
 type 2 diabetes ( t2d ) mellitus is a chronic metabolic disease with  epidemic  proportions .
its global prevalence was estimated to be 6.4% worldwide ( 285 million adults in 2010 ) and is predicted to rise to approximately 7.7% ( 439 million ) by 2030 .
t2d is a multifactorial disorder resulting from an interaction between genetic and environmental conditions ( sedentary lifestyle and western diet ) and characterized by a peripheral insulin resistance , hyperglycaemia , and pancreatic  cell dysfunctions .
two defects have been reported during diabetes development , a gradual deterioration of  cell functions and a reduction in pancreatic  cells mass .
 cell failure is not limited to t2d but is rather a common feature of all forms of diabetes , including the autoimmune type 1 diabetes ( t1d ) , autosomal dominant onset diabetes of young ( mody ) , wolfram syndrome , and wolcott - rallison syndrome ( wrs ) . in the early stage of diabetes development ,
the response of pancreatic islets challenged by nutrients and/or insulin resistance is a hypersecretion of insulin to maintain normoglycaemia . to this end ,
the process of  cell compensation is a combination of  cell mass expansion and an increase of acute glucose - stimulated insulin secretion .
postmortem analyses of pancreas of nondiabetic obese patients show an increase of  cell volume , implying postnatal plasticity of  cell mass . moreover the  cell compensation process is associated with an improved capacity of the secretory machinery to support increased insulin production .
subsequently , the production of large amounts of insulin by compensating islet  cells places a continuous demand on the er for proper protein synthesis , folding , trafficking , and secretion . when the folding capacity of the er is exceeded , misfolded or unfolded proteins accumulate in the er lumen , resulting in er stress .
paradoxically , upr signalling activation leads to opposite cell fates , that is , adaptation / survival versus death . increasing evidence links the endoplasmic reticulum ( er ) stress to  cell deterioration and apoptosis [ 2 , 3 ] .
recent experiments performed in db / db mice and ob / ob mice models at different times of disease progression revealed that the maintenance ( or suppression ) of adaptive upr is associated with  cell compensation ( or failure ) in obese mice .
moreover , engin et al . recently showed a progressive loss of upr mediator expression before the onset of diabetes in nod mice .
the administration of the chemical chaperone tauroursodeoxycholic acid to rescue the deleterious er stress response improved pathophysiological signs of diabetes with a recovery of  cell survival and adaptation to stress .
in addition , the authors showed a decline of the upr mediator in both experimental models and t2d human islets , suggesting that decreased expression of  cell upr actors can play a central role in  cell compensation and subsequently t2d occurrence .
three canonical er resident molecules mediate upr response , namely , protein kinase r - like er kinase ( perk ) , inositol - requiring enzyme 1 ( ire1 ) , and activating transcription factor 6 ( atf6 ) , which are maintained inactive by their association with the immunoglobulin heavy chain - binding protein ( bip , grp78 ) in normal conditions ( figure 1(a ) ) .
the accumulation of unfolded proteins in the er leads to the release of perk , ire , and atf6 and their subsequent activation [ 7 , 8 ] .
the downstream signalling effectors from these pathways converge to the nucleus and activate upr target genes , finally reducing the er input ( figure 1(a ) ) .
their action is bipartite , with an acute programme that attenuates the er workload and a latent transcriptional one that builds er capacity .
perk is a type 1 er transmembrane kinase with a stress sensing luminal n - terminal domain . during er
stress perk phosphorylates the -subunit of eif2- on serine 51 leading to a delivery inhibition of the initiator methionyl - trnai to the ribosome and ultimately resulting in global protein translation attenuation   ( figure 1(a ) ) .
this phosphorylation event directly contributes to the reduction of er stress and protects cells from er stress - mediated apoptosis .
intriguingly , the mrna transcription of upr target genes is selectively activated by eif2 phosphorylation , as these polycistronic mrnas have inhibitory upstream open reading frames ( uprfs ) and are thus preferentially translated by the ribosome .
