Novel Stable Isotope Analyses Demonstrate Significant Rates of Glucose Cycling in Mouse Pancreatic Islets

Wall, Martha L.; Pound, Lynley D.; Trenary, Irina; O’Brien, Richard M.; Young, Jamey D.

doi:10.2337/db14-0745

Cited by 26 publications

(32 citation statements)

References 45 publications

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“…G6PC2 acts by hydrolyzing glucose-6-phosphate (G6P) in the ER, thus opposing the action of the glucokinase (9,42). Islets from G6pc2 −/− mice display increased cytosolic [Ca 2+ ] and enhanced GSIS (9).…”

Section: Discussionmentioning

confidence: 99%

Sorcin Links Pancreatic β-Cell Lipotoxicity to ER Ca2+ Stores

et al. 2016

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Preserving β-cell function during the development of obesity and insulin resistance would limit the worldwide epidemic of type 2 diabetes. Endoplasmic reticulum (ER) calcium (Ca2+) depletion induced by saturated free fatty acids and cytokines causes β-cell ER stress and apoptosis, but the molecular mechanisms behind these phenomena are still poorly understood. Here, we demonstrate that palmitate-induced sorcin downregulation and subsequent increases in glucose-6-phosphatase catalytic subunit-2 (G6PC2) levels contribute to lipotoxicity. Sorcin is a calcium sensor protein involved in maintaining ER Ca2+ by inhibiting ryanodine receptor activity and playing a role in terminating Ca2+-induced Ca2+ release. G6PC2, a genome-wide association study gene associated with fasting blood glucose, is a negative regulator of glucose-stimulated insulin secretion (GSIS). High-fat feeding in mice and chronic exposure of human islets to palmitate decreases endogenous sorcin expression while levels of G6PC2 mRNA increase. Sorcin-null mice are glucose intolerant, with markedly impaired GSIS and increased expression of G6pc2. Under high-fat diet, mice overexpressing sorcin in the β-cell display improved glucose tolerance, fasting blood glucose, and GSIS, whereas G6PC2 levels are decreased and cytosolic and ER Ca2+ are increased in transgenic islets. Sorcin may thus provide a target for intervention in type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Sorcin Links Pancreatic β-Cell Lipotoxicity to ER Ca2+ Stores

et al. 2016

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“…Experiments comparing wild type (WT) and G6pc2 knockout (KO) mouse islets suggest that G6pc2 opposes the action of the beta cell glucose sensor, glucokinase, which catalyzes the formation of G6P from glucose (Iynedjian 2009; Matschinsky 2005). In isolated G6pc2 KO islets G6Pase activity (Pound, et al 2013) and glucose cycling (Wall, et al 2015) are abolished. This results in leftward shift in the dose response curve for glucose-stimulated insulin secretion (GSIS) (Pound et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Effects of G6pc2 deletion on body weight and cholesterol in mice

Boortz

Syring

Pound

et al. 2017

Journal of Molecular Endocrinology

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Genome wide association study (GWAS) data have linked the G6PC2 gene to variations in fasting blood glucose (FBG). G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit that forms a substrate cycle with the beta cell glucose sensor glucokinase. This cycle modulates the glucose sensitivity of insulin secretion and hence FBG. GWAS data have not linked G6PC2 to variations in body weight but we previously reported that female C57BL/6J G6pc2 knockout (KO) mice were lighter than wild-type littermates on both a chow and high fat diet. The purpose of this study was to compare the effects of G6pc2 deletion on FBG and body weight in both chow fed and high fat fed mice on two other genetic backgrounds. FBG was reduced in G6pc2 KO mice largely independently of gender, genetic background or diet. In contrast, the effect of G6pc2 deletion on body weight was markedly influenced by these variables. Deletion of G6pc2 conferred a marked protection against diet-induced obesity in male mixed genetic background mice whereas in 129SvEv mice deletion of G6pc2 had no effect on body weight. G6pc2 deletion also reduced plasma cholesterol levels in a manner dependent on gender, genetic background and diet. An association between G6PC2 and plasma cholesterol was also observed in humans through electronic health record-derived phenotype analyses. These observations suggest that the action of G6PC2 on FBG is largely independent of the influences of environment, modifier genes or epigenetic events whereas the action of G6PC2 on body weight and cholesterol are influenced by unknown variables.

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“…Studies on G6pc2 knockout (KO) mice show that G6pc2 is a negative regulator of glucose-stimulated insulin secretion (GSIS) [ 11 , 16 ]. G6pc2 acts by hydrolyzing G6P, thereby increasing glucose cycling and presumably decreasing glycolytic flux [ 16 , 18 ]. As such, G6pc2 opposes the action of the glucose sensor glucokinase [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Functional Analysis of Mouse G6pc1 Mutations Using a Novel In Situ Assay for Glucose-6-Phosphatase Activity and the Effect of Mutations in Conserved Human G6PC1/G6PC2 Amino Acids on G6PC2 Protein Expression

et al. 2016

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Elevated fasting blood glucose (FBG) has been associated with increased risk for development of type 2 diabetes. Single nucleotide polymorphisms (SNPs) in G6PC2 are the most important common determinants of variations in FBG in humans. Studies using G6pc2 knockout mice suggest that G6pc2 regulates the glucose sensitivity of insulin secretion. G6PC2 and the related G6PC1 and G6PC3 genes encode glucose-6-phosphatase catalytic subunits. This study describes a functional analysis of 22 non-synonymous G6PC2 SNPs, that alter amino acids that are conserved in human G6PC1, mouse G6pc1 and mouse G6pc2, with the goal of identifying variants that potentially affect G6PC2 activity/expression. Published data suggest strong conservation of catalytically important amino acids between all four proteins and the related G6PC3 isoform. Because human G6PC2 has very low glucose-6-phosphatase activity we used an indirect approach, examining the effect of these SNPs on mouse G6pc1 activity. Using a novel in situ functional assay for glucose-6-phosphatase activity we demonstrate that the amino acid changes associated with the human G6PC2 rs144254880 (Arg79Gln), rs149663725 (Gly114Arg) and rs2232326 (Ser324Pro) SNPs reduce mouse G6pc1 enzyme activity without affecting protein expression. The Arg79Gln variant alters an amino acid mutation of which, in G6PC1, has previously been shown to cause glycogen storage disease type 1a. We also demonstrate that the rs368382511 (Gly8Glu), rs138726309 (His177Tyr), rs2232323 (Tyr207Ser) rs374055555 (Arg293Trp), rs2232326 (Ser324Pro), rs137857125 (Pro313Leu) and rs2232327 (Pro340Leu) SNPs confer decreased G6PC2 protein expression. In summary, these studies identify multiple G6PC2 variants that have the potential to be associated with altered FBG in humans.

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Novel Stable Isotope Analyses Demonstrate Significant Rates of Glucose Cycling in Mouse Pancreatic Islets

Cited by 26 publications

References 45 publications

Sorcin Links Pancreatic β-Cell Lipotoxicity to ER Ca2+ Stores

Sorcin Links Pancreatic β-Cell Lipotoxicity to ER Ca2+ Stores

Effects of G6pc2 deletion on body weight and cholesterol in mice

Functional Analysis of Mouse G6pc1 Mutations Using a Novel In Situ Assay for Glucose-6-Phosphatase Activity and the Effect of Mutations in Conserved Human G6PC1/G6PC2 Amino Acids on G6PC2 Protein Expression

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