KEGG   PATHWAY: hsa04911Help
Entry
hsa04911                    Pathway                                

Name
Insulin secretion - Homo sapiens (human)
Description
Pancreatic beta cells are specialised endocrine cells that continuously sense the levels of blood sugar and other fuels and, in response, secrete insulin to maintain normal fuel homeostasis. Glucose-induced insulin secretion and its potentiation constitute the principal mechanism of insulin release. Glucose is transported by the glucose transporter (GLUT) into the pancreatic beta-cell. Metabolism of glucose generates ATP, which inhibits ATP-sensitive K+ channels and causes voltage-dependent Ca2+ influx. Elevation of [Ca2+]i triggers exocytotic release of insulin granules. Insulin secretion is further regulated by several hormones and neurotransmitters. Peptide hormones, such as glucagon-like peptide 1 (GLP-1), increase cAMP levels and thereby potentiate insulin secretion via the combined action of PKA and Epac2. Achetylcholine (ACh), a major parasympathetic neurotransmitter, binds to Gq-coupled receptors and activates phospholipase C- (PLC-), and the stimulatory effects involve activation of protein kinase C (PKC), which stimulates exocytosis. In addition, ACh mobilizes intracellular Ca2+ by activation of IP3 receptors.
Class
Organismal Systems; Endocrine system
BRITE hierarchy
Pathway map
hsa04911  Insulin secretion
hsa04911

Ortholog table
Disease
H00409  Type 2 diabetes mellitus
H01947  Fanconi-Bickel syndrome
Drug
D00219  Acetohexamide (JP17/USP/INN)
D00271  Chlorpropamide (JP17/USP/INN)
D00294  Diazoxide (JAN/USP/INN)
D00335  Glipizide (USP/INN)
D00336  Glyburide (USP)
D00379  Tolazamide (JAN/USP/INN)
D00380  Tolbutamide (JP17/USP/INN)
D00593  Glimepiride (JP17/USP/INN)
D00594  Repaglinide (JAN/USP/INN)
D01111  Nateglinide (JP17/USAN/INN)
D01356  Glymidine sodium (JAN/USAN/INN)
D01599  Gliclazide (JP17/INN)
D01799  Glyclopyramide (JAN/INN)
D01854  Mitiglinide calcium hydrate (JP17)
D02425  Carbutamide (INN)
D02427  Glibornuride (USAN/INN)
D02430  Gliquidone (INN)
D02693  Devazepide (USAN/INN)
D02710  Tarazepide (INN)
D04121  Exenatide (JAN/USAN/INN)
D04739  Linogliride (USAN/INN)
D04740  Linogliride fumarate (USAN)
D06177  Tolbutamide sodium, sterile
D06404  Liraglutide (USAN/INN)
D07117  Metahexamide (INN)
D07118  Glisoxepide (INN)
D08843  Albiglutide (USAN)
D09723  Taspoglutide (USAN/INN)
D09729  Lixisenatide (JAN/INN)
D09889  Dulaglutide (USAN/INN)
D10025  Semaglutide (USAN/INN)
D10970  Pegapamodutide (USAN)
D11360  Tirzepatide (USAN)
D11418  Avexitide (USAN)
D11419  Avexitide acetate (USAN)
Other DBs
GO: 0030073
Organism
Homo sapiens (human) [GN:hsa]
Gene
6513  SLC2A1; solute carrier family 2 member 1 [KO:K07299]
6514  SLC2A2; solute carrier family 2 member 2 [KO:K07593]
2645  GCK; glucokinase [KO:K12407] [EC:2.7.1.2]
54795  TRPM4; transient receptor potential cation channel subfamily M member 4 [KO:K04979]
476  ATP1A1; ATPase Na+/K+ transporting subunit alpha 1 [KO:K01539] [EC:7.2.2.13]
477  ATP1A2; ATPase Na+/K+ transporting subunit alpha 2 [KO:K01539] [EC:7.2.2.13]
478  ATP1A3; ATPase Na+/K+ transporting subunit alpha 3 [KO:K01539] [EC:7.2.2.13]
480  ATP1A4; ATPase Na+/K+ transporting subunit alpha 4 [KO:K01539] [EC:7.2.2.13]
23439  ATP1B4; ATPase Na+/K+ transporting family member beta 4 [KO:K01540]
481  ATP1B1; ATPase Na+/K+ transporting subunit beta 1 [KO:K01540]
482  ATP1B2; ATPase Na+/K+ transporting subunit beta 2 [KO:K01540]
483  ATP1B3; ATPase Na+/K+ transporting subunit beta 3 [KO:K01540]
486  FXYD2; FXYD domain containing ion transport regulator 2 [KO:K01538]
6833  ABCC8; ATP binding cassette subfamily C member 8 [KO:K05032]
3767  KCNJ11; potassium voltage-gated channel subfamily J member 11 [KO:K05004]
775  CACNA1C; calcium voltage-gated channel subunit alpha1 C [KO:K04850]
776  CACNA1D; calcium voltage-gated channel subunit alpha1 D [KO:K04851]
778  CACNA1F; calcium voltage-gated channel subunit alpha1 F [KO:K04853]