these include the bzip transcription factor 4 ( atf4 ) that acts as a regulator of upr target genes such as c / ebp - homologous protein ( chop ) and growth arrest and dna damage inducible gene 34 ( gadd34 ) , as well as genes involved in the redox balance and amino acid synthesis .
gadd34 interacts with the catalytic subunit of protein phosphatase ( pp1c ) and controls the level of eif2- phosphorylation by a negative feedback loop , allowing the restoration of an upr basal state once er stress is resolved .
ire1 is a central regulator of upr . like perk , ire1 is also a type 1 transmembrane kinase with an n - terminal luminal domain that senses er stress signalling .
two homologues of ire1 have been described , ire1 and ire1. ire1 is expressed ubiquitously , showing high expression levels in the pancreas and placenta , whereas ire1 is only expressed in the intestinal epithelium and lung .
once the er stress is triggered , ire1 activates its rnase domain through its dimerization and transautophosphorylation and causes an unconventional splicing by the removal of 26-nucleotide intron from the x - box binding protein 1 ( xbp1 ) mrna ( figure 1(a ) ) .
the subsequent spliced xbp1 ( xbp1s ) mrna encodes a leucine zipper transcription factor with a high transcriptional activity that upregulates genes encoding er protein chaperones , er associated protein degradation ( erad ) , and lipid biosynthetic enzymes [ 15 , 16 ] .
ire1 has also a nonspecific rnase activity that degrades mrnas localized near the er membrane , thereby reducing protein import into the er lumen .
high levels of er stress also activate the kinase activity of ire1 and initiate a signalling cascade of apoptosis signal - regulating kinase 1 ( ask1)/cjun amino terminal kinase ( jnk ) , which can participate in the apoptotic cell fate .
atf6 is an er located type 2 transmembrane protein with a basic leucine zipper dna binding domain ( figure 1(a ) ) .
two ubiquitously expressed isoforms of atf6 have been described , atf6 and atf6 . under er stress conditions , atf6 translocates from the er to the golgi apparatus , where it is cleaved by site-1 protease and site-2 protease ( s1p / s2p ) .
the newly generated cytosolic fragment migrates to the nucleus and activates upr gene transcription [ 20 , 21 ] . the exclusive or the combined action of cleaved atf6 and xbp1s is able to activate all three er stress response elements : erse , upre , and erse2 .
atf6 was first described as a repressor of atf6 . however , mouse embryonic fibroblasts generated from atf6 null mice did not show altered upr gene induction , suggesting a minor role for atf6 in er stress response .
in contrast , atf6 null mice have a significant alteration in their upr gene expression profile , suggesting a central role for atf6 in er protein quality control and protection against er stress .
as the double atf6/ knockdown is lethal , the authors suggested that atf6 and atf6 provide a complementary function during early development .
moreover atf6 activity is regulated by the wolfram syndrome 1 ( wfs1 ) protein , which targets atf6 to the e3 ubiquitin ligase hrd1 , consequently resulting in its ubiquitination and proteasomal degradation .
a number of other er stress transducers that share a high sequence homology with atf6 have been identified , such as luman , oasis , bbf2h7 , crebh , and creb4 ( reviewed in ) . however , despite their structural similarities , each atf6 homolog seems to have specific functions in upr regulated processes in specific organs and tissues . 

 cell is a highly specialized secretory cell which responds to elevated postprandial glycaemia by increasing mrna proinsulin translation and insulin secretion .
the periodic waves of proinsulin mrna translation generate biosynthetic loads that induce upr . to manage this burden imposed by proinsulin synthesis
,  cells increase their er size , as exemplified during diabetes development . in the prediabetic state
,  cell must adapt its er machinery to the new hyperglycaemic environment , promoting  cell compensation .
the use of genetically modified mouse models and genetic studies from human diabetic patients demonstrated that upr actors support this adaptation as well as  cell compensatory mechanism [ 4 , 28 ] .
