A04f5153-3653-4336-a779-828f1b332386 - samples
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ABSTRACT:
PROVIDER: EGAD00001009740 | EGA |
REPOSITORIES: EGA
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Project description:Genome-wide studies have uncovered multiple independent signals at the RREB1 locus associated with altered type 2 diabetes risk and related glycemic traits. However, little is known about the function of the zinc finger transcription factor RREB1 in glucose homeostasis or how changes in its expression and/or function influences diabetes risk.
| EGAS00001006314 | EGA
Project description:Zinc finger protein overexpression improves glucose homeostasis in mice
| PRJNA326278 | ENA
Project description:Inter-tissue communication is a fundamental feature of systemic metabolic regulation and the liver is central to this process. We have identified sparc-related modular calcium-binding protein 1 (SMOC1) as a glucose-responsive hepatokine and potent regulator of glucose homeostasis. Acute administration of recombinant SMOC1 improves glycemic control and insulin sensitivity, independent of changes in insulin secretion. SMOC1 exerts its favourable glycemic effects by inhibiting cAMP-PKA-CREB signaling in the liver, leading to decreased gluconeogenic gene expression and suppression of hepatic glucose output. Over expression of SMOC1 in the liver or once-weekly injections of a stabilized SMOC1-FC fusion protein induces durable improvements in glucose tolerance and insulin sensitivity in db/db mice, without significant adverse effects on adiposity, liver histopathology or inflammation. Furthermore, SMOC1 correlates with systemic insulin sensitivity and is decreased in obese, insulin resistant humans. Together, these findings identify SMOC1 as a potential pharmacological target for the management of glycemic control in type 2 diabetes.
2020-08-21 | PXD015767 | Pride
Project description:Glycemic control is a strong predictor of long-term cardiovascular risk in patients with diabetes mellitus, and poor glycemic control influences long-term risk of cardiovascular disease even decades after optimal medical management. This phenomenon, termed glycemic memory, has been proposed to occur due to stable programs of cardiac and endothelial cell gene expression. This transcriptional remodeling has been shown to occur in the vascular endothelium through a yet undefined mechanism of cellular reprogramming. Epigenetics offers a novel mechanism whereby a transient glycemic stress is capable of modifying endothelial susceptibility to the pathological remodeling of cardiovascular disease. In the current study, we show that transient glucose exposure triggers widespread alterations in endothelial DNA methylation which may control several recognized pathological mechanisms of cardiovascular disease, such as the nitric oxide signaling cascade. Future mechanistic studies should therefore investigate the extent to which differential methylation potentiates endothelial dysfunction in response to transient glycemic stress.
2020-12-19 | GSE163510 | GEO
Project description:Diabetes mellitus is associated with serious long-term complications, including increased cardiovascular risk and a higher occurrence of infections. These diabetes-related complications are suggestive of altered responses of the innate immune system. Recent studies have shown that energy metabolism of monocytes is a crucial determinant of their functionality. Here we investigate whether metabolism and function of monocytes are changed in patients with diabetes and aim to identify diabetes-associated factors driving these alterations. Patients with type 1 diabetes (T1D) and healthy age-, sex- and BMI-matched nondiabetic controls were recruited and detailed characteristics related to disease status including diabetes duration and glycemic burden (HbA1c levels) were collected. Monocytes were isolated from peripheral blood to determine immune functionality, metabolic responses and to perform transcriptome analyses. Upon ex vivo stimulation with TLR-4 agonist LPS or TLR-2 agonist P3C, monocytes of patients with T1D secreted lower levels of various cytokines (TNFα, IL-1β and IL-1Ra) and had lower glycolytic rates in comparison to monocytes isolated from matched controls. Stratification based on HbA1c levels revealed that a lower cytokine secretion was coupled to a higher glycolytic rate of monocytes in patients with a higher glycemic burden. Gene expression signatures of circulating monocytes displayed an enhanced inflammatory expression pattern that was associated with this high glycemic burden. A high glycemic burden in patients with T1D promotes expression of inflammatory genes of monocytes in vivo and is coupled to an impaired relationship between metabolism and inflammatory function upon activation ex vivo.
