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Biochimica et Biophysica Acta 1801 (2010) 289–298 Contents lists available at ScienceDirect Biochimica et Biophysica Acta Glucolipotoxicity of the pancreatic beta cell Vincent Poitout a,b,c,⁎, Julie Amyot a,b, Meriem Semache a,b, Bader Zarrouki a,b, Derek Hagman a,Ghislaine Fontés a a Montreal Diabetes Research Center, CRCHUM, University of Montreal, Montreal, QC, Canadab Department of Medicine, University of Montreal, Montreal, QC, Canadac Department of Biochemistry, University of Montreal, Montreal, QC, Canada The concept of glucolipotoxicity refers to the combined, deleterious effects of elevated glucose and fatty acid Received 2 July 2009 levels on pancreatic beta-cell function and survival. Significant progress has been made in recent years Received in revised form 13 August 2009 towards a better understanding of the cellular and molecular basis of glucolipotoxicity in the beta cell. The Accepted 13 August 2009 permissive effect of elevated glucose on the detrimental actions of fatty acids stems from the influence of Available online 26 August 2009 glucose on intracellular fatty acid metabolism, promoting the synthesis of cellular lipids. The combination ofexcessive levels of fatty acids and glucose therefore leads to decreased insulin secretion, impaired insulin Keywords:Fatty acid gene expression, and beta-cell death by apoptosis, all of which probably have distinct underlying mechanisms. Recent studies from our laboratory have identified several pathways implicated in fatty acid Islet of Langerhans inhibition of insulin gene expression, including the extracellular-regulated kinase (ERK1/2) pathway, the metabolic sensor Per-Arnt-Sim kinase (PASK), and the ATF6 branch of the unfolded protein response. We have also confirmed in vivo in rats that the decrease in insulin gene expression is an early defect whichprecedes any detectable abnormality in insulin secretion. While the role of glucolipotoxicity in humans isstill debated, the inhibitory effects of chronically elevated fatty acid levels has been clearly demonstrated inseveral studies, at least in individuals genetically predisposed to developing type 2 diabetes. It is thereforelikely that glucolipotoxicity contributes to beta-cell failure in type 2 diabetes as well as to the decline in beta-cell function observed after the onset of the disease.
2009 Elsevier B.V. All rights reserved.
aggravates metabolic perturbations, and so on. While elevated levelsof glucose or fatty acids can, by themselves, be demonstrated to have Over the last 20 years, the central role of pancreatic beta-cell detrimental effects on beta-cell function in many experimental dysfunction in the development of type 2 diabetes has become systems, the combination of both nutrients is synergistically harmful, increasingly appreciated [1]. It is now generally accepted that when which has led to the concept of glucolipotoxicity [7,8]. However, insulin resistance develops in response to environmental cues such as despite years of investigation and significant progress made in the obesity, a subset of genetically predisposed individuals fails to discovery of the underlying molecular and cellular mechanisms of adequately compensate for the increased insulin demand, and beta- glucolipotoxicity, its contribution to beta-cell failure in type 2 diabetes cell failure ensues [2]. In addition, longitudinal studies in humans remains debated. We speculate that this uncertainty stems from have clearly demonstrated that beta-cell function deteriorates during several reasons. First, by nature of their long-term design, experi- the years following diagnosis of type 2 diabetes, regardless of the ments to test cause-and-effect relationships between chronic meta- therapeutic regimen [3,4]. Although the cause of this metabolic bolic perturbations and functional outcomes are plagued with deterioration is unknown, several hypotheses have been proposed.
confounding variables and therefore difficult to interpret. Second, Amongst them, chronic hyperglycemia (glucotoxicity [5]), chronic the inherent limitations of in vivo models have prompted the dislipidemia (lipotoxicity [6]), or the combination of both (glucoli- development of many in vitro systems to test the hypothesis and potoxicity [7]), have been postulated to contribute to the worsening of define its underlying mechanisms. As further discussed in this review, beta-cell function over time, creating a vicious cycle by which these systems also have important caveats. Third and perhaps most metabolic abnormalities impair insulin secretion, which further importantly, there is no clear consensus on the definition of the termglucolipotoxicity. While its root (toxicity) implies the presence of celldeath, it is often employed more loosely to refer to the functionaleffects of the combination of high glucose and elevated lipids on the ⁎ Corresponding author. CRCHUM, Technopole Angus, 2901 Rachel Est, Montreal, QC, beta cell, for instance on insulin secretion or gene expression. Also, H1W 4A4, Canada. Tel.: +1 514 890 8000x23603; fax: +1 514 412 7648.
