Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniPathway vocabulary mapping
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Combined Automated Annotation using Multiple IEA Methods
Cloning and characterization of the human and rat islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) genes.
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Human IGRP expression is restricted to islets, which the authors read as pointing to a role in islet metabolism and insulin secretion; the rat gene does not encode a protein and is not expressed in islets.
"Since IGRP gene expression is restricted to islets, this suggests a possible role in the regulation of islet metabolism and, hence, insulin secretion induced by metabolites."
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Rat IGRP is a non-expressed pseudogene, traced to a TATA-box mutation.
"rat IGRP mRNA, unlike mouse and human IGRP mRNA, is not expressed in islets or islet-derived cell lines"
Enzymatic characterization of the pancreatic islet-specific glucose-6-phosphatase-related protein (IGRP).
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Recombinant IGRP hydrolyses glucose 6-phosphate with Km 0.29-0.45 mM.
"The K(m) and V(max) values determined using glucose-6-phosphate as the substrate were 0.45 mm and 32 nmol/mg/min by malachite green assay, and 0.29 mm and 77 nmol/mg/min by glucose oxidase/peroxidase coupling assay, respectively."
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A selective inhibitor distinguishes IGRP from liver G6Pase.
"Interestingly, this inhibitor did not affect LG-6-Pase activity, while conversely LG-6-Pase inhibitors did not affect IGRP activity."
The islet-specific glucose-6-phosphatase-related protein, implicated in diabetes, is a glycoprotein embedded in the endoplasmic reticulum membrane.
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Human IGRP is an ER glycoprotein held in the membrane by nine transmembrane domains, glycosylated at Asn92, and degraded mainly by the proteasome when unglycosylated.
"IGRP is a glycoprotein, held in the endoplasmic reticulum by nine transmembrane domains"
Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels.
A variant in the G6PC2/ABCB11 locus is associated with increased fasting plasma glucose, increased basal hepatic glucose production and increased insulin release after oral and intravenous glucose loads.
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In elderly Danish twins, carriers of the fasting-glucose-raising rs560887 G allele had nominally higher basal hepatic glucose production during a clamp.
"Among elderly twins, G allele carriers had higher basal hepatic glucose production (p = 0.04)."
Genetic and functional assessment of the role of the rs13431652-A and rs573225-A alleles in the G6PC2 promoter that are strongly associated with elevated fasting glucose levels.
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The fasting-glucose-raising rs13431652-A allele is associated with higher G6PC2 promoter activity, the direction the knockout phenotype predicts; rs573225 behaves in the opposite direction.
"the rs13431652-A allele is associated with both elevated FPG (Table 1) and G6PC2 promoter activity"
Effects of GCK, GCKR, G6PC2 and MTNR1B variants on glucose metabolism and insulin secretion.
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G6PC2 rs16856187 is associated with fasting glucose in 6,822 Shanghai Chinese participants.
"We replicated the association between GCK rs1799884, G6PC2 rs16856187 and MTNR1B rs10830963 and fasting glucose in our samples"
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The same variant is associated with first-phase insulin secretion, and the fasting-glucose-raising allele tracks with lower secretion (beta -0.0245, p = 0.0108 in Table 2).
"G6PC2 rs16856187 showed evidence for association to first-phase insulin secretion (p = 0.0108), and second-phase insulin secretion under a dominant genetic model (p = 0.0431)."
G6PC2: a negative regulator of basal glucose-stimulated insulin secretion.
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Knockout islets have reduced glucose-6-phosphatase activity, and deletion shifts the glucose dose-response of insulin secretion leftward without changing its maximum.
"These data suggest that G6pc2 represents a novel, negative regulator of basal GSIS that acts by hydrolyzing glucose-6-phosphate, thereby reducing glycolytic flux."
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The authors considered and rejected a hepatic explanation for the human fasting-glucose association.
"The latter explanation appears less likely since human G6PC2 (6,35) and mouse G6pc2 (9,36) are only expressed in islets and not in liver."
Novel stable isotope analyses demonstrate significant rates of glucose cycling in mouse pancreatic islets.
