Incretin synthesis, secretion, and inactivation (Homo sapiens)

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7, 11, 29171, 103, 6, 8, 13, 15...1, 5, 10, 12, 262, 3, 6, 14, 16...42420, 23, 25199, 20, 28GPR119Fatty Acid PC1calcium cofactor Ligands of GPR119 hTCF-4 hTCF-4Beta-catenin GPR120 Fatty Acid endoplasmic reticulum lumenLigands of FFAR1 Signal Peptidase FFAR1fatty acid cytosolFatty acid ligands of GPR120 secretory granulenucleoplasmGustducin Complex Ca2+ 1-acyl LPC SEC11C GRP11,14,17-eicosatrienoic acid PALM GNAT3STEA GNB3 ELDA SEC11A GATA4FFAR4 ISL1Pentadecanoic acid GPR119 GPR119Fatty AcidGLA Gustducin Complex GCGGIPSPCS3 PAX6CDX2DPA Pmoa mature GLP-1GlcGCGOLEA GLP-1 8,11,14-Eicosatrienoic acid GIPmature GLP-1Signal PeptidaseGPR120 Fatty Acidall-cis-icosa-pentaenoic acid PC1calcium cofactorGIPDTTA hTCF-4Beta-cateninSPCS2 OLEA DHA FFAR1 GNG13 DDCX PCSK1 GCGDipeptidyl Peptidase 4GIPTCF7L2 ALA FFAR1fatty acidLEPGIPRGZ n-Oleoylethanolamide MYSA GIPSPCS1 PALM AcCho2113


Description

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. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=400508