E-mail address: Vincent.poitout@umontreal.ca (V. Poitout).
while the concept of glucolipotoxicity implicitly refers to a chronic 1388-1981/$ – see front matter 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbalip.2009.08.006


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V. Poitout et al. / Biochimica et Biophysica Acta 1801 (2010) 289–298 situation, the notion of chronicity is variable, spanning from a few transported into the mitochondria via the enzyme carnitine- hours of ex vivo cell culture to many years in diabetic patients. This is palmitoyl transferase-1 (CPT-1) for beta-oxidation, which has particularly problematic since fatty acids have a dual and time- essentially no functional consequences. In contrast, when both dependent effect on beta-cell function, acutely stimulatory but glucose and fatty acid concentrations are elevated, intracellular chronically inhibitory. Thus, there are virtually as many definitions metabolism of glucose leads to the formation of cataplerotic signals, of the term glucolipotoxicity as groups studying it, which has created such as citrate, and the generation of malonyl-CoA in the cytosol.
confusion in the field. For the purpose of this article, we propose to Since fatty acid synthase activity is lower than that of acetyl-CoA define glucolipotoxicity as the combined, deleterious effects of carboxylase in the beta cell [33], the predominant effect of malonyl- elevated glucose and fatty acid levels on pancreatic beta-cell function CoA is to inhibit CPT-1 activity, which in turn blocks fatty acid and/or survival. This review focuses on recent developments in the oxidation and leads to accumulation of long-chain acyl-CoA esters field of glucolipotoxicity from both in vitro and in vivo studies.
(LC-CoA) in the cytosol [7]. Accumulation of cytosolic LC-CoA, eitherdirectly or via generation of lipid-derived signals, adversely affects 2. Cellular and molecular mechanisms of glucolipotoxicity in the beta-cell function [8]. In addition to its metabolic effects directing fatty acid partitioning into esterification, glucose coordinatelyactivates the expression of genes involved in lipogenesis [34]. A Considering the complexity of designing mechanistic studies in key player in this mechanism is the enzyme AMP-activated protein vivo to investigate the chronic effects of fuel oversupply, a number kinase (AMPK), acting as a metabolic sensor that directs the beta cell of in vitro models, using insulin-secreting cells and isolated islets, into a "storage mode" in the face of nutrient oversupply [35], as it have been employed to identify the cellular and molecular basis of does in myocytes and hepatocytes [36]. Indeed, AMPK activity is glucolipotoxicity. In these systems, prolonged exposure to elevated inversely correlated with the glucose concentration [37] and is levels of fatty acids is associated with inhibition of glucose-induced stimulated by palmitate [38] in beta cells. Downstream of AMPK, the insulin secretion [9–12], impairment of insulin gene expression [13–18], and induction of cell death by apoptosis [19–28].
(SREBP1c), which regulates the expression of genes controlling Importantly, several of these studies have provided evidence that fatty acid synthesis [39], translates the metabolic signal sensed by lipotoxicity only occurs in the presence of concomitantly elevated AMPK into changes in gene expression, leading to enhanced glucose levels [15,16,28], an observation also confirmed in vivo lipogenesis. Glucose also increases the expression of liver X receptor [29,30]. The biochemical basis for this permissive effect of glucose (LXR) which then contributes to enhancing SREBP1c expression and will be discussed first in this section, followed by a review of the lipid synthesis [40].
mechanisms underlying the functional manifestations of glucolipo- While it is now generally accepted that fatty acid partitioning toxicity on the beta cell (insulin secretion, insulin gene expression, towards esterification and cellular lipid synthesis underpins the and cell survival).
cellular mechanisms of glucolipotoxicity in pancreatic beta cells, thenature of the lipid-derived metabolites directly responsible for the 2.1. Biochemical pathways and lipid intermediates implicated in deleterious effects of fatty acids is still elusive. It is unlikely that triglyceride accumulation itself might be the culprit, since triglycer-ides represent a relatively innocuous form of fat storage that can The permissive effect of glucose on the deleterious actions of actually protect against lipotoxicity [41]. Studies have shown that chronic fatty acids stems from its influence on intracellular monounsaturated fatty acids are less toxic and can actually protect metabolism of fatty acids [31,32]. Prentki and Corkey [7] first from the detrimental effects of unsaturated fatty acids because they proposed that glucose determines fatty acid partitioning in pancre- are more readily esterified into triglycerides [26,41]. Consistent with atic beta cells (Fig. 1). At low glucose concentrations, fatty acids are this notion is the observation that stearoyl CoA desaturase-1 (SCD1)protects from lipoapoptotic cell death induced by palmitate [42]. Infact, whereas deletion of SCD1 in mice improves insulin sensitivity[43], when introduced on the obese, leptin-deficient ob/ob back-ground the SCD1 deletion leads to a worsening of diabetes associatedwith triglyceride and cholesterol overload in islets [44].
Nolan and Prentki [45] and Prentki and Madiraju [46] have proposed the elegant concept that increased glycerolipid/fatty acidcycling represents a mean by which the beta cell attempts to protectitself from nutrient oversupply while remaining fuel-responsive so asto be capable of releasing insulin in the face of increased demand. Inturn, the unintended consequence of this fuel detoxification mech-anism is the generation of harmful intermediates from increased fluxthrough the cycle. The question remains that if triglyceride accumu-lation is merely a marker of enhanced esterification flux but does notcause glucolipotoxicity by itself, then what are the lipid-derivedmolecules directly responsible for the impairment of beta-cellfunction? The role of intermediates of the esterification pathway(e.g. lysophosphatidic acid, phosphatidic acid, diacylglycerols) hasbeen suggested [2] but, to our knowledge, not formally demonstrated.
