2023-07-19 テキサス A&M大学
◆p38α MAPKの阻害によって、タイプ2糖尿病患者の血糖バランスが改善される可能性が示唆されており、治療のターゲットとなる可能性があります。しかし、人間においてこのシグナリングがどのように活性化されるかについては、さらなる調査が必要です。この研究は、タイプ2糖尿病の治療に向けた新しい知見を提供し、治療法の開発につながる可能性を示していますが、具体的な治療法の特定にはまだ多くの課題が残っています。
<関連情報>
- https://agrilifetoday.tamu.edu/2023/07/19/study-provides-new-insights-into-type-2-diabetes/
- https://link.springer.com/article/10.1007/s00125-023-05916-5
肝p38αMAPKは、マウスのグルカゴンシグナル伝達中にFOXO1のS273でのリン酸化を介して糖新生を制御する Hepatic p38α MAPK controls gluconeogenesis via FOXO1 phosphorylation at S273 during glucagon signalling in mice
Wanbao Yang,Wang Liao,Xiaopeng Li,Weiqi Ai,Quan Pan,Zheng Shen,Wen Jiang & Shaodong Guo
Diabetologia Published:19 May 2023
DOI:https://doi.org/10.1007/s00125-023-05916-5
Abstract
Aims/hypothesis
Hyperglucagonaemia-stimulated hepatic glucose production (HGP) contributes to hyperglycaemia during type 2 diabetes. A better understanding of glucagon action is important to enable efficient therapies to be developed for the treatment of diabetes. Here, we aimed to investigate the role of p38 MAPK family members in glucagon-induced HGP and determine the underlying mechanisms by which p38 MAPK regulates glucagon action.
Methods
p38α, β, γ and δ MAPK siRNAs were transfected into primary hepatocytes, followed by measurement of glucagon-induced HGP. Adeno-associated virus serotype 8 carrying p38α MAPK short hairpin RNA (shRNA) was injected into liver-specific Foxo1 knockout, liver-specific Irs1/Irs2 double knockout and Foxo1S273D knockin mice. Foxo1S273A knockin mice were fed a high-fat diet for 10 weeks. Pyruvate tolerance tests, glucose tolerance tests, glucagon tolerance tests and insulin tolerance tests were carried out in mice, liver gene expression profiles were analysed and serum triglyceride, insulin and cholesterol levels were measured. Phosphorylation of forkhead box protein O1 (FOXO1) by p38α MAPK in vitro was analysed by LC–MS.
Results
We found that p38α MAPK, but not the other p38 isoforms, stimulates FOXO1-S273 phosphorylation and increases FOXO1 protein stability, promoting HGP in response to glucagon stimulation. In hepatocytes and mouse models, inhibition of p38α MAPK blocked FOXO1-S273 phosphorylation, decreased FOXO1 levels and significantly impaired glucagon- and fasting-induced HGP. However, the effect of p38α MAPK inhibition on HGP was abolished by FOXO1 deficiency or a Foxo1 point mutation at position 273 from serine to aspartic acid (Foxo1S273D) in both hepatocytes and mice. Moreover, an alanine mutation at position 273 (Foxo1S273A) decreased glucose production, improved glucose tolerance and increased insulin sensitivity in diet-induced obese mice. Finally, we found that glucagon activates p38α through exchange protein activated by cAMP 2 (EPAC2) signalling in hepatocytes.
Conclusions/interpretation
This study found that p38α MAPK stimulates FOXO1-S273 phosphorylation to mediate the action of glucagon on glucose homeostasis in both health and disease. The glucagon-induced EPAC2–p38α MAPK–pFOXO1-S273 signalling pathway is a potential therapeutic target for the treatment of type 2 diabetes.
