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FX5 as a non-steroidal GR antagonist improved glucose homeostasis in type 2 diabetic mice via GR/HNF4?/miR-122-5p pathway.

ABSTRACT: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by glucose metabolic disorders, and gluconeogenesis inhibiting is a promisingly therapeutic strategy for T2DM. Glucocorticoid receptor (GR) is tightly implicated in the regulation of gluconeogenesis, although the underlying mechanism remains obscure. Here, we discovered that small molecule, 5-chloro-N-[4-chloro-3-(trifluoromethyl)phenyl]thiophene-2-sulfonamide (FX5) as a new non-steroidal GR antagonist efficiently ameliorated glucose homeostasis in db/db and HFD/STZ-induced T2DM mice. The mechanism underlying the suppression of FX5 against gluconeogenesis was highly investigated. FX5 suppressed gluconeogenetic genes G6Pase and PEPCK in mouse primary hepatocytes and liver tissues of T2DM mice. Results of mammalian one-hybrid and transactivation as well as nuclear translocation assays totally evaluated the antagonistic features of FX5 against GR. Moreover, siRNA and overexpression related assays verified that FX5 alleviated gluconeogenesis either directly by antagonizing GR or indirectly through GR/HNF4?/miR122-5p signaling pathway. Our work has presented a new mode for GR antagonist in the regulation of gluconeogenesis, which is expected to highlight the potential of FX5 in the treatment of T2DM.

SUBMITTER: Xu X

PROVIDER: S-EPMC7880398 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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FX5 as a non-steroidal GR antagonist improved glucose homeostasis in type 2 diabetic mice via GR/HNF4α/miR-122-5p pathway.

Xu Xin X Chen Yidi Y Zhu Danyang D Zhao Tong T Xu Rui R Wang Jiaying J Hu Lihong L Shen Xu X

Aging 20201209 2

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by glucose metabolic disorders, and gluconeogenesis inhibiting is a promisingly therapeutic strategy for T2DM. Glucocorticoid receptor (GR) is tightly implicated in the regulation of gluconeogenesis, although the underlying mechanism remains obscure. Here, we discovered that small molecule, 5-chloro-N-[4-chloro-3-(trifluoromethyl)phenyl]thiophene-2-sulfonamide (FX5) as a new non-steroidal GR antagonist efficiently ameli ...[more]

PMID: 33316780

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Project description:Abstract Background: Data are scant on use of finerenone in diabetic kidney disease (DKD). We undertook this meta-analysis to address this knowledge gap. Methods: Electronic databases were searched for randomized controlled trials (RCTs) involving diabetes patients receiving finerenone compared to controls. The primary outcome was changes in urine albumin-creatinine ratio (UACR). Secondary outcomes were time to kidney failure (decline in GFR by >40% from baseline over 4 weeks), time to end-stage kidney disease, hospitalization for any cause, death and adverse events reported. Results: From initially screened 79 articles, data from 7 RCTs involving 13,783 patients were analyzed (3 in active control group [ACG] defined as having eplerenone/spironolactone as active comparator; 4 in passive control group [PCG] defined as having placebo as controls). Patients receiving finerenone had greater percentage lowering of UACR from baseline as compared to PCG [MD23.82% (95%CI: –24.87 to –22.77); P < 0.01; I2 = 96%] at 90 days, after 2 years [MD 37.9% (95%CI: –38.09 to –37.71); P < 0.01] and 4 years [MD 25.20%(95%CI: –25.63 to –24.77);P < 0.01] of treatment. Patients receiving finerenone has lower chance of >40% decline in GFR (OR 0.83 [95%CI: 0.75 to 0.92];P < 0.01; I2 = 0%). Patients receiving finerenone had lower occurrence of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for heart failure, as compared to placebo/eplerenone (OR0.86 [95%CI: 0.78 to 0.95]; P = 0.003; I2 = 0%). TAEs was similar (RR0.97 [95%CI: 0.88–1.07]; P = 0.56; I2 = 0%), but SAEs significantly lower (RR0.91 [95%CI: 0.84 to 0.97]; P < 0.01; I2 = 0%) in finerenone-group compared to controls. Conclusion: This meta-analysis provides reassuring data on beneficial impact of finerenone in reducing UACR and GFR decline as compared to placebo. We still lack head-to-head comparison of renal outcomes of finerenone vs eplerenone/spironolactone in DKD.

Dataset Information

FX5 as a non-steroidal GR antagonist improved glucose homeostasis in type 2 diabetic mice via GR/HNF4?/miR-122-5p pathway.

Publications

FX5 as a non-steroidal GR antagonist improved glucose homeostasis in type 2 diabetic mice via GR/HNF4α/miR-122-5p pathway.

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