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1 Highlights

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5 Multiple roles of glucose-6-phosphatases in pathophysiology6 State of the art and future trends

7 Paola Marcolongo a, Rosella Fulceri a, Alessandra Gamberucci a, Ibolya Czegle b, Gabor Banhegyi c, Angelo Benedetti a,⁎

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a Department of Pathophysiology, Experimental Medicine and Public Health, University of Siena, Siena, Italy10

b 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary11

c Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary

1213► The glucose-6-phosphatase (G6PC) gene family presently includes three members. ► G6PC isoforms show similar intracellular location, membrane14topology and catalytic site. ► G6PC isoforms function as glucose producer, glucose sensor or antiapoptotic factor. ► Mutations of G6PCs are associated with15human diseases.

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Please cite this article as: P. Marcolongo, et al., Multiple roles of glucose-6-phosphatases in pathophysiology, Biochim. Biophys. Acta (2012),http://dx.doi.org/10.1016/j.bbagen.2012.12.013

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Review

Multiple roles of glucose-6-phosphatases in pathophysiologyState of the art and future trends

Paola Marcolongo a, Rosella Fulceri a, Alessandra Gamberucci a, Ibolya Czegle b,Gabor Banhegyi c, Angelo Benedetti a,⁎a Department of Pathophysiology, Experimental Medicine and Public Health, University of Siena, Siena, Italyb 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungaryc Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary

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Abbreviations: G6PC, glucose-6-phosphatase, G6Pase;isoform 2; G6PC3, glucose-6-phosphatase isoform 3; ERglucose-6-phosphate; Pi, inorganic phosphate; G6PT, glucoglucokinase; PEPCK, phosphoenolpyruvate carboxykinase; Sreceptor coactivator 2; RORα, retinoid-related orphan recedisease type 1; GSD1a, inherited deficiency of G6PC; GSD1NOD, non-obese diabetic mice; SNP, single-nucleotide polylevel⁎ Corresponding author at: Viale A. Moro 2, 53100-Sien

fax: +39 0577 234009.E-mail address: benedetti@unisi.it (A. Benedetti).

0304-4165/$ – see front matter © 2012 Published by Elhttp://dx.doi.org/10.1016/j.bbagen.2012.12.013

Please cite this article as: P. Marcolongo, ethttp://dx.doi.org/10.1016/j.bbagen.2012.12

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TED PReceived 8 October 2012

Received in revised form 11 December 2012Accepted 13 December 2012Available online xxxx

Keywords:Glucose-6-phosphataseEndoplasmic reticulumGlycemiavon Gierke diseaseDiabetesCongenital neutropenia

Background: The endoplasmic reticulum enzyme glucose-6-phosphatase catalyzes the hydrolysis ofglucose-6-phosphate to glucose and inorganic phosphate. The enzyme is a part of a multicomponent systemthat includes several integral membrane proteins; the catalytic subunit (G6PC) and transporters forglucose-6-phosphate, inorganic phosphate and glucose. The G6PC gene family presently includes threemembers, termed as G6PC, G6PC2, and G6PC3. Although the three isoforms show a moderate amino acidsequence homology, their membrane topology and catalytic site are very similar. The isoforms are expresseddifferently in various tissues. Mutations in all three genes have been reported to be associated with humandiseases.Scope of review: The present review outlines the biochemical features of the G6PC gene family products, theregulation of their expression, their role in the human pathology and the possibilities for pharmacologicalinterventions.Major conclusions: G6PCs emerge as integrators of extra- and intracellular glucose homeostasis. Beside the

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ECwell known key role in blood glucose homeostasis, the members of the G6PC family seem to play a role as

sensors of intracellular glucose and of intraluminal glucose/glucose-6-phosphate in the endoplasmicreticulum.General significance: Since mutations in the three G6PC genes can be linked to human pathophysiologicalconditions, the better understanding of their functioning in connection with genetic alterations, alteredexpression and tissue distribution has an eminent importance.

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NCO1. Introduction

The “classic” glucose-6-phosphatase enzyme (G6PC, G6Pase, EC3.1.3.9), highly expressed in glucogenic organs, i.e. liver and kidney, hasbeen extensively investigated since the fifties [see 1 for a review].

More recently, isoforms of G6PC have been identified and a varietyof studies investigated their functions [see 2 for a review]. In

G6PC2, glucose-6-phosphatase, endoplasmic reticulum; G6P,se-6-phosphate transporter; GK,I, small intestine; SRC-2, steroidptor α; GSD1, glycogen storageb, inherited deficiency of G6PT;morphisms; FGL, fasting glucose

a, Italy. Tel.: +39 0577 234021;

sevier B.V.

al., Multiple roles of glucose-.013

particular at least two other isoforms – coded by different genes –

have been described; their properties are reported in Table 1. Theaim of the present review is to summarize the biochemical featuresof the G6PC gene family products, the regulation of their expression,the role of mutations in the corresponding genes in the human pa-thology and the future possibilities for pharmacological interventions.

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2. The “classic” G6Pase, G6PC

The enzyme is known for a long time to be localized in the endoplas-mic reticulum (ER)membrane [3], and its catalytic site faces the lumen ofthe ER [4]. Its positioning, therefore, requires the permeation of thecytosolic substrate glucose-6-phosphate (G6P) [1,5] as well as of thehydrolysis products inorganic phosphate (Pi) and glucose [1,5] acrossthe ER membrane (Fig. 1). In agreement with this assumption, a G6Ptransporter (G6PT, SLC37A4) has been identified, cloned [6] andimmunolocalized [7]. G6P has been shown to be counter-transported

6-phosphatases in pathophysiology, Biochim. Biophys. Acta (2012),

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Table 1t1:1

t1:2 Properties of the glucose-6-phosphatase isoforms.Q2

t1:3 Isoform G6PC G6PC2 G6PC3

t1:4 Synonymous G6PC1, G6Pase α Islet specific G6PC relatedprotein (IGRP).

