in addition to this nonshivering thermogenesis , human bat may also combat weight gain by becoming more active in the setting of increased whole - body energy intake .
this suggests that activation of human bat could be used as a safe treatment for obesity and metabolic dysregulation and further help to cure dm . in view of the ucp1 gene expressed in the other tissues , more attention
may be paid to the role of ucp1 in muscle tissue , islet cells , and thymus function in the future .
ucp2 is the most widely distributed ucp and highly expressed in pancreatic -cells in dm , so it is the most frequently studied one concerning its role in dm .
ross activate ucp2 , which results in proton leak across the mitochondrial inner membrane , and this leads to reduced -cell atp synthesis and content , which is a critical parameter in regulating glucose - stimulated insulin secretion ( gsis ) .
the recent reviews about ucp2 and dm were published in 2009 and 2011 [ 2325 ] .
early in 2001 , just 4 years after the discovery of ucp2 , it was reported that ucp2 negatively regulated insulin secretion and was a major link between obesity , -cell dysfunction , and dm2 . in a model of obesity - induced diabetes mice ( ob / ob mice )
the ucp2-deficient mice had higher islet atp levels and increased gsis ; this indicated that ucp2 negatively regulates insulin secretion .
the ob / ob mice lacking ucp2 had restored first - phase insulin secretion , increased serum insulin levels , and greatly decreased levels of glycemia . in recent years , the mitochondrial ros generation or oxidative stress in -cell was found to be a prominent role in the effect of ucp2 on insulin secretion , although the consequences were not always consistent . in a study published in 2009 ,
all of the three highly congenic strain backgrounds ( c57bl/6j , a / j , 129/svimj ) ucp2/ mice exhibited increased oxidative stress , and the gsis in ucp2/ islets of each congenic strain was significantly decreased .
ucp2 knockdown in ins-1e insulinoma cells improved the gsis , and this can be annulled completely by the cell - permeative antioxidant mntmpyp . in the islets of -cell - specific ucp2 knockout mice ,
all of these three studies described a ros - related pathway about the role of ucp2 and gsis .
that is to say , the ucp2 knockdown will cause elevation of ros and/or oxidative stress and then the enhancement of gsis .
a study about the associations between polymorphisms in ucp2 and ucp3 with dm2 was carried out in korea and found that the ucp2 5331g > a and ucp3 2078c > t polymorphisms are susceptibility markers for dm2 among koreans . among the other three studies , no significant association of the ucp2 866g / a polymorphism with dm2 risk
the study about asian indians indicated that ala55val polymorphism at ucp2 and 55c / t polymorphism at ucp3 are associated with a significantly reduced risk of developing dm2 . while these correlations are different between europeans and asian descent : neither the ucp2 ala55val nor the ucp3 55c / t polymorphism showed any significant association with dm2 risk in europeans ( or 1.04 , 95% ci 0.98 , 1.09 for ala55val ; or 1.04 , 95% ci 1.00 , 1.09 for 55c / t ) ; and in contrast , a statistically significant association was observed for both polymorphisms in participants of asian descent ( or 1.23 , 95% ci 1.12 , 1.36 for ala55val ; or 1.15 , 95% ci 1.03 , 1.28 for 55c / t ) . in a study of the relationship between ucp2 polymorphisms and proliferative diabetic retinopathy ( pdr ) ,
three ucp2 polymorphisms were selected ( 866g / a ( rs659366 ) , ala55val ( rs660339 ) , and 45  bp insertion / deletion ( ins / del ) ) , and the haplotype [ a val ins ] was an independent risk factor for pdr in both types 1 and 2 diabetic groups .
three studies focused on the relationship between 866g / a polymorphism and obesity in a balinese population , ischemic stroke in chinese dm2 patients , and obesity in danes and showed a significant association between them [ 3537 ] .
american ginseng stimulates insulin production and prevents apoptosis through downregulation of ucp2 in cultured -cells .
inhibited ucp2 expression by an antisense oligonucleotide can reverse diet - induced dm mice models by the effects on both insulin secretion and action .
microrna-15a positively regulates insulin synthesis by directly targeting and inhibiting ucp2 gene expression . a chinese medicine , kaiyuqingre formula , improves insulin secretion via decreasing the overexpression of ucp2 in cultured ins-1 cells .
korean red ginseng promoted the expression of insulin and downregulated the expression of ucp2 in the spontaneously diabetic goto - kakizaki rats .
most of the studies about the role of ucp2 in dm focused on the ucp2 functions in -cells , and the results indicated a deleterious effect of ucp2 on dm .
as ucp2 is widely expressed in many tissues , the antioxidative activities ( downregulating mitochondrial ros generation ) of this protein should be evaluated in the future .
much fewer studies focused on the role of ucp3 in dm , for it was thought to be expressed restrictedly in skeletal muscle for a long time .
ucp3 mrna and protein levels are decreased in skeletal muscle of patients with dm2 compared to healthy control subjects .
ucp3 protein content is reduced in prediabetic subjects ( i.e. , impaired glucose tolerance ) and dm2 , and eight weeks of rosiglitazone treatment significantly increases insulin sensitivity and restores skeletal muscle ucp3 protein in diabetic patients .
