Incretins are peptide hormones produced by the gut that enhance the ability of glucose to stimulate insulin secretion from beta cells in the pancreas. Two incretins have been identified: Glucagon-like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP, initially named Gastric Inhibitory Peptide). Both are released by cells of the small intestine, GLP-1 from L cells and GIP from K cells. The control of incretin secretion is complex. Fatty acids, phospholipids, glucose, acetylcholine, leptin, and Gastrin-releasing Peptide all stimulate secretion of GLP-1. Fatty acids and phospholipids are the primary stimulants of secretion of GIP in humans (carbohydrates have more effect in rodents). Incretins secreted into the bloodstream are subject to rapid inactivation by Dipeptidyl Peptidase IV (DPP IV), which confers half-lives of only a few minutes onto GLP-1 and GIP. Inhibitors of DPP IV, for example sitagliptin, are now being used in the treatment of Type 2 diabetes.
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The Free fatty acid receptor 1 (FFAR1 or GPR40) is located on pancreatic beta cells and binds to medium and long chain fatty acids (fatty acids having more than 12 carbon groups). FFAR1 is a G-protein coupled receptor that is coupled to Gq.
The transcription factors PDX-1 and PAX6 binds the promoter of the human GIP gene between 145 and 184 nucleotides upstream of the start of transcription and enhance transcription of GIP. In mouse Pdx-1 also increases the number of GIP-producing K cells. Consensus binding sites for other transcription factors such as AP-1, AP-2, and Sp1 have been identified in the promoter of the GIP gene but their role is unknown. The human GIP promoter is responsive to cAMP by an unknown mechanism.
Dipeptidyl Peptidase IV (DPP4) cleaves 2 amino acids from the N-terminus of GLP-1, inactivating it. DPP4 determines the half life of GLP-1 in the bloodstream. It is unknown if the soluble form of DPP4, the membrane-bound form, or both catalyze the cleavage of GLP-1.
GIP is secreted by intestinal K-cells in response to glucose, amino acids, and fats. In mice fatty acids act to increase GIP secretion by binding the G-protein coupled receptors GPR40 and GPR119 present on intestinal K-cells. The stimulation is dependent on adenyl cyclase and intracellular calcium but the exact mechanism is unknown.
The GIP mRNA is translated by ribosomes at the outer surface of the rough endoplasmic reticulum. The nascent peptide enters the endoplasmic reticulum through the translocon complex and the signal peptide is cleaved by the signal peptidase.
In secretory granules of intestinal L cells, proglucagon is proteolytically cleaved by prohormone convertase 1 (PC1) at two sites to yield GLP-1 (7-36) or GLP-1 (7-37). In humans almost all circulating GLP-1 is GLP-1 (7-36) amidated at the C-terminus. Experiments in knockout mice have shown that PC1 is necessary for cleavage. Carboxypeptidase E and peptidylglycine alpha-amidating monooxygenase may be involved in trimming and amidating the C-terminus.
The GCG (Proglucagon) mRNA is translated by ribosomes at the outer surface of the rough endoplasmic reticulum. The nascent peptide enters the endoplasmic reticulum through the translocon complex and the signal peptide is cleaved by the signal peptidase.
Dipeptidyl Peptidase IV (DPP4) cleaves 2 amino acids from the N-terminus of GIP, inactivating it. DPP4 determines the half life of GIP in the bloodstream. It is unknown if the soluble form of DPP4, the membrane-bound form, or both catalyze the cleavage of GIP.
Secretion of GLP-1 from intestinal L-cells is dependent on a rise in cytosolic calcium which, in turn, is stimulated by glucose (requires the GLUT2 glucose transporter), fatty acids (especially monounsaturated fatty acids, requires the GPR120 and GPR40 receptors), insulin, leptin, gastrin-releasing peptide, cholinergic transmitters (requires M1 and M2 muscarinic receptors), amino acids (requires mitogen activated protein kinase pathway), beta-adrenergic transmitters, and peptidergic transmitters. The exact mechanisms controlling secretion have not been elucidated.
TCF-4 and Beta-Catenin form a heterodimer that bind the G2 element of the promoter of the Proglucagon (GCG) gene in L2 cells of the intestine. CDX-2 binds an AT-rich sequence in the G1 enhancer element of the GCG promoter. Transcription of the GCG gene is enhanced by cAMP, calcium, and insulin and the Beta-Catenin:TCF-4 binding region of the promoter is necessary for this regulation. It is therefore postulated that the Wnt signaling pathway (Beta-Catenin) crosstalks with the cAMP-PKA pathway and/or the cAMP-EPAC pathway.
The control of incretin secretion is complex. Fatty acids, phospholipids, glucose, acetylcholine, leptin, and Gastrin-releasing Peptide all stimulate secretion of GLP-1. Fatty acids and phospholipids are the primary stimulants of secretion of GIP in humans (carbohydrates have more effect in rodents).
Incretins secreted into the bloodstream are subject to rapid inactivation by Dipeptidyl Peptidase IV (DPP IV), which confers half-lives of only a few minutes onto GLP-1 and GIP. Inhibitors of DPP IV, for example sitagliptin, are now being used in the treatment of Type 2 diabetes.
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