Hyperuricemia Predisposes to the Onset of Diabetes
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PROVIDER: PRJNA596990 | ENA |
REPOSITORIES: ENA
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Project description:To further examine the mechanisms of urate in islet β-cell death, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish primacy of streptozotocin (STZ) vs. urate. Islets were isolated from Uox-KO and WT mice with and without multiple low-dose STZ. Differentially expressed genes (DEGs) in islets of the hyperuricemic and/or diabetic mice in comparison to their respective controls represented specific Gene Ontology (GO) pathways and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional meanings.
2020-05-04 | GSE142421 | GEO
Project description:RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell function
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Project description:Increased plasma uric acid (hyperuricemia) has been associated with worse outcomes for chronic kidney disease (CKD). But some attempts to control uric acid (UA) in large-cohort clinical trials did not produce clinically meaningful benefits for CKD. Some studies suggest that only hyperuricemia with crystals, but not asymptomatic hyperuricemia promotes the progression of CKD. Salt-sensitivity (SS) in blood pressure is a prevalent trait that is sexually dimorphic and results in kidney damage. But the connection between hyperuricemia and SS hypertension (HTN) is still unclear. Here we tested the connection between the two using both male and female Dahl SS rats, a well-establish model of SS HTN. We hypothesized that mild asymptomatic hyperuricemia is beneficial in controlling the progression of SS HTN. A uricase inhibitor, oxonic acid (2%) (Oxo) was used to induce hyperuricemia and high-salt (HS) (4% NaCl) diet was used to induce SS HTN. After 3 weeks, in response to oxonic acid supplementation, both sexes showed a significant increase of UA in plasma compared to their respective HS-only controls (Males: 0.63 ±0.07 vs. 2.17 ±0.34; Females: 0.78 ±0.15 vs. 2.04 ±0.35 mg/dl, HS vs. HS/oxo). Interestingly, only male HS/oxo rats showed a significant increase in uricosuria (Males: 0.23 ±0.03 vs. 0.45 ±0.06; Femaels: 0.26 ±0.06 vs. 0.26 ±0.001 UA/Cre, HS vs. HS/oxo). Moreover, the mild hyperuricemia was associated with a significant attenuation of the progression and magnitude of the mean arterial pressure in male but not female rats (Males: 157 ±3 vs. 136 ±3; Females: 155 ±6 vs. 154 ±5 mmHg, HS vs. HS/oxo). Xanthine oxidase (XO) is one of the enzymes that produce UA, and its activity has been shown to affect HTN as well. Therefore, we examined the level of XO activity in the plasma after the treatment. While there was no difference in the activity based on the diet within each sex, females had significantly lower levels of XO activity compared to males in each of the diets. To further investigate the beneficial phenotype seen in male rats, we evaluate changes in the progression of renal pathology. The HS/oxo group compared to the HS group had a lower kidney weight/body weight ratio and lower protein cast accumulation, indicating lower kidney damage. Furthermore, the HS/Oxo treated males had less oxidative damage in their tubules than the HS-only males. Bulk-RNA seq done on the male kidneys revealed that attenuated HTN phenotype was associated with an increased expression in Mas1 (MAS receptor), Klk-1 (Kallikrein-1), and Pcsk6 (PCSK6 enzyme) which can all lead to the activation of different vasodilatory pathways. Our study showed that in male but not female Dahl SS rats, asymptomatic mild hyperuricemia accompanied by hyperuricosuria ameliorates the progression of SS HTN and protects kidneys from further damage. Thus, our findings challenge the notion of hyperuricemia being inherently detrimental to health and highlight that this is an oversimplified view of UA’s role in disease.
