Introduction
Synthesis and recovery of Bile acid
Bile acid and type 2 diabetes mellitus
Bile acids and diabetes drugs (metformin and acarbose)
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] |
Bile acids and bariatric metabolic surgery
Bile acid and intestinal flora
Hypoglycemic mechanism of bile acid
FXR and bile acid
TGR5 and bile acid
FXR/TGR5 | Animal models | Gene knockout targets | Intervention measures | Main Performance | Main mechanism | Change in blood glucose |
---|---|---|---|---|---|---|
FXR–/– | C57BL/6 J Mice | body | GW4064 | GW4064 do not raise blood glucose, while 8-CPT-cAMP (PKA activator) raise blood glucose | In the presence of glucagon, GW4064 promote gluconeogenesis through the CCG-PKA signaling pathway by promoting Fbp1, Pck1, and G6pc expression In the presence of cAMP analogs, it inhibits gluconeogenesis through the SHP / Nr0b2 signaling pathway | Raise [94] |
FXR–/– | C57BL/6JMice | body | VSG | Body weight and blood glucose are not improved after VSG | Reduce expression of FXR transcriptional target genes 2. no change in intestinal Bacteroides 3. BA in the liver remained unchanged, while CA, TCA and GCA in the intestine decreased 4.TCA supplementation reverses the metabolic benefits of VSG | Unchange [96] |
FXR–/– | Not mentioned | body | – | Raise blood glucose and blood lipids Aggravate diabetic cardiomyopathy, diabetic myocardial fibrosis | Increase expression of lipid synthesis and lipid transport genes in diabetic cardiomyocytes (SCD-1, SREBP-1c, FAS, ACC, LOX-1, LDLR) | Raise [108] |
FXR–/– | Not mentioned | body | BD | FXR-/- mice are resistant to HFD-induced obesity | 1.BD significantly increase the expression of PGC-1ß in the liver of WT mice, but BD faile to promote FXR-/- mice 2.Increase in Proteobacteria, decrease in Bacteroides | Rasie [109] |
FXR–/– | C57BL/6 J mice | body | RYGB | FXR-/- mice slow weight gain and improve glucose homeostasis | The GLP-1 antagonist Ex-9 attenuate the postoperative hypoglycemic effect of RYGB in the control group but do not alter the FXR-/-group, suggesting an association with the FXR-GLP-1 axis | Reduce [110] |
FXR–/– | C57BL/6 mice | intestine | GB-IL | No change in weight after GB-IL, no improvement in glucose tolerance | Failure of BAs to activate FXR pathway and unaltered GLP-1 levels | Unchange [88] |
FXR–/– | Not mentioned | intestine | GS3972 | 1. ileal expression of Fgf15 was significantly reduced, Cyp7a1 expression was significantly higher in the liver, and Cyp8b1 was not affected 2. Long-term HFD resulted in impaired glucose metabolism and reduced insulin sensitivity in WT mice and FXR-/- mice | 1.Liver: GS3972 treatment significantly increase the expression of FXR target genes SHP in WT and FXR-KO mice, while Cyp7a1 and Cyp8b1 expression is significantly decreased 2.Ileum: Fgf15 and ileal bile acid binding protein (I-BABP) are expressed in the ileum of WT mice after GS3972 treatment, but not in FXR-KO mice | Unchange [95] |
FXR–/– | C57BL/6 J Mice | intestine | VSG | Reduce body weight and improve insulin sensitivity | intestine:decreased levels of taurine-conjugated BAs 2.Increase in Firmicutes and Lactobacillus | Reduce [96] |
FXR–/– | C57BL/6 J Mice | Liver | VSG | Reduce body weight and improve insulin sensitivity | 1.intestine:decreased levels of taurine-conjugated BAsBAs 2.Increase in Firmicutes and Lactobacillus | Reduce [96] |
FXR–/– | C57BL/6 J Mice | Adipocyte | – | Do not improve HFD-induced obesity but improve insulin sensitivity | Promote AKT phosphorylation, promote GSTA4 expression and reduce oxidative stress | Reduce [111] |
TGR5–/– | C57BL/6 J Mice | body | VSG | Decrease in body weight, no change in energy expenditure, no change in plasma insulin concentration | Cyp8b1 expression is inhibited and the ratio of 12α-OH:non-12α-OH BAs is increased | Unchange [112] |
TGR5–/– | C57BL/6 J Mice | body | HDCA | 1. insulin secretion is higher and there is no effect on blood glucose 2. ω-MCA and HDCA levels in the portal vein are increased only in the WT mice. group, but not in the TGR5- KO mice group, | HDCA promotes insulin secretion and regulates blood glucose by activating the TGR5-GLP-1 signaling pathway | Unchange [113] |
TGR5–/– | C57BL/6 Mice | body | GB-IL | GB-IL postoperative weight loss and improved glucose tolerance | Associated with activation of FXR by BAs and promotion of GLP-1 secretion | Reduce [88] |
TGR5 overexpression | C57BL/6 mice | skeletal muscle | TLCA | Levels of glucose 6-phosphate (G6P) and fructose 6-phosphate (F6P) are significantly reduced in Tg mice | Promote glycolysis, do not improve muscle insulin sensitivity, do not improve insulin resistance | Unchange [105] |