Deletion of the G6pc2 Gene Encoding the Islet-Specific Glucose-6-Phosphatase Catalytic Subunit–Related Protein Does Not Affect the Progression or Incidence of Type 1 Diabetes in NOD/ShiLtJ Mice

Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP/G6PC2) is a major autoantigen in both mouse and human type 1 diabetes. IGRP is selectively expressed in islet β cells and polymorphisms in the IGRP gene have recently been associated with variations in fasting blood glucose levels and cardiovascular-associated mortality in humans. Chromatin immunoprecipitation (ChIP) assays have shown that the IGRP promoter binds the islet-enriched transcription factors Pax-6 and BETA2. We show here, again using ChIP assays, that the IGRP promoter also binds the islet-enriched transcription factors MafA and Foxa2. Single binding sites for these factors were identified in the proximal IGRP promoter, mutation of which resulted in decreased IGRP fusion gene expression in βTC-3, Hamster insulinoma tumor (HIT), and Min6 cells. ChiP assays have shown that the islet-enriched transcription factor Pdx-1 also binds the IGRP promoter, but mutational analysis of four Pdx-1 binding sites in the proximal IGRP promoter revealed surprisingly little effect of Pdx-1 binding on IGRP fusion gene expression in βTC-3 cells. In contrast, in both HIT and Min6 cells mutation of these four Pdx-1 binding sites resulted in a ∼50% reduction in fusion gene expression. These data suggest that the same group of islet-enriched transcription factors, namely Pdx-1, Pax-6, MafA, BETA2, and Foxa2, directly or indirectly regulate expression of the two major autoantigens in type 1 diabetes.

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Faculty Opinions recommendation of A type 1 diabetes-related protein from wheat (Triticum aestivum). cDNA clone of a wheat storage globulin, Glb1, linked to islet damage.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1008244.163658 ◽

2002 ◽

Author(s):

Jin-Xiong She

Keyword(s):

Triticum Aestivum ◽

Type 1 Diabetes ◽

Cdna Clone ◽

Related Protein

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Association of single nucleotide polymorphisms in the gene encoding GLUT1 and diabetic nephropathy in Brazilian patients with type 1 diabetes mellitus

Clinica Chimica Acta ◽

10.1016/j.cca.2015.02.025 ◽

2015 ◽

Vol 444 ◽

pp. 170-175 ◽

Cited By ~ 8

Author(s):

T. Marques ◽

T.A. Patente ◽

M.B. Monteiro ◽

A.M. Cavaleiro ◽

M.S. Queiroz ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Diabetic Nephropathy ◽

Single Nucleotide Polymorphisms ◽

Type 1 Diabetes Mellitus ◽

Nucleotide Polymorphisms ◽

Gene Encoding ◽

Single Nucleotide

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Association analysis in type 1 diabetes of the PRSS16 gene encoding a thymus-specific serine protease

Human Immunology ◽

10.1016/j.humimm.2007.03.009 ◽

2007 ◽

Vol 68 (7) ◽

pp. 592-598 ◽

Cited By ~ 5

Author(s):

Benedicte A. Lie ◽

Marte K. Viken ◽

Hanne E. Akselsen ◽

Siri T. Flåm ◽

Flemming Pociot ◽

...

Keyword(s):

Type 1 Diabetes ◽

Serine Protease ◽

Association Analysis ◽

Gene Encoding

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Glutathione peroxidase 4 functional variant rs713041 modulates the risk for cardiovascular autonomic neuropathy in individuals with type 1 diabetes

Diabetes and Vascular Disease Research ◽

10.1177/1479164118820641 ◽

2019 ◽

Vol 16 (3) ◽

pp. 297-299 ◽

Cited By ~ 2

Author(s):

Sharon Nina Admoni ◽

Daniele Pereira Santos-Bezerra ◽

Ricardo Vesoni Perez ◽

Thiago Andrade Patente ◽

Maria Beatriz Monteiro ◽

...

