GIP and GLP-1 as incretin hormones: lessons from single and double incretin receptor knockout mice

Mar 23, 2005Regulatory peptides

Roles of GIP and GLP-1 hormones studied in mice missing one or both hormone receptors

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Abstract

Elimination of incretin receptor action in double incretin receptor knockout (DIRKO) mice results in a significant decrease in glucose-stimulated insulin secretion following oral glucose challenge.

GIP and GLP-1 are gut hormones that enhance insulin secretion in response to food intake.
GLP-1 inhibits gastric emptying and glucagon secretion, unlike GIP.
Individuals with Type 2 diabetes show resistance to GIP's effects but not to GLP-1 receptor agonists.
Knockout mice lacking incretin receptors show only modest glucose homeostasis impairment.
DIRKO mice maintain normal body weight and plasma glucagon levels but have decreased insulin secretion after oral glucose.
The effectiveness of DPP-IV inhibitors in lowering glucose levels is lost in DIRKO mice.

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Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut-derived incretins secreted in response to nutrient ingestion. Both incretins potentiate glucose-dependent insulin secretion and enhance beta-cell mass through regulation of beta-cell proliferation, neogenesis and apoptosis. In contrast, GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake. Furthermore, human subjects with Type 2 diabetes exhibit relative resistance to the actions of GIP, but not GLP-1R agonists. The physiological importance of both incretins has been investigated through generation and analysis of incretin receptor knockout mice. Elimination of incretin receptor action in GIPR-/- or GLP-1R-/- mice produces only modest impairment in glucose homeostasis. Similarly, double incretin receptor knockout (DIRKO) mice exhibit normal body weight and normal levels of plasma glucagon and hypoglycemic responses to exogenous insulin. However, glucose-stimulated insulin secretion is significantly decreased following oral but not intraperitoneal glucose challenge in DIRKO mice and the glucose lowering actions of dipeptidyl peptidase-IV (DPP-IV) inhibitors are extinguished in DIRKO mice. Hence, incretin receptor signaling exerts physiologically relevant actions critical for glucose homeostasis, and represents a pharmacologically attractive target for development of agents for the treatment of Type 2 diabetes.

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GIP and GLP-1 as incretin hormones: lessons from single and double incretin receptor knockout mice

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