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Islets cycle a substantial fraction of net glucose uptake, and cycling is abolished in G6pc2 knockout islets.
"glucose cycling was abolished in G6pc2 KO mouse islets, confirming that G6pc2 opposes the action of the glucose sensor glucokinase by hydrolyzing G6P"
Pancreatic islet beta cell-specific deletion of G6pc2 reduces fasting blood glucose.
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Beta-cell-specific deletion is sufficient to lower fasting glucose without changing fasting insulin.
"In adult mice, beta cell-specific deletion of G6pc2 was sufficient to reduce FBG without changing FPI."
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G6pc2 dominates islets, where G6pc1 is not detected.
"G6pc2 expression is much higher than G6pc3 in both pancreas and islets with G6pc1 expression not detected"
G6PC2 confers protection against hypoglycemia upon ketogenic diet feeding and prolonged fasting.
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G6pc2 knockout mice become hypoglycaemic on a ketogenic diet or a 24 h fast.
"blood glucose fell to 70 mg/dl or less in G6pc2 KO but not WT mice, suggesting that G6PC2 may have evolved, in part, to prevent hypoglycemia"
Haplotypes of the genes (GCK and G6PC2) underlying the glucose/glucose-6-phosphate cycle are associated with pancreatic beta cell glucose sensitivity in patients with newly diagnosed type 2 diabetes from the VNDS study (VNDS 11).
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In 794 newly diagnosed type 2 diabetes patients, two G6PC2 variants were associated with both modelled parameters of insulin secretion and with fasting C-peptide.
"Two G6PC2 variants (rs13387347 and rs560887) were associated to both parameters of insulin secretion (DC and PC) and to fasting C-peptide levels"
Nonsynonymous single-nucleotide polymorphisms in the G6PC2 gene affect protein expression, enzyme activity, and fasting blood glucose.
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Human G6PC2 expressed in islet-derived 832/13 cells gives measurable microsomal G6Pase activity, which several nonsynonymous variants reduce.
"The in vitro G6Pase assay showed that the Gly8Glu and Ile273Val variants did not affect activity, whereas the Gly114Arg, Met126Val, Val219Leu, and Phe256Leu variants were associated with reduced activity"
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G6PC1 has much higher G6Pase activity than G6PC2 at matched protein expression.
"G6PC1 exhibited much higher G6Pase activity than G6PC2 in these in vitro assays"
Glucose-6-phosphatase catalytic subunit 2 negatively regulates glucose oxidation and insulin secretion in pancreatic β-cells.
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G6pc2 deletion raises glycolytic and citric acid cycle flux by about 60% and roughly doubles glucose-stimulated insulin secretion in a beta-cell line.
"deletion of G6pc2 led to ∼60% increases in glycolytic and citric acid cycle (CAC) fluxes at both 5 and 11 mM glucose concentrations"
G6PC1 and G6PC2 influence G6P flux but not HSD11B1 activity.
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Overexpressing G6PC1 or G6PC2 blunts glucose-stimulated fusion-gene expression in islet cells without affecting glucocorticoid-stimulated expression.
"While overexpression of G6PC1 and G6PC2 blunted glucose-stimulated fusion gene expression, it had minimal effect on glucocorticoid-stimulated fusion gene expression."
Identification of structural motifs critical for human G6PC2 function informed by sequence analysis and an AlphaFold2-predicted model.
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Mutating one residue in each of the six regions of the predicted PAP2 motif of human G6PC2, including the predicted catalytic residues Arg79, His115, Arg168 and His174, significantly reduces G6P hydrolysis.
"The data show that individual mutation of residues in all six regions of the PAP2 motif resulted in a significant decrease in enzyme activity"
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The AlphaFold2 model predicts a lumenal disulfide bond (Cys105-Cys243) required for protein expression and a substrate cavity whose residues affect specificity.
"These data indicate that these two cysteine residues are critical for G6PC2 expression, supporting the existence of an intramolecular disulfide bond in G6PC2, as suggested by the AF2 model."
Biochemical and metabolic characterization of a G6PC2 inhibitor.
