Bile Acids and Type 2 Diabetes: Roles in Glucose Homeostasis and Therapeutic Opportunities
Abstract
1. Introduction
2. Bile Acids Synthesis and Enterohepatic Circulation
3. Mechanisms of BAs in the Regulation of Glucose Homeostasis
3.1. Receptor-Mediated Mechanisms
3.1.1. FXR
3.1.2. TGR5
3.1.3. Other Receptors
3.2. Non-Receptors-Mediated Mechanism
4. BA Profile Alterations in T2DM Pathogenesis
4.1. Unconjugated BAs
4.2. Conjugated or Acylated BAs
4.3. Compare the Contributions of Conjugated and Unconjugated BAs to T2DM
5. Bile Acid-Targeted Therapeutic Strategies for T2DM
5.1. Targeting the Enterohepatic Circulation of Bile Acids
5.2. Targeting Bile Acid Receptors
5.3. Bile Acid Supplementation
5.4. Challenges in Developing BA-Targeted Drugs
6. Future Perspectives and Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Study | Population | Study Design | Biological Sample | Methods | Tested Bile Acids | Key Findings | Ref. |
---|---|---|---|---|---|---|---|
China Cardiometabolic Disease and Cancer Cohort (4C) Study, Chinese | 1707 matched case subject–control subject pairs with a median follow-up of 3.03 years | Nested case–control study | Fasting serum | Targeted, UPLC-MS/MS | 23 BA species | Increased level in individuals with T2DM: GCDCA, GCA, GUDCA, GCDCAS, TCDCA, TCA, and TUDCA; Decreased level in individuals with T2DM: DCA, CA, and GCDCA-glucuronide Inversely associated with T2DM risk: CA, CDCA, and DCA; Positively associated with T2DM risk: GCA, TCA, GCDCA, TCDCA, and GCDCS | [97] |
Uppsala Longitudinal Study of Adult Men (ULSAM), Swedish; Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), Swedish; A case-cohort subset of the TwinGene study, Swedish; the Cooperative Health Research in the Region of Augsburg (KORA) S4 cohort, German | ULSAM: 1060 non-DM/78 T2DM, 21 years; PIVUS: 900 non-DM/70 T2DM, 5 years; TwinGene: 1508 non-DM/122 T2DM, 6 years; KORA S4: 767 non-DM/88 T2DM, 7 years. | Cohort, prospective, population-based | ULSAM: Plasma PIVUS, TwinGene and KORA: Serum | Non-targeted, LC-MS | 5961 metabolic features (including BAs: not provided) | Associated with a high risk of prevalent T2DM: GDCA, GCA, DCA, and GCDCA. | [98] |
Finnish Diabetes Prevention Study (DPS), Finland | 96 T2DM, 5 years; 104 non-DM, 15 years | Nested case–control study | Fasting serum | Non-targeted, LC-MS | 8607 metabolic features (including BAs: not provided) | Increased risk of T2DM: GCA, TCDCA, GCDCA, GDCA, DCA, and CA | [99] |
Discovery Cohort: Latino Adolescents at Risk (SOLAR), Hispanic Replication Cohort: MetaAir cohort, mixed-ethnicity | SOLAR: 143 adolescents with overweight or obesity and without baseline prediabetes/38 prediabetes or T2DM, 1.2 years; MetaAir cohort: 56 young adults without baseline prediabetes/15 prediabetes or T2DM, 4.1 years | Cohort, prospective, population-based | Plasma (2h-OGTT) | Non-targeted, LC-HRMS | 23,166 metabolic features (including BAs: not provided) | Discovery analysis: TCA was associated with an elevated risk of prediabetes; Replication analysis: TCA was associated with a reduced risk of prediabetes | [100] |
Caregivers of the Birth to Twenty Plus cohort (BT20+), African | NGT-NGT: 28 individuals, 13 years NGT-IGT: 27 individuals, 13 years NGT-T2DM: 20 individuals, 13 years | Cohort, prospective, population-based | Serum | Non-targeted, GC-TOF/MS LC-TOF/MS | 1076 putative metabolites with 252 identified metabolites (including 9 BAs) | At baseline: NGT-T2D group had lower levels of CDCA and UDCA At follow-up: NGT-T2D group had higher levels of DCA and GDCA | [101] |
IGT Microbiota cohort, Swedish; Swedish Cardiopulmonary Bioimage Study (SCAPIS)-Gothenburg cohort, Swedish | IGT Microbiota cohort: 45 T2DM and 45 NGT; SCAPIS-Gothenburg cohort: 45 T2DM and 45 NGT | Cross-sectional | Plasma and fecal | Targeted, UPLC-MS/MS | 28 BA species | Plasma levels increased in individuals with T2DM: DCA, isoDCA, 12-epiDCA, TDCA, GCA, GCDCA, GDCA, GHDCA, LCA, isoUDCA, and 12-oxoDCA; Both plasma and fecal DCA were positively associated with HOMA-IR, FBG, HbA1c, and insulin | [102] |
