Genetic sequencing of MODY patients.
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ABSTRACT:
PROVIDER: EGAS00001001699 | EGA |
REPOSITORIES: EGA
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Project description:Increasing evidence suggests that loss of beta cell characteristics may cause insulin secretory deficiency in diabetes but the underlying mechanisms remain unclear. Here we show that Rfx6, whose mutation leads to neonatal diabetes in man, is essential to maintain key features of functionally mature beta cells in mice. Rfx6 loss in adult beta cells leads to glucose intolerance, impaired beta cell glucose sensing and to defective insulin secretion. This is associated with reduced expression of core components of the insulin secretion pathway including GLucokinase, the Abcc8/SUR1 subunit of KATP channels and voltage-gated Ca2 channels, which are direct targets of Rfx6. Moreover, Rfx6 contributes to the silencing of the vast majority of “disallowed” genes, a group usually specifically repressed in adult beta cells, and thus to the maintenance of beta cell maturity. These findings raise the possibility that changes in Rfx6 expression or activity may contribute to beta cell failure in man.
2014-12-11 | GSE62844 | GEO
Project description:We performed whole genome, whole or targeted exome sequencing for 289 individuals from India. This included 152 clinically diagnosed MODY and 137 control samples. Whole genome libraries were constructed using TruSeqNano DNA Library Preparation Kit (Illumina, CA) and sequenced on Illumina HiSeq2500 (Illumina, CA). The whole exome analysis was performed using Agilent SureSelect (Santa Clara, CA) Human All Exome kit v5 (50 Mb). Exome capture libraries were sequenced on HiSeq 2500 (Illumina, CA). Targeted exome sequencing was performed using custom probes corresponding to 1965 genes implicated in pancreatic cell biology and/or diabetes.
| EGAD00001003919 | EGA
Project description:Increasing evidence suggests that loss of beta cell characteristics may cause insulin secretory deficiency in diabetes but the underlying mechanisms remain unclear. Here we show that Rfx6, whose mutation leads to neonatal diabetes in man, is essential to maintain key features of functionally mature beta cells in mice. Rfx6 loss in adult beta cells leads to glucose intolerance, impaired beta cell glucose sensing and to defective insulin secretion. This is associated with reduced expression of core components of the insulin secretion pathway including GLucokinase, the Abcc8/SUR1 subunit of KATP channels and voltage-gated Ca2 channels, which are direct targets of Rfx6. Moreover, Rfx6 contributes to the silencing of the vast majority of M-bM-^@M-^\disallowedM-bM-^@M-^] genes, a group usually specifically repressed in adult beta cells, and thus to the maintenance of beta cell maturity. These findings raise the possibility that changes in Rfx6 expression or activity may contribute to beta cell failure in man. Two ChIP-Seq experiments have been performed : 1) anti-HA ChIP-Seq on 3HA-Rfx6 transfected Min6b1 cells and 2) anti-HA ChIP-Seq on Min6b1 cells
2014-12-11 | E-GEOD-62844 | biostudies-arrayexpress
Project description:Insulin resistance is necessary but not sufficient for the development of type 2 diabetes. Diabetes results when pancreatic beta-cells fail to compensate for insulin resistance by increasing insulin production through an expansion of beta-cell mass or increased insulin secretion. Communication between insulin target tissues and beta-cells may initiate this compensatory response. Correlated changes in gene expression between tissues can provide evidence for such intercellular communication. We profiled gene expression in six tissues of mice from an obesity-induced diabetes-resistant and a diabetes-susceptible strain before and after the onset of diabetes. We studied the correlation structure of mRNA abundance and identified 105 co-expression gene modules. We provide an interactive gene network model showing the correlation structure between the expression modules within and among the six tissues. This resource also provides a searchable database of gene expression profiles for all genes in six tissues in lean and obese diabetes-resistant and diabetes-susceptible mice, at 4 and 10 weeks of age. A cell cycle regulatory module in islets predicts diabetes susceptibility. The module predicts islet replication; we found a strong correlation between ^2 H_2 O incorporation into islet DNA /in vivo/ and the expression pattern of the cell cycle module. This pattern is highly correlated with that of several individual genes in insulin target tissues, including IGF2, which has been shown to promote beta-cell proliferation, suggesting that these genes may provide a link between insulin resistance and beta-cell proliferation. Keywords: time course, mouse strain comparison, effect of obesity, Type 2 diabetes is a disorder that involves an increased demand for insulin brought about by insulin resistance, together with a failure to compensate with sufficient insulin production. Although Insulin resistance occurs in most obese individuals, diabetes is generally forestalled through compensation with increased insulin. This increase in insulin occurs through an expansion of beta-cell mass and/or increased insulin secretion by individual beta-cells. Failure to compensate for insulin resistance leads to type 2 diabetes. One way to understand the pathophysiology of diabetes is to examine the coordinate changes in gene