G6Pase β, ubiquitously expressed G6PCrelated protein (UGRP).

t1:5 Human gene chromosomal location 17q21 [153] 2q31 [108] 17q21 [133]t1:6 Mw of the product (kDa) 35 kDa [152] 40.7 [2] 38.7 [2]t1:7 Amino acid sequence homology % of

G6PC100 50 [2] 36 [2]

t1:8 Membrane topology Nine ER transmembrane domains[4,154].Intralumenal residues predictedto play a role incatalysis: Arg83, His119 and His176 [2].

Nine ER transmembranedomains [155].Catalytically important residuesakin to G6PC [107].

Nine ER transmembrane domains [57,156].Catalytically important residues akin toG6PC [57,156].

t1:9 Tissue distribution Liver, kidney, pancreatic ß-cells,intestinal mucosa [1].

Pancreatic ß-cells [2,108]. Ubiquitous [57,133].

t1:10 G6Pase activity Well known activity [see 1]. No activity of the recombinantprotein [107].Activity present in the recombinantprotein [2,109]; Km and Vmaxlower than G6PC [109].

No activity of the recombinant protein [133].Activity present in the recombinant protein[57,136]; Km higher, but Vmax lower thanG6PC [57]. Skeletal muscle activity ofendogenous G6PC3 approx. 40-times lowerthan liver G6PC [136].

t1:11 Involvement in pathophysiology Inherited deficiency: glycogenstorage disease type 1a (GSD1a) [81,82].Overexpression in type 2 diabetes[2,95,96].

Autoantigen in type 1 diabetes? [111–117].Regulation of fasting glucose levels[118–125].

Inherited deficiency: congenital neutropeniaanddevelopmental alterations [144–150].

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with Pi in a model system (liposomes including the reconstituted G6PTprotein) [8], but very recent evidence indicates that G6PT acts as a facili-tative uniporter in native liver ER derived vesicles (microsomes) [9].According to the counter transport hypothesis [8], Pi transport would bedependent on that of G6P, but direct evidences for a G6P independentPi permeability of liver microsomes have been forwarded [9,10]. More-over, anion channels permeable to Pi are present in the sarcoplasmicreticulum membrane [11]. ER glucose permeability has been character-ized in liver microsomes [12–14] and in cell models [15] but the putativetransporter(s) is still elusive. Recently, the glucose transporter, GLUT10,has been localized to ER in model cells [16], and in HepG2 cells(Marcolongo el al preliminary results), its role however is still to be defined.Alternatively, plasma membrane glucose transporters may also functionas ER glucose transporter during their posttranslational transit [17].

The properties of the catalytic subunit of the G6Pase system,referred as G6PC, are outlined in Table 1.

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UNCO2.1. Liver and kidney G6PC

The main physiological function of liver G6PC is to regulate wholebody glucose homeostasis, in particular to maintain the blood glucoselevel constant [18]. This can be done since G6PC catalyzes thecommon terminal reaction of gluconeogenesis and glycogenolysis(Fig. 1). The high expression of both the G6PC and G6PT proteins inthe liver ER, together with their uneven distribution in the ER mem-branes [19] can guarantee an efflux of glucose from the liver ade-quately high to affect the glycemia under fasting conditions. KidneyG6PC can also contribute to whole-body glucose turnover up to 25%in the deep fasting status [e.g. 20,21] and diabetes [e.g. 22], conditionsunder which kidney works as a major gluconeogenetic site. A role forkidney G6PC is also demonstrated by the fact that in the anhepaticphase of liver transplantation the renal glucose production can com-pensate the liver glucose production [23,24]. These results have beenrecently confirmed and further characterized in liver specific G6pc−/−

mice [25]. These mice, different from the global G6pc−/− mice [26], donot present with a marked hypoglycemia, can survive in the absenceof dietary glucose and exhibit a marked glucagon-induced increase ofrenal gluconeogenesis during fasting status.

Please cite this article as: P. Marcolongo, et al., Multiple roles of glucosehttp://dx.doi.org/10.1016/j.bbagen.2012.12.013

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2.2. G6PC in non-glucogenic tissues

Many old studies addressed the presence of G6Pase activity in tissuesother than liver and kidney. In many instances, G6Pase activity was mea-sured by properly taking into account G6P hydrolysis due to unspecificphosphatases. It has been done by inactivating the unspecific phospha-tases with preincubation at pH 5.0, by evaluating the hydrolysis of poorsubstrates of G6Pase (e.g. glucose-1-phosphate or β-glycerophosphate),by using highly purifiedmicrosomal fractions and by electronmicroscopylocalization of the enzyme activity products within the ER cisternae.On the basis of these observations, as well as of more recent data onthe expression of G6PC mRNA and protein, G6PC appears to be alsopresent – although at a low extent – in pancreatic ß-cells andintestinal mucosa [1].

2.2.1. Pancreatic ß-cellsIt has been observed for a long time that rodent pancreatic islets

possess G6Pase activity [27–29]. Rodent ß-cells also express the G6PC/G6PT mRNA [30]. The enzyme activity together with the G6PC proteinappear to become expressed – along with the glucose-induced insulinsecretion – in the INS1 rat insulinoma cell line as compared to the parent,glucose-insensitive, RINm5F cells [31].

It has been proposed that islet G6Pase activity – similar to the liverone [32,33] – can stimulate the Mg-ATP dependent ER calcium accu-mulation and regulate calcium signaling-activated insulin secretion[29,34]. Glucose feeding enlarges the agonist-sensitive ER calciumpool in ß-cells [e.g. 35,36] and INS1 cells [37], and the uptake of calci-um by the ER is also modulated by the glucose concentration of themedium of mouse pancreatic ß-cells suspensions [38]. In theory,these effects might be due to either the increase in ATP:ADP ratio orin the cytosolic levels of G6P [29]. Both parameters oscillate uponglucose challenging [39]. In any event, the possible relationshipsbetween the ß-cells G6Pase activity and calcium homeostasis remainlargely unexplored.