Africa America Diabetes Mellitus study (AADM), Nigerians | Cross-sectional | Cross-sectional study | Plasma | Non-targeted, UPLC-MS/MS | 1116 metabolites or compounds (including BAs: not provided) | Increased level in individuals with T2DM: GCA, TCA, DCA, GDCA, and TDCA | [103] |
Volunteers, Chinese | 28 T2DM/18 non-T2DM | Cross-sectional study | Fecal | Targeted, LC-QTOF | 15 BA species (including 4 3-O-acyl-CAs) | Decreased level in individuals with T2DM: 3-O-acyl-CAs | [27] |
Shanghai Obesity Study (SHOS), Chinese; Volunteers, Chinese; Shanghai Diabetes Study (SHDS), Chinese; Physical examination centers in Beijing, Chinese | SHOS: 1107 participants; Volunteers: 91 participants; SHDS: 132 participants, 10 years; Physical examination centers: 207 participants, 5 years | SHOS: Nested case–control study Volunteers: Cross-sectional study SHDS: longitudinal study Physical examination centers: longitudinal study | SHOS: Fasting serum Volunteers: Fasting serum and fecal SHDS: Fasting serum Physical examination centers: Fasting serum | Targeted, UPLC-MS | 23 BA species (27 BAs species in physical examination centers) | Decreased level in individuals with T2DM: HCA, HDCA, GHCA, GHDCA; Inversely associated with fasting and post-load blood glucose levels: HCA, HDCA, GHCA, GHDCA; Decreased risk of T2DM: HCA, HDCA, GHCA, GHDCA | [104] |
Nurses’ Health Study, American | 224 matched case subject–control subject pairs with a median follow-up of 3.9 years | Nested case–control study | Blood | LC-MS | 170 known metabolites (including 3 BAs) | Increased risk of T2DM: GCA, GDCA, GCDCA | [105] |
BAs | Key Findings from Observational Studies | Mechanism |
---|---|---|
Unconjugated BAs | ||
CA | Decreased risk of T2DM; Decreased level in T2DM | FXR (+): promote glycolysis, inhibit gluconeogenesis, enhance glycogen synthesis TGR5 (+): enhance GLP-1 secretion, promote glycolysis, inhibit gluconeogenesis, stimulate insulin release, inhibit glucagon secretion, enhance energy expenditure |
CDCA | Decreased risk of T2DM; | FXR (+): promote glycolysis, inhibit gluconeogenesis, enhance glycogen synthesis; TGR5 (+): enhance GLP-1 secretion, promote glycolysis, inhibit gluconeogenesis, stimulate insulin release, inhibit glucagon secretion, enhance energy expenditure; Non-receptor-mediated: bind and stabilize NAPE-PLD to inhibit gluconeogenesis, enhance glycogen synthesis and GLP-1 secretion, enhance FOXO1 activity to improve insulin sensitivity |
HCA | Decreased risk of T2DM; Inversely associated with HOMA-IR, FBG, and post-load blood glucose levels | FXR (−): enhance GLP-1 secretion; TGR5 (+): enhance GLP-1 secretion |
DCA * | Increased/Decreased risk of T2DM; Increased/Decreased level in T2DM; Positively associated with HOMA-IR, FBG, HbA1c, and insulin | FXR (+): promote glycolysis, inhibit gluconeogenesis, enhance glycogen synthesis TGR5 (+): enhance GLP-1 secretion, promote glycolysis, inhibit gluconeogenesis, stimulate insulin release, inhibit glucagon secretion, enhance energy expenditure; Non-receptor-mediated: Bind and stabilize NAPE-PLD; affect membranes; upregulate the expression of ATGL, HSL, and UCP1 |
LCA | Increased level in T2DM | FXR (+): promote glycolysis, inhibit gluconeogenesis, enhance glycogen synthesis; TGR5 (+): enhance GLP-1 secretion, promote glycolysis, inhibit gluconeogenesis, stimulate insulin release, inhibit glucagon secretion, enhance energy expenditure; VDR(+): maintain immunity homeostasis, enhance GLP-1 and insulin secretion PXR(+) CAR(+): inhibit CYP7A1 |
UDCA | Decreased risk of T2DM | FXR (−): improve insulin resistance, inhibit glucose absorption, enhance GLP-1 secretion; TGR5 (+): enhance GLP-1 secretion, promote glycolysis, inhibit gluconeogenesis, stimulate insulin release, inhibit glucagon secretion, enhance energy expenditure |
HDCA | Decreased risk of T2DM; Inversely associated with fasting and post-load blood glucose | FXR (−): improve insulin resistance, inhibit glucose absorption, enhance GLP-1 secretion; TGR5 (+): enhance GLP-1 secretion, promote glycolysis, inhibit gluconeogenesis, stimulate insulin release, inhibit glucagon secretion, enhance energy expenditure |
Conjugated BAs | ||
GCA | Increased risk of T2DM; Increased level in T2DM; | TGR5 (+): enhance GLP-1 secretion, promote glycolysis, inhibit gluconeogenesis, stimulate insulin release, inhibit glucagon secretion, enhance energy expenditure |
