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Pathway Description
Incretins - Insulin release Pathway
Homo sapiens
Physiological Pathway
Created: 2023-09-14
Last Updated: 2024-01-20
Endogenous incretins such as such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are hormones regulating insulin secretion and glucose metabolism in mammals. Incretin acts by stimulating β cells of the pancreas to release more insulin in the blood. GIP is secreted by the enteroendocrine K-cells that are present in high density in the duodenum and upper jejunum but are present throughout the small intestine. Oral ingestion and subsequent absorption of nutrients such as glucose, high amounts of amino acids, and long-chain fatty acids trigger the secretion of GIP.
Glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GIP), both incretin hormones inactivated by dipeptidyl peptidase-4 (DPP-4), stimulate insulin secretion after an oral glucose load via the incretin effect. In type 2 diabetes, this process can become blunted or even be absent; however, the utilization of pharmacological levels of GLP-1 can revive insulin excretion. The benefits of this form of therapy to treat type 2 diabetes include delayed gastric emptying and inhibiting the production of glucagon from pancreatic alpha cells if blood sugar levels are high. Furthermore, GLP-1 receptor agonists can decrease pancreatic beta-cell apoptosis while promoting their proliferation.
GIP acts on class-II G-protein coupled receptors. The signaling mechanism for these receptors primarily involves the activation of adenylate cyclase/protein kinase A as well as phospholipase C/protein C cascades. High levels of GIP receptors get expressed in the beta cells of the pancreatic islets. Binding of GIP to its receptor increases the intracellular cAMP levels with a downstream increase in calcium ion concentration and exocytosis of insulin. GIP is rapidly inactivated by the ubiquitous enzyme dipeptidyl peptidase 4 (DPP-4), which is the same enzyme that cleaves GLP-1. However, the inactivation of GIP occurs at a slower rate than GLP-1, giving GIP a half-life of 5 to 7 minutes. DPP-4 cleaves alanine and proline residues in position 2 of the N-terminus in peptide chains. Thus, the substitution of L-alanine for D-alanine residue at position 2 of GIP makes it resistant to the action of DPP-4 and enhances its incretin effect.
Incretins binds to the ATP-sensitive potassium channels on the pancreatic cell surface. This binding causes the reduction of the potassium conductance and, in consequence, the depolarization of the membrane. This depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which results in the secretion (exocytosis) of insulin. These incretins are released in response to food intake and regulate both basal insulin secretion and meal-stimulated insulin release.
References
Incretins - Insulin release Pathway References
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