misfolding of proinsulin is associated with er stress and severe dysfunctions leading to a massive destruction of  cells . in vivo evidences
were observed in both akita and munich mice carrying cysteine residues mutations that interfere with disulphide bond formation [ 29 , 30 ] .
interestingly , inactivation of the upr induced proapoptotic chop gene delayed the onset of diabetes in heterozygous akita mice , suggesting a key role for chop in er stress - mediated  cell apoptosis .
diabetes of youth ( midy ) is a syndrome caused by a heterozygous mutation of the coding sequence of proinsulin leading to an autosomal - dominant and insulin - deficient diabetes .
this mutation has been shown to be the second most common cause of permanent neonatal diabetes related to er stress [ 32 , 33 ] . in line with these observations , inducible expression of the human analogue proinsulin c96y mutation of akita mice in rat insulinoma-1 ( ins-1 ) caused er stress and cell apoptosis
. however , upregulation of upr and erad seems to have a protective effect . in vivo expression of the same proinsulin mutant driven by the weak ins1 promoter
altogether these data demonstrate a clear link between misfolding of proinsulin and er stress induction .
loss of function mutation in the eif2ak3 gene - encoding perk was associated with wrs , which has been confirmed by the functional characterisation of perk knockout mice .
embryonic development of these mice is normal but they exhibit a postnatal growth retardation , skeletal dysplasia , and progressive loss of  cells , associated with defects in er secretory machinery and proinsulin folding [ 37 , 38 ] .
however , generation of  cell specific perk knockout mice revealed that  cell death was not increased , but rather  cell proliferation and differentiation were repressed during the embryonic and postnatal state .
other studies on these mice models demonstrated an impaired er to golgi anterograde trafficking , retrotranslocation out of the er , and proteasomal degradation , showing requirement of perk for er and golgi integrity and processing of atf6 .
in contrast to the first rapport , specific  cell inducible perk deletion in mice showed a rapid progression of insulin dependent diabetes regardless of mice age . the authors showed , on the one hand , that this phenotype was due to an increased  cell proliferation after the induction of perk deletion due to the increased activation cyclin d - dependent kinase activity . on the other hand
, they showed a significant increase in  cell death , associated with an activation of other upr actors and a disturbance in calcium homeostasis .
moreover , a recent work demonstrated that perk , in concert with calcineurin , regulates er calcium reuptake through calnexin interaction and a negative regulation of the sarcoplasmic endoplasmic reticulum calcium atpase pump ( serca )   ( figure 1(a ) ) .
perk thus appears to sense glucose by direct sensing of er calcium levels , raising the possibility that the primary function of perk in  cell is to modulate proinsulin quality control and trafficking . within the  cell , phosphorylation of elf2
mice harbouring a homozygote knock - in mutation at the perk - mediated phosphorylation site ( ser51ala ) of elf2 display a severe  cell deficiency detectable in late stage embryos and die within 18  h after birth as a consequence of hyperglycaemia associated with defective neoglucogenesis .
heterozygote mice development is normal ; however , when challenged with a high fat diet , they develop severe obesity , glucose intolerance , and impaired insulin release . in this genetic context reduced insulin content , fewer granules , er distension , and a prolonged association of proinsulin with bip
thus , elf2 phosphorylation is required for upr to prevent  cell failure when insulin demand is increased .
these findings demonstrate a central role of elf2 phosphorylation in  cell adaptation during compensation .
these mice exhibit a high rate of  cell apoptosis , likely caused by hypoinsulinemia , severe glucose intolerance , and hyperglycaemia .
furthermore , the authors showed er distension and mitochondrial damage associated with a lower basal expression of the majority of upr genes and  cell antioxidant responsive genes .
altogether these data indicate that the correct upr and antioxidant response controlled by perk - elf2 signalling are required for  cell adaptation and survival .
phosphorylation of elf2 leads to attenuate global translation of most mrna although translation of atf4 is selectively stimulated in this context   ( figure 1(b ) ) .
