Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism.
Level 5 - mechanism / opinion, no new human data
Preclinical animal and cell mechanistic study with an observational human cohort.
PubMed 33338411 · doi:10.1016/j.cmet.2020.11.017
What was done
Researchers investigated the metabolic effects and mechanism of hyocholic acid (HCA) species across animal, cellular, and human models. They assessed bile acid depletion in pigs regarding glucagon-like peptide-1 (GLP-1) secretion and blood glucose. In diabetic mouse models, they compared the effects of HCA administration versus tauroursodeoxycholic acid on fasting GLP-1 and glucose homeostasis. Signaling mechanisms were evaluated in enteroendocrine cells and validated in TGR5 knockout, intestinal FXR activation, and GLP-1 receptor-inhibited mouse models. Finally, serum HCA concentrations were measured and correlated with diabetes status and glycemic markers in a clinical cohort.
What was found
HCA constitutes approximately 76% of the bile acid pool in pigs. Bile acid depletion in pigs suppressed GLP-1 secretion and increased blood glucose levels. HCA administration in diabetic mice improved fasting GLP-1 secretion and glucose homeostasis to a greater extent than tauroursodeoxycholic acid. In enteroendocrine cells, HCA upregulated GLP-1 production and secretion via simultaneous TGR5 activation and FXR inhibition. In the clinical cohort, lower serum HCA concentrations were associated with diabetes and glycemic markers. The abstract reports no quantitative values or effect sizes for these findings.
Why it matters
This study identifies a unique mechanism by which HCA regulates glucose homeostasis through concurrent TGR5 activation and FXR inhibition, offering a potential target for type 2 diabetes therapies inspired by porcine diabetes resistance.
Limits
Sample sizes, demographic details, and numerical effect sizes for both animal experiments and the clinical cohort are absent from the abstract. The human data are strictly correlational, and therapeutic administration was not tested in humans.
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