SCH772984 ameliorates lipopolysaccharide induced hypoglycemia in mice through reversing MEK/ERK/Foxo1 mediated gluconeogenesis suppression

This study intends to investigate the signaling pathways involved in LPS-induced hypoglycemia and potential efficacy of ERK inhibitor SCH772984. The effects of LPS and SCH772984 on gluconeogenesis, glucose absorption and glycogenolysis were evaluated by pyruvate tolerance test (PTT), oral glucose tolerance test (OGTT) and glucagon test, respectively. After a single intraperitoneal injection of 0.5 mg/kg LPS, the mice's blood glucose levels and gluconeogenesis ability were significantly lower than that of control group. Besides, mRNA and protein expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) decreased significantly after LPS treatment. LPS induced the phosphorylation of ERK1/2, MEK1/2 and Foxo1 while inhibited Foxo1 expression in the nucleus, indicating an important role of the MEK/ERK/Foxo1 signaling in the inhibition of gluconeogenesis by LPS. Furthermore, SCH772984 elevated blood glucose, increased the G6Pase and PEPCK expression, and inhibited pERK1/2 and pFoxo1 expression in LPS-induced mice. In summary, LPS inhibited gluconeogenesis and induced hypoglycemia through the MEK/ERK/Foxo1 signal pathway, and ERK inhibitor could effectively reverse decreased blood glucose in mice with LPS treatment. These findings provide a novel therapeutic target for LPS-induced hypoglycemia.PMID:37944129 | DOI:10.1139/cjpp-2023-0133
Source: Canadian Journal of Physiology and Pharmacology - Category: Drugs & Pharmacology Authors: Source Type: research