GIP and GLP-1 as incretin hormones: lessons from single and double incretin receptor knockout mice.
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.
Hansotia
Tanya
T
Department of Medicine, Banting and Best Diabetes Centre, Toronto General Hospital, and the University of Toronto, 200 Elizabeth Street MBRW4R-402, Toronto, Ontario, Canada M5G 2C4.
Drucker
Daniel J
DJ
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics / Q000502:physiology*; D005768:Gastrointestinal Hormones / Q000235:genetics / Q000502:physiology*; D005934:Glucagon / Q000235:genetics / Q000502:physiology*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000187:drug effects; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology*; D011498:Protein Precursors / Q000235:genetics / Q000502:physiology*; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics*; D018027:Receptors, Glucagon / Q000235:genetics*
C000593833:GLP1R protein, human; D005768:Gastrointestinal Hormones; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D011498:Protein Precursors; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; C041086:gastric inhibitory polypeptide receptor; D005947:Glucose