De novo synthesis of ceramide has been shown to play a role both in Fig. 1. Effects of glucose on lipid partitioning in the beta cell. In the presence ofsimultaneously elevated levels of glucose and fatty acid (FA), the increase in cytosolic fatty acid-induced beta-cell death [47] and fatty acid inhibition of malonyl-CoA resulting from glucose metabolism inhibits the enzyme carnitine- insulin gene expression [17] but not in the impairment of insulin palmitoyl transferase-1 (CPT-1). Transport of long-chain acyl-CoA (LC-CoA) in the secretion [48]. These observations illustrate an important point, which mitochondria is reduced, and the esterification pathway is preferentially activated, may in part explain why the lipid-derived intermediates mediating leading to cytosolic accumulation of lipid-derived signaling molecules such as glucolipotoxicity have remained elusive: the mechanisms underlying ceramide, diglycerides (DG), phosphatidic acid (PA), phospholipids (PL), andtriglycerides (TG).
the various functional manifestations of glucolipotoxicity are likely Author's personal copy
V. Poitout et al. / Biochimica et Biophysica Acta 1801 (2010) 289–298 distinct. For example, accumulation of ceramide impairs insulin gene insulin secretion [65,66] and that UCP2 KO animals on a mixed genetic expression and, under certain circumstances, induces cell death, background have increased circulating insulin levels and are protected without affecting insulin secretion. Therefore, our view is that the full from diabetes [63,67]. This contention has been recently challenged by array of functional defects associated with glucolipotoxic conditions is the observation that KO of UCP2 on 3 different congenic backgrounds in due to the generation of several intracellular metabolites acting on the mouse leads to oxidative stress and impaired insulin secretion [68].
various signaling pathways and cellular functions rather than to a Thus, the increase in UCP2 expression observed in islets after high-fat feeding in rodents [30,66] or exposure to fatty acids in vitro [69,70] While most studies investigating the mechanisms of glucolipo- likely represents a cellular defense mechanism against fuel overload and toxicity in the beta cell have focused on the esterification pathway and oxidative stress rather than a deleterious response. Consistent with this triglyceride synthesis, cholesterol metabolism has recently been possibility is the observation that transgenic overexpression of UCP2 shown to also play an important role. Exposure of beta cells to does not alter mitochondrial function or glucose-induced insulin oxidized low-density lipoproteins (LDL) induces apoptosis [49] and secretion but decreases reactive oxygen species production [71].
decreases insulin gene expression [50], whereas native LDL particles Overall, it appears unlikely that an increase in UCP2 expression in have no effect and high-density lipoproteins (HDL) are protective.
response to fatty acids represents a causal mechanism of the Beta-cell specific knock-out (KO) of the ATP-binding cassette impairment of insulin secretion under glucolipotoxic conditions.
transporter subfamily A member 1 (ABCA1), which mediates reverse Activation of the lipid-regulated isoform PKCɛ has also been cholesterol efflux, results in increased cellular cholesterol content and suggested as a possible candidate signaling molecule underlying the impaired insulin secretion downstream of glucose metabolism, decrease in insulin secretion in glucolipotoxicity. Work by Schmitz- probably at the level of insulin exocytosis [51]. In addition, the ability Peiffer et al. [72] has shown that the normalization of glucose tolerance of the thiazolidinedione rosiglitazone to improve glucose tolerance in in PKCɛ KO mice under high-fat feeding was due to improved insulin high-fat diet fed mice requires a functional ABCA1 in beta cells [51].
secretion. Further, they demonstrated that islets isolated from PKCɛ Finally, forcing cholesterol synthesis in beta cells by transgenic knock-out mice were protected from the deleterious effects of fatty acids overexpression of SREBP2 under the rat insulin promoter results in on insulin secretion in vitro and that inhibition of PKCɛ was capable of a severe loss of beta-cell mass and a diabetic phenotype [52]. Since restoring insulin secretion in islets from db/db mice [72]. More recently, LXR regulates ABCA1 expression [51] and is itself directly regulated by this group has shown that the improvement in insulin secretion in PKCɛ glucose [53], glucose therefore coordinately increases fatty acid knock-out islets in the face of glucolipotoxicity was due to selective esterification and intracellular cholesterol synthesis.
restoration of the amplifying pathway of insulin release, probably due to The premise to the hypotheses described above that intermediates the generation of a lipolytic intermediate [73]. Interestingly, this is generated during triglyceride or cholesterol synthesis are mechanisti- consistent with the concept proposed by Peyot et al. [74] that lipolysis- cally involved in glucolipotoxicity is that extracellular fatty acids are generated signals contribute to the regulation of insulin secretion and first transported across the plasma membrane and act intracellularly.
that, more generally, glycerolipid/fatty acid cycling in the beta cell This concept has been challenged by the deorphanization of the G- provides essential coupling factors for insulin secretion but becomes protein coupled receptor GPR40 [54,55]. GPR40 is specifically expressed detrimental under conditions of fuel oversupply [45,46].
in pancreatic beta cells and is activated by long-chain fatty acids, which Finally, evidence suggests that fatty acids might alter one or more raises the possibility that some of the functional effects of fatty acids on late steps of insulin exocytosis in beta cells. Kato et al. [75] have shown the beta-cell might be mediated by activation of a cell surface receptor.
