Metformin Intervention in children and adolescents with obesity.A parallel, three arms, randomized, 6 months, multi-center study with metformin extended release (XR) plus lifestyle or metformin immediate release (IR) plus lifestyle or lifestyle alone.

开始日期2020-12-07

申办/合作机构-

NCT04143282 / Completed临床2期IIT

Evaluation of the Effect of Metformin on Metastatic Breast Cancer as Adjuvant Treatment

This study aims to determine the effect of metformin along with standard cancer treatment, and its effect on the prognosis of the metastatic breast in non-diabetic patients.

开始日期2019-10-20

申办/合作机构

Beni-Suef University

100 项与 GPR40 x AMPK 相关的临床结果

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100 项与 GPR40 x AMPK 相关的转化医学

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0 项与 GPR40 x AMPK 相关的专利（医药）

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项与 GPR40 x AMPK 相关的文献（医药）

2024-06-01·Diabetes, Obesity and Metabolism

The GPR40 novel agonist SZZ15‐11 improves non‐alcoholic fatty liver disease by activating the AMPK pathway and restores metabolic homeostasis in diet‐induced obese mice

Article

作者: Chen, Leilei ; Li, Caina ; Huan, Yi ; Lei, Liran ; Feng, Cunyu ; Lei, Lei ; Pan, Xuan ; Liu, Zhanzhu ; Gao, Xuefeng ; Zhai, Jiayu ; Shen, Zhufang ; Cao, Hui ; Liu, Shuainan ; Li, Pingping ; Liu, Quan

AbstractAimNon‐alcoholic fatty liver is the most common cause of chronic liver disease. GPR40 is a potential therapeutic target for energy metabolic disorders. GPR40 is a potential therapeutic target for energy metabolic disorders. SZZ15‐11 is a newly synthesized GPR40 agonist. In this study, we estimate the potency of SZZ15‐11 in fatty liver treatment.MethodsIn vivo, diet‐induced obese (DIO) mice received SZZ15‐11 (50 mg/kg) and TAK875 (50 mg/kg) for 6 weeks. Blood glucose and lipid, hepatocyte lipid and liver morphology were analysed. In vitro, HepG2 cells and GPR40‐knockdown HepG2 cells induced with 0.3 mM oleic acid were treated with SZZ15‐11. Triglyceride and total cholesterol of cells were measured. At the same time, the AMPK pathway regulating triglycerides and cholesterol esters synthesis was investigated via western blot and quantitative polymerase chain reaction in both liver tissue and HepG2 cells.ResultsSZZ15‐11 was found to not only attenuate hyperglycaemia and hyperlipidaemia but also ameliorate fatty liver disease in DIO mice. At the same time, SZZ15‐11 decreased triglyceride and total cholesterol content in HepG2 cells. Whether examined in the liver of DIO mice or in HepG2 cells, SZZ15‐11 upregulated AMPKα phosphorylation and then downregulated the expression of the cholesterogenic key enzyme 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase and inhibited acetyl‐CoA carboxylase activity. Furthermore, SZZ15‐11 promotes AMPK activity via [cAMP]i accumulation.ConclusionThis study confirmed that SZZ15‐11, a novel GPR40 agonist, improves hyperlipidaemia and fatty liver, partially via Gs signalling and the AMPK pathway in hepatocytes.

2024-01-01·Molecular Metabolism

Hypothalamic free fatty acid receptor-1 regulates whole-body energy balance

Article

作者: Claret, Marc ; Estevez-Salguero, Ánxela ; Morari, Joseane ; Milbank, Edward ; Pires, Leticia ; Haddad-Tóvolli, Roberta ; Nóvoa, Eva ; Rexen Ulven, Elisabeth ; Ulven, Trond ; Diéguez, Carlos ; Velloso, Licio A ; Dragano, Nathalia R V ; Capelli, Valentina ; Nogueiras, Ruben ; González-García, Ismael ; Fondevilla, Marcos F ; Barca-Mayo, Olga ; Beiroa, Daniel ; Garrido-Gil, Pablo ; López, Miguel ; Zanesco, Ariane Maria ; Labandeira-García, José L ; Solon, Carina