It has been alsohypothesized thatG6Pase activity in combinationwithglucokinase (GK), creates a futile substrate cycle in which ATP is utilized,thereby reducing the ATP:ADP ratio and hence glucose-stimulated insulinsecretion by ß-cell [40–43]. Alternatively – or in addition – G6Pase canfunction antagonistically to GK by acting as a sink for G6P thus reducing

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Fig. 1. Schematic role of G6PC in carbohydratemetabolism in liver and kidney. Themetabolic flux under conditions of enhanced glucose production (e.g. fasting status, type 2 diabetes, T2D) isrepresented by continuous arrows. G6PC activity is abolished in glycogen storage disease type 1a (GSD1a) or enhanced in T2D. G6PT activity is abolished in glycogen storage disease type 1b(GSD1b). Glucose, Gluc.; glucose-6-phosphate, G6P; glucose-1-phosphate, G1P; fructose-6-phosphate, F6P; fructose-1,6-bisphosphate, F1-6P2; glucokinase, GK.

3P. Marcolongo et al. / Biochimica et Biophysica Acta xxx (2012) xxx–xxx

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RREthe glycolitic flux and ultimately lowering ATP:ADP ratio. These

possibilities are supported by several experimental results. (i) Indiabetic ob/ob mice, increases in islet G6Pase activity lead to fastinghyperglicaemia, increased glucose cycling and glucose unrespon-siveness [40–42]. (ii) Islets of GK/Wistar rats with spontaneoustype 2 diabetes exhibit a 5 fold higher glucose cycling and a reducedbasal and glucose-stimulated insulin secretion [44]. (iii) Recombinantadenovirus was used to overexpress G6PC in the rat glucose-sensitiveINS-1 cells [45]; the overexpression of G6PC caused a fourfold increasein G6P hydrolysis, a 32% decrease in glycolytic rate relative to controls,and a proportional decrease in glucose-stimulated insulin secretion.Similar results have been obtained in the mouse β-cell line MIN6 overexpressing G6PC [46]. More recently the discovery that mouse andhuman – but not rat – ß-cells selectively express the G6Pase isoformG6PC2 [2] renewed the interest on the role of G6Pase activity in thepathophysiology of ß-cells as we discuss in Section 3.

2.2.2. Intestinal mucosaThe small intestine (SI) also expresses G6PC and exhibit G6Pase

activity, which can vary, however, depending on the species. Adetectable activity was reported to be absent in rat SI homogenates[47], but it was measurable in SI from Guinea pig [48], rabbit[48,49], hamster [50] and humans [50,51]. In mice, a little activitywas observed by localizing the hydrolysis product Pi within the ERcisternae [52], but a much higher activity appeared upon fructosefeeding [53]. Subsequent studies reported a rat SI G6Pase activityapproximately 12 fold lower than that of liver [54–56]. However,the activity of rat SI was evidenced by subtracting a very high level

Please cite this article as: P. Marcolongo, et al., Multiple roles of glucose-http://dx.doi.org/10.1016/j.bbagen.2012.12.013

of unspecific G6P hydrolysis [e.g. 55]. It should be noted that theG6PC3 isoform is also expressed in the rat SI [57,58], and that thisisoform may contribute to overall G6P hydrolysis.

Low levels of G6PC mRNA and protein are present in rat SI —

compared to liver/kidney [54,55,58,59]. It has been also reported thatG6PC3 mRNA abundance is 8 to 19 fold higher than that of G6PC [58].

Western blot analysis showed an immunoreactive G6PC band inrat [56] and mouse [60] SI lysates, but no comparison with liver hasbeen reported. An immunohistochemical positive reaction for G6PCwas observed in the rat SI epithelium, particularly in the apical partof enterocytes [56].

Evidences for increases in SI mRNA G6PC levels and G6Pase activityhave been forwarded after prolonged fasting status in rats (48–72 h)[61], by glucagon treatment of mice [25], in streptozotocin-induceddiabetes of rats [54], and under high-protein feeding of mice [62]. It hasbeen also reported that there is a higher SI G6PC mRNA abundance infed as compared to overnight fasted rats and that, in both conditions,feeding with a high amino acid diet does not affect mRNA abundance[58]. The same study reported a very similar behavior for the SI G6PC3levels.

Based on the expression of G6Pase – and of phosphoenolpyruvatecarboxykinase (PEPCK) – the SI has been proposed as a gluconeogeneticsite [55,25] and evidence for glucose release from rat SI has beenforwarded in the deep fasting status, experimental type 1 diabetes [55and refs. therein] and high protein content diet [62]. However, asignificant SI glucose production has not been confirmed by otherstudies in rats [63], dogs [64] and humans [24]. Moreover, glutaminegluconeogenesis in the SI of 72 h-fasted adult rats was found to be

6-phosphatases in pathophysiology, Biochim. Biophys. Acta (2012),

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undetectable [65] and the Km of SI PEPCK is too low for accounting for thecalculated rate of gluconeogenesis [61]. Furthermore, the very low glyco-gen stores of the SI epithelium cannot account for the SI glucose releasemeasured in [25,54,61,62] as discussed in [65].