pioneer studies showed that atf4 knockout mice on a 129sv genetic background are lean , hypoglycaemic , and resistant to diet - induced obesity , probably as a result of increased energy expenditure .
however , no effect was observed on plasma insulin level when mice were fed with normal diet , whereas insulin levels were shown to be lower in atf4 null mice compared to wild - type mice when fed with a high fat diet [ 46 , 47 ] .
paradoxically , other studies using atf4 ko mice on c57bl6/j genetic background demonstrated that these mice are hypoglycaemic and hyperinsulinemic with an increased  cell mass and function .
the phenotype of these mice could be secondary to an overexpression of osteocalcin in osteoblasts , a bone derived secreted molecule promoting insulin secretion and insulin sensitivity .
the role of atf4 in insulin synthesis and  cell adaptation to er stress remains unclear , and further studies using a  cell specific atf4 ko mouse model may be useful to answer this question .
atf4 activation by elf2 also leads to the transcription of elf4-e binding protein ( 4e - bp-1 ) , a well - documented gene involved in  cells adaptation to stress .
in fact , translation attenuation by elf2 phosphorylation is transient , subsequently leading to the feedback dephosphorylation by gadd34 , whereas 4e - bp1 suppresses prolonged translation by the inhibition of cap - dependent translation [ 49 , 50 ] .
 cell specific 4e - bp1 ko mice are normal without any metabolic disorder when fed normal diet but are insulin resistant and show  cell defects under high fat diet due to induced er stress [ 49 , 51 , 52 ] . moreover
, the inactivation of 4e - bp1 gene in min6 cell line results in sensitization to er stress and increased  cell loss and hyperglycaemia in diabetic mouse models .
these findings suggest a central role of 4e - bp1 in  cell adaptation to er stress .
in contrast , other groups indicated that suppression of 4e - bp1 expression is involved in beneficial effects of high - density lipoproteins on  cells survival , suggesting that the role of atf4 in  cell compensation might depend on several cellular interactions .
ire1 is the major isoform expressed in the pancreas and plays a central role in  cell adaptation to er stress ( figure 1(b ) ) .
ire1 is required for embryonic development as demonstrated by the embryonic lethality of global ire1 ko mice .
the generation of ire1 conditional ko mice revealed that ire1 deletion caused mild hyperinsulinemia and hyperglycaemia and a lower body mass under normal diet .
physiological activation of upr by glucose results in ire1 phosphorylation , without increasing xbp1 mrna splicing .
moreover , knockdown of ire1 in ins-1 insulinoma cell line resulted in decreased proinsulin biosynthesis or insulin content without impacting global protein synthesis or insulin secretion , suggesting a beneficial effect of ire1 activation by transit exposure to glucose in  cells . however , chronic exposure to high glucose leads to hyperphosphorylation of ire1 , which in turn results in selective degradation of proinsulin mrna . this may be part of the  cell protective mechanism from apoptosis under chronic
this adaptative mechanism combined to upr activation may explain the reduced insulin secretion in type 2 diabetic patients in the absence of  cell death .
ire1 dephosphorylation is mediated by proteins phosphatase a2 ( pp2a ) through ternary complex containing the scaffold protein rack1 ( receptor for activated c kinase 1 ) . under glucose stimulation or er stress ,
rack1 mediates ire1 , rack1 , and pp2a complex formation and promotes ire1 dephosphorylation by pp2a , thereby inhibiting ire1 activation and attenuating ire1-dependent increase in insulin production .
moreover , ire1 activation is increased and rack1 abundance is decreased in db / db mice .
the endoplasmic activity of ire1 is also involved in the activation of a key metabolic enzyme , amp - activated kinase ( ampk ) , in response to nitric oxide ( no ) and er stress in  cells .
ampk is a holoenzyme activated by changes in amp / atp ratio , shifting from glucose to the use of lipids as an energy source in order to respond to cellular demand .
activated ampk by gtpase dynamin related protein 1 ( drp1 ) phosphorylation prevents er and mitochondrial alteration in stressed  cells .
