From: Research progress on the relationship between bile acid metabolism and type 2 diabetes mellitus
Drugs | Animal experiment or clinical study | Change of bile acid | Main mechanism | Change in blood glucose |
---|---|---|---|---|
CA | Animal experiment(WKAH/HkmSlc rat) | – | Increase in Phylum Firmicutes and decrease in Bacteroides | Not mentioned [64] |
CA | Animal experiment(WKAH rat) | Increase levels of TCA and DCA | 1.Promote G6PD activation and pentose phosphate pathway 2.Increase in Phylum Firmicutes and decrease in Bacteroides | Not mentioned [65] |
CDCA | Cell experiment(HIECs cell and IEC-6 cell) | – | Activate MEK/ERK signaling pathway, increase GLUT2 expression and promote glucose absorption | Reduce [42] |
CDCA | Animal experiment(C57BL/6 mice) | – | Activate AC-PKA-cAMP pathway and stimulate hepatic spexin expression | Not mentioned [43] |
TUDCA | Animal experiment(Swiss mice) | – | Activate TGR5-PKA-CREB pathway to promote insulin secretion | Reduce [44] |
TUDCA | Animal experiment(C57BL/6 mice) | – | 1.Increases insulin secretion without altering insulin clearance 2.Improve endoplasmic reticulum stress | Reduce [31] |
TUDCA | Animal experiment(C57BL/6 mice) | – | Activate TGR5-cAMP-PKA pathway to promote insulin secretion | Reduce [45] |
TUDCA | Animal experiment(db/db (C57BLKS/J-LepRdb/LepRdb) mice) | – | Inhibit endoplasmic reticulum stress and reduce the level of ER stress-related proteins (GRP78 and CHOP) | Reduce [66] |
HCA | Animal experiment and Cell experiment(Bama miniature pigs (Sus scrofa), C57BL/6 J mice, STC-1 cell and NCI-H716 cell) | – | Inhibit FXR transcriptional activity, activate TGR5 pathway, promote GLP-1 secretion and insulin secretion | Reduce [46] |
GUDCA | Animal experiment (C57BL/Ksj-db/db mice) | Increase UDCA、LCA、TUDCA、GUDCA、TLCA、T-α-MCA | Activate TGR5 pathway, promote PGC1A secretion and stimulate tissue thermogenesis | Reduce [47] |
HS218 | Animal experiment (C57BL/6 mice) | Inhibit FXR target genes SHP and BSEP, Reduce the mRNA levels of G6Pase and PEPCK | Reduce [48] | |
Gly-MCA | Animal experiment (C57BL/6N mice) | – | 1. Inhibit ileal FXR-neuramide axis but do not affect the liver 2. No effect on TGR5-GLP1 signaling pathway | Reduce [49] |
Gly-MCA | Animal experiment (C57BL/6N mice) | – | Inhibit ileal FXR-neuramide axis and reducs endoplasmic reticulum stress in the liver 2.Decrease SHP, Fgf15 and IBAP mRNA levels and unchange mRNA levels of Asbt | Not mentioned [50] |
Fexaramine | Animal experiment (C57BL/6 J mice) | 1.Bile: increase T-β-MCA, decrease T-α-MCA and TDCA, but do not affect TCA 2.Ileum: decrease CA, increase LCA 3.Colon: increase DCA and LCA 4.Serum: increase UDCA and TLCA | 1.Increase secretion of FGF15 and FGF21 and GLP1 2.Increase expression of FXR target genes SHP, Fgf15, Osta/bRNAs, but not Asbt mRNA 3.Inhibitie expression of PEPCK and G6pase mRNA | Reduce [51] |
Fexaramine | Animal experiment (foz/foz (Alsm1 −/−) and WT (Alms1 +/+) mice) | No change in LCA | 1.Activate intestinal FXR signaling pathway but do not affect the liver 2.Do not affect the TGR5 signaling pathway | Reduce [52] |