that expression of granuphilin, an effector of the small GTP-binding Consistent with this possibility, a role for GPR40 in mediating fatty acid protein Rab27a, which plays a key role in the docking of insulin inhibition of insulin secretion has been suggested by the observation secretory granules to the plasma membrane, is increased in islets that islets from GPR40 KO mice are insensitive to the inhibitory effects exposed to palmitate as a consequence of upregulation of SREBP1c. This of prolonged fatty acids [56]. Using a different line of GPR40 KO mice, in turn inhibits insulin secretion in response to fuel and non-fuel stimuli.
we were unable to reproduce these findings and found that deletion of In addition, Olofsson et al. [76] demonstrated that prolonged exposure the receptor does not protect islets from fatty acid inhibition of glucose- of mouse islets to glucose and fatty acids inhibited insulin secretion at a induced insulin secretion [57]. In addition, subsequent studies also very late stage of exocytosis by interfering with the release of insulin at using whole-body KO found that GPR40 deletion did not protect mice the fusion pore. These findings suggest that the mechanisms by which from high-fat diet-induced glucose intolerance [58,59]. This conclusion fatty acids affect insulin secretion might, at least in part, lie at the level of was further supported by the observation that small molecule GPR40 the exocytotic machinery and, consequently, impair insulin secretion in agonists improved glucose tolerance in mice with high-fat diet-induced response not only to glucose but also to other secretagogues.
obesity [60]. Therefore, we do not favor the view that GPR40 plays amajor role in the mechanisms of glucolipotoxicity in the beta cell.
2.2.2. Fatty acid impairment of insulin gene expression We [15–18,77] and others [13,14] have shown that prolonged 2.2. Mechanisms underlying the functional manifestations of exposure to fatty acids impairs insulin gene expression in the presence of high glucose. The mechanisms whereby fatty acids affectinsulin gene expression are distinct from those by which they impair 2.2.1. Fatty acid impairment of insulin secretion insulin secretion. First, whereas both palmitate and oleate inhibit Prolonged exposure of beta cells to fatty acids in vitro inhibits insulin secretion, only palmitate affects insulin gene expression [48].
glucose-stimulated insulin secretion [9–12], a phenomenon also This is due to the fact that only palmitate can serve as a substrate for observed in vivo in rats [61] and humans [62]. In recent years, several de novo ceramide synthesis [17]. The transcriptional mechanisms by potential mechanisms have been investigated, including upregulation which palmitate inhibits insulin gene expression do not involve of uncoupling protein 2 (UCP2), activation of the novel isoform of changes in insulin mRNA stability but, rather, inhibition of glucose- protein kinase C PKCɛ, and late exocytotic events.
induced insulin promoter activity [17]. This is associated with UCP2 is a ubiquitously expressed mitochondrial carrier which has decreased binding activity of the transcription factors pancreas– been suggested to uncouple the respiratory chain from ATP synthesis duodenum homeobox 1 (PDX-1) and MafA [18]. PDX-1 is affected in [63], although its biological functions are still unclear [64]. Initial its ability to translocate to the nucleus, whereas MafA is affected at evidence suggested that UCP2 might modulate insulin secretion and the level of its expression [18]. This is in contrast to the mechanisms thereby play a role in glucolipotoxicity. This was based on the of glucotoxicity, which involve post-translational modifications of observations that increasing UCP2 expression in beta cells impairs


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V. Poitout et al. / Biochimica et Biophysica Acta 1801 (2010) 289–298 The mechanisms whereby ceramide generation from palmitate contribute to the overall decrease in insulin gene expression [84] impairs PDX-1 subcellular localization and MafA expression are (Fig. 2). Although our initial study revealed that palmitate mostly unknown, although recent studies have identified potential candi- affects PDX-1 in its subcellular localization rather than its whole-cell dates. The c-jun NH2-terminal kinase JNK is a known target of expression levels [18], overexpression of a kinase dead mutant of ceramide [79] and can repress insulin gene transcription both via c- PASK also reduces PDX-1 mRNA levels. This suggests that reduction jun-dependent inhibition of E1-mediated transcription [80,81] and of PDX-1 expression might also contribute to decreasing its binding c-jun independent inhibition of PDX-1 binding [82]. In addition, activity under glucolipotoxic conditions. Whether PASK can directly Solinas et al. [83] have shown that palmitate activates JNK in beta phosphorylate PDX-1 and, thereby, alter its nuclear translocation is cells and that the resulting phosphorylation of insulin receptor unknown and currently under investigation. Recently, expression of substrates 1 and 2 at sites that impair insulin signaling decreases the CAAT enhancer-binding protein β (C/EBPβ), a negative regulator insulin gene transcription.
of insulin gene transcription [89], has been shown to increase in beta Recent studies in our laboratory have also attempted to identify cells in response to fatty acids [90]. Interestingly, we also observed a the signaling mechanisms implicated in palmitate inhibition of marked increase in C/EBPβ mRNA levels upon overexpression of the insulin gene expression. First, we have shown that palmitate dominant-negative PASK mutant in MIN6 cells [84]. This raises the enhances glucose-induced phosphorylation of the extracellular- possibility that, as demonstrated under glucotoxic conditions [91], regulated kinases (ERK) 1/2 and that pharmacological inhibition of C/EBPβ binds to the transcription factor nuclear factor of activated T ERK1/2 partially restores insulin gene expression in insulin- cells (NFAT) on the insulin promoter and thereby inhibits MafA secreting cells and isolated islets exposed to palmitate or ceramide binding activity.
