Xelaglifam, a novel GPR40/FFAR1 agonist, exhibits enhanced ß-arrestin recruitment and sustained glycemic control for type 2 diabetes.
Biomed Pharmacother
; 177: 117044, 2024 Aug.
Article
em En
| MEDLINE
| ID: mdl-38941892
ABSTRACT
Xelaglifam, developed as a GPR40/FFAR1 agonist, induces glucose-dependent insulin secretion and reduces circulating glucose levels for Type 2 diabetes treatment. This study investigated the effects of Xelaglifam in comparison with Fasiglifam on the in vitro/in vivo anti-diabetic efficacy and selectivity, and the mechanistic basis. In vitro studies on downstream targets of Xelaglifam were performed in GPR40-expressing cells. Xelaglifam treatment exhibited dose-dependent effects, increasing inositol phosphate-1, Ca2+ mobilization, and ß-arrestin recruitment (EC50 0.76â¯nM, 20â¯nM, 68â¯nM), supporting its role in Gq protein-dependent and G-protein-independent mechanisms. Despite a lack of change in the cAMP pathway, the Xelaglifam-treated group demonstrated increased insulin secretion compared to Fasiglifam in HIT-T15 ß cells under high glucose conditions. High doses of Xelaglifam (<30â¯mg/kg) did not induce hypoglycemia in Sprague-Dawley rats. In addition, Xelaglifam lowered glucose and increased insulin levels in diabetic rat models (GK, ZDF, OLETF). In GK rats, 1â¯mg/kg of Xelaglifam improved glucose tolerance (33.4â¯% and 15.6â¯% for the 1 and 5â¯h) after consecutive glucose challenges. Moreover, repeated dosing in ZDF and OLETF rats resulted in superior glucose tolerance (34â¯% and 35.1â¯% in ZDF and OLETF), reducing fasting hyperglycemia (18.3â¯% and 30â¯% in ZDF and OLETF) at lower doses; Xelaglifam demonstrated a longer-lasting effect with a greater effect on ß-cells including 3.8-fold enhanced insulin secretion. Co-treatment of Xelaglifam with SGLT-2 inhibitors showed additive or synergistic effects. Collectively, these results demonstrate the therapeutic efficacy and selectivity of Xelaglifam on GPR40, supportive of its potential for the treatment of Type 2 diabetes.
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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Glicemia
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Receptores Acoplados a Proteínas G
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Diabetes Mellitus Tipo 2
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Beta-Arrestinas
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Biomed Pharmacother
Ano de publicação:
2024
Tipo de documento:
Article