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Vmax for G6P hydrolysis is much lower for G6PC2 than for G6PC1.
"the observed Vmax for G6P hydrolysis by G6PC1 was considerably greater than that for G6PC2 and G6PC3"
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The human G6PC2 inhibitor VU0945627 does not inhibit mouse G6PC2.
"VU0945627 does not inhibit mouse G6PC2 despite its 84% sequence identity with human G6PC2."
Multiple promoter and enhancer differences likely contribute to augmented G6PC2 expression in human versus mouse pancreatic islet alpha cells.
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G6PC2 is about 5-fold beta-cell biased in human but about 20-fold in mouse, which the authors took to mean an alpha-cell role would matter more in human.
"In contrast, in humans, relative to mice, G6PC2 expression is reduced in β-cells (695 vs 1097 RPLM) and elevated in α-cells (141 vs 59 RPLM)"
The role of glucose-6-phosphatase activity in glucose homeostasis and its potential for diabetes therapy.
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The review frames G6PC1 and G6PC2 jointly as regulating glycolysis, gluconeogenesis and glycogenolysis, while stressing that the two have distinct tissue distributions, kinetics and physiological functions.
"Despite their structural and functional similarities, G6PC1 and G6PC2 exhibit distinct tissue-specific expression patterns, G6P hydrolysis kinetics, and physiological functions."
G6PC2 controls glucagon secretion by defining the set point for glucose in pancreatic α cells.
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Inducible alpha-cell-specific deletion of G6pc2 in mice shifts the glucose set point for suppression of amino-acid-stimulated glucagon secretion leftward, so that mutant islets secrete less glucagon at 0.5-5 mM glucose although secretion at zero glucose is unchanged.
"when incubated in the presence of 0.5mM, 1mM, 3mM, or 5mM glucose, α-G6PC2KO islets secreted significantly (P < 0.0001) less glucagon relative to control islets, confirming a left shift in the glucose response curve for glucagon release"
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In vivo, fasting and glucose-suppressed plasma glucagon are lower in alpha-cell-specific knockouts with insulin unchanged, and islet composition, hormone content and proliferation are unaffected.
"revealed lower glucagon concentrations in both male and female α-G6PC2KO mice relative to controls"
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G6PC2 protein is detectable in human alpha cells, and shRNA knockdown in sorted primary human alpha cells makes glucagon secretion more glucose-sensitive without changing glucagon content.
"we normalized the results to the KCl response, and found the shG6PC2-exressing α cell pseudoislets to be significantly (P < 0.05 at 1mM glucose, P < 0.01 at 3, 5 and 9 mM glucose) more sensitive to glucose"
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The glucose/G6P cycle runs in human alpha cells; 2-NBDG efflux falls on G6PC2 knockdown.
"the efflux of 2-NBDG from human α cells was significantly reduced after shRNA-mediated suppression of G6PC2"
G6PC2 hydrolyzes G6P to form Glc and Pi (islet)
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Reactome curates the G6PC2 reaction as an ER-membrane-associated hydrolysis of glucose 6-phosphate by an enzyme expressed in islet cells.
"G6PC2 (Glucose-6-phosphatase 2), associated with the endoplasmic reticulum membrane catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose (Glc) and orthophosphate (Pi)."
Gluconeogenesis
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Reactome's own pathway summary restricts gluconeogenesis to liver and kidney cells, although the pathway contains the islet G6PC2 reaction.
"Gluconeogenesis is confined to cells of the liver and kidney"
human/G6PC2/G6PC2-uniprot.txt
human/G6PC2/G6PC2-bioinformatics/RESULTS.md
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Human G6PC2 is islet- and pancreas-dominant, while G6PC1 dominates liver, kidney and intestine and is absent from sampled beta cells.
"**G6PC1**: epithelial cell of pancreas absent (gold, 52); pancreatic ductal cell absent (silver, 49); type B pancreatic cell absent (gold, 49); islet of Langerhans present (gold, 69)"
human/G6PC2/G6PC2-deep-research-claude-code.md