2020-10-09 | GSE154609 | GEO
Project description:The intersection of genome-wide association analyses with physiological and functional data indicates that variants regulating islet gene transcription influence type 2 diabetes (T2D) predisposition and glucose homeostasis. However, the specific genes through which these regulatory variants act remain poorly characterized. To identify such effector transcripts for T2D and glycemic traits, we generated expression quantitative trait locus (eQTL) data in 118 human islet samples using RNA-sequencing and high-density genotyping.
| EGAD00001001601 | EGA
Project description:Variants close to the VPS13C/C2CD4A/C2CD4B locus are associated with altered risk of type 2 diabetes in genome-wide association studies. Whilst previous functional work has suggested roles for VPS13C and C2CD4A in disease development, none has explored the role of C2CD4B. Here, we show that systemic inactivation of C2cd4b in mice leads to marked, but highly sexually dimorphic, changes in body weight and glucose homeostasis. Female C2cd4b mice display unchanged body weight but abnormal glucose tolerance and defective in vivo, but not in vitro, insulin secretion, associated with a marked decrease in follicle stimulating hormone levels. In sharp contrast, male C2cd4b null mice displayed normal glucose tolerance but an increase in body weight and fasting glycemia after maintenance on high fat diet. No metabolic disturbances were observed after global inactivation of C2cd4a in mice, or in pancreatic β cell function at larval stages in C2cd4ab null zebrafish. These studies suggest that C2cd4b may act centrally to influence sex-dependent circuits which control pancreatic β cell function and glucose tolerance in rodents. However, the absence of sexual dimorphism in the impact of diabetes risk variants argues for additional roles for C2CD4A or VPS13C in the control of glucose homeostasis in man.
2020-11-16 | PXD021597 | Pride
Project description:The rare SLC30A8 mutation encoding a truncating p.Arg138* variant (R138X) in zinc transporter 8 (ZnT8) is associated with a 65% reduced risk for type 2 diabetes. To determine whether ZnT8 is required for beta cell development and function, we derived human pluripotent stem cells carrying the R138X mutation and differentiated them into insulin-producing cells. We found that human pluripotent stem cells with homozygous or heterozygous R138X mutation and the null (KO) mutation have normal efficiency of differentiation towards insulin-producing cells, but these cells show diffuse granules that lack crystalline zinc-containing insulin granules. Insulin secretion is not compromised in vitro by KO or R138X mutations in human embryonic stem cell-derived beta cells (sc-beta cells). Likewise, the ability of sc-beta cells to secrete insulin and maintain glucose homeostasis after transplantation into mice was comparable across different genotypes. Interestingly, sc-beta cells with the ZnT8 KO mutation showed increased cytoplasmic zinc, and cells with either KO or R138X mutation were resistant to apoptosis when extracellular zinc was limiting. These findings are consistent with a protective role of zinc in cell death and with the protective role of zinc in T2D.
2022-02-11 | GSE166641 | GEO
Project description:Recent genome-wide association studies (GWAS) identified Dusp8, a dual-specificity phosphatase targeting MAP kinases, as type 2 diabetes risk gene. Here, we unravel Dusp8 as gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male but not female Dusp8 loss-of-function mice, either with global or CRH neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic–pituitary–adrenal (HPA) axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of male Dusp8 KO mice, respectively. This sex-specific and rheostatic role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity and systemic glucose tolerance was consistent with fMRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. In summary, our findings suggest GWAS-identified gene Dusp8 as novel hypothalamic factor that plays a functional role in the etiology of type 2 diabetes.
2020-08-17 | PXD019451 | Pride
Project description:Terahertz (THz) radiation has been exploited for biomedical applications for non-invasive manipulation of living cells. Here we describe an apparatus to apply high-field THz excitation on highly environmental sensitive human induced pluripotent stem cells (hiPSCs), and manipulate the gene expression networks associated with zinc-finger (ZNF) transcription factors.
2020-06-02 | GSE151549 | GEO