Table 1 Hypoglycemic mechanism and glucose outcome of bile acid-related drugs

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]