in addition ire1 modulates nuclear factor  light chain enhancer ( nf-b ) target gene expression and il-1 activation under mild er stress , which could contribute to chemokine - induced  cell death . upon upr
several reports indicated that xpb1s target genes and its downstream effect are cell specific and might be dependent on the activating pathways .
like ire1 , xbp1 deficient mice died between 10.5 and 14.5 day after birth because of cardiac myocyte defects .
heterozygous xbp1 mice exhibited significant increase in body mass associated with a progressive hyperinsulinemia and glucose intolerance when fed with a high fat diet .
these mice showed increased er stress and decreased insulin receptor expression in the liver . the  cell - specific deletion of xbp1 in mice resulted in a modest hyperglycaemia and glucose intolerance caused by decreased insulin secretion .
the loss of xbp1 markedly decreased the number of insulin granules and impaired proinsulin processing .
further analysis revealed that xbp1 deficiency not only participated in the er stress in  cells but also caused constitutive hyperactivation of its upstream activator , ire1 , which could degrade a subset of mrnas encoding proinsulin - processing enzymes . in summary ,  cell defects in xbp1 mutant mice result from a combined effect of xbp1 suppression on canonical upr and its negative feedback activation of ire1. altogether these findings suggest a dual and opposite role for ire1 in  cells .
a precise regulated feedback circuit involving ire1 and its product xbp1s is required to achieve optimal insulin secretion and glucose control .
in contrast , sustain production of xbp1s leads to inhibition of pdx1 and mafa expressions , promoting  cells dysfunction and apoptosis .
both atf6 isoforms are required for positive regulation of upr . however , the transcriptional activity of atf6 is lower than that of atf6. the double knockdown of the two isoforms caused an embryonic lethality demonstrating overlapping functions of atf6 and atf6 , which are essential for embryonic development .
atf6 ko mice demonstrated a severe hypoglycaemia suggesting that suppression of atf6 increased insulin sensitivity .
treatment of these mice with a pharmacological er stress inducer leads to liver dysfunction and steatosis .
furthermore , when fed with a high fat diet , atf6 null mice developed insulin resistance associated with impaired insulin secretion and lower insulin content , reinforcing the idea of a key role of atf6 in  cells adaptation and insulin resistance . recently , a basal expression of active atf6 was demonstrated to be essential for  cell survival even under unstressed conditions .
interestingly , specific functions of atf6 have been revealed depending on its interaction with xbp1 .
when atf6 is acting alone , it induces the expression of a cluster of genes involved in protein folding such as bip and grp94 .
when it heterodimerizes with xbp-1 they are modulating the expression of specific class of target genes , such as genes involved in protein degradation ( edem , herpude1 , hrd1 , and p58ipk ) .
in contrast , a deleterious effect of active atf6 overexpression on  cell function and expression of insulin , pdx1 , and mafa in ins-1 cells was shown .
interestingly , some reports demonstrated that some atf6 variants are associated with type 2 diabetes and new onset diabetes after transplantation ( nodat ) , suggesting potential links between atf6 and human diabetes pathophysiology [ 68 , 69 ] .
it is important to note that , from the myriad of atf6 homolog described until now , only old astrocyte specifically induced substance ( oasis ) was identified in  cell .
however , microarray analysis of ins-1  cell line overexpressing the active form of oasis showed its implication in extracellular matrix production and protein transport but not in the classical er stress response .
a great interest has been focused on the atf6 negative regulator wfs1 because of its association with the wolfram syndrome , a rare genetic disorder [ 71 , 72 ] .
loss of function mutation in the wfs1 gene encoding wolframin protein caused neurodegenerative disorders characterised by juvenile onset diabetes mellitus , optic atrophy , and hearing impairment [ 73 , 74 ] .
wfs1 ko mice exhibit an activated er stress especially in  cells , leading to  cell loss through impaired cell cycle progression and increased apoptosis .
conditional wfs1 knockdown in  cell induced diabetes as a result of enhanced er stress and apoptosis .