similar to ucp2 , ucp3 was found to be expressed in pancreatic -cells in 2008 , where it also influenced insulin secretion , although the physiological function of ucp3 in -cells is still not known .
ucp3 mrna is expressed in human islets ; the relative abundance of ucp2 mrna was 8.1-fold higher ( p < 0.05 ) ; immunohistochemical analysis confirmed colocalization of ucp3 protein with mitochondria in human -cells .
ucp2 protein expression in human islets was increased approximately 2-fold after high glucose exposure , whereas ucp3 protein expression was decreased by approximately 40% ( p < 0.05 ) .
these results indicated that ucp2 and ucp3 may have distinct roles in regulating -cell function ; increased expression of ucp2 and decreased expression of ucp3 in humans with chronic hyperglycemia may contribute to impaired glucose - stimulated insulin secretion .
early in the year 2000 , a study carried out french caucasians found the association between the 55c / t polymorphism of the ucp3 gene and dm2 ; the study found that subjects bearing the tt genotype have a lower risk for developing dm2 than the others do .
this result is the same as reported in the asian indians cohort   but differs from another study in europeans which could not find any significant association with dm2 risk .
these inconsistent results may be due to the different gene background between different human species .
another report about finnish cohort indicated that the ucp3 gene variant rs3781907 was associated with a higher risk of dm2 .
the ucp2 and ucp3 genes are located within 8  kb of each other in a gene cluster on chromosome 11q13 .
several genetic variants in the ucp2-ucp3 gene cluster have been examined in multiple studies , including 866g / a ( rs659366 ) , ala55val ( rs660339 ) , a 45-bp insertion / deletion ( i / d ) in the 3 untranslated region ( utr ) of exon 8 in ucp2 , and the 55c / t ( rs1800849 ) polymorphism in ucp3 , and the associations with obesity and/or diabetes were also reported .
many of these ucp2 and ucp3 gene polymorphisms ( such as 866g / a , ala55val of ucp2 , and 55c / t of ucp3 ) are also evaluated within ucp2-ucp3 gene cluster variation studies ; the difference between the polymorphisms and the cluster study may be just that the cluster variation studies are often focusing on many variations at the same time .
a research published in 2006 evaluated the impact of the ucp2 866g > a and ucp3 55c > t variants on prospective risk of dm2 and found that these variations in the ucp2-ucp3 gene cluster are associated with an increased risk of dm2 . in 2008 , a report focused on 14 tag single nucleotide polymorphisms ( tsnp ) ( rs637028 , rs653263 , rs622064 , rs2306820 , rs673494 , rs655717 , rs643064 , rs660339 , rs659366 , rs591758 , rs668514 , rs647126 , rs1800006 , and rs1800849 ) , for each of the 14 tsnps across the genomic region of the ucp2-ucp3 gene cluster ; they did not observe significant effects on dm2 .
however , haplotype - based analyses suggest that a haplotype set defined by rs591758 , rs668514 , rs647126 , and rs1800006 was significantly associated with dm2 risk in caucasian women only , especially among those who were overweight .
this may be emphasizing that the dm2 development is driven by a multifactor model more than a single - factor one . in a finnish diabetes prevention study ,
three variants in the ucp2 gene , one variant in the ucp2-ucp3 intergenic region , and five variants in the ucp3 gene were explored .
the authors concluded that the genetic variations in the ucp2-ucp3 gene cluster may act as a modifier increasing serum lipid levels and indices of abdominal obesity and may thereby also contribute to the metabolic aberrations observed in obesity and dm2 .
another study analyzed other 14  tsnps ( rs622064 , rs2306820 , rs655717 , rs660339 , rs17132534 , rs659366 , rs668514 , rs3741135 , rs1626521 , rs2734827 , rs3781907 , rs1800849 , rs1685333 , and rs826071 ) in ucp2-ucp3 gene cluster and could not find an association of any of the 14  tsnps tested with dm2 risk .
this result is similar to the other 14  tsnps study mentioned previously , and they may both imply the same fact that the development of dm2 is a multifactor style ; any one of the 14  tsnps is not enough to affect the dm2 .
it is important to illustrate how the polymorphisms of ucp genes are involved in the development of dm , and this may help to develop new strategies for dm prevention and/or treatment .
the present data indicated that all of the three ucps ( ucp1 , ucp2 , and ucp3 ) have some kind of relationships with the development of dm ( figure 3 ) .
as dm is a multifactorial disease , the ethnic differences , gender , genomic factors , age , nutritional characteristics , lifestyle , and even environmental factors are all related to the outcomes .
the single ucp or single ucp gene variation may not be enough to affect the results .
more importantly , the physiological function of ucps , at least ucp2 and ucp3 , is still unclear , which may limit this kind of study very much .
so , it is better to keep on exploring the physiological function of ucps in the future , and based on this , the synergetic studies on the multisite of ucps variations may help to elucidate the relationship between ucps and dm .
 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 -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 . 
1. Introduction
2. Role of UCP1 in DM
3. Role of UCP2 in DM
4. Role of UCP3 in DM
5. Conclusion and Future Directions