GW4064 | Animal experiment ( C57BL/6 mice) | – | Activate intestinal FXR signaling pathway and increase SHP and FGF15 expression | Raise [62] |
GW4064 | Animal experiment and Cell experiment (C57BL/6 J mice and HK-2 cell) | – | Activate FXR-SHP signaling pathway and inhibite expression of PEPCK | Reduce [53] |
GW4064 | Animal experiment (C57BL/6 J mice) | – | Alleviation of hepatic steatosis and islet cell hypertrophy and improvement of insulin resistance, possibly related to NO metabolism | Reduce [54] |
Cilofexor | Animal experiment (Wistar rat) | – | Activate FXR signaling pathway and promote expression of SHP and FGF15 | Not mentioned [67] |
INT-767 | Animal experiment (C57BL/6 J mice) | 1.Serum: decrease TCA, T-α-MCA, T-β-MCA, TDCA, T-CDCA, T-HCDA and T-MCDA 2.Liver:Increase T-β-MCA and T-α-MCA but decrease TCA 3.Ileum: decrease TCA and increase T-β-MCA and T-α-MCA | 1.Liver: inhibit CYP7A1/cyp8b1 synthesis by activating the FXR-SHP signaling pathway 2.Ileum: activate FXR-FGF15-SHP pathway 3.Increase in Phylum Firmicutes and decrease in Bacteroides | Reduce [55] |
INT-777 | Animal experiment (foz/foz (Alsm1 −/−) and WT (Alms1 +/+) mice) | – | Activate TGR5 signaling pathway and promote GLP-1 secretion without affecting FXR | Reduce [52] |
RO5527239 | Animal experiment (foz/foz (Alsm1 −/−) and WT (Alms1 +/+) mice) | – | Activate TGR5 signaling pathway and promote GLP-1 secretion without affecting FXR | Reduce [52] |
Colesevelam | Animal experiment (Zucker diabetic rats) | – | Promote miR-96/182/183 expression and inhibit MED1 expression | Reduce [56] |
Metformin | Animal experiment and Cell experiment (Wistar rat and HepG2 cell) | Decrease CA | 1.HEPG2 cells: promote FXR and MAFG expression and inhibit CYP8B1 expression 2.Mice: promote FXR and MAFG expression and inhibit CYP8B1 and CYP7A1 expression | Reduce [37] |
Metformin | Animal experiment (C57BL/6 J mice) | Increase TUDCA | 1.Activate Nrf2/ARE signaling pathway to improve insulin resistance 2.Decrease in bifidobacteria and increase in A. muciniphia | Reduce [57] |
Metformin | Animal experiment (C57BL/6 J mice) | Increase CA、CDCA and decrease DCA | 1.Inhibition of duodenal, colonic and ileal glucose transporter protein 5 expression 2.Increase in Verrucomicrobia | Unchanged (decrease but not statistically significant) [58] |
Acarbose | Clinical study | Decrease DCA, taurine-conjugated BAs | Increase in lactobacillus and Bifidobacterium, decrease in Bacteroides | Reduce [41] |
OCA | Animal experiment (db/db diabetic and obese mice) | – | Activate FXR-NrF2 signaling pathway and promote the expression of antioxidant enzymes SOD1, SOD2, CAT, GCLC and GPx | Reduce [59] |
OCA | Clinical study | Decrease CA and TCA | 1.Activate FXR signaling pathway to inhibit bile acid synthesis 2.Increase in Phylum Firmicutes | Not mentioned [60] |
OCA and UDCA | Animal experiment (C57BL/6 J mice) | UDCA: Increase T-βMCA and TUDCA | UDCA: Activate TGR5 signaling pathway instead of FXR signaling pathway UDCA and OCA: 1.increase GLP-1 and FGF15 expression 2.decrease in Bacteroides | Reduce [61] |
NGM282 | Clinical study | – | Reduce HOMA-IR and suppress C4 levels | Unchange [63] |