moreover wfs1 is essential for glucose and glucagon - like peptide 1 ( glp1 ) stimulated amp production and regulation of insulin biosynthesis and secretion . under glucose stimulation , wfs1 translocates from the er to plasma membrane , where it stimulates cyclic adenosine monophosphate   synthesis through an interaction with adenylyl cyclase 8 ( ac8 ) , which subsequently promoted insulin secretion   ( figure 1(a ) ) . a recent report using induced pluripotent stem ( ips ) cells to create  cells from individuals with wolfram syndrome confirmed these observations . in this study ,
wfs1 deficient  cells showed increased levels of upr genes and decreased insulin content , leading to  cell dysfunctions as previously described in mouse models .
the inability of upr outputs to restore homeostasis may generate continuous signalling from these sensors , tipping the balance in favour of apoptosis .
the er might actually serve as a site where apoptotic signals are generated and integrated to elicit the death response .
several stimuli have been linked to er stress - induced apoptosis including hyperglycaemia , exposure to long - chain free fatty acids ( e.g. , palmitate ) [ 7981 ] , hyperinsulinemia occurring in the prediabetic stage , glucose deprivation , islet amyloid polypeptide ( iapp ) expression , and exposure to inflammatory cytokine .
players involved in the cell death response include perk / elf2-dependent transcriptional induction of proapoptotic transcription factor chop which represses bcl-2 , ire1-mediated activation of ask1/jnk , and cleavage and activation of procaspase 12 ( caspase 4 in humans ) [ 87 , 88 ] .
the induction of chop is regulated by atf4 [ 11 , 90 ] and atf6 [ 9193 ] and its role in er stress - induced apoptosis was demonstrated both in vitro and in vivo .
mice lacking chop are protected from renal toxicity of the er stressor tunicamycin , an inhibitor of glycosylation .
chop deletion promotes  cells survival in both genetic and diet - induced insulin resistant mice models [ 30 , 92 ] .
pancreatic  cells are also sensitive to oxidative stress , but  cells from chop knockout mice are protected and maintain insulin secretion under oxidative stress [ 92 , 95 ] .
moreover , islets from these mice showed resistance to no , a chemical agent implicated in  cells disruption in type 1 diabetes . in contrast , chop deficiency in a genetic background of nonobese diabetic mice ( nod - chop/ ) did not affect the development of insulitis , diabetes , and  cells apoptosis .
interestingly , chop knockout mice on a c57bl/6 background showed a different phenotype , with abdominal obesity and hepatic steatosis , while preserving normal glucose tolerance and insulin sensitivity . under er stress chop positively regulates the expression of genes involved in apoptosis including gadd34 [ 50 , 99 ] , the er oxidoreductin 1  ( ero1 ) , death receptor 5 ( dr5 ) , and the pseudokinase tribbles related 3 ( trb3 ) . as shown for chop deletion , genetic inactivation of these genes protected against  cell er stress - induced apoptosis [ 100 , 103105 ] .
additionally , chop represses the expression of the antiapoptotic gene bcl2 and enhances oxidant injury .
finally , deletion of chop was reported to prevent the cytokine - mediated cleavage of caspase 9 and caspase 3 and subsequent  cells apoptosis by reducing cytokine - induced nf-b activity and the expression of key nf-b target genes involved in apoptosis and inflammation .
er stress - mediated apoptosis can also be signalled through ire1 dependent activation of jnk pathway . ire1
interacts with tbf receptor associated factor 2 ( traf2 ) and ask1 mediating jnk phosphorylation [ 18 , 108 ] .
the analysis of ask1 deficient mice showed that ask1 loss of function attenuated insulin resistance , cardiac inflammation and fibrosis , vascular endothelial dysfunction , and remodelling induced by diet - induced obesity .
moreover , deletion of ask1 in homozygous akita mice protected  cells from er induced apoptosis and delayed the onset of diabetes .
