Transcriptome analysis of islets from diabetes-resistant and diabetes-prone obese mice reveals novel gene regulatory networks involved in beta cell compensation and failure
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PROVIDER: PRJNA716068 | ENA |
REPOSITORIES: ENA
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Project description:Diabetes-resistant and diabetes-prone female New Zealand Obese mice were classified based on liver fat content and early blood glucose concentrations at 10 weeks of age before the onset of T2D. By using transcriptome and DNA methylome analysis of Langerhans islets, we identified early epigenetic alteration in mice and humans which could serve as putative epigenetic biomarkers
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Project description:We carried out genome-wide transcriptome analysis of islets to investigate the gene expression landscape of ob/ob and db/db mouse models at 6 and 16 weeks of age. The purpose of this study is to determine the changes in the islet transcriptomic landscape that mediate the processes of beta cell compensation and failure in ob/ob and db/db mice.
2021-12-20 | GSE169275 | GEO
Project description:Obesity is a strong risk factor for the development of type 2 diabetes. We have previously reported that in adipose tissue of obese (ob/ob) mice, the expression of adipogenic genes is decreased. When made genetically obese, the BTBR mouse strain is diabetes susceptible and the C57BL/6J (B6) strain is diabetes resistant. We used DNA microarrays and RT-PCR to compare the gene expression in BTBR-ob/ob versus B6-ob/ob mice in adipose tissue, liver, skeletal muscle, and pancreatic islets. Our results show: 1) there is an increased expression of genes involved in inflammation in adipose tissue of diabetic mice; 2) lipogenic gene expression was lower in adipose tissue of diabetes-susceptible mice, and it continued to decrease with the development of diabetes, compared with diabetes-resistant obese mice; 3) hepatic expression of lipogenic enzymes was increased and the hepatic triglyceride content was greatly elevated in diabetes-resistant obese mice; 4) hepatic expression of gluconeogenic genes was suppressed at the prediabetic stage but not at the onset of diabetes; and 5) genes normally not expressed in skeletal muscle and pancreatic islets were expressed in these tissues in the diabetic mice. We propose that increased hepatic lipogenic capacity protects the B6-ob/ob mice from the development of type 2 diabetes. Diabetes 52:688â700, 2003 Experiment Overall Design: Four B6-ob/ob and four BTBR-ob/ob male mice at 14 weeks of age were used in the microarray study. RNA samples from two individuals were pooled for each tissue, and each pooled RNA sample was applied to an Affymetrix MGU74AV2 array. Because of the scarcity of islets in the BTBR-ob/ob mice, 4 additional mice were pooled to obtain islet RNA from these animals. Sixteen MGU74Av2 arrays (2 strains X 4 tissues X 2 replicates = 16 arrays) were used to monitor the expression level of â12,000 genes or ESTs.
2007-08-31 | E-GEOD-2899 | biostudies-arrayexpress
Project description:The aim of this study was to investigate which intrinsic differences are present in the islets of Langerhans from diabetes-prone non-obese diabetic (NOD) mice before the onset of insulitis.