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Bibliography

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  4. Reimer RA.; ''Meat hydrolysate and essential amino acid-induced glucagon-like peptide-1 secretion, in the human NCI-H716 enteroendocrine cell line, is regulated by extracellular signal-regulated kinase1/2 and p38 mitogen-activated protein kinases.''; PubMed Europe PMC Scholia
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  6. Varndell IM, Bishop AE, Sikri KL, Uttenthal LO, Bloom SR, Polak JM.; ''Localization of glucagon-like peptide (GLP) immunoreactants in human gut and pancreas using light and electron microscopic immunocytochemistry.''; PubMed Europe PMC Scholia
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  12. Jang HJ, Kokrashvili Z, Theodorakis MJ, Carlson OD, Kim BJ, Zhou J, Kim HH, Xu X, Chan SL, Juhaszova M, Bernier M, Mosinger B, Margolskee RF, Egan JM.; ''Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1.''; PubMed Europe PMC Scholia
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  14. Chu ZL, Carroll C, Alfonso J, Gutierrez V, He H, Lucman A, Pedraza M, Mondala H, Gao H, Bagnol D, Chen R, Jones RM, Behan DP, Leonard J.; ''A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like Peptide-1 and glucose-dependent insulinotropic Peptide release.''; PubMed Europe PMC Scholia
  15. Baggio LL, Drucker DJ.; ''Biology of incretins: GLP-1 and GIP.''; PubMed Europe PMC Scholia
  16. Todd JF, Bloom SR.; ''Incretins and other peptides in the treatment of diabetes.''; PubMed Europe PMC Scholia
  17. Pauly RP, Rosche F, Wermann M, McIntosh CH, Pederson RA, Demuth HU.; ''Investigation of glucose-dependent insulinotropic polypeptide-(1-42) and glucagon-like peptide-1-(7-36) degradation in vitro by dipeptidyl peptidase IV using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. A novel kinetic approach.''; PubMed Europe PMC Scholia
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  20. Anini Y, Brubaker PL.; ''Muscarinic receptors control glucagon-like peptide 1 secretion by human endocrine L cells.''; PubMed Europe PMC Scholia
  21. Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, Sugimoto Y, Miyazaki S, Tsujimoto G.; ''Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120.''; PubMed Europe PMC Scholia
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  23. Deacon CF, Johnsen AH, Holst JJ.; ''Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo.''; PubMed Europe PMC Scholia
  24. Someya Y, Inagaki N, Maekawa T, Seino Y, Ishii S.; ''Two 3',5'-cyclic-adenosine monophosphate response elements in the promoter region of the human gastric inhibitory polypeptide gene.''; PubMed Europe PMC Scholia
  25. Sandström O, El-Salhy M.; ''Ageing and endocrine cells of human duodenum.''; PubMed Europe PMC Scholia
  26. Edfalk S, Steneberg P, Edlund H.; ''Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion.''; PubMed Europe PMC Scholia
  27. Mentlein R, Gallwitz B, Schmidt WE.; ''Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum.''; PubMed Europe PMC Scholia
  28. Theodorakis MJ, Carlson O, Michopoulos S, Doyle ME, Juhaszova M, Petraki K, Egan JM.; ''Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP.''; PubMed Europe PMC Scholia
  29. Gorrell MD.; ''Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114648view16:11, 25 January 2021ReactomeTeamReactome version 75
113096view11:15, 2 November 2020ReactomeTeamReactome version 74
112330view15:25, 9 October 2020ReactomeTeamReactome version 73
101229view11:12, 1 November 2018ReactomeTeamreactome version 66
100767view20:38, 31 October 2018ReactomeTeamreactome version 65
100311view19:15, 31 October 2018ReactomeTeamreactome version 64
99857view15:59, 31 October 2018ReactomeTeamreactome version 63
99414view14:35, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94049view13:53, 16 August 2017ReactomeTeamreactome version 61
93675view11:30, 9 August 2017ReactomeTeamreactome version 61
87173view19:27, 18 July 2016MkutmonOntology Term : 'peptide and protein metabolic process' added !
86799view09:26, 11 July 2016ReactomeTeamreactome version 56
83360view10:58, 18 November 2015ReactomeTeamVersion54
81761view10:07, 26 August 2015ReactomeTeamVersion53
76946view08:21, 17 July 2014ReactomeTeamFixed remaining interactions
76651view12:02, 16 July 2014ReactomeTeamFixed remaining interactions
75981view10:04, 11 June 2014ReactomeTeamRe-fixing comment source
75684view11:01, 10 June 2014ReactomeTeamReactome 48 Update