Alternatively, the SI G6Pase system – whatever the hydrolasemoiety is G6PC or G6PC3 – might be involved in glucose absorptionor in the conversion of fructose to glucose. Experiments with theintestinal GLUT2 knockout mouse suggest that G6P hydrolysis in ERcan result in a glucose release in the blood possibly via a secretory(GLUT2-independent) process [66], but the physiological significancefor this pathway remains undetermined. On the other hand, it isknown by long time that the SI of several species, including man, iscapable of converting fructose to glucose by the classical pathwayinvolving fructokinase, aldolase B, triokinase, fructose 1,6-bisphosphataseand G6Pase [50,67 and refs. therein]. Depending on the species,different rates of conversion of fructose to glucose by SI have beenreported. A high rate was measured in the dog [68], guinea pig[48,69,70], rabbit [67] and hamster [71] while this conversion wasmoderate [69,72] or negligible in rats [48,73]. In humans, at least aportion of absorbed fructose – but not of galactose – leaves the gutas glucose [74], and evidences for a fructose-to-glucose conversionhave been obtained in SI preparations in vitro [50]. Fructose feedingresults in an evident increase of G6Pase activity – associated with ERhypertrophy – in mouse enterocytes [53]. Moreover, fructoseappears to upregulate G6PC mRNA expression in rat SI [75]. In thislatter study, fructose also induced the mRNA expression of G6PT,as well as of fructokinase and fructose 1,6-bisphosphatase. Presently,the physiological role of SI G6Pase (G6PC and/or G6PC3) remains to beclearly defined, in particular specie differences and diet composition(e.g., fructose content) should be taken into account.

2.3. Regulation of G6PC expression

The expression G6PC appears to be upregulated by glucose,glucagon, glucorticoids, and fatty acids, and down regulated by insu-lin. The transcription factors and the promoters involved have beensummarized in [2].

Interestingly, it has been observed that the deficiency of thesteroid receptor coactivator 2 (SRC-2) in mice recapitulates severalaspects of the inherited deficiency of G6PC (von Gierke's disease,see below) [76,77]. This appears to be due to the transcriptionalregulation of G6pc by a complex of SRC-2 with the retinoid-relatedorphan receptor α (RORα) [76,77]. SRC-2 would act as co-activatorof RORα and the complex would bind to an evolutionarily conservedRORα response element close to the transcriptional start site [76]. Theactivation of G6pc by SRC-2-RORα complex seems to be specific inthat the other key genes of the gluconeogenic pathway (i.e., PEPCK,fructose-1,6-bisphosphatase 1, G6PT) are not induced [76,77]. However,the relationships between SRC-2–RORα and the other well knowtranscription factors/expression regulatory pathways of G6PC [2] remainundetermined.

The role of the Forkhead box-containing transcription factors ofthe FoxO subfamily as key effectors of insulin action in metabolicprocesses, including hepatic glucose production has been establishedin the last decade [2,78 and refs therein]. Very recently, it has beenshown that Notch1 and Wnt–β-catenin signaling are involved inhepatic glucose production since they induce liver G6PC expres-sion [78,79]. Both the signaling pathways act in a FoxO1-dependentmanner [78,79].

2.4. Pathology of G6PC

Glycogen storage disease type 1 (GSD1) was originally described byvon Gierke in 1929 [80] and Cori and Cori demonstrated in the 50ththat the disorder is caused by the absence of liver G6Pase activity [18].GSD1 comprises the inherited deficiency of G6PC (termed 1a subtype)

Please cite this article as: P. Marcolongo, et al., Multiple roles of glucosehttp://dx.doi.org/10.1016/j.bbagen.2012.12.013

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and G6PT (termed 1b subtype). In both instances, G6P hydrolysis isprevented, particularly in liver/kidney (Fig. 1). A number of inactivatingmutations have been found in the genes encoding both the proteins[see 81 for refs.]. Both the subtypes are characterized primarily by alarge accumulation of glycogen in liver and kidney associatedwith severehypoglycemia in thepostabsorptive state, hyperlipidemia, hyperuricemia,and lactic acidemia [81,82]. In addition, patients present with growthretardation, hepatic steatosis, hepatic adenomas, and renal failure[81,82]. GSD1b also results in severe infectious complications due to neu-tropenia and neutrophil and monocyte functional defects. G6PC is notexpressed in polymorphonuclear neutrophils despite the presence ofG6PT in that cell type, which led to investigations to identify othergenes encoding G6Pase, as we discuss in Section 4. Knock-out mice forG6PC and G6PT largely recapitulate the human diseases [26,83]. Sincethe SRC-2-RORα complex appears to be involved inG6PC expression [76],it has been speculated [77] that mutations in SRC-2 (or RORα) mightunderlie some cases of GSD1 that have not been accounted for bymutations in G6Pase or G6PT.

GSD1 pathology is primarily due to the loss of G6PC-mediatedglucose production by hepatocytes and kidney epithelial cells and tothe subsequent storage of glycogen in these tissues. The mainmechanisms linking these events with the other metabolic/cellderangements (e.g., hyperlipidemia, hepatic steatosis, hyperuricemia,lactic acidemia) have been reviewed in [81,82]. Certain molecularpathogenetic pathways, however, deserve attention. G6pc−/− micepresent with neutrophilia and elevated serum cytokines [84] as wellas with hepatic necrotic foci and infiltrating neutrophils [85]. Consis-tently, GSD1a patients exhibit increased peripheral neutrophil countsand serum interleukin-8, which suggests at least a discrete liverinjury and inflammatory status [85]. While the hepatic necrotic focimight be the substrate (via regeneration) for liver adenomas,chromosome 6 alterations appear to be an early event in GSD1 livertumorigenesis [86]. A serious complication of GSD1 is renal failurethat culminates with tubular atrophy and interstitial fibrosis. InG6pc knock-out mice, the components of the angiotensin systemand transforming growth factor-β1 – that mediate most of theprofibrogenic effects of angiotensin II – are upregulated and couldultimately result in interstitial fibrosis [87]. Further data in theG6D1a murine model suggest that angiotensin/transforming growthfactor-β1 pathway can also elicit renal damage through oxidativestress [88]. Interestingly, in the apparently disparate disease GSD1and diabetes, a very similar nephropathy ensues, and commonpathogenetic pathways, involving the tubular angiotensin system,protein kinase C and TGF-β1 have been proposed [89]. However,clinical trials in GSD1 patients showed only a partial renopreservativeeffect of angiotensin-converting-enzyme inhibitors [90,91], whichmight be due to the late onset of this therapy [90,91]. Additional trialsare necessary to clarify this point.