Keyword(s):

Type 1 Diabetes ◽

Glutathione Peroxidase ◽

Autonomic Neuropathy ◽

Microvascular Complications ◽

Diabetic Complication ◽

Cardiac Autonomic Neuropathy ◽

Inverse Association ◽

Gene Encoding ◽

Functional Variant

Cardiac autonomic neuropathy is a neglected diabetic chronic complication for which genetic predictors are rarely reported. Oxidative stress is implicated in the pathogenesis of microvascular complications, and glutathione peroxidase 4 is involved in the detoxification of peroxides and of reactive oxygen species. Thus, the association of a functional variant in the gene encoding glutathione peroxidase 4 (rs713041) with this diabetic complication was investigated in 341 individuals with type 1 diabetes evaluated for cardiac autonomic neuropathy status (61.7% women, 34 [27–42] years old; diabetes duration: 21 [15–27] years; HbA1c: 8.3% [7.4–9.4]; as median [interquartile interval]). Cardiac autonomic neuropathy was present in 29% of the participants. There was an inverse association of the minor T allele of rs713041 with cardiac autonomic neuropathy (odds ratio = 0.39; 95% confidence interval = 0.17–0.90; p = 0.0271) after adjustment for potential confounders. The functional glutathione peroxidase 4 variant rs713041 modulated the risk for cardiac autonomic neuropathy in the studied population with type 1 diabetes.

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Identification and characterization of a cDNA and the gene encoding the mouse ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0320033 ◽

2004 ◽

Vol 32 (1) ◽

pp. 33-53 ◽

Cited By ~ 15

Author(s):

JN Boustead ◽

CC Martin ◽

JK Oeser ◽

CA Svitek ◽

SI Hunter ◽

...

Keyword(s):

Fusion Gene ◽

Gene Promoter ◽

Catalytic Subunit ◽

Mouse Tissue ◽

Related Protein ◽

Subunit Gene ◽

Chromosome 11 ◽

Gene Encoding ◽

Identification And Characterization

Glucose-6-phosphatase (G6Pase) catalyzes the final step in the gluconeogenic and glycogenolytic pathways, the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate. This paper describes the identification and characterization of a cDNA and the gene encoding the mouse ubiquitously expressed G6Pase catalytic subunit-related protein (UGRP). The open reading frame of this UGRP cDNA encodes a protein (346 amino acids (aa); Mr 38,755) that shares 36% overall identity (56% similarity) with the mouse G6Pase catalytic subunit (357 aa; Mr 40,454). UGRP exhibits a similar predicted transmembrane topology and conservation of many of the catalytically important residues with the G6Pase catalytic subunit; however, unlike the G6Pase catalytic subunit, UGRP does not catalyze G6P hydrolysis and does not contain a carboxy-terminal di-lysine endoplasmic reticulum retention signal. UGRP mRNA was detected by RNA blot analysis in every mouse tissue examined with the highest expression in heart, brain, testis and kidney. Database analysis showed that the mouse UGRP gene is composed of six exons, spans approximately 4.2 kbp of genomic DNA and is located on chromosome 11 along with the G6Pase catalytic subunit gene. The UGRP gene transcription start sites were mapped by primer extension analysis, and the activity of the mouse UGRP gene promoter was analyzed using luciferase fusion gene constructs. In contrast to the G6Pase catalytic subunit gene promoter, the UGRP promoter was highly active in all cell lines examined.

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Association studies between the HSD11B2 gene (encoding human 11beta-hydroxysteroid dehydrogenase type 2), type 1 diabetes mellitus and diabetic nephropathy

Acta Endocrinologica ◽

10.1530/eje.0.1460553 ◽

2002 ◽

pp. 553-558 ◽

Cited By ~ 10

Author(s):

GG Lavery ◽

CL McTernan ◽

SC Bain ◽

TA Chowdhury ◽

M Hewison ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Diabetic Nephropathy ◽