75040view13:55, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74684view08:45, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
1-acyl LPC MetaboliteCHEBI:17504 (ChEBI)
11,14,17-eicosatrienoic acid MetaboliteCHEBI:53460 (ChEBI)
8,11,14-Eicosatrienoic acid MetaboliteCHEBI:53486 (ChEBI)
ALA MetaboliteCHEBI:27432 (ChEBI)
AcChoMetaboliteCHEBI:15355 (ChEBI)
CDX2ProteinQ99626 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
DDCX MetaboliteCHEBI:30805 (ChEBI)
DHA MetaboliteCHEBI:28125 (ChEBI)
DPA MetaboliteCHEBI:53488 (ChEBI)
DTTA MetaboliteCHEBI:53487 (ChEBI)
Dipeptidyl Peptidase 4REACT_24264 (Reactome)
ELDA MetaboliteCHEBI:27997 (ChEBI)
FFAR1 fatty acidComplexREACT_19781 (Reactome) 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.
FFAR1 ProteinO14842 (Uniprot-TrEMBL)
FFAR4 ProteinQ5NUL3 (Uniprot-TrEMBL)
GATA4ProteinP43694 (Uniprot-TrEMBL)
GCGProteinP01275 (Uniprot-TrEMBL)
GIPProteinP09681 (Uniprot-TrEMBL)
GLA MetaboliteCHEBI:28661 (ChEBI)
GLP-1 ProteinREACT_24381 (Reactome)
GNAT3ProteinA8MTJ3 (Uniprot-TrEMBL)
GNB3 ProteinP16520 (Uniprot-TrEMBL)
GNG13 ProteinQ9P2W3 (Uniprot-TrEMBL)
GPR119 Fatty AcidComplexREACT_24051 (Reactome)
GPR119 ProteinQ8TDV5 (Uniprot-TrEMBL)
GPR120 Fatty AcidComplexREACT_21753 (Reactome)
GRPProteinP07492 (Uniprot-TrEMBL)
GlcMetaboliteCHEBI:17925 (ChEBI)
Gustducin Complex ComplexREACT_24604 (Reactome)
ISL1ProteinP61371 (Uniprot-TrEMBL)
LEPProteinP41159 (Uniprot-TrEMBL)
MYSA MetaboliteCHEBI:28875 (ChEBI)
OLEA MetaboliteCHEBI:16196 (ChEBI)
PALM MetaboliteCHEBI:15756 (ChEBI)
PAX6ProteinP26367 (Uniprot-TrEMBL)
PC1 calcium cofactorComplexREACT_17306 (Reactome)
PCSK1 ProteinP29120 (Uniprot-TrEMBL)
Pentadecanoic acid MetaboliteCHEBI:42504 (ChEBI)
Pmoa MetaboliteCHEBI:28716 (ChEBI)
RGZ MetaboliteCHEBI:50122 (ChEBI)
SEC11A ProteinP67812 (Uniprot-TrEMBL)
SEC11C ProteinQ9BY50 (Uniprot-TrEMBL)
SPCS1 ProteinQ9Y6A9 (Uniprot-TrEMBL)
SPCS2 ProteinQ15005 (Uniprot-TrEMBL)
SPCS3 ProteinP61009 (Uniprot-TrEMBL)
STEA MetaboliteCHEBI:9254 (ChEBI)
Signal PeptidaseComplexREACT_15945 (Reactome)
TCF7L2 ProteinQ9NQB0 (Uniprot-TrEMBL)
all-cis-icosa-pentaenoic acid MetaboliteCHEBI:28364 (ChEBI)
hTCF-4 Beta-cateninComplexREACT_24275 (Reactome)
mature GLP-1ProteinREACT_19088 (Reactome)
mature GLP-1ProteinREACT_24372 (Reactome)
n-Oleoylethanolamide Metabolite5283454 (PubChem Compound)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
AcChoArrowREACT_24006 (Reactome)
CDX2ArrowREACT_24009 (Reactome)
Dipeptidyl Peptidase 4REACT_23859 (Reactome)
Dipeptidyl Peptidase 4REACT_23981 (Reactome)
FFAR1 fatty acidArrowREACT_23868 (Reactome)
FFAR1 fatty acidArrowREACT_24006 (Reactome)
GATA4ArrowREACT_23838 (Reactome)
GPR119 Fatty AcidArrowREACT_23868 (Reactome)
GPR119 Fatty AcidArrowREACT_24006 (Reactome)
GPR120 Fatty AcidArrowREACT_24006 (Reactome)
GRPArrowREACT_24006 (Reactome)
GlcArrowREACT_24006 (Reactome)
Gustducin Complex ArrowREACT_24006 (Reactome)
ISL1ArrowREACT_23838 (Reactome)
LEPArrowREACT_24006 (Reactome)
PAX6ArrowREACT_23838 (Reactome)
PAX6ArrowREACT_24009 (Reactome)
PC1 calcium cofactorREACT_23880 (Reactome)
PC1 calcium cofactorREACT_23895 (Reactome)
REACT_23838 (Reactome) 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.
REACT_23843 (Reactome) ProGIP transits from the lumen of the endoplasmic reticulum to secretory granules.
REACT_23848 (Reactome) Proglucagon transits from the lumen of the endoplasmic reticulum to secretory granules.
REACT_23859 (Reactome) 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.
REACT_23868 (Reactome) 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.
REACT_23880 (Reactome) Prohormone Convertase 1/3 in secretory granules cleaves Glucose Insulinotropic Polypeptide at Arg51 and Arg93, liberating the mature 42 amino acid GIP molecule.
REACT_23888 (Reactome) 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.
REACT_23895 (Reactome) 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.
REACT_23907 (Reactome) 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.
REACT_23981 (Reactome) 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.
REACT_24006 (Reactome) 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.
REACT_24009 (Reactome) 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.
Signal PeptidaseREACT_23888 (Reactome)
Signal PeptidaseREACT_23907 (Reactome)
hTCF-4 Beta-cateninArrowREACT_24009 (Reactome)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP2728"
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