The Hypoglycemic Effect Of Acarbose Required Bile Acid Signal

Background and Study Objects Gut microbiota cross-talked with host via multiple signals,including host-bacterial cometabolites,such as bile acids(BAs).BA signaling,including BA receptor Farnesoid X receptor(FXR),is crucial to host metabolism homeostasis and can mediate the microbial related therapeutic benefits of antidiabetic medications,such as acarbose(alpha glucosidase inhibitor,AGI)and metformin.However,the specific mechanism of gut microbiome/host BA regulation is yet to be delineated.Therefore,we treated different diabetes mouse models with AGI(an antidiabetic drug known for regulating BA metabolism),observed their phenotypes and BA profiles in cecum and plasma,and explored BA/FXR signaling in different organs such as liver,gut,islet to reveal the potential metabolism benefits of BA/FXR signaling,Materials and Methods We treated leptin receptor knockout(db/db)mice and high fat high sucrose(HFHS)fed Fxr knockout mice with(AGI).We evaluated the changes in metabolic phenotypes and BA profiles,enterohepatic BA signaling in transcription and protein expression levels by molecular biology approaches.We also assayed pancreatic β cell function,cell mass and cell proliferation.We analyzed the RNA sequencing data of primary pancreatic islets.Results We found AGI can improve metabolic phenotypes of both db/db mice and HFHS fed mice and BA profile alterations in cecum and plasma.But ablating host Fxr could in part abrogate the AGI hypoglycemia and hypolipidemia effects but not body weight reduction.The effects of AGI improving hepatic insulin resistance,reducing hepatic lipids and glycogenesis and decelerating β cell replication so as to recovered insulin hypersecretion were all dependent on FXR signaling.The AGI decreased the cecum TβMCA to block gut Fxr and increased the plasma TβMCA to activate liver Fxr synergistically improve liver glucose and lipid metabolism,and induced plasma levels of ursodeoxycholic acid(UDCA)and ratio of unconjugated/conjugated BAs that favor islet function in Human T2 D.Islet RNA seq data showed significant decreased expression of genes regulating cell proliferation after AGI treatment and dependent on Fxr acitiviy.While genes of pancreatic TFs or regulating granule secretion or lipotoxicity were not significantly affected by AGI treatment.Conclusion Our results manifested that AGI orchestrated BA/FXR signaling in multiple organs including gut,liver and those in β cell to mediate its effects on insulin resistance alleviation and β cell preservation.Targeted by AGI,BA/FXR signaling could serve as a brake for the vicious cycle of insulin hypersecretion and insulin resistance.