Enteroendocrine cell

Gene

Internal medicine

Downregulation and upregulation

Endocrinology

Unfolded protein response

Endoplasmic reticulum

Receptor

Farnesoid X receptor

Glucagon-like peptide-1

Type 2 diabetes

Insulin resistance

Tauroursodeoxycholic acid

Bile acid

Glucose homeostasis

G protein-coupled bile acid receptor

Endocrine system

Secretion

Biochemistry

Diabetes mellitus

Homeostasis

Nuclear receptor

Hormone

Medicine

Transcription factor

Biology

Cell Metabolism

Hyocholic acid (HCA) and its derivatives are found in trace amounts in human blood but constitute approximately 76% of the bile acid (BA) pool in pigs, a species known for its exceptional resistance to type 2 diabetes. Here, we show that BA depletion in pigs suppressed secretion of glucagon-like peptide-1 (GLP-1) and increased blood glucose levels. HCA administration in diabetic mouse models improved serum fasting GLP-1 secretion and glucose homeostasis to a greater extent than tauroursodeoxycholic acid. HCA upregulated GLP-1 production and secretion in enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor (FXR), a unique mechanism that is not found in other BA species. We verified the findings in TGR5 knockout, intestinal FXR activation, and GLP-1 receptor inhibition mouse models. Finally, we confirmed in a clinical cohort, that lower serum concentrations of HCA species were associated with diabetes and closely related to glycemic markers.

Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism