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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Potential new approaches to modifying intestinal GLP-1 secretion in patients with type 2 diabetes mellitus : focus on bile acid sequestrants. / Holst, Jens Juul; McGill, Maria A.
In: Clinical Drug Investigation, Vol. 32, No. 1, 2012, p. 1-14.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Potential new approaches to modifying intestinal GLP-1 secretion in patients with type 2 diabetes mellitus
T2 - focus on bile acid sequestrants
AU - Holst, Jens Juul
AU - McGill, Maria A
PY - 2012
Y1 - 2012
N2 - Type 2 diabetes mellitus is associated with a progressive decline in insulin-producing pancreatic ß-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, a-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, a-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.
AB - Type 2 diabetes mellitus is associated with a progressive decline in insulin-producing pancreatic ß-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, a-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, a-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.
KW - Bile
KW - Diabetes Mellitus, Type 2
KW - Glucagon-Like Peptide 1
KW - Humans
KW - Incretins
KW - Intestines
U2 - 10.2165/11595370-000000000-00000
DO - 10.2165/11595370-000000000-00000
M3 - Journal article
C2 - 21958333
VL - 32
SP - 1
EP - 14
JO - Clinical Drug Investigation
JF - Clinical Drug Investigation
SN - 1173-2563
IS - 1
ER -
ID: 38532793