Review article: the emerging interplay among the gastrointestinal tract, bile acids and incretins in the pathogenesis of diabetes and non-alcoholic fatty liver disease

Abstract

Background: Recent research has led to an interest in the role of the gut and liver in type 2 diabetes mellitus (T2DM).

Aim: To review the role of the gastrointestinal system in glucose homoeostasis, with particular focus on the effects of incretin hormones, hepatic steatosis and bile acids.

Methods: PubMed and Google Scholar were searched using terms such as incretin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase-4 (DPP-4), hepatic steatosis, bile acid and gastric bypass. Additional relevant references were identified by reviewing the reference lists of articles.

Results: Perturbations of incretin hormones and bile acid secretion contribute to the pathogenesis of T2DM, leading to their potential as therapeutic targets. The incretin hormones (GIP and GLP-1) are deactivated by DPP-4. GLP-1 agonists and DPP-4 inhibitors improve glycaemic control in patients with T2DM. Hepatic steatosis, along with insulin resistance, may precede the development of T2DM, and may benefit from anti-diabetes medications. Bile acids play an important role in glucose homoeostasis, with effects mediated via the farnesoid X receptor (FXR) and the cell surface receptor TGR5. The bile acid sequestrant colesevelam has been shown to be effective in improving glycaemic control in patients with T2DM. Altered gastrointestinal anatomy after gastric bypass surgery may also affect enterohepatic recirculation of bile acids and contribute to improved glycaemic control.

Conclusions: Research in recent years has led to new pathways and processes with a role in glucose homoeostasis, and new therapeutic targets and options for type 2 diabetes mellitus.

Figure 1

Potential mechanism(s) of action for the glycemic effects of a bile acid sequestrant. FGF, fibroblast growth factor; FGFR, FGF receptor; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide-1; GR, glucocorticoid receptor; HNF-4, hepatocyte nuclear factor-4; JNK, c-Jun N-terminal kinase; LRH-1, liver receptor homolog-1; SHP, small heterodimer partner. Reprinted with permission from Wright WL. The management of type 2 diabetes mellitus: a novel approach for addressing glycemic and lipid control with colesevelam HCl. Adv Nurse Pract. 2009;17 (11):suppl 1-16.