Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases, but no effective anti-fibrotic therapy is currently available. Glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP1R) are both peptide hormone receptors involved in energy metabolism of epithelial cells. However, their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored. Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn's disease as well as in the fibrotic colon of mice with chronic colitis. The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate, resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition (EMT). Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo. We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation. Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.

Objective To explore the effect of alpha lipoic acid and Shuxuetong on oxidative stress and insulin resistance in patient with type 2 diabetes mellitus(T2DM)and to guide the clinical therapy for T2DM.Methods Totally 90 cases of T2DM pa-tients were sellected from Hainan Province Nongken Hospital.The patients were divided into Shuxuetong group(group A,n=30), alpha lipoic acid group(group B,n=30)and alpha lipoic acid and Shuxuetong group(group C,n =30).HOMA-IR,HOMA-β,and HOMA-ISI was calculated.SOD was determined by xanthine oxidase method.MDA was detected by Thiobarbituric acid method. The expression of IL-6 and TNF-αwas determined by ELISA analysis.Results Before treatment,SOD,MDA,IL-6,TNF-α,HO-MA-IR,HOMA-ISI,and HOMA-βwas no significant difference among the three groups(P >0.05).After treatment,all of which was significantly changed(P <0.05 and P <0.01).SOD,HOMA-ISI and HOMA-βin group C was significantly higher than that in group B(P <0.05),and which was significantly higher in group B than that in group A (P <0.05).MDA and HOMA-IR in group C was significantly lower than that in group B(P <0.05),and which was significantly lower in group B than that in group A (P <0.05).IL-6 and TNF-αin group C was lower than that in group A and group B(P <0.01),and which was no significant difference between group A and group B(P >0.05).Conclusion Alpha lipoic acid combined with Shuxuetong injection can significantly im-prove the oxidative stress state of T2DM patients,inhibit the inflammatory reaction,improve insulin resistance and patient′s sensi-tivity to insulin.Which was contribute to clinical treatment for T2DM.