title: Potential New Approaches to Modifying Intestinal GLP-1 Secretion in Patients with Type 2 Diabetes Mellitus : Focus on Bile Acid Sequestrants.
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.
authors.affiliation: Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark. jjholst@sund.ku.dk.
authors.forename: Jens Juul
authors.initials: JJ
authors.lastname: Holst
authors.affiliation: inScience Communications, Yardley, PA, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: McGill
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D000069472:Colesevelam Hydrochloride / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D065089:Glycoside Hydrolase Inhibitors / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D054795:Incretins / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000187:drug effects; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists
chemical_list: D001647:Bile Acids and Salts; D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents; D054795:Incretins; D047492:Peroxisome Proliferator-Activated Receptors; D052216:Glucagon-Like Peptide 1; D000069472:Colesevelam Hydrochloride