[84]. Second, we have observed that palmitate blocks the induction A role for the unfolded protein response (UPR) and endoplasmic of the Per-Arnt-Sim kinase (PASK) by glucose [84]. PASK is an reticulum (ER) stress in beta-cell failure has received considerable evolutionarily conserved serine/threonine protein kinase, containing attention in the past few years, in part because the beta cell's intense a PAS domain sensitive to the intracellular environment which secretory activity makes it particularly susceptible to perturbations of regulates the kinase domain to transduce the signal [85]. In budding ER homeostasis [92]. As discussed in more details in the next section, yeast, it coordinates sugar storage and protein synthesis with markers of ER stress have been shown to be induced by prolonged carbohydrate availability [86]. In mammals, it has been demonstrat- exposure to fatty acids in several studies [93–101]. In most cases, the ed to be an important regulator of glycogen synthase and cellular strong induction of ER stress markers in response to fatty acids is energy balance [87]. In pancreatic beta cells, PASK is required for associated with apoptosis. Under our culture conditions of isolated rat glucose-induced insulin gene transcription [88]. In our recent study islets in the presence of glucose and palmitate, which are not [84], we observed that overexpression of PASK prevents the associated with significant cell death [84,102], we have not been inhibitory effect of palmitate on insulin mRNA and PDX-1 mRNA able to detect any activation of the inositol requiring ER-to-nucleus and protein expression in MIN6 cells. In addition, adenoviral- signal kinase (IRE) or protein kinase R-like ER kinase (PERK) branches mediated overexpression of wild-type PASK increased, whereas a of the UPR (unpublished data). In contrast, we have observed cleavage kinase dead mutant of PASK acting as a dominant negative of the transcription factor ATF6 under these conditions. Since ATF6 is a decreased, insulin mRNA and PDX-1 protein expression in islets.
negative regulator of insulin gene transcription [103], these prelim- Interestingly, the PASK pathway appears to be independent from the inary results led us to hypothesize that an early activation of the ATF6 ERK1/2 pathway and to have no effect on MafA expression in our branch of the unfolded protein response upon exposure to fatty acids system, suggesting that at least 3 independent signaling arms might represent a protective mechanism whereby the beta cellattempts to further decrease the load to the ER by inhibiting insulingene expression. This would occur as part of the unfolded proteinresponse, before overt ER stress and associated apoptosis develops. Inlater stages of more severe ER stress associated with cell death, it ispossible that alterations in PDX-1 function [96,104] or insulin mRNAstability [105] also contribute to the decrease in insulin geneexpression.
Overall, available data regarding the mechanisms of fatty acid inhibition of the insulin gene reveal a complex picture which appearsto involve several independent pathways that all concur to decreaseits expression, which is an early, and possibly protective, response ofthe beta cell in the face of nutrient oversupply (Fig. 2). Importantly,the decrease in insulin gene expression under glucolipotoxic condi-tions is also observed in vivo ([77]; see Section 3).
2.2.3. Fatty acid induction of beta-cell death Saturated fatty acids can induce beta-cell death by apoptosis in the presence of high glucose [22,26,28], whereas unsaturated fattyacids are usually protective [21,22,28]. As mentioned above, thisdifference is likely due to the greater ability of unsaturated fattyacids to form intracellular triglycerides [21,41,42]. Several mechan- Fig. 2. Working model of the mechanisms of fatty acid inhibition of insulin gene isms have been implicated, including ceramide formation expression. Several signaling pathways are activated in beta cells in the presence of [20,23,26,47], oxidative stress [25,27,106,107], and inflammation simultaneously elevated levels of palmitate and glucose. First, de novo ceramidesynthesis [17] leads to sustained activation of ERK1/2 [82] and exclusion of PDX-1 from [108]. Recently, as mentioned above, considerable evidence has been the nuclear compartment [18]. Second, palmitate blocks glucose-induction of PASK provided in support of a role for the UPR and ER stress in saturated expression, which results in decreased PDX-1 expression and increased C/EBPβ fatty acid-induced cell death ([93–101] and reviewed in [59]). The expression [82]. Third, palmitate decreases MafA expression [18]. These 3 pathways mechanisms by which saturated fatty acids such as palmitate induce result in decreased binding activities of PDX-1 and MafA on the insulin promoter. In ER stress are thought to involve depletion of ER calcium stores addition, palmitate induces the cleavage of ATF6, which also represses insulin genetranscription (our unpublished data).