expression that occur in insulin-responsive tissues and pancreatic islets in obese animals that either compensate for insulin resistance or progress to type 2 diabetes. In each case, there are groups of genes that undergo changes in expression in a highly correlated fashion. By identifying groups of correlated transcripts (gene expression modules) during the compensation and development of diabetes, we can gain insight into potential pathways and regulatory networks in obesity-induced diabetes. We study two strains of mice that differ in obesity-induced diabetes susceptibility. In this study, we surveyed gene expression in six tissues of lean and obese C57BL/6 (B6) and BTBR mice aged 4 wks and 10 wks. B6 mice remain essentially non-diabetic at all ages, irrespective of obesity. When obese, BTBR mice become severely diabetic by 10 weeks of age. By analyzing the correlation structure of the genes under three contrast conditions, obesity, strain, and age, we identified gene expression modules associated with the onset of diabetes and provide an interactive co-expression network model of type 2 diabetes. We found a key module that is comprised of cell cycle regulatory genes. In the islet, the expression profile of these transcripts accurately predicts diabetes and is highly correlated with islet cell proliferation.
2008-03-14 | E-GEOD-10785 | biostudies-arrayexpress
Project description:<p>The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases.</p> <p>Neonatal diabetes mellitus (ND) is a rare form of monogenic diabetes (90,000-260,000 live births) that is diagnosed in the first 6 months of life. The disease has been classified as transient or permanent and although it can be inherited, more frequently is sporadic as a result of 'de novo' mutations. Defects in 12 genes have been found as responsible for the disease (defects in the paternally imprinted chromosomal region 6q24, IPF1, SLCA2A, INS, EIF2AK3, GCK, FOXP3, GLIS3, PTF1A, HNF1Beta, KCNJ11 and ABCC8). The two subunits of the ATP-sensitive K channel (ABCC8 and KCNJ11) and the insulin gene (INS), account for almost half of the cases and similar to CHI, the other half, remains genetically unexplained.</p> <p>We became part of this study when we submitted 4 DNA samples for exome sequencing, from patients with NDM of Caucasian ancestry, which had no mutations identified in ABCC8 or KCNJ1, with the goal to identify new mutations in known genes or new mutations or genetic variants in new genes.</p>
| phs000542 | dbGaP
Project description:Insulin resistance is necessary but not sufficient for the development of type 2 diabetes. Diabetes results when pancreatic beta-cells fail to compensate for insulin resistance by increasing insulin production through an expansion of beta-cell mass or increased insulin secretion. Communication between insulin target tissues and beta-cells may initiate this compensatory response. Correlated changes in gene expression between tissues can provide evidence for such intercellular communication. We profiled gene expression in six tissues of mice from an obesity-induced diabetes-resistant and a diabetes-susceptible strain before and after the onset of diabetes. We studied the correlation structure of mRNA abundance and identified 105 co-expression gene modules. We provide an interactive gene network model showing the correlation structure between the expression modules within and among the six tissues. This resource also provides a searchable database of gene expression profiles for all genes in six tissues in lean and obese diabetes-resistant and diabetes-susceptible mice, at 4 and 10 weeks of age. A cell cycle regulatory module in islets predicts diabetes susceptibility. The module predicts islet replication; we found a strong correlation between ^2 H_2 O incorporation into islet DNA /in vivo/ and the expression pattern of the cell cycle module. This pattern is highly correlated with that of several individual genes in insulin target tissues, including IGF2, which has been shown to promote beta-cell proliferation, suggesting that these genes may provide a link between insulin resistance and beta-cell proliferation. Keywords: time course, mouse strain comparison, effect of obesity,
2008-03-15 | GSE10785 | GEO
Project description:Mutations in several transcription factors lead to a subtype of type 2 diabetes called maturity-onset diabetes of the young (MODY), which are characterized by autosomal dominant inheritance, an early age of disease onset, and development of marked hyperglycemia with a progressive impairment in insulin secretion (Shih and Stoffel, 2002). The most frequent form of MODY is caused by mutations in the gene encoding hepatocyte nuclear factor-1a (HNF-1a, TCF1). Mutant mice with loss of Tcf1 function as well as transgenic mice expressing a naturally occurring dominant-negative form of human TCF1(P291fsinsC) in pancreatic beta cells develop progressive hyperglycemia due to impaired glucose-stimulated insulin secretion (Hagenfeldt-Johansson et al., 2001; Yamagata et al., 2002). Importantly, these mice exhibit a progressive reduction in beta cell number, proliferation rate, and pancreatic insulin content. These data indicate that Tcf-1 target genes are also required for maintenance of normal beta cell mass. In this study we sought to identify target genes of Tcf-1 that may be responsible of mediating beta cell growth by comparing gene expression profiles of Tcf-1 knock-out and wild-type littermates in isolated pancreatic islets.