OBJECTIVEFree fatty acid receptor-1 (FFAR1) is a medium- and long-chain fatty acid sensing G protein-coupled receptor that is highly expressed in the hypothalamus. Here, we investigated the central role of FFAR1 on energy balance.METHODSCentral FFAR1 agonism and virogenic knockdown were performed in mice. Energy balance studies, infrared thermographic analysis of brown adipose tissue (BAT) and molecular analysis of the hypothalamus, BAT, white adipose tissue (WAT) and liver were carried out.RESULTSPharmacological stimulation of FFAR1, using central administration of its agonist TUG-905 in diet-induced obese mice, decreases body weight and is associated with increased energy expenditure, BAT thermogenesis and browning of subcutaneous WAT (sWAT), as well as reduced AMP-activated protein kinase (AMPK) levels, reduced inflammation, and decreased endoplasmic reticulum (ER) stress in the hypothalamus. As FFAR1 is expressed in distinct hypothalamic neuronal subpopulations, we used an AAV vector expressing a shRNA to specifically knockdown Ffar1 in proopiomelanocortin (POMC) neurons of the arcuate nucleus of the hypothalamus (ARC) of obese mice. Our data showed that knockdown of Ffar1 in POMC neurons promoted hyperphagia and body weight gain. In parallel, these mice developed hepatic insulin resistance and steatosis.CONCLUSIONSFFAR1 emerges as a new hypothalamic nutrient sensor regulating whole body energy balance. Moreover, pharmacological activation of FFAR1 could provide a therapeutic advance in the management of obesity and its associated metabolic disorders.

2023-12-01·Acta Pharmacologica Sinica

Vincamine as an agonist of G-protein-coupled receptor 40 effectively ameliorates diabetic peripheral neuropathy in mice

Article

作者: Yang, Juan-Zhen ; Huang, Yu-Jie ; Shen, Xu ; Ling, Yun ; Wang, Jia-Ying ; Xu, Xu ; Wang, Yan-Chun ; Xu, Jia-Wen

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, which has yet no curable medication. Neuroinflammation and mitochondrial dysfunction are tightly linked to DPN pathology. G-protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic β-cells, but also in spinal dorsal horn and dorsal root ganglion (DRG) neurons, regulating neuropathic pain. We previously have reported that vincamine (Vin), a monoterpenoid indole alkaloid extracted from Madagascar periwinkle, is a GPR40 agonist. In this study, we evaluated the therapeutic potential of Vin in ameliorating the DPN-like pathology in diabetic mice. Both STZ-induced type 1 (T1DM) and db/db type 2 diabetic (T2DM) mice were used to establish late-stage DPN model (DPN mice), which were administered Vin (30 mg·kg^-1·d^-1, i.p.) for 4 weeks. We showed that Vin administration did not lower blood glucose levels, but significantly ameliorated neurological dysfunctions in DPN mice. Vin administration improved the blood flow velocities and blood perfusion areas of foot pads and sciatic nerve tissues in DPN mice. We demonstrated that Vin administration protected against sciatic nerve myelin sheath injury and ameliorated foot skin intraepidermal nerve fiber (IENF) density impairment in DPN mice. Moreover, Vin suppressed NLRP3 inflammasome activation through either β-Arrestin2 or β-Arrestin2/IκBα/NF-κB signaling, improved mitochondrial dysfunction through CaMKKβ/AMPK/SIRT1/PGC-1α signaling and alleviated oxidative stress through Nrf2 signaling in the sciatic nerve tissues of DPN mice and LPS/ATP-treated RSC96 cells. All the above-mentioned beneficial effects of Vin were abolished by GPR40-specific knockdown in dorsal root ganglia and sciatic nerve tissues. Together, these results support that pharmacological activation of GPR40 as a promising therapeutic strategy for DPN and highlight the potential of Vin in the treatment of this disease.