[99,101] and result in the activation of JNK [99,100], although JNK


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V. Poitout et al. / Biochimica et Biophysica Acta 1801 (2010) 289–298 activation can, under some conditions, be detected prior to the 3. In vivo studies appearance of ER stress [98]. Interestingly, palmitate was shown toinduce a rapid degradation of carboxypeptidase E, which resulted 3.1. Rodent models of glucolipotoxicity not only in altered proinsulin maturation, but also in ER stress andapoptosis [109]. The changes in CPE levels were demonstrated to For the reasons described above, the findings of in vitro studies occur prior to the development of any sign of ER stress and to should be confirmed in vivo before they can be extrapolated to require palmitate metabolism and calcium influx, although the physiological or pathological situations. In this regard, pioneering precise mechanisms by which palmitate initiates CPE degradation studies by the group of Unger in the Zucker diabetic fatty (ZDF) rat were remain to be clarified [109]. Of note, however, a study by Lai et al.
instrumental in establishing the concept of lipotoxicity and identifying [110] using insulin-secreting cells and isolated islets provided some of its basic mechanisms (reviewed in [120]). In particular, these evidence that palmitate-induced apoptosis can also occur in the studies first identified the key role for ceramide as an intracellular absence of detectable ER stress. Finally, markers of ER stress are mediator of glucolipotoxicity. Thus, in this model, accumulation of increased in pancreatic sections of type 2 diabetic patients [111].
intra-islet ceramide is detected prior to beta-cell dysfunction [121] and These observations raise the question as to whether fatty acid- inhibition of ceramide synthesis prevents beta-cell death [47]. In more induced apoptosis in beta cells is primarily mediated by ER stress or recent studies, the beneficial effects of pharmacological inhibition of the mitochondrial death pathway. Intrinsic defects in mitochondrial sphingolipid synthesis on beta-cell function and diabetes progression function have been well documented under conditions of nutrient have been confirmed not only in the ZDF rat but also in other rodent overload [112], and perturbations in mitochondrial permeability are models [122–124]. However, since ceramide is also implicated in the observed early in the development of fatty acid-induced cell death in mechanisms of insulin resistance [123], it is difficult in these in vivo beta cells [113]. Luciani et al. [114] have recently shown that depletion studies to distinguish between the effects of the treatment on insulin of ER calcium stores under conditions of ER stress can lead secondarily sensitivity and those on beta-cell function.
to mitochondrial dysfunction, suggesting that perhaps under gluco- Non-genetic models of glucolipotoxicity have been developed lipotoxic conditions ER stress is a primary event which leads to and most often use prolonged infusions of Intralipid, a soybean oil triggering of several proapoptotic pathways, including mitochondrial- emulsion which generates a mixture of mostly unsaturated fatty mediated cell death.
acids [125] when co-injected with heparin. In these models, the Finally, a recent study by Lovis et al. [115] has shown that effects of Intralipid or fatty acid infusion on beta-cell function have increased expression of the microRNAs miR34a and miR146 also been inconsistent, leading to either unaffected [77], enhanced contributes directly to palmitate-induced cell death in insulin- [126,127], or reduced [9,61,128,129] insulin secretion. These dis- secreting cells and isolated islets, and the overall role of microRNAs crepancies are likely due to differences in strain, sex, age, or infusion in glucolipotoxicity will hopefully become clearer as progress towards rates. For instance, Mason et al. [61] and Goh et al. [128] suggested understanding their implications in beta-cell function continues to be that female Wistar rats are more susceptible to the deleterious effects of prolonged high fatty acid levels, and Steil et al. [127] haveobserved that a 96-h Intralipid infusion did not affect insulin 2.3. Limitations of in vitro studies of glucolipotoxicity secretion in male Sprague-Dawley rats. The influence of geneticpredisposition on the insulin secretory response to excessive fatty While in vitro models using insulin-secreting cells and isolated acid levels is also illustrated by the observation that insulin secretion islets have proven extremely valuable in dissecting the cellular and is impaired to a greater extent in heterozygous lean ZDF rats than in molecular mechanisms of glucolipotoxicity, they also have significant Wistar rats after Intralipid infusion [128]. Recent studies in our limitations which should be borne in mind when interpreting the laboratory also highlight the importance of the age of the animals in results obtained in these systems. First, there appears to be species- the response to chronic fuel overload. In a first study, we infused 8- related differences in the sensitivity to fatty acid-induced cell death week-old male Wistar rats alternatively with glucose for 4 h and [110]. For instance, whereas a 24-h exposure of human islets to Intralipid + heparin for 4 h, for a total of 72 h [77]. Hyperglycemic elevated glucose and palmitate is sufficient to observe apoptosis [28],we have not detected any cell death in rat islets after 72 h of cultureunder similar conditions [17,48,84]. Second, the concentrations offatty acids used in vitro vary amongst publications. The keydeterminant of fatty acid potency is the fraction that is unbound toBovine Serum Albumin (BSA) which depends on the molar ratio offatty acids to albumin as well as the mode of preparation. Using afluorescent probe that specifically measures the unbound fraction offatty acids [116], we observed that when palmitate at a totalconcentration of 0.5 mM was pre-complexed to BSA with a fattyacid-to-albumin molar ratio of 5:1, the unbound concentration is in therange of 200 nM (Fig. 3), which represents approximately 3 times theunbound concentration measured in the plasma of lean individuals bythe same method [117]. Finally, the concentrations of fatty acids in thevicinity of the beta cells in vivo are unknown and are probablydetermined by several different factors, including the activity oflipoprotein lipase, which accounts for some of the local delivery offatty acids to the cells [118]. In fact, it is likely that lipoprotein lipaseactivity is an important control point for fatty acid delivery to betacells, since both beta-cell specific deletion and overexpression of itsgene in the mouse impair glucose homeostasis and insulin secretion Fig. 3. Concentrations of unbound fatty acids (FA) in solution as a function of the fattyacid-to-BSA ratio for a fixed total palmitate concentration of 0.5 mM. Unbound fatty [119]. Thus, the results of in vitro experiments using fatty acids should acids were measured using the fluorescent probe ADIFAB [114]. Data are the average of be interpreted with caution, particularly when marked cytotoxicity is 2 independent experiments. Also represented are the mean ± SD of unbound FA levels measured in human plasma using the same method, from Lovis et al. [115].