To our knowledge, the inherited deficiency of G6PC does notpresent with clear-cut symptoms consistent with the lack of G6Paseactivity in SI [see 92] and pancreatic β-cells. A minor storage ofglycogen has been reported in the SI epithelium [93], and thealterations in carbohydrate and hormonal metabolism of GSD1patients may mask the G6PC defect in pancreatic β-cells. It shouldbe also considered that SI also expresses the isoform G6PC3 (Section 4.),and that pancreatic β-cells express the isoform G6PC2 (Section 3.).

On the other hand, the overexpression of G6PC affects glucosemetabolism in diabetic status by favoring hepatic glucose production(Fig. 1). As a consequence of insulin resistance, the ability of insulin tostimulate peripheral glucose utilization and repress hepatic glucoseproduction is reduced in diabetic status. Glucose itself induces theexpression of G6PC [2]. In animal models of both type 1 and 2diabetes, hepatic G6PC activity and G6PC mRNA levels are increased[2,94]. Moreover, the activity of the hepatic GK/G6PC glucose cycleis increased in patients with type 2 diabetes, and this is postulatedto contribute to the elevated hepatic glucose production [2,95].

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Being G6PC the gatekeeper for glucose production by the liver, theenzyme – or the functionally coupled G6PT – can be regarded aspharmacological targets.

2.5. Pharmacology of the G6PC/G6PT system

A variety of inhibitors of G6PC or G6PT, including peroxyvanadiumcompounds, and chlorogenic acid and its derivatives has been studiedin experimental models [reviewed in 1 and 95]. The direct pharmaco-logical inhibition of liver G6Pase activity, however, cannot be “toutcourt” used in diabetic patients because it is expected to result insevere hypoglycemia and/or hepatic steatosis [96]. Moreover, theinhibition of G6PT might have additional extrahepatic consequencessuch as neutrophil and monocyte functional defects similar to thoseof GSD1b patients [97].

Nonetheless, a repertoire of natural components of the diet, aswell as of their synthetic derivatives, inhibits liver G6Pase in vitro;therefore these compounds have been proposed as antidiabeticagents. Examples are chlorogenic acid in coffee extract [98 and refstherein], phenolic derivatives from Ruprechtia polystachya flavonoids[99 and refs therein], tea catechins such as epigallocatechin gallate[100 and refs therein]. While chlorogenic acid may contribute to thewell-known prevention of type 2 diabetes by dietary coffee consump-tion [101], the pharmacology of these natural compounds remainslargely to be assessed.

A promising potential therapeutic strategy to reduce the G6PCexpression might involve the inhibition of FoxO1 [102] function, aswell as of Notch and Wnt-β-catenin signaling [78,79]. Inhibitors ofFoxO1 can reduce G6pc expression and improve fasting glycemia indiabetic db/db mice without affecting glycemia levels in controlmice [e.g., 103,104]. A study in genetically manipulated mice showedthat Notch signaling inhibition ameliorates insulin resistance both indiabetic ob/ob and diet-induced obese mice [78]. The same studyalso showed that pharmacological blockade of Notch signaling withγ-secretase inhibitors reduces G6pc expression and improves insulinsensitivity following in vivo administration in insulin-resistant mice.It has been also recently observed [79] that the hepatic deletion ofβ-catenin – the downstream mediator of canonical Wnt signaling –

in mice results in more than 60% reduction of G6pc (and PEPK)expression and improves glucose homeostasis in a model of diet-induced obesity [79]. On these bases, targeting the components ofthe aforementioned signaling pathways involved in G6PC regulationmay represent a future therapeutic strategy for diabetes.

On the other hand, the genetic therapy (viral vector-based) of GSD1ahas been proposed, see [105] for a recent review. In this respect, not onlyG6pc−/− mice but also dogs – spontaneously affected by a GSD1a-likesyndrome due to inactivating mutations of G6PC – can be regarded asan experimental model [105 and refs therein].

3. G6PC2

Because of the putative impact of β-cells G6Pase on the glucose-regulated insulin secretion, genomic investigations were performed anda G6PC isoform was discovered from the mouse betaTC3 insulinoma celllines [106]. The isoform is also expressed in human islets [107]. In thesestudies, at least two alternatively spliced variants that differ for thepresence or absence of the exon 4 were detected. The full-length cDNAencodes a 40 kDa proteinwith 50% overall identity to liver G6PC, a similarpredicted transmembrane topology, and catalytically important residues(see Table 1). In the mouse, the shorter transcript encodes two possibleopen reading frames missing the catalitically relevant His174 residue[106]. The corresponding G6PC2 splice forms have been observed inhuman pancreas [108].

The mRNAs are highly specific to the islets and the encoded(full-length) protein was initially called “islet specific G6PC relatedprotein”, IGRP. It was subsequently renamed as G6PC2 [2]. The

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G6PC2 gene in the rat it is a pseudogene, and rats therefore do notexpress a functional G6PC2 protein [107]. The transcription factorsbinding the G6pc2 promoters have been outlined in [2].

Original experiments in G6PC2 transfected COS1 cells failed todemonstrate a G6Pase activity of this isoform [106,107]. However, itwas subsequently shown that G6PC2 overexpressed in insect cellspossesses enzymatic activity comparable to the previously describedG6Pase activity in islets [109]. Moreover, significant levels of G6Phydrolysis – although at a lower rate than achieved with G6PC –

have been observed in the “ER in situ”, i.e. in permeabilized COS1cells overexpressing G6PC2 [2]. These results suggest that G6PC2might be easily denatured upon cell disruption possibly because ofperturbation of the intracellular ER membrane architecture asdiscussed in [2].