Type 1 Diabetes Mellitus ◽

Association Studies ◽

Hydroxysteroid Dehydrogenase ◽

Salt Sensitivity ◽

Gene Encoding

OBJECTIVE: Mutations in the HSD11B2 gene (encoding human 11beta-hydroxysteroid dehydrogenase type 2) explain the syndrome of apparent mineralocorticoid excess where cortisol acts as a mineralocorticoid. A microsatellite marker within the HSD11B2 gene associates with salt sensitivity and hypertension--phenotypes characterising diabetic nephropathy. Here, we evaluate the HSD11B2 gene as a susceptibility locus for diabetic nephropathy. DESIGN: 150 patients with type 1 diabetes and nephropathy (DN), 145 patients with type 1 diabetes with a long duration of non-nephropathy (LDNN) and 151 normal controls were studied. METHODS: We determined allele frequencies for the (CA)n repeat marker within intron I of the HSD11B2 gene. Duration of type 1 diabetes, diabetic status and renal function were recorded. RESULTS: 11 alleles (138-158) for the marker were observed. Allele 152 was significantly increased in controls compared with LDNN (70.5% vs 57.6%, P(c)<0.05 where P(c) is the P value corrected for multiple comparisons) but no difference was observed between DN and LDNN subjects. Allele 154 was significantly increased in the LDNN compared with the DN subjects (15.9% vs 7.0%, P(c)<0.01) but no difference was observed between DN and controls. A greater proportion of subjects carried at least 1 allele <152 in DN compared with control subjects (47.3% vs 28.5%, P(c)<0.01), but no difference was observed in LDNN compared with control and DN subjects. CONCLUSIONS: Weak associations are reported between the HSD11B2 gene, type 1 diabetes mellitus and nephropathy. The increased frequency of HSD11B2 short alleles in the diabetic groups may reflect reduced renal 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity and may, in part, explain the enhanced salt sensitivity observed in patients with type 1 diabetes.

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Deletion of the Gene Encoding the Ubiquitously Expressed Glucose-6-phosphatase Catalytic Subunit-related Protein (UGRP)/Glucose-6-phosphatase Catalytic Subunit-β Results in Lowered Plasma Cholesterol and Elevated Glucagon

Journal of Biological Chemistry ◽

10.1074/jbc.m605858200 ◽

2006 ◽

Vol 281 (52) ◽

pp. 39982-39989 ◽

Cited By ~ 16

Author(s):

Yingda Wang ◽

James K. Oeser ◽

Chunmei Yang ◽

Suparna Sarkar ◽

Seija I. Hackl ◽

...

Keyword(s):

Plasma Cholesterol ◽

Catalytic Subunit ◽

Related Protein ◽

Gene Encoding

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Identification and characterization of a human cDNA and gene encoding a ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0290205 ◽

2002 ◽

Vol 29 (2) ◽

pp. 205-222 ◽

Cited By ~ 60

Author(s):

CC Martin ◽

JK Oeser ◽

CA Svitek ◽

SI Hunter ◽

JC Hutton ◽

...

Keyword(s):

Fusion Gene ◽

Gene Promoter ◽

Catalytic Subunit ◽

Related Protein ◽

Subunit Gene ◽

Gene Encoding ◽

Human Cdna ◽

Highly Active ◽

Identification And Characterization

Glucose-6-phosphatase (G6Pase) catalyzes the final step in the gluconeogenic and glycogenolytic pathways, the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate. This paper describes the identification and characterization of a human cDNA and gene encoding a ubiquitously expressed G6Pase catalytic subunit-related protein (UGRP). The ORF of this UGRP cDNA encodes a protein (346 amino acids (aa); M(r) 38 709) which shares 36% overall identity to the human G6Pase catalytic subunit (357 aa; M(r) 40 487). UGRP exhibits a similar predicted transmembrane topology and conservation of many of the catalytically important residues with the G6Pase catalytic subunit; however, unlike the G6Pase catalytic subunit, UGRP does not catalyze G6P hydrolysis. UGRP mRNA was detected by RNA blot analysis in every tissue examined with the highest expression in muscle. Database analysis showed that the human UGRP gene is composed of six exons, spans approximately 5.4 kbp of genomic DNA and is located on chromosome 17q21 with the G6Pase catalytic subunit gene. The UGRP gene transcription start sites were mapped by primer extension analysis, and the activity of the UGRP gene promoter was analyzed using luciferase fusion gene constructs. In contrast to the G6Pase catalytic subunit gene promoter, the UGRP promoter was highly active in all cell lines examined.

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