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V. Poitout et al. / Biochimica et Biophysica Acta 1801 (2010) 289–298 clamps performed at the end of the infusion failed to detect any by Intralipid infusion in vivo in humans, suggesting the possible effects of the glucose + Intralipid infusion regimen on insulin contribution of oxidative stress [139].
secretion in vivo, as compared to control, saline-infused animals.
Finally, the group of Cusi and De Fronzo has carried out a series of Similarly, insulin secretion in response to glucose in isolated islets studies in non-diabetic subjects with and without family history of was unaffected. In animals infused with glucose only, we observed type 2 diabetes which clearly highlights the importance of genetic an increase in insulin mRNA levels, PDX-1 nuclear localization, and predisposition on the effects of chronically elevated fatty acids in PDX-1 binding to the endogenous insulin gene promoter in islets. In humans. They showed that a 4-day Intralipid infusion enhances contrast, in islets from animals infused with glucose + Intralipid, insulin secretion (taking into account insulin sensitivity) in control insulin mRNA levels were reduced, PDX-1 localization was shifted subjects but inhibits glucose-induced insulin secretion in individuals towards the cytosol, and occupancy of the endogenous insulin with a family history of type 2 diabetes [140]. This suggests that the promoter by PDX-1 was markedly diminished [77]. These results genetic predisposition to developing type 2 diabetes might be demonstrate that fatty acid inhibition of the insulin gene also occurs dependent, at least in part, on the ability of the beta cell to increase in vivo and represents an early defect that can be detected prior to insulin secretion in response to elevated fatty acid levels. Importantly, any alteration in insulin secretion. The lack of effect of the infusion treatment of susceptible subjects with Acipimox to decrease circulat- on insulin secretion in 8-week-old rats prompted us to assess ing fatty acid levels ameliorates insulin secretion [141].
whether older animals would be more susceptible to nutrientoverload. To test this possibility, we recently conducted a second study in which glucose and Intralipid were infused simultaneouslyand continuously for 72 h to either 8-week-old or 6-month-old In recent years, major progress has been made towards a better Wistar rats (unpublished results). As in our first study, this infusion understanding of the cellular and molecular mechanisms of regimen did not alter insulin secretion in 8-week-old rats, as glucolipotoxicity in the beta cell. The biochemical basis for the assessed by hyperglycemic clamps at the end of the infusion. In permissive effect of elevated glucose on the deleterious actions of marked contrast, infusion of glucose + Intralipid in 6-month-old rats fatty acids is better delineated; the mechanisms by which the resulted in marked insulin resistance which was not adequately combination of excessive levels of fatty acids and glucose alter beta compensated for by a sufficient increase in insulin secretion in vivo cell function are beginning to be unraveled; and it is becoming clear and in defective insulin secretion in vitro in isolated islets. The that the various functional effects of fatty acids (i.e., decreased results from these two studies yield two important conclusions. First, insulin secretion, impaired insulin gene expression, and beta-cell defective insulin gene expression under glucolipotoxic conditions death by apoptosis) have different underlying mechanisms. Despite occurs in vivo and precedes abnormalities in insulin secretion. This significant progress, however, a number of important questions confirms the physiological relevance of our previous in vitro findings remain. While it is now clear that triglyceride accumulation is more [17,18] and suggests that impaired insulin gene transcription might a symptom than a cause of glucolipotoxicity, the nature of the lipid- represent an early defect in nutrient-induced beta-cell failure.