3.1. Function of G6PC2

To evaluate the function of G6PC2, a G6pc2−/− mice strain wasestablished [110]. A small but significant decrease in blood glucosewas observed in both male (14%) and female (11%) G6pc2−/− micefollowing a 6-h fast, whereas plasma insulin and glucagon concentra-tions were unchanged. It was hypothesized that deletion of the G6pc2gene removes a brake to GK, and hence enhances glycolytic flux andATP production, and increases glucose sensitivity (Fig. 2). On thebasis of these data pancreatic islet G6PC2 is considered as a “negative”glucose sensor [110]. A similar function might be performed by G6PCin rats [2].

3.2. Pathophysiology of G6PC2

3.2.1. G6PC2 as an autoantigen in type 1 diabetesThe observation that an autoantigen targeted by a prevalent

õpopulation of pathogenic CD8 T cells in non-obese diabetic mice(NOD) is the G6PC2 protein which suggests its involvement in type1 diabetes [111]. Consistently, in vivo administration of G6PC2 epitopepeptides to NOD mice appears to abrogate or delay the disease process[112]. Moreover the depletion of G6PC2-reactive CD8+ T cells delaystype 1 diabetes onset in NOD mice [113]. G6PC2-reactive CD4+ T cellshave been demonstrated both in type 1 diabetic and control humans[114]. On the other hand, it was suggested that autoimmunity towardG6PC2 is a secondary event, with insulin being the primary autoantigenin NOD mice [115]. More recently it has been observed that deletion ofthe G6pc2 gene does not affect the progression or incidence of type 1diabetes in NOD/ShiLtJ mice [116]. We can conclude that the pathogenicrole for G6PC2 as an autoantigen in type 1 diabetes, possibly associatedto proinsulin autoimmunity [117], is still undefined.

3.2.2. G6PC2 in the regulation of glucose homeostasisGenome wide association studies and cohort examinations

[118–125] identified the major allele of single-nucleotide polymor-phisms (SNP) rs560887-G of G6PC2 to be robustly associated withincreased fasting glucose levels (FGL). The SNP rs560887-A – associatedwith decreased FGL – is also associated with a decreased level ofglycosylated hemoglobin (HbA1c) [118] and lower body massindex and body fat values [125]. Insulin basal levels are not affectedby the SNP rs560887-A, and this SNP is also associated with aparadoxical reduction in insulin secretion during glucose tolerancetests [122,125,126]. This data are consistent with the observationthat G6pc2 knockout mice display decreased FGL, a reduced adiposityand normal insulin sensitivity [110]. The SNP rs560887 does notappear to be a risk factor for type 2 diabetes [118,120,122,124].

Assuming that G6PC2 solely opposes GK and hence moderates theglycolytic pathway and glucose-stimulated insulin secretion (Fig. 2),one would expect that its lower activity/expression caused by theSNP rs560887-A would be associated not only with reduced FGL,but also with increased insulin secretion. This is not the case as

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Fig. 2. Schematic role of G6PC2 in regulating glycolytic flux and insulin secretion in the pancreatic β-cell. G6PC2 is functionally expressed in mice and humans, but not in rats. In rats,G6PC may vicariate G6PC2 functions. Blood glucose (Gluc) enters in the cytosol via GLUT2 where it is phosphorylated to glucose-6-phosphate (G6P) by glucokinase (GK). GK ac-tivity increases the cytosolic G6P concentration, glycolytic flux and hence ATP/ADP ratio. Increased ATP/ADP ratio closes ATP-sensitive K+ channels and depolarizes the β-cell. De-polarization, in turn, activates plasma membrane Ca2+ channels allowing the entry of extracellular Ca2+, and the increased concentration of cytosolic Ca2+ ultimately promotesexocytosis of insulin granules. Since G6P can also enter in the ER compartment where it is hydrolysed to Gluc (and Pi) by G6PC2 (or G6PC), G6Pase activity tends to reduce cytosolicG6P concentration and ultimately insulin secretion. A reduction in the expression level of functional G6PC2, as in the case of single nucleotide polymorphisms (SNP) of G6PC2 (e.g.rs560887-G), may result in increased cytosolic concentration of G6P and insulin secretion. This would explain the reduced fasting blood glucose levels present in humans bearingSNPs of G6PC2.

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Rmentioned above. Moreover, GK rs1799884-A – which results in areduced GK activity – is associated to the expected pattern of reducedinsulin secretion and reciprocal increase in fasting glucose, whereasglucose level and insulin secretion change in parallel with G6PC2rs560887 [125]. Therefore, the association of G6PC2 SNP rs560887with FGL and glucose-stimulated insulin secretion is likely causedby independent mechanisms. It has been speculated that variationsin G6PC2 levels could also alter a characteristic of insulin secretion,which in turn alter the normal signaling between the pancreas andliver, resulting in both insulin secretion and glucose changing intandem. A hypothetical effect of G6PC2 on the pulsatility of insulinsecretion, which is required for the insulin action at the liver [e.g., 127]may underline this paradoxical phenomenon as discussed in [125].Since pulsatility of insulin secretion is likely connected with oscillationof cytosolic calcium levels, one can further speculate on the involvementof G6PC2 in β-cell calcium homeostasis (see Section 2.2.1).

The mechanism linking the SNP rs560887-A to reduced G6PC2activity might be connected to the relative expression of thefull-length active protein [106,108]. Indeed, it has been hypothesizedthat the positioning of this SNP in the exon 3 just 26 bp proximal toexon 4, may play a role in whether the full-length transcript is formed[118,119].

The rs13431652 and rs573225 SNPs located in the distal andproximal promoter of G6PC2, respectively, are also associated to FGL

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[123,128]. Interestingly, genetic and in situ functional data supporta potential role for rs13431652 as a causative SNP linking G6PC2 tovariations in FGL [128]. Actually, the rs13431652-A allele – associatedto increased FGL – is also associated to elevated G6PC2 promoteractivity and increased binding of the CCAAT-binding transcriptionfactor, NF-Y [128]. On the other hand, the mechanism linking thers573225 SNP to G6PC2 expression/activity remains undetermined[128].

