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Potential New Approaches to Modifying Intestinal GLP-1 Secretion in Patients with Type 2 Diabetes Mellitus

Focus on Bile Acid Sequestrants

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Abstract

Type 2 diabetes mellitus is associated with a progressive decline in insulinproducing pancreatic β-cells, an increase in hepatic glucose production, and a decrease in insulin sensitivity. The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) stimulate glucose-induced insulin secretion; however, in patients with type 2 diabetes, the incretin system is impaired by loss of the insulinotropic effects of GIP as well as a possible reduction in secretion of GLP-1. Agents that modify GLP-1 secretion may have a role in the management of type 2 diabetes. The currently available incretin-based therapies, GLP-1 receptor agonists (incretin mimetics) and dipeptidyl peptidase-4 (DPP-4) inhibitors (CD26 antigen inhibitors) [incretin enhancers], are safe and effective in the treatment of type 2 diabetes. However, they may be unable to halt the progression of type 2 diabetes, perhaps because they do not increase secretion of endogenous GLP-1. Therapies that directly target intestinal L cells to stimulate secretion of endogenous GLP-1 could possibly prove more effective than treatment with GLP-1 receptor agonists and DPP-4 inhibitors. Potential new approaches to modifying intestinal GLP-1 secretion in patients with type 2 diabetes include G-protein-coupled receptor (GPCR) agonists, α-glucosidase inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, metformin, bile acid mimetics and bile acid sequestrants. Both the GPCR agonist AR231453 and the novel bile acid mimetic INT-777 have been shown to stimulate GLP-1 release, leading to increased insulin secretion and improved glucose tolerance in mice. Similarly, a study in insulin-resistant rats demonstrated that the bile acid sequestrant colesevelam increased GLP-1 secretion and improved glucose levels and insulin resistance. In addition, the bile acid sequestrant colestimide (colestilan) has been shown to increase GLP-1 secretion and decrease glucose levels in patients with type 2 diabetes; these results suggest that the glucose-lowering effects of bile acid sequestrants may be partly due to their ability to increase endogenous GLP-1 levels. Evidence suggests that GPCR agonists, α-glucosidase inhibitors, PPAR agonists, metformin, bile acid mimetics and bile acid sequestrants may represent a new approach to management of type 2 diabetes via modification of endogenous GLP-1 secretion.

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Acknowledgements

Funding for medical writing services was provided by Daiichi Sankyo, Inc., Parsippany, NJ, USA. Dr Holst has received research grants from Merck and Novartis, served as a consultant for Merck and NovoNordisk, and served as a speaker for Amylin Pharmaceuticals, GlaxoSmithKline, Novartis and NovoNordisk. Maria McGill is a medical writer employed by inScience Communications, a Wolters Kluwer business.

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  1. Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark

    Jens Juul Holst

  2. inScience Communications, Yardley, PA, USA

    Maria A. McGill

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Correspondence to Jens Juul Holst.

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Holst, J.J., McGill, M.A. Potential New Approaches to Modifying Intestinal GLP-1 Secretion in Patients with Type 2 Diabetes Mellitus. Clin Drug Investig 32, 1–14 (2012). https://doi.org/10.2165/11595370-000000000-00000

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