2016-11-30 | E-MTAB-5264 | biostudies-arrayexpress
Project description:Obesity is a strong risk factor for the development of type 2 diabetes. We have previously reported that in adipose tissue of obese (ob/ob) mice, the expression of adipogenic genes is decreased. When made genetically obese, the BTBR mouse strain is diabetes susceptible and the C57BL/6J (B6) strain is diabetes resistant. We used DNA microarrays and RT-PCR to compare the gene expression in BTBR-ob/ob versus B6-ob/ob mice in adipose tissue, liver, skeletal muscle, and pancreatic islets. Our results show: 1) there is an increased expression of genes involved in inflammation in adipose tissue of diabetic mice; 2) lipogenic gene expression was lower in adipose tissue of diabetes-susceptible mice, and it continued to decrease with the development of diabetes, compared with diabetes-resistant obese mice; 3) hepatic expression of lipogenic enzymes was increased and the hepatic triglyceride content was greatly elevated in diabetes-resistant obese mice; 4) hepatic expression of gluconeogenic genes was suppressed at the prediabetic stage but not at the onset of diabetes; and 5) genes normally not expressed in skeletal muscle and pancreatic islets were expressed in these tissues in the diabetic mice. We propose that increased hepatic lipogenic capacity protects the B6-ob/ob mice from the development of type 2 diabetes. Diabetes 52:688–700, 2003 Keywords: Genetic modifications
2005-07-12 | GSE2899 | GEO
Project description:Overnutrition contributes to insulin resistance, obesity and metabolic stress, initiating a loss of functional beta-cells and diabetes development. Whether these damaging effects are amplified in advanced age is barely investigated. Therefore, New Zealand Obese (NZO) mice, a well-established model for the investigation of human obesity-associated type 2 diabetes, were fed a metabolically challenging diet with a high-fat, carbohydrate restricted period followed by a carbohydrate intervention in young as well as advanced age. Interestingly, while young NZO mice developed massive hyperglycemia in response to carbohydrate feeding, leading to beta-cell dysfunction and cell death, aged counterparts compensated the increased insulin demand by persistent beta-cell function and beta-cell mass expansion. Beta-cell loss in young NZO islets was linked to increased expression of thioredoxin-interacting protein (TXNIP), presumably initiating an apoptosis-signaling cascade via caspase-3 activation. In contrast, islets of aged NZOs exhibited a sustained redox balance without changes in TXNIP expression, associated with higher proliferative potential by cell cycle activation. These findings support the relevance of a maintained proliferative potential and redox homeostasis for preserving islet functionality under metabolic stress, with the peculiarity that this adaptive response emerged with advanced age in diabetes-prone NZO mice.
2020-11-02 | GSE150281 | GEO
Project description:Single-cell RNA sequencing of pancreatic islets from 18-week-old male New Zealand Obese (NZO/HIBomDife) and B6.V-Lepob/ob (OB) mice were fed a standard diet or a carbohydrate-enriched diet for 2 additional days (+CH / -CH).
2022-07-07 | GSE159211 | GEO
Project description:Genome-wide association studies in human type 2 diabetes (T2D) have renewed interest in the pancreatic islet as a major site of T2D risk. In this study, microarray data collected from mouse islets were used to identify genes that are regulated by cytokines at levels consistent with the chronic low-grade inflammation observed in T2D. The most cytokine-sensitive genes were then examined for association of single nucleotide polymorphisms (SNPs) with acute insulin response to glucose (AIRg) measured in the Genetics UndeRlying DIAbetes in HispaNics (GUARDIAN) study. In GUARDIAN, there was evidence of association of AIRg with SNPs in ARAP3 (5q31.3), F13A1 (6p25.3), KLHL6 (3q27.1), NID1 (1q42.3), PAMR1 (11p13), RIPK2 (8q21.3), and STEAP4 (7q21.12). These data support the mouse islet microarray data in detection of seven novel genes with potential importance to islet dysfunction in T2D. To further assess each gene, murine islets were exposed for 48-hrs to the following stressors representing models of beta-cell failure: 20nM rotenone (oxidative stress), 100nM thapsigargin (ER stress), 10pg/ml IL-1B + 20pg/ml IL-6 (cytokines/low-grade inflammation), 28mM glucose (hyperglycemia), or 50uM palmitate + 100uM oleate + 50uM linoleate (lipotoxicity). RT-PCR revealed that F13a1 was downregulated 3.3-fold by cytokines (P<0.05) and 2.6-fold by rotenone (P<0.05), Klhl6 was upregulated 4.3-fold by thapsigargin (P<0.01), Ripk2 was mildly (1.5-3-fold) but significantly upregulated by all stressors (P<0.05), and STEAP4 was profoundly cytokine-sensitive (167-fold upregulation, P<0.01). These findings reveal promising leads in elucidating islet dysfunction during the development of T2D.
2015-06-01 | GSE62868 | GEO
Project description:Single-cell RNA sequencing of pancreatic islets from obese mice with different diabetes risk reveals diabetes-susceptible β cell clusters
| PRJNA667953 | ENA
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