In Asian populations, several SNPs both in the 5′ region and in the3′ region – between G6PC2 and the neighboring gene ABCB11 – havebeen found to be associated with FGL and eventually with type 2diabetes risk [129–132], but the mechanisms linking these SNPs toG6PC2 expression/activity is still undefined.

Altogether, findings related to G6PC2 might suggest a kind of anegative glucose sensor role for the protein. This function is primarilymanifested in the regulation of FGL, as observed in case of SNPs of theG6PC2. Further studies are needed to find mechanistic links betweenG6PC2 and G6PC2 expression, as well as between G6PC2 functionsand the regulation of FGL and insulin secretion.

4. G6PC3

Searching for homologs of G6PC2, a human cDNA and geneencoding G6PC3 was identified [133]. The encoded protein was

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originally named “ubiquitously expressed G6Pase catalytic subunit-related protein” (UGRP) because its mRNA was detected in a variety oftissues [133] (Table 1). Subsequently, human G6PC3 was cloned bydatabase analysis and RT-PCR of brain mRNA [57].

The predicted 346-amino acid protein has a calculated molecularmass of 38.7 kD and shares approximately 36% and 37% identitywith G6PC and G6PC2, respectively [133]. G6PC3 has 9 transmem-brane domains and conserved G6Pase catalytic residues (Table 1),but unlike G6PC and G6PC2, it lacks N-linked glycosylation sites andthe C-terminal KKxx motif characteristic of ER-resident transmem-brane proteins [57]. mRNA expression was highest in skeletal muscle,intermediate in heart, brain, placenta, kidney, colon, thymus, spleen,and pancreas, and low in liver, lung, small intestine, and leukocytes[57,133]. G6PC3 is also expressed in human blood neutrophils [134].RT-PCR showed that mouse leukocytes, neutrophils, and bonemarrow cells also express G6pc3 at similar levels [134].

Initial attempts to demonstrate a G6Pase activity of G6PC3 intransiently transfected COS7 cells failed [133,135]. However G6PC3exhibits hydrolase activity when expressed at higher levels using astable transfection strategy [57] or adenoviral infection [136]. Thekinetic behavior of G6Pase activity of G6PC3 was assessed in stablytransfected CHO cells [57]: as compared to rat liver G6PC activity,the optimal pH is lower, the Km higher and the Vmax 7-fold lower.Moreover, G6Pase activity is present skeletal muscle microsomes[136], and muscle expresses negligible amounts of G6PC, but evidentamounts of G6PC3 [136].

4.1. Function of G6PC3

A G6pc3 knockout mouse was generated and it exhibited a mildphenotype as compared to G6pc−/− mice [135,137]. No alterationsof hepatic glycogen and blood glucose levels were present. A reduc-tion in G6P hydrolysis was present in brain and testis homogenatesonly. Female, but not male, G6pc3−/− mice exhibit growth retardationand elevated plasma glucagon levels [137]. In a subsequent study[134], G6pc3−/− mice presented with a similar phenotype but withadditional defects in neutrophil number and functions, whichresulted in increased susceptibility to bacterial infection.

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Fig. 3. Schematic role of G6PC3 in neutrophil homeostasis. Cytosolic glucose-6-phosphate (Glyzed to glucose (Gluc) and Pi by the G6Pase activity of G6PC3. A possible physiological roleficiency of G6PT (glycogen storage disease type 1b) or G6PC3 (certain inherited neutropeneutrophil proteins, and hence in defects in neutrophil number and functions.

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While the G6pc3−/− mice indicate that G6PC is the major G6Pase ofphysiological importance for glucose homeostasis in vivo, the neutrophildefects attracted further attention. Neutrophils/macrophages expressG6PTwhose activity is crucial for survival and functioning as demonstrat-ed by its inherited deficiency (GSD1b disease, see Fig. 3), and by thegenetic [83] and pharmacological ablation [97] of this transporter. SinceG6PC is absent in neutrophils/macrophages, and G6pc3−/− mice presentwith neutrophil/macrophage defects similar to G6pt−/− mice [83,134], itappears logic to conclude that the ER G6PC3 enzyme has a key physiolo-gical role in these cells. HowG6PC3 acts in themaintenance of neutrophilhomeostasis remains to be clarified. It has been hypothesized thatER-localized G6P cannot be recycled to the cytoplasm in G6pc3−/−

(and G6pt−/−) neutrophils/macrophages (Fig. 3) [138]. Consequently,G6pc3−/− neutrophils/macrophages exhibit reduced glucose uptake,lower expression of the plasma membrane glucose transporter GLUT1,and impaired energy homeostasis – including reduced hexosemonophosphate shunt and NADPH oxidase activity – leading to impairedfunctionality. However, it is hard to postulate how the lack of the futilecycle (G6P-glucose) at the ER can regulate cell energy status or directlyaffect the expression of GLUT1. Moreover, since ER is a minor compart-ment in these cells, it is difficult to imagine how it can sequester a signi-ficant amount of G6P in the lumen. Alternatively, the G6P hydrolysiswithin the ER can prevent ER stress and apoptosis, phenomena presentin neutrophils from G6pt−/− [139] and G6pc3−/− mice [134] as well asfrom patients suffering of the inherited deficiency of G6PT [140] andG6PC3 (see Section 4.3.). Themechanism for this “protection” is presentlyundefined. Recently, mass spectrometric glycomic profiling revealedaberrant glycosylation of proteins in neutrophils, including of theelectron-transporting subunit of the NADPH oxidase, gp91phox in patientsaffected by both inherited deficiency of G6PC3 and G6PT [141]. Thiswould imply a role of G6PC3 in protein glycosylation (Fig. 3).