2024-07-10 | GSE269511 | GEO
Project description:OBJECTIVE: Novel biomarkers of disease progression after type 1 diabetes onset are needed. RESEARCH DESIGN AND METHODS: We profiled peripheral blood (PB) monocyte gene expression in 6 healthy subjects and 16 children with type 1 diabetes diagnosed ~3 months previously, and analyzed clinical features from diagnosis to 1 year. RESULTS: Monocyte expression profiles clustered into two distinct subgroups, representing mild and severe deviation from healthy controls, along the same continuum. Patients with strongly divergent monocyte gene expression had significantly higher insulin dose-adjusted HbA1c levels during the first year, compared to patients with mild deviation. The diabetes-associated expression signature identified multiple perturbations in pathways controlling cellular metabolism and survival, including endoplasmic reticulum and oxidative stress (e.g. induction of HIF1A, DDIT3, DDIT4 and GRP78). qPCR quantitation of a 9-gene panel correlated with glycaemic control in 12 additional recent-onset patients. The qPCR signature was also detected in PB from healthy first-degree relatives. CONCLUSIONS: A PB gene expression signature correlates with glycaemic control in the first year after diabetes diagnosis, and is present in at-risk subjects. These findings implicate monocyte phenotype as a candidate biomarker for disease progression pre- and post-onset, and systemic stresses as contributors to innate immune function in type 1 diabetes. CD14+ monocytes from a total of 16 children with recent-onset type 1 diabetes and 6 adult healthy controls were profiled in 2 independent microarrays.
2012-05-31 | E-GEOD-33440 | biostudies-arrayexpress
Project description:Clinical studies have shown a link between hyperuricemia (HU) and diabetes, while the exact effect of soluble serum urate on glucose metabolism remains elusive. This study aims to characterize the glucose metabolic phenotypes and investigate the underlying molecular mechanisms using a novel spontaneous HU mouse model in which the uricase (Uox) gene is absent. In an attempt to study the role of HU in glycometabolism, we implemented external stimulation on Uox knockout (KO) and wild-type (WT) males with a high-fat diet (HFD) and/or injections of multiple low-dose streptozotocin (MLD-STZ) to provoke the potential role of urate. Notably, while Uox-KO mice developed glucose intolerance in the basal condition, no mice spontaneously developed diabetes, even with aging. HFD-fed Uox-KO mice manifested similar insulin sensitivity compared with WT controls. HU augmented the existing glycometabolism abnormality induced by MLD-STZ and eventually led to diabetes, as evidenced by the increased random glucose. Reduced β-cell masses and increased terminal deoxynucleotidyl TUNEL-positive β-cells suggested that HU-mediated diabetes was cell death dependent. However, urate-lowering therapy (ULT) cannot ameliorate the diabetes incidence or reverse β-cell apoptosis with significance. ULT displayed a significant therapeutic effect of HU-crystal-associated kidney injury and tubulointerstitial damage in diabetes. Moreover, we present transcriptomic analysis of isolated islets, using Uox-KO versus WT mice and streptozotocin-induced diabetic WT (STZ-WT) versus diabetic Uox-KO (STZ-KO) mice. Shared differentially expressed genes of HU primacy revealed Stk17β is a possible target gene in HU-related β-cell death. Together, this study suggests that HU accelerates but does not cause diabetes by inhibiting islet β-cell survival.
| S-EPMC7243290 | biostudies-literature
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
2020-10-28 | GSE143875 | GEO
Project description:OBJECTIVE: Novel biomarkers of disease progression after type 1 diabetes onset are needed. RESEARCH DESIGN AND METHODS: We profiled peripheral blood (PB) monocyte gene expression in 6 healthy subjects and 16 children with type 1 diabetes diagnosed ~3 months previously, and analyzed clinical features from diagnosis to 1 year. RESULTS: Monocyte expression profiles clustered into two distinct subgroups, representing mild and severe deviation from healthy controls, along the same continuum. Patients with strongly divergent monocyte gene expression had significantly higher insulin dose-adjusted HbA1c levels during the first year, compared to patients with mild deviation. The diabetes-associated expression signature identified multiple perturbations in pathways controlling cellular metabolism and survival, including endoplasmic reticulum and oxidative stress (e.g. induction of HIF1A, DDIT3, DDIT4 and GRP78). qPCR quantitation of a 9-gene panel correlated with glycaemic control in 12 additional recent-onset patients. The qPCR signature was also detected in PB from healthy first-degree relatives. CONCLUSIONS: A PB gene expression signature correlates with glycaemic control in the first year after diabetes diagnosis, and is present in at-risk subjects. These findings implicate monocyte phenotype as a candidate biomarker for disease progression pre- and post-onset, and systemic stresses as contributors to innate immune function in type 1 diabetes.
