Incretin synthesis, secretion, and inactivation (Homo sapiens)

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4, 6, 98, 17, 19, 21, 22, 24...1-3, 8, 14...12, 16, 177, 10, 20, 2811, 17, 18157, 10513277, 107, 10, 20, 28, 29endoplasmic reticulum lumennucleoplasmcytosolsecretory granuleDHA hTCF-4:Beta-cateninRGZ GLP-1 (7-37) DTTA GRP(24-50)GCG geneGCG(21-180)11,14,17-eicosatrienoic acid GCG(21-180)SPCS1 OLEA FFAR1 ArgN-GCG(98-127) GPR119 OLEA PALM GIP(1-153)FFAR4:FFAR4 ligandsGIP geneGLP-1 (7-37) 8,11,14-Eicosatrienoic acid SPCS3 GATA4PALM GIP(22-153)EPA DPA Ca2+ MYSA GNB3 GNG13 GPR119:Fatty AcidDPP4(39-766)PAX6DPP4(1-766)GIP(52-93)ISL1Pmoa FFAR4 1-acyl LPC CTNNB1 GIP(52-93)GIP(54-93)GLA DDCX Signal PeptidaseSTEA FFAR1:FFAR1 ligandsGCG(100-128) GCG(1-180)mature GLP-1ALA PCSK1 n-Oleoylethanolamide AcChoGlcPC1:calcium cofactorELDA Pentadecanoic acid TCF7L2 GLP-1 (Cleaved atN-terminus)Gustducin Complex(alpha, beta, gammasubunits)ArgN-GCG(98-127) SEC11A GNAT3 GIP(22-153)ArgN-GCG(100-127) LEPCDX2SPCS2 SEC11C mature GLP-1231


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. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 400508
Reactome version: 66
Reactome Author 
Reactome Author: May, Bruce

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  1. 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
  2. Cani PD, Holst JJ, Drucker DJ, Delzenne NM, Thorens B, Burcelin R, Knauf C.; ''GLUT2 and the incretin receptors are involved in glucose-induced incretin secretion.''; PubMed Europe PMC
  3. 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
  4. Kim W, Egan JM.; ''The role of incretins in glucose homeostasis and diabetes treatment.''; PubMed Europe PMC
  5. 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
  6. Todd JF, Bloom SR.; ''Incretins and other peptides in the treatment of diabetes.''; PubMed Europe PMC
  7. Gorrell MD.; ''Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders.''; PubMed Europe PMC
  8. Anini Y, Brubaker PL.; ''Muscarinic receptors control glucagon-like peptide 1 secretion by human endocrine L cells.''; PubMed Europe PMC
  9. Baggio LL, Drucker DJ.; ''Biology of incretins: GLP-1 and GIP.''; PubMed Europe PMC
  10. 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
  11. Fujita Y, Chui JW, King DS, Zhang T, Seufert J, Pownall S, Cheung AT, Kieffer TJ.; ''Pax6 and Pdx1 are required for production of glucose-dependent insulinotropic polypeptide in proglucagon-expressing L cells.''; PubMed Europe PMC
  12. 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
  13. Takeda J, Seino Y, Tanaka K, Fukumoto H, Kayano T, Takahashi H, Mitani T, Kurono M, Suzuki T, Tobe T.; ''Sequence of an intestinal cDNA encoding human gastric inhibitory polypeptide precursor.''; PubMed Europe PMC
  14. Tolhurst G, Reimann F, Gribble FM.; ''Nutritional regulation of glucagon-like peptide-1 secretion.''; PubMed Europe PMC
  15. Bonic A, Mackin RB.; ''Expression, purification, and PC1-mediated processing of human proglucagon, glicentin, and major proglucagon fragment.''; PubMed Europe PMC
  16. Edfalk S, Steneberg P, Edlund H.; ''Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion.''; PubMed Europe PMC
  17. 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
  18. 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
  19. Solcia E, Fiocca R, Capella C, Usellini L, Sessa F, Rindi G, Schwartz TW, Yanaihara N.; ''Glucagon- and PP-related peptides of intestinal L cells and pancreatic/gastric A or PP cells. Possible interrelationships of peptides and cells during evolution, fetal development and tumor growth.''; PubMed Europe PMC
  20. Bär J, Weber A, Hoffmann T, Stork J, Wermann M, Wagner L, Aust S, Gerhartz B, Demuth HU.; ''Characterisation of human dipeptidyl peptidase IV expressed in Pichia pastoris. A structural and mechanistic comparison between the recombinant human and the purified porcine enzyme.''; PubMed Europe PMC
  21. Reimer RA, Darimont C, Gremlich S, Nicolas-Métral V, Rüegg UT, Macé K.; ''A human cellular model for studying the regulation of glucagon-like peptide-1 secretion.''; PubMed Europe PMC
  22. Anini Y, Brubaker PL.; ''Role of leptin in the regulation of glucagon-like peptide-1 secretion.''; PubMed Europe PMC
  23. 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
  24. Rozengurt N, Wu SV, Chen MC, Huang C, Sternini C, Rozengurt E.; ''Colocalization of the alpha-subunit of gustducin with PYY and GLP-1 in L cells of human colon.''; PubMed Europe PMC
  25. Eissele R, Göke R, Willemer S, Harthus HP, Vermeer H, Arnold R, Göke B.; ''Glucagon-like peptide-1 cells in the gastrointestinal tract and pancreas of rat, pig and man.''; PubMed Europe PMC
  26. Brubaker PL, Anini Y.; ''Direct and indirect mechanisms regulating secretion of glucagon-like peptide-1 and glucagon-like peptide-2.''; PubMed Europe PMC
  27. Sandström O, El-Salhy M.; ''Ageing and endocrine cells of human duodenum.''; PubMed Europe PMC
  28. 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
  29. 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