2007-02-27 | E-CBIL-21 | biostudies-arrayexpress
Project description:We determined the genes that were differentially expressed between fulminant type 1 diabetes and classical type 1A diabetes using gene expression microarray in peripheral blood cells. Ten patients with type 1 diabetes (5 fulminant and 5 classical type 1A) were enrolled in this study. All patients had recovered from ketosis or ketoacidosis at disease onset and had been receiving intensive insulin injection therapy for at least 1 month, which means that all patients and healthy controls were free of metabolic derangements at the time of blood sampling. To determine the genes that were differentially expressed between classical type 1A and fulminant type 1 diabetes, a volcano plot analysis (fold change >1.5 and p-value <0.05) was performed.
2014-01-01 | E-GEOD-44313 | biostudies-arrayexpress
Project description:Pancreatic b-cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of b-cell mass. It’s unclear how one begets the other. We have shown that loss of b-cell mass can be ascribed to impaired FoxO1 function in different models of diabetes. Here we show that ablation of the three FoxO genes (1, 3a, and 4) in mature b-cells results in early-onset, maturity onset diabetes of the young (MODY)-like diabetes, with signature abnormalities of the MODY networks of Hnf4a, Hnf1a, and Pdx1. Transcriptome and functional analyses reveal that FoxO-deficient b-cells are metabolically inflexible, i.e., they preferentially utilize lipids rather than carbohydrates as source of acetyl-CoA for mitochondrial oxidative phosphorylation. This results in impaired ATP generation, and reduced Ca2+-dependent insulin secretion. When viewed in the context of prior data illustrating a role of FoxO1 in b-cell dedifferentiation, the present findings define a seamless FoxO-dependent mechanism linking the twin abnormalities of b-cell function in diabetes. We used microarrays to detail the change of gene expression in pancreatic beta cells after knocking out FoxO1,3 and 4. Primary islets were isolated from pancretic beta cell- specific triple FoxO(1,3, and 4) KO and their littermates control (WT) mice. Gene expression was analyzed by microarray.
2014-08-20 | E-GEOD-60505 | biostudies-arrayexpress
Project description:The relationship between loss of hypothalamic function and onset of diabetes mellitus remains elusive. Therefore, we generated a targeted oxidative-stress murine model utilizing conditional knockout of selenocysteine-tRNA (Trsp) using rat insulin promoter-driven-Cre (RIP-Cre). These Trsp-knockout (TrspRIPKO) mice exhibit deletion of Trsp in both hypothalamic cells and pancreatic β-cells leading to increased hypothalamic oxidative stress and severe insulin resistance. Leptin signals were suppressed and numbers of proopiomelanocortin-positive neurons in the hypothalamus were decreased. In contrast, a Trsp-knockout mouse (TrspIns1KO) expressing Cre specifically in pancreatic β-cells, but not in the hypothalamus, did not display insulin and leptin resistance, demonstrating a critical role of the hypothalamus in the onset of diabetes mellitus. Nrf2 (NF-E2-related-factor-2) regulates antioxidant gene expression. Gene-driven increase in Nrf2 signaling suppressed hypothalamic oxidative stress and improved insulin and leptin resistance in TrspRIPKO mice. Thus, Nrf2 harbors the potential to prevent the onset of diabetic mellitus by reducing hypothalamic oxidative damage.
2017-02-06 | GSE92235 | GEO