2012-06-01 | GSE33440 | GEO
Project description:Background Currently, it is not possible to predict whether patients with hyperuricemia (HUA) will develop gout and how this progression may be affected by urate-lowering treatment (ULT). Our study aimed to evaluate differences in plasma lipidome between patients with asymptomatic HUA detected < 40 years (HUA<40) and > 40 years, gout patients with disease onset < 40 years (Gout<40) and > 40 years, and normouricemic healthy controls (HC).
Methods Plasma samples were collected from 94 asymptomatic HUA (77% HUA<40) subjects, 196 gout patients (59% Gout<40), and 53 HC. A comprehensive targeted lipidomic analysis was performed to semi-quantify 608 lipids in plasma. Univariate and multivariate statistics and advanced visualizations were applied.
Results Both HUA and gout patients showed alterations in lipid profiles with the most significant upregulation of phosphatidylethanolamines and downregulation of lysophosphatidylcholine plasmalogens/plasmanyls. More profound changes were observed in HUA<40 and Gout<40 without ULT. Multivariate statistics differentiated HUA<40 and Gout<40 groups from HC with an overall accuracy of > 95%.
Conclusion Alterations in the lipidome of HUA and Gout patients show a significant impact on lipid metabolism. The most significant glycerophospholipid dysregulation was found in HUA<40 and Gout<40 patients, together with a correction of this imbalance with ULT.
Keywords LC-MS, Lipidomics, Glycerophospholipids, Hyperuricemia, Gout, Urate-lowering treatment
Study was published and is accessible under this DOI: https://doi.org/10.1186/s13075-023-03204-6
Please cite as follows: Kvasni?ka, A., Friedecký, D., Brumarová, R. et al. Alterations in lipidome profiles distinguish early-onset hyperuricemia, gout, and the effect of urate-lowering treatment. Arthritis Res Ther 25, 234 (2023). https://doi.org/10.1186/s13075-023-03204-6
2023-10-11 | MSV000093082 | MassIVE
Project description:Hyperuricemia is an essential risk factor in chronic kidney disease (CKD), while urate-lowering therapy to prevent or delay CKD is controversial. Alternatively activated macrophages in response to local microenvironment play diverse roles in kidney diseases. Here, we aim to investigate whether and how macrophage integrin αM (ITGAM) contributes to hyperuricemia-related CKD. In vivo, we explored dynamic characteristics of renal tissue in C57BL/6J mice with hyperuricemia-related CKD. By incorporating transcriptomics and phosphoproteomics data, we analyzed gene expression profile, hub genes and potential pathways. In vitro, we validated bioinformatic findings under different conditions with interventions corresponding to core nodes. We found that hyperuricemia-related CKD was characterized by elevated serum uric acid levels, impaired renal function, activation of macrophage alternative (M2) polarization, and kidney fibrosis. Integrated bioinformatic analyses revealed Itgam as the potential core gene and was associated with focal adhesion signaling. Notably, we confirmed the upregulated expression of macrophage ITGAM, activated pathway, and macrophage M2 polarization in injured kidneys. In vitro, through silencing Itgam, inhibiting p-FAK or p-AKT1 phosphorylation, and concurrent inhibiting of p-FAK while activating p-AKT1 all contributed to the modulation of macrophage M2 polarization. Our results indicated targeting macrophage ITGAM might be a promising therapeutic approach for preventing CKD.
2024-06-26 | GSE262687 | GEO
Project description:Epigenetic changes in Langerhans islets preceding the onset of diabetes
| PRJNA601954 | ENA