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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


View all...
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)
ArgN-GCG(100-127) ProteinP01275 (Uniprot-TrEMBL)
ArgN-GCG(98-127) ProteinP01275 (Uniprot-TrEMBL) The amide group at the C-terminus is not necessary for biological activity.
CDX2ProteinQ99626 (Uniprot-TrEMBL)
CTNNB1 ProteinP35222 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
DDCX MetaboliteCHEBI:30805 (ChEBI)
DHA MetaboliteCHEBI:28125 (ChEBI)
DPA MetaboliteCHEBI:53488 (ChEBI)
DPP4(1-766)ProteinP27487 (Uniprot-TrEMBL)
DPP4(39-766)ProteinP27487 (Uniprot-TrEMBL)
DTTA MetaboliteCHEBI:53487 (ChEBI)
ELDA MetaboliteCHEBI:27997 (ChEBI)
EPA MetaboliteCHEBI:28364 (ChEBI)
FFAR1 ProteinO14842 (Uniprot-TrEMBL)
FFAR1:FFAR1 ligandsComplexR-HSA-400420 (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.
FFAR4 ProteinQ5NUL3 (Uniprot-TrEMBL)
FFAR4:FFAR4 ligandsComplexR-HSA-400543 (Reactome)
GATA4ProteinP43694 (Uniprot-TrEMBL)
GCG geneGeneProductENSG00000115263 (Ensembl)
GCG(1-180)ProteinP01275 (Uniprot-TrEMBL)
GCG(100-128) ProteinP01275 (Uniprot-TrEMBL)
GCG(21-180)ProteinP01275 (Uniprot-TrEMBL)
GIP geneGeneProductENSG00000159224 (Ensembl)
GIP(1-153)ProteinP09681 (Uniprot-TrEMBL)
GIP(22-153)ProteinP09681 (Uniprot-TrEMBL)
GIP(52-93)ProteinP09681 (Uniprot-TrEMBL)
GIP(54-93)ProteinP09681 (Uniprot-TrEMBL)
GLA MetaboliteCHEBI:28661 (ChEBI)
GLP-1 (7-37) ProteinP01275 (Uniprot-TrEMBL)
GLP-1 (Cleaved at N-terminus)ComplexR-HSA-400520 (Reactome)
GNAT3 ProteinA8MTJ3 (Uniprot-TrEMBL)
GNB3 ProteinP16520 (Uniprot-TrEMBL)
GNG13 ProteinQ9P2W3 (Uniprot-TrEMBL)
GPR119 ProteinQ8TDV5 (Uniprot-TrEMBL)
GPR119:Fatty AcidComplexR-HSA-400482 (Reactome)
GRP(24-50)ProteinP07492 (Uniprot-TrEMBL)
GlcMetaboliteCHEBI:17925 (ChEBI)
Gustducin Complex

