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Sökning: WFRF:(Gloyn Anna L.)

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21.
  • Mattis, Katia K, et al. (författare)
  • Loss of RREB1 in pancreatic beta cells reduces cellular insulin content and affects endocrine cell gene expression
  • 2023
  • Ingår i: Diabetologia. - : Springer Nature. - 0012-186X .- 1432-0428. ; 66:4, s. 674-694
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS/HYPOTHESIS: Genome-wide studies have uncovered multiple independent signals at the RREB1 locus associated with altered type 2 diabetes risk and related glycaemic traits. However, little is known about the function of the zinc finger transcription factor Ras-responsive element binding protein 1 (RREB1) in glucose homeostasis or how changes in its expression and/or function influence diabetes risk.METHODS: A zebrafish model lacking rreb1a and rreb1b was used to study the effect of RREB1 loss in vivo. Using transcriptomic and cellular phenotyping of a human beta cell model (EndoC-βH1) and human induced pluripotent stem cell (hiPSC)-derived beta-like cells, we investigated how loss of RREB1 expression and activity affects pancreatic endocrine cell development and function. Ex vivo measurements of human islet function were performed in donor islets from carriers of RREB1 type 2 diabetes risk alleles.RESULTS: CRISPR/Cas9-mediated loss of rreb1a and rreb1b function in zebrafish supports an in vivo role for the transcription factor in beta cell mass, beta cell insulin expression and glucose levels. Loss of RREB1 also reduced insulin gene expression and cellular insulin content in EndoC-βH1 cells and impaired insulin secretion under prolonged stimulation. Transcriptomic analysis of RREB1 knockdown and knockout EndoC-βH1 cells supports RREB1 as a novel regulator of genes involved in insulin secretion. In vitro differentiation of RREB1KO/KO hiPSCs revealed dysregulation of pro-endocrine cell genes, including RFX family members, suggesting that RREB1 also regulates genes involved in endocrine cell development. Human donor islets from carriers of type 2 diabetes risk alleles in RREB1 have altered glucose-stimulated insulin secretion ex vivo, consistent with a role for RREB1 in regulating islet cell function.CONCLUSIONS/INTERPRETATION: Together, our results indicate that RREB1 regulates beta cell function by transcriptionally regulating the expression of genes involved in beta cell development and function.
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22.
  • Orho-Melander, Marju, et al. (författare)
  • GCKR : How genetic variation across the allelic spectrum influences protein function and metabolic traits in humans
  • 2016
  • Ingår i: The Genetics of Type 2 Diabetes and Related Traits: Biology, Physiology and Translation. - Cham : Springer International Publishing. - 9783319015743 - 9783319015736 ; , s. 317-336
  • Bokkapitel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) have generated considerable interest in glucokinase regulatory protein (GKRP; gene name GCKR) which is an inhibitor of hepatic glucokinase (GCK), an enzyme that plays a critical role in glucose update and disposal in liver. From the initial discovery of GCKR variants associated with triglyceride and glucose levels through the identification of pleiotropic associations with a wide variety of metabolic phenotypes, we have learned a great deal about the importance of GKRP as a critical node in hepatic metabolism. GKRP remains one of the few well-studied GWAS loci where attempts have been made to understand the functional as well as the phenotypic impact of genetic variants across the allelic spectrum. Given the interest in developing liver-specific glucokinase activators and small molecules which disrupt the GKRP:GCK interaction for the treatment of type 2 diabetes, these genetic insights provide a wealth of information regarding efficacy and potential adverse on-target effects in humans.
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23.
  • Thanabalasingham, Gaya, et al. (författare)
  • Mutations in HNF1A Result in Marked Alterations of Plasma Glycan Profile
  • 2013
  • Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 62:4, s. 1329-1337
  • Tidskriftsartikel (refereegranskat)abstract
    • A recent genome-wide association study identified hepatocyte nuclear factor 1-alpha (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MOD?) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups. The DG9-glycan index, which is the ratio of fucosylated to nonfucosylated triantennary glycans, provided optimum discrimination in the pilot study and was examined further among additional subjects with HNF1A-MODY (n = 188), glucokinase (GCE)-MODY (n = 118), hepatocyte nuclear factor 4-alpha (HNF4A)-MODY (n = 40), type 1 diabetes (n = 98), type 2 diabetes (n = 167), and nondiabetic controls (n = 98). The DG9-glycan index was markedly lower in HNF1A-MODY than in controls or other diabetes subtypes, offered good discrimination between HNF1A-MODY and both type 1 and type 2 diabetes (C statistic >= 0.90), and enabled us to detect three previously undetected HNF1A mutations in patients with diabetes. In conclusion, glycan profiles are altered substantially in HNF1A-MODY, and the DG9-glycan index has potential clinical value as a diagnostic biomarker of HNF1A dysfunction.
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24.
  • Travers, Mary E., et al. (författare)
  • Insights Into the Molecular Mechanism for Type 2 Diabetes Susceptibility at the KCNQ1 Locus From Temporal Changes in Imprinting Status in Human Islets
  • 2013
  • Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 62:3, s. 987-992
  • Tidskriftsartikel (refereegranskat)abstract
    • The molecular basis of type 2 diabetes predisposition at most established susceptibility loci remains poorly understood. KCNQ1 maps within the 11p15.5 imprinted domain, a region with an established role in congenital growth phenotypes. Variants intronic to KCNQ1 influence diabetes susceptibility when maternally inherited. By use of quantitative PCR and pyrosequencing of human adult islet and fetal pancreas samples, we investigated the imprinting status of regional transcripts and aimed to determine whether type 2 diabetes risk alleles influence regional DNA methylation and gene expression. The results demonstrate that gene expression patterns differ by developmental stage. CDKN1C showed monoallelic expression in both adult and fetal tissue, whereas PHLDA2, SLC22A18, and SLC22A18AS were biallelically expressed in both tissues. Temporal changes in imprinting were observed for KCNQ1 and KCNQ10T1, with monoallelic expression in fetal tissues and biallelic expression in adult samples. Genotype at the type 2 diabetes risk variant rs2237895 influenced methylation levels of regulatory sequence in fetal pancreas but without demonstrable effects on gene expression. We demonstrate that CDKN1C, KCNQ1, and KCNQ10T1 are most likely to mediate diabetes susceptibility at the KCNQ1 locus and identify temporal differences in imprinting status and methylation effects, suggesting that diabetes risk effects may be mediated in early development. Diabetes 62:987-992, 2013
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