1662-P: Lower Expression of Bile Acid Transporters and Fibroblast Growth Factor 19 in Mucosa Biopsies from the Ileocecal Region in Persons with Type 2 Diabetes Compared with Healthy Controls

Abstract

Background and Aims: Bile acids stimulate the secretion of gluco-regulatory and appetite-regulating gut hormones (including glucagon-like peptide 1 and fibroblast factor 19 (FGF19)) and increase energy expenditure. Changes in postprandial concentrations of circulating bile acids (primarily determined by the apical sodium-dependent bile acid transporter (ASBT) and organic solute transporter α/β (OSTα/β) in the terminal ileum) have been linked to type 2 diabetic pathophysiology. Methods: In a cross-sectional study, 12 persons with type 2 diabetes (T2D) (mean[range] age 51[34-63] years, BMI 26.8[23.7-31.5] kg/m2, HbA1c 48[36-85] mmol/mol) and 12 gender, age and BMI-matched nondiabetic controls (CTRLs) (age 50[41-67] years, BMI 27.1[20.3-30.8] kg/m2, HbA1c 34[29-43] mmol/mol) underwent upper and lower double-balloon enteroscopy with retrieval of mucosal biopsies from every 30 cm along the entire intestinal tract. The biopsies were subjected to full mRNA sequencing and here, the expression of ASBT, OSTα/β and FGF19 is reported. Results: For both groups, robust expression (reads per kilobase million (RPKM) ≥1) of ASBT and OSTα/β was evident in the duodenum and this increased along the small intestine, with highest expression of ASBT in the ileocecal region and highest expression of OSTα/β in terminal ileum. Compared to healthy controls, persons with T2D exhibited significantly lower ASBT and OSTα/β expression in the ileocecal region (P<0.05). Compared to persons with T2D in whom expression of FGF19 was below 1 RPKM in all locations, the control group had robust and significantly greater expression of FGF19 in the terminal ileum (P<0.01). Conclusions: T2D is associated with reduced expression of ASBT, OSTα/β and FGF19 in the terminal ileum and the proximal colon. This may point to a link between dysfunctional enterohepatic circulation of bile acids and type 2 diabetic pathophysiology. Disclosure H.H. Nerild: Employee; Spouse/Partner; Novo Nordisk A/S. A. Brønden: None. A. El Haddouchi: None. T. Jorsal: None. D.P. Sonne: None. J. Jelsing: Board Member; Self; Gubra. Stock/Shareholder; Self; Gubra. K. Rigbolt: Employee; Self; Gubra. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S.