Review Article: The Emerging Interplay Among the Gastrointestinal Tract, Bile Acids and Incretins in the Pathogenesis of Diabetes and Non-alcoholic Fatty Liver Disease

A. Zarrinpar; R. Loomba

Disclosures

Aliment Pharmacol Ther. 2012;36(10):909-921. 

In This Article

Abstract and Introduction

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.

Introduction

Diabetes mellitus (DM) refers to a group of endocrine diseases that are all characterised by hyperglycaemia. It is one of the most rapidly rising diseases in the United States, affecting 25.8 million people (about 8.3% of the population), and is now the seventh leading cause of death in the United States.[1] Because of the glycaemic dysregulation related to these diseases, the secondary pathophysiological effects of DM on multiple organ systems impose an additional burden on the healthcare system. DM is the leading cause of end-stage renal disease, lower extremity amputations and blindness in adults, as well as a known aggravator of cardiovascular disease. Type 2 DM (T2DM), the most common type of DM, is classically described as a heterogeneous group of disorders that is characterised by a decline in insulin-producing pancreatic β cells, an increase in peripheral insulin resistance, an increase in hepatic glucose production, or a combination of these factors.

For decades, therapies for T2DM have focused on this 'triad' of characteristics, acting on the liver, pancreas, muscle and adipose tissue to reduce hepatic glucose production (e.g. biguanides), increase insulin secretion (e.g. sulphonylureas), and improve insulin sensitivity (e.g. thiazolidinediones). However, recent research suggests that other organs and processes play a vital role in glucose homoeostasis and the pathogenesis of T2DM, and that these new pathways have potent therapeutic potential. Of particular interest has been the role of the gut in glucose homoeostasis, through the direct action of incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).

Processes occurring in the liver may also play a role in the pathogenesis of T2DM, although a causal link has not yet been definitively demonstrated. Hepatic steatosis (an excess of triglyceride accumulation in hepatocytes) is often observed in the presence of insulin resistance, including in T2DM. Emerging data suggest that hepatic insulin resistance and hepatic steatosis precede the development of T2DM. Diet and pharmacological therapies used in the management of T2DM have been shown to decrease hepatic triglyceride content, in addition to improving glycaemic control.

Emerging research also shows the importance of bile acids in glucose homoeostasis, which may lead to an understanding of how bariatric surgery mediates its immediate effect on T2DM. Both the liver and intestines are involved in bile acid metabolism.

Various components of the gastrointestinal system contribute to the pathogenesis of T2DM and may be potential therapeutic targets. In the 2011 American Association of Clinical Endocrinologists clinical practice guidelines for DM, incretin therapy has been recommended in controlling fasting glucose in patients with DM.[2] It is likely that incretin therapies will play a much wider role in the treatment of T2DM in the future. In this article, the role of the gastrointestinal system in glucose homoeostasis will be reviewed, with particular focus on the effects of incretin hormones, hepatic steatosis and bile acids.

PubMed and Google Scholar were searched using terms such as incretin, GIP, 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

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