Duodenal mucosal resurfacing with a GLP-1 receptor agonist increases postprandial unconjugated bile acids in patients with insulin-dependent type 2 diabetes

Abstract

Duodenal mucosal resurfacing (DMR) is a new endoscopic ablation technique aimed at improving glycemia and metabolic control in patients with type 2 diabetes mellitus (T2DM). DMR appears to improve insulin resistance, which is the root cause of T2DM, but its mechanism of action is largely unknown. Bile acids function as intestinal signaling molecules in glucose and energy metabolism via the activation of farnesoid X receptor and secondary signaling [e.g., via fibroblast growth factor 19 (FGF19)], and are linked to metabolic health. We investigated the effect of DMR and glucagon-like peptide-1 (GLP-1) on postprandial bile acid responses in 16 patients with insulin-dependent T2DM, using mixed meal tests performed at the baseline and 6 mo after the DMR procedure. The combination treatment allowed discontinuation of insulin treatment in 11/16 (69%) of patients while improving glycemic and metabolic health. We found increased postprandial unconjugated bile acid responses (all P < 0.05), an overall increased secondary bile acid response (P = 0.036) and a higher 12α-hydroxylated:non-12α-hydroxylated ratio (P < 0.001). Total bile acid concentrations were unaffected by the intervention. Postprandial FGF19 and 7-α-hydroxy-4-cholesten-3-one (C4) concentrations decreased postintervention (both P < 0.01). Our study demonstrates that DMR with GLP-1 modulates the postprandial bile acid response. The alterations in postprandial bile acid responses may be the result of changes in the microbiome, ileal bile acid uptake and improved insulin sensitivity. Controlled studies are needed to elucidate the mechanism linking the combination treatment to metabolic health and bile acids.NEW & NOTEWORTHY Glycemic and metabolic improvements are seen in patients with type 2 diabetes after replacing their insulin therapy with DMR and GLP-1. These changes are accompanied by changes in postprandial bile acid concentrations: increased unconjugated and secondary bile acids.

Keywords: DMR; bile acids; diabetes type 2; duodenal ablation; duodenal mucosal resurfacing.

Graphical abstract

Figure 1.

Postprandial excursions of total bile acids (A), CA (B), CDCA (C), DCA (D), and UDCA (E). Effects of the combination treatment were analyzed with a mixed effect model. *P ≤ 0.05 and ***P ≤ 0.001. Concentrations are presented as means (SE). CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; UDCA, ursodeoxycholic acid.

Figure 2.

Postprandial excursions of the primary:secondary bile acid ratio (A) and hydroxylated:non-12α-hydroxylated bile acid ratio (B). The primary:secondary bile acid ratio was calculated by the sum of CA and CDCA (plus their conjugates gCA, tCA, gCDCA, and tCDCA) concentrations divided by the sum of DCA, LCA, and UDCA (plus their conjugates gDCA, tDCA, gLCA, tLCA, gUDCA, and tUDCA) concentrations for all time points. The 12α-hydroxylated:non-12α-hydroxylated bile acid ratio was calculated by the sum of CA and DCA (plus their conjugates gCA, tCA, gDCA, and tDCA) concentrations divided by the sum of CDCA, LCA, and UDCA (plus their conjugates gCDCA, tCDCA, gLCA, tLCA, gUDCA, and tUDCA). Effects of the combination treatment were analyzed with a mixed effect model. ***P ≤ 0.001. Concentrations are presented as means (SE). BAs, bile acids; CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; g-, glycine-conjugated; gCA, glycocholic acid; gCDCA, glycochenodeoxycholic acid; gDCA, glycodeoxycholic acid; gLCA, glycodeoxycholic acid; gUDCA, glycoursodeoxycholic; LCA, lithocholic acid; t-, taurine conjugated; tCA, taurocholic acid; tCDCA, taurochenodeoxycholic acid; tLCA, taurolithocholic acid; tDCA, taurodeoxycholic acid; tUDCA, tauroursodeoxycholic acid; UDCA, ursodeoxycholic acid.

Figure 3.

Postprandial excursions of the primary bile acids (A), the secondary bile acids (B), the 12α-hydroxylated bile acids (C) and the non-12α-hydroxylated bile acids (D). Effects of the combination treatment were analyzed with a mixed effect model. *P ≤ 0.05. Concentrations are presented as mean (SE). BA, bile acids.

Figure 4.

Postprandial excursions of FGF19 (A) and C4 (B). The unit of fasting and peak concentrations is pg/mL for FGF19 and ng/mL for C4. Effects of the combination treatment were analyzed with a mixed effect model. **P ≤ 0.01 and ***P ≤ 0.001. Concentrations are presented as mean (SE). C4, 7-α-hydroxy-4-cholesten-3-one; FGF19, fibroblast growth factor 19.