TCA * | Increased/Decreased risk of T2DM; Increased level in T2DM | TGR5 (+): enhance GLP-1 secretion, promote glycolysis, inhibit gluconeogenesis, stimulate insulin release, inhibit glucagon secretion, enhance energy expenditure |
GCDCA | Increased risk of T2DM; Increased level of T2DM; | TGR5 (+): enhance GLP-1 secretion, promote glycolysis, inhibit gluconeogenesis, stimulate insulin release, inhibit glucagon secretion, enhance energy expenditure |
TCDCA | Increased risk of T2DM | FXR (+): promote glycolysis, inhibit gluconeogenesis, enhance glycogen synthesis, aggravate insulin resistance |
GHCA | Decreased risk of T2DM; Decreased level in T2DM; Inversely associated with fasting and post-load blood glucose | FXR (−): enhance GLP-1 secretion; TGR5 (+): enhance GLP-1 secretion |
THCA | Not reported | FXR (−): enhance GLP-1 secretion; TGR5 (+): enhance GLP-1 secretion |
GDCA | Increased risk of T2DM | TGR5 (+): enhance GLP-1 secretion, promote glycolysis, inhibit gluconeogenesis, stimulate insulin release, inhibit glucagon secretion, enhance energy expenditure; Non-receptor-mediated: inhibits insulin clearance to aggravate insulin resistance |
TDCA | Increased level in T2DM; Positively associated with FGB/HOMA-IR | TGR5 (+): enhance GLP-1 secretion, promote glycolysis, inhibit gluconeogenesis, stimulate insulin release, inhibit glucagon secretion, enhance energy expenditure; Non-receptor-mediated: downregulate the expression of CAR 1 and upregulate the expression of UCP-1 to enhance energy expenditure, inhibit insulin clearance to aggravate insulin resistance |
GLCA | Not reported | TGR5 (+): enhance GLP-1 secretion, promote glycolysis, inhibit gluconeogenesis, stimulate insulin release, inhibit glucagon secretion, enhance energy expenditure |
TLCA | Not reported | TGR5 (+): enhance GLP-1 secretion, promote glycolysis, inhibit gluconeogenesis, stimulate insulin release, inhibit glucagon secretion, enhance energy expenditure |
GUDCA | Decreased level in T2DM | FXR (−): improve insulin resistance, inhibit glucose absorption, enhance GLP-1 secretion; TGR5 (+): enhance GLP-1 secretion, promote glycolysis, inhibit gluconeogenesis, stimulate insulin release, inhibit glucagon secretion, enhance energy expenditure |
TUDCA | Increased risk of T2DM | FXR (−): improve insulin resistance, inhibit glucose absorption, enhance GLP-1 secretion; TGR5 (+): enhance GLP-1 secretion, promote glycolysis, inhibit gluconeogenesis, stimulate insulin release, inhibit glucagon secretion, enhance energy expenditure; Non-receptor-mediated: improve pancreatic islet function and enhance insulin secretion by alleviating ER stress, blocking SUR1, binding with insulin receptors, and activating the cAMP/PKA/CREB signaling pathway |
GHDCA | Decreased risk of T2DM; Decreased level in T2DM; Inversely associated with fasting and post-load blood glucose | FXR (−): enhance GLP-1 secretion; TGR5 (+): enhance GLP-1 secretion |
THDCA | Decreased level in T2DM; | FXR (−): enhance GLP-1 secretion; TGR5 (+): enhance GLP-1 secretion |
3-O-acyl-CA | Decreased level in T2DM | FXR (−): enhance energy metabolism and insulin sensitivity Non-receptor-mediated: promote microbial balance |
CA7S | Not reported | TGR5(+): enhance GLP-1 secretion |
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Lin, Y.; Hu, C.; Wang, S.; Lin, H. Bile Acids and Type 2 Diabetes: Roles in Glucose Homeostasis and Therapeutic Opportunities. Metabolites 2025, 15, 401. https://doi.org/10.3390/metabo15060401
Lin Y, Hu C, Wang S, Lin H. Bile Acids and Type 2 Diabetes: Roles in Glucose Homeostasis and Therapeutic Opportunities. Metabolites. 2025; 15(6):401. https://doi.org/10.3390/metabo15060401
Chicago/Turabian StyleLin, Yiting, Chunyan Hu, Shuangyuan Wang, and Hong Lin. 2025. "Bile Acids and Type 2 Diabetes: Roles in Glucose Homeostasis and Therapeutic Opportunities" Metabolites 15, no. 6: 401. https://doi.org/10.3390/metabo15060401
APA StyleLin, Y., Hu, C., Wang, S., & Lin, H. (2025). Bile Acids and Type 2 Diabetes: Roles in Glucose Homeostasis and Therapeutic Opportunities. Metabolites, 15(6), 401. https://doi.org/10.3390/metabo15060401