derived intermediates directly responsible for the detrimental Second, young rats are resistant to the effects of nutrient oversupply, effects of fatty acids is still elusive. In that regard, a role for and such studies are probably better conducted in older animals, cholesterol accumulation is also likely. Amongst the several which more closely resemble the typical setting of type 2 diabetes in candidates recently proposed to explain fatty acid inhibition of humans. Whether or not this age-dependent susceptibility to insulin secretion, the role of UCP2 has become unclear, while nutrient oversupply is related to the reduced beta-cell proliferative convincing evidence seems to implicate the novel isoform PKCɛ as capacity in older rodents [130,131] is unknown and currently under well as late exocytotic events. Regarding fatty acid impairment of the insulin gene, a complex picture has emerged which includesprolonged activation of ERK1/2 via de novo ceramide synthesis,downregulation of PASK, and altered binding activities of the 3.2. Studies in humans transcription factors PDX-1, MafA, and C/EBPβ. The role of theUPR under conditions of mild glucolipotoxicity (i.e., not associated As in experimental animals, studies examining the effects of with cell death) appears limited, although our current hypothesis is prolonged fatty acids on insulin secretion in humans have led to that early activation of ATF6 represses insulin gene transcription conflicting results. Initial reports from Boden et al. indicated that a 48- and thereby contributes to the reduction in proinsulin biosynthesis h lipid infusion induces an appropriate insulin secretory response in in an attempt to decrease the load to the ER. As conditions healthy subjects [132] but is defective in type 2 diabetic patients deteriorate, unresolved and sustained unfolded protein response [133]. In contrast, Carpentier et al. [134] showed in non-diabetic likely leads to ER stress and, consequently, to beta-cell apoptosis individuals that an acute (90-min) lipid infusion elicits an increase in under severe glucolipotoxic conditions. The necessity to confirm in insulin secretion which disappears when the infusion is prolonged for vitro findings under physiological conditions has prompted several 48 h. The loss of insulin secretion is specific to the response to glucose, groups, including ours, to address these questions in in vivo models.
as the response to arginine remains normal [135]. The same group Our studies have confirmed that the decrease in insulin gene further showed that obese, but not diabetic, subjects are susceptible to expression is an early defect, which precedes any detectable the inhibitory effect of lipids on glucose-induced insulin secretion abnormality in insulin secretion, and have established that pro- [136]. Importantly, the increase in insulin secretion observed in non- longed infusions of glucose and Intralipid impairs beta-cell function diabetic subjects in response to a 24-h glucose infusion does not occur in old, but not young, animals, raising caution on the use of younger if lipids are infused simultaneously with glucose [137]. Xiao et al.
rodents to examine mechanisms of beta-cell failure. While still [138] confirmed that fatty acids also alter beta-cell function in obese debated, the role of glucolipotoxicity in humans has been clearly individuals when ingested orally, and observed interesting differences demonstrated in several studies, at least in individuals genetically between saturated and polyunsaturated fatty acids. While polyunsat- predisposed to developing type 2 diabetes.
urated fatty acids impair insulin secretion directly, saturated fatty We propose that the uncertainties regarding the role of acids induce insulin resistance which was not adequately compen- glucolipotoxicity and its manifestations stem from the fact that it is sated for by an increase in beta-cell function [138]. The same group being considered, as its name implies, as a deleterious phenomenon, further observed that concomitant administration of the antioxidant while in fact the beta cell's response to nutrient excess likely taurine improved insulin resistance and beta-cell dysfunction induced represents a continuum encompassing all stages of beta-cell


Author's personal copy
V. Poitout et al. / Biochimica et Biophysica Acta 1801 (2010) 289–298 Fig. 4. Hypothetical representation of the progression from beta-cell compensation to failure in the face of obesity-induced insulin resistance and the role of glucolipotoxicity.
According to this hypothesis, the decrease in insulin sensitivity is initially matched by a marked increase in insulin secretion, insulin gene expression, and beta-cell mass. At thisstage, the beta cell adapts to nutrient oversupply by switching to preferential utilization of fatty acids, as part of the compensatory response (glucolipoadaptation [2]). In geneticallypredisposed individuals, the beta cell eventually becomes unable to further compensate and glucolipoadaptation evolves towards glucolipotoxicity, in which excursions of bloodglucose levels outside of the normal range become permissive for the detrimental effects of elevated fatty acids. This phase is characterized by an early loss of insulin gene expression,decreased insulin secretion (relative to the degree of insulin resistance), and reduced beta-cell mass. Finally, beta-cell failure occurs when glucose levels are permanently in thehyperglycemic range. At that stage, both glucotoxicity and glucolipotoxicity contribute to the continued deterioration of beta-cell function.
compensation and beta-cell failure. In that sense, some of the early rodents, but additional investigation is necessary to ascertain the manifestations of glucolipotoxicity should actually be considered as a precise contribution of glucolipotoxicity to the pathogenesis of type 2 positive response and would be more appropriately named «gluco- diabetes in humans.
lipoadaptation», as proposed by Prentki and Nolan [2]. Examples ofsuch adaptive responses are the early decrease in insulin gene expression, as an attempt to protect the ER from overload [77], or theincrease in UCP2 expression, as a defense mechanism against Work performed in our laboratory was supported by the US oxidative stress [68].
National Institutes of Health (R01-DK58096 from NIDDK) and the The hypothesis that glucolipotoxicity represents a continuum from Canadian Institutes of Health Research (MOP 77686). V.P. holds the an adaptive response to a deleterious outcome is illustrated in Fig. 4.
Canada Research Chair in Diabetes and Pancreatic Beta-cell Function.
According to this view, in normoglycemic individuals experiencing G.F. is supported by a post-doctoral fellowship from the Canadian weight gain, the beta cell mounts a compensatory response to counter Diabetes Association. B.Z. is supported by the Montreal Diabetes insulin resistance associated with obesity. This response involves Research Center/Merck Frosst post-doctoral fellowship.
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