From: Research progress on the relationship between bile acid metabolism and type 2 diabetes mellitus
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] |