G6PC3 is ubiquitously expressed, but its function appears to beminor – or somehow compensated – in cells/tissues other thanleukocytes, at least in mice. A “silent” role in blood glucose homeostasishas been hypothesized [136]. G6PC3 of the skeletal muscle maycontribute to endogenous glucose production and consequently accountfor the decrease in susceptibility to hypoglycemia in GSD1a patientsafter puberty. However, it should be noted that muscle – different from

6P) enters into the ER lumen through its transporter G6PT and is subsequently hydro-for this pathway is to allow the glycosylation of neutrophil proteins. The inherited de-nia syndromes) would result in the lack of G6PC3 activity, aberrant glycosylation of

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liver – does not possesses high KM insulin-independent glucose trans-porters such as GLUT2, and therefore can hardly export glucose to theblood.

While in the mouse the role of G6PC3 appears to be largelyrestricted to neutrophils and macrophages [134,142], in humans itlikely has crucial functions in the development of other tissues, as inindicated by its inherited deficiency (see Section 4.3.).

4.2. Regulation of G6PC3 expression

Differently from the G6PC and G6PC2 promoters, the G6PC3promoter does not contain a TATA box, and therefore, transcriptionalinitiation occurs at multiple locations [2]. Recently [143], the regula-tion of the G6PC3 promoter activity was investigated in HeLa cells.Promoter activity increased by 2.4 fold as glucose was raised from 1to 5.5 mM, but no further stimulation was present at higher glucoseconcentrations. The same study showed that the regulation of theG6PC3 promoter is different from that of G6PC, particularly in thelack of response to high glucose, hormones involved in the regulationof glycemia and fatty acid metabolites. Nonetheless, the regulatoryagents/mechanisms are yet largely undetermined.

4.3. Pathology of G6PC3

The phenotype of G6pc3−/− mice prompted to search for by G6PC3mutations in humans. Indeed, a syndrome associating severe congenitalneutropenia with extra-hematopoietic features was present in patientswith bi-allelic mutations in the gene encoding G6PC3 [144,145] (Fig. 3).Subsequently, a number of G6PC3 homozygous mutations were foundin patients presenting with this syndrome [146]. The phenotype ofG6PC3 deficiency comprises neutropenia and developmental alterations[144,146,147]. Developmental aberration may include congenital heartdefects, urogenital malformations, increased visibility of superficialveins, growth retardation, endocrine abnormalities, facial dysmorpho-logy, and cutis laxa [e.g., 146]. Neutropenia appears to be associatedwith myeloid hypoplasia and/or maturation arrest in the majority ofpatients [144,146,148] suggesting that the mechanism of neutropenia isa lack of neutrophil production. However, in a minority of patients thebonemarrow is hypercellular or normocellular [146,148–150].Moreover,the samemutation (e.g., p.R253H, see [148]) can cause either maturationarrest or hypercellular or normocellular bone marrow. At present, thereason for variability of the phenotype in patients with mutations inG6PC3 is unknown.

It should be noted that the G6PT-deficient phenotype (GSD1b) doesnot appear to be present with the extra-hematopoietic alterations of theG6PC3-deficient patients (except for the growth retardation). Thismight be explained by the expression of G6P transporters – other thanG6PT – in tissues other than leucocytes (and liver/kidney), and operativeinGSD1b. Indeed,microsomal fractions derived fromfibroblasts of GSD1bpatients present with a facilitate transport activity of G6P comparable tocontrols [151]. In addition, other gene products related to G6PT – i.e. theSLC37A1 and SLC37A2 products – are expressed in various tissues [152and refs therein].

ER stress and apoptosis are well documented in neutrophils fromG6PC3-deficient patients [138,144,149]. It is possible – at least inhumans – that ER stress/apoptosis of G6PC3-deficient extra-hematopoietic cells cause alterations in the development processes.The reason why little developmental alterations are present in theG6pc3−/− mice remains obscure.

Upstream events – directly related to G6PC3 functions – shouldresult in ER stress and increased apoptosis. As discussed inSection 4.1, G6PC3 deficiency can result in impaired G6P-glucosecycling and, subsequently, of cell energy status [138]. The defectiveenergy status can promote ER stress and apoptosis. Nonetheless, theprecise link between the reduction of a putative G6P-glucose futilecycle at the ER level and the impairment of cell glucose uptake and

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energy status remains unclear. Alternatively, the aberrant glycosylationof neutrophil proteins observed in the deficiency of G6PC3 (or of G6PT)[141] might cause the downstream alterations including those of theenergy status. This likely implies a novel function of G6PC3 in glycosyla-tion and warrants further investigation.

5. Concluding remarks

Despite the recent progress, many important questions remainedunsolved concerning G6PC gene family members. In case of G6PC,the understanding of the integration of transcription factors regulat-ing G6PC expression can provide a basis for therapeutic strategiesfor the reduction of hepatic glucose production. With respect toG6PC2, further studies are needed to find mechanistic links betweenG6PC2 SNPs and G6PC2 expression, as well as between G6PC2 func-tions and the regulation of blood glucose level and insulin secretion.Finally, the possible novel function of G6PC3 in glycosylation mayprovide an explanation of the antiapoptotic role of the protein incertain cell types. Moreover, the ubiquitous expression of G6PC3and the fact that its inherited deficiency comprises, not only neutropenia,but also a variety of developmental alterations can suggest a moregeneral, presently enigmatic function for this protein in different tissues.In summary, G6PCs emerge as integrators of extra- and intracellularglucose homeostasis. Beside the well known key role in the maintenanceof blood glucose level, the newmembers of the G6PC family can functionas sensors of intracellular glucose and of intraluminal glucose/G6P in theER. Themutations in all the threeG6PC genes are associatedwith differenthuman pathophysiological conditions, the better understanding of theirfunctioning in connection with genetic alterations, altered expressionand tissue distribution can provide a basis for the treatment.

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