(alpha, beta, gamma

ComplexR-HSA-400532 (Reactome)
ISL1ProteinP61371 (Uniprot-TrEMBL)
LEPProteinP41159 (Uniprot-TrEMBL)
MYSA MetaboliteCHEBI:28875 (ChEBI)
OLEA MetaboliteCHEBI:16196 (ChEBI)
PALM MetaboliteCHEBI:15756 (ChEBI)
PAX6ProteinP26367 (Uniprot-TrEMBL)
PC1:calcium cofactorComplexR-HSA-378974 (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 PeptidaseComplexR-HSA-264960 (Reactome)
TCF7L2 ProteinQ9NQB0 (Uniprot-TrEMBL)
hTCF-4:Beta-cateninComplexR-HSA-201922 (Reactome)
mature GLP-1ComplexR-HSA-381662 (Reactome)
mature GLP-1ComplexR-HSA-879886 (Reactome)
n-Oleoylethanolamide MetaboliteCHEBI:71466 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
AcChoArrowR-HSA-383313 (Reactome)
ArrowR-HSA-383313 (Reactome)
CDX2ArrowR-HSA-381799 (Reactome)
DPP4(1-766)mim-catalysisR-HSA-9023627 (Reactome)
DPP4(1-766)mim-catalysisR-HSA-9023633 (Reactome)
DPP4(39-766)mim-catalysisR-HSA-9023626 (Reactome)
DPP4(39-766)mim-catalysisR-HSA-9023632 (Reactome)
FFAR1:FFAR1 ligandsArrowR-HSA-400509 (Reactome)
FFAR4:FFAR4 ligandsArrowR-HSA-383313 (Reactome)
GATA4ArrowR-HSA-400500 (Reactome)
GCG geneR-HSA-381799 (Reactome)
GCG(1-180)ArrowR-HSA-381799 (Reactome)
GCG(1-180)R-HSA-400459 (Reactome)
GCG(21-180)ArrowR-HSA-400459 (Reactome)
GCG(21-180)ArrowR-HSA-421416 (Reactome)
GCG(21-180)R-HSA-381798 (Reactome)
GCG(21-180)R-HSA-421416 (Reactome)
GIP geneR-HSA-400500 (Reactome)
GIP(1-153)ArrowR-HSA-400500 (Reactome)
GIP(1-153)R-HSA-400496 (Reactome)
GIP(22-153)ArrowR-HSA-400496 (Reactome)
GIP(22-153)ArrowR-HSA-421426 (Reactome)
GIP(22-153)R-HSA-400492 (Reactome)
GIP(22-153)R-HSA-421426 (Reactome)
GIP(52-93)ArrowR-HSA-400492 (Reactome)
GIP(52-93)ArrowR-HSA-400509 (Reactome)
GIP(52-93)R-HSA-400509 (Reactome)
GIP(52-93)R-HSA-9023626 (Reactome)
GIP(52-93)R-HSA-9023627 (Reactome)
GIP(54-93)ArrowR-HSA-9023626 (Reactome)
GIP(54-93)ArrowR-HSA-9023627 (Reactome)
GLP-1 (Cleaved at N-terminus)ArrowR-HSA-9023632 (Reactome)
GLP-1 (Cleaved at N-terminus)ArrowR-HSA-9023633 (Reactome)
GPR119:Fatty AcidArrowR-HSA-383313 (Reactome)
GPR119:Fatty AcidArrowR-HSA-400509 (Reactome)
GRP(24-50)ArrowR-HSA-383313 (Reactome)
GlcArrowR-HSA-383313 (Reactome)
Gustducin Complex

(alpha, beta, gamma

ArrowR-HSA-383313 (Reactome)
ISL1ArrowR-HSA-400500 (Reactome)
LEPArrowR-HSA-383313 (Reactome)
PAX6ArrowR-HSA-381799 (Reactome)
PAX6ArrowR-HSA-400500 (Reactome)
PC1:calcium cofactormim-catalysisR-HSA-381798 (Reactome)
PC1:calcium cofactormim-catalysisR-HSA-400492 (Reactome)
R-HSA-381798 (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.
R-HSA-381799 (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.
R-HSA-383313 (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.
R-HSA-400459 (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.
R-HSA-400492 (Reactome) Prohormone Convertase 1/3 in secretory granules cleaves Glucose Insulinotropic Polypeptide at Arg51 and Arg93, liberating the mature 42 amino acid GIP molecule.
R-HSA-400496 (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.
R-HSA-400500 (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.
R-HSA-400509 (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.
R-HSA-421416 (Reactome) Proglucagon transits from the lumen of the endoplasmic reticulum to secretory granules.
R-HSA-421426 (Reactome) ProGIP transits from the lumen of the endoplasmic reticulum to secretory granules.
R-HSA-9023626 (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.
R-HSA-9023627 (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.
R-HSA-9023632 (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.
R-HSA-9023633 (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.
Signal Peptidasemim-catalysisR-HSA-400459 (Reactome)
Signal Peptidasemim-catalysisR-HSA-400496 (Reactome)
hTCF-4:Beta-cateninArrowR-HSA-381799 (Reactome)
mature GLP-1ArrowR-HSA-381798 (Reactome)
mature GLP-1ArrowR-HSA-383313 (Reactome)
mature GLP-1R-HSA-383313 (Reactome)
mature GLP-1R-HSA-9023632 (Reactome)
mature GLP-1R-HSA-9023633 (Reactome)
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