the ire1/traf2 complexes also contributes to er stress - induced apoptosis by promoting the clustering of procaspase-12 and its activation by cleavage in response to er stress .
in addition , the ire1/traf2 complex interacts with ikk , an inhibitor of nf-b , mediating its activation and promoting cell apoptosis in response to er stress [ 112 , 113 ] . finally , members of bcl2 family including bax , bak , bim , and puma have been reported to directly interact with ire1 demonstrating a physical link between members of the core apoptotic pathway and the upr [ 114 , 115 ] .
in contrast , ire1 forms a stable protein complex with bax inhibitor-1 ( bi-1 ) protein , suppressing cell death .
the ire1/bi-1 association decreased the ribonuclease activity of ire1 and seemed to be required for early adaptive responses against er stress - induced apoptosis .
the control of ire1 activity appears to be central in the mechanism protecting  cells from er stress - induced apoptosis .
further studies are needed to understand the various aspect of ire1 regulation and the contribution of the others actors of upr in the er stress - induced apoptosis .
clear evidence of the existence of er stress in human  cells has been reported in the last decade [ 2 , 3 , 6 , 117 ] .
first analysis of islets from human t2d patients showed an er extension but modest signs of er stress marker in human pancreatic samples and isolated islets .
however , glucose stimulation induced increased upr in t2d islets cells . some markers of er stress are increased in t1d human islets with partial er stress [ 117 , 118 ] .
a recent report shows an alteration in the expression of specific branches of upr mediators in t2d  cells .
these findings support the hypothesis of a decline in  cell adaptation / compensation during the progression of diabetes in human .
the  cell has a marked capacity to adapt to environment changes by increasing its mass and function .
diabetic signs occur when this adaptative mechanism fails to compensate for the increasing insulin demand .
activation of upr actors is triggered in the early stage of the compensatory mechanism and may play a central role in  cell adaptation and subsequent functions .
further studies are required to understand the physiological significance and the direct implication of er stress and upr in the early stage of diabetes physiopathology . moreover , the relationships among upr actors , their activation , and  cell fate ( adaptation / survival versus  cell dysfunction / apoptosis ) remain to be fully clarified . theoretically , the size of  cell mass is controlled by a balance between proliferation and apoptosis .
either increase of  cell apoptosis or decrease in  cell adaptation and compensation could , therefore , reduce the  cell mass in t2d patients .
studies carried out during diabetes development are required to better understand the mechanism of compensatory capacity and subsequent  cell loss in humans .
this is of particular interest , since it could have beneficial impact for the treatment of metabolic diseases such as diabetes .
it is important to note that most upr molecules have an adaptive function in  cells .
their role in the switch from survival to apoptosis is clearly demonstrated in vitro and in animal models but it remains unclear whether the same mechanisms occur in human  cell . isolating and culturing primary  cells may be very stressful and do not perfectly reflect the in vivo context . therefore the use of alternative method such as immunohistochemistry is powerful to determine the role of each branch of upr in diabetes .
 pancreatic  cell failure leads to diabetes development . during disease progression , 
  cells adapt their secretory capacity to compensate the elevated glycaemia and the peripheral insulin resistance . 
 this compensatory mechanism involves a fine - tuned regulation to modulate the endoplasmic reticulum ( er ) capacity and quality control to prevent unfolded proinsulin accumulation , a major protein synthetized within the  cell . 
 these signalling pathways are collectively termed unfolded protein response ( upr ) . 
 the upr machinery is required to preserve er homeostasis and  cell integrity . moreover 
 , upr actors play a key role by regulating er folding capacity , increasing the degradation of misfolded proteins , and limiting the mrna translation rate . 
 recent genetic and biochemical studies on mouse models and human upr sensor mutations demonstrate a clear requirement of the upr machinery to prevent  cell failure and increase  cell mass and adaptation throughout the progression of diabetes . in this review 
 we will highlight the specific role of upr actors in  cell compensation and failure during diabetes . 
1. Introduction
2. The UPR Pathway
3. Conclusion