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

Abstract

Introduction: 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 signalling molecules in glucose and energy metabolism via the activation of farnesoid X receptor and secondary signalling (e.g. via fibroblast growth factor 19[FGF19]), and are linked to metabolic health. Methods: We investigated the effect of DMR and GLP-1 on postprandial bile acid responses in 16 patients with insulin-dependent T2DM, using mixed meal tests performed at baseline and six months after the DMR procedure. Results: The combination treatment allowed discontinuation of insulin treatment in 11/16 (69%) of patients while improving glycaemic 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:non12α-hydroxylated ratio (p<0.001). Total bile acid concentrations were unaffected by the intervention. Postprandial FGF19 and 7-alpha-hydroxy-4-cholesten-3-one (C4) concentrations decreased post-intervention (both p<0.01). Conclusion and discussion: 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.

A Changed Gut Microbiota Diversity Is Associated With Metabolic Improvements After Duodenal Mucosal Resurfacing With Glucagon-Like-Peptide-1 Receptor Agonist in Type 2 Diabetes in a Pilot Study

“…We can not exclude that this non-responder population affected the results in this rather small pilot population. Interestingly, in another spin-off report of this study, we observed increased postprandial unconjugated bile acids and increased secondary bile acids in the complete population (19). These findings suggest that the gut microbiota composition did change considerably in our patients, since bile acid deconjugation, conversion, and active uptake of bile acids are executed by gut bacteria.…”

Eliminating exogenous insulin therapy in patients with type 2 diabetes by duodenal ablation and GLP-1RA decreases risk scores for cardiovascular events

“…We hypothesize that its insulin sensitizing effect can occur due to changes in either the gut-brain axis or local signalling to the liver and pancreas, cellular or histological changes in the duodenal mucosa, bile acid composition and microbiota diversity. In patients included in this INSPIRE study, we observed changes in bile acid composition [20] and minor changes in gut microbiota diversity [21]. We have taken duodenal biopsies before and 3 months after DMR to assess histological changes, this data is under evaluation.…”

Small intestine‐targeted endoscopic bariatrics: Current status and future perspectives

“…Indeed, previous studies have shown that in most patients with T2DM, the combination of a single DMR and GLP-1RA could eliminate the need for insulin therapy for up to 18 months. 52,55 The combination of small bowel-targeted EBMTs with adjuvant pharmacotherapy is a promising strategy for improving weight loss and metabolic benefits.…”