779  CACNA1S; calcium voltage-gated channel subunit alpha1 S [KO:K04857]
815  CAMK2A; calcium/calmodulin dependent protein kinase II alpha [KO:K04515] [EC:2.7.11.17]
817  CAMK2D; calcium/calmodulin dependent protein kinase II delta [KO:K04515] [EC:2.7.11.17]
816  CAMK2B; calcium/calmodulin dependent protein kinase II beta [KO:K04515] [EC:2.7.11.17]
818  CAMK2G; calcium/calmodulin dependent protein kinase II gamma [KO:K04515] [EC:2.7.11.17]
3778  KCNMA1; potassium calcium-activated channel subfamily M alpha 1 [KO:K04936]
157855  KCNU1; potassium calcium-activated channel subfamily U member 1 [KO:K05274]
3779  KCNMB1; potassium calcium-activated channel subfamily M regulatory beta subunit 1 [KO:K04937]
10242  KCNMB2; potassium calcium-activated channel subfamily M regulatory beta subunit 2 [KO:K04938]
27094  KCNMB3; potassium calcium-activated channel subfamily M regulatory beta subunit 3 [KO:K04939]
27345  KCNMB4; potassium calcium-activated channel subfamily M regulatory beta subunit 4 [KO:K04941]
3780  KCNN1; potassium calcium-activated channel subfamily N member 1 [KO:K04942]
3781  KCNN2; potassium calcium-activated channel subfamily N member 2 [KO:K04943]
3782  KCNN3; potassium calcium-activated channel subfamily N member 3 [KO:K04944]
3783  KCNN4; potassium calcium-activated channel subfamily N member 4 [KO:K04945]
2641  GCG; glucagon [KO:K05259]
2740  GLP1R; glucagon like peptide 1 receptor [KO:K04581]
2695  GIP; gastric inhibitory polypeptide [KO:K05258]
139760  GPR119; G protein-coupled receptor 119 [KO:K08424]
116  ADCYAP1; adenylate cyclase activating polypeptide 1 [KO:K05262]
117  ADCYAP1R1; ADCYAP receptor type I [KO:K04587]
2778  GNAS; GNAS complex locus [KO:K04632]
107  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
108  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
109  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
196883  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
111  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
112  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
113  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
114  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
115  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
5566  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
5567  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
5568  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
1385  CREB1; cAMP responsive element binding protein 1 [KO:K05870]
1386  ATF2; activating transcription factor 2 [KO:K04450]
468  ATF4; activating transcription factor 4 [KO:K04374]
10488  CREB3; cAMP responsive element binding protein 3 [KO:K09048]
90993  CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048]
64764  CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048]
84699  CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048]
148327  CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048]
9586  CREB5; cAMP responsive element binding protein 5 [KO:K09047]
1388  ATF6B; activating transcription factor 6 beta [KO:K09049]
3651  PDX1; pancreatic and duodenal homeobox 1 [KO:K07594]
3630  INS; insulin [KO:K04526]
11069  RAPGEF4; Rap guanine nucleotide exchange factor 4 [KO:K04351]
9699  RIMS2; regulating synaptic membrane exocytosis 2 [KO:K15297]
27445  PCLO; piccolo presynaptic cytomatrix protein [KO:K16882]
5864  RAB3A; RAB3A, member RAS oncogene family [KO:K07882]
885  CCK; cholecystokinin [KO:K05226]
886  CCKAR; cholecystokinin A receptor [KO:K04194]
1131  CHRM3; cholinergic receptor muscarinic 3 [KO:K04131]
2864  FFAR1; free fatty acid receptor 1 [KO:K04325]
2776  GNAQ; G protein subunit alpha q [KO:K04634]
2767  GNA11; G protein subunit alpha 11 [KO:K04635]
23236  PLCB1; phospholipase C beta 1 [KO:K05858] [EC:3.1.4.11]
5330  PLCB2; phospholipase C beta 2 [KO:K05858] [EC:3.1.4.11]
5331  PLCB3; phospholipase C beta 3 [KO:K05858] [EC:3.1.4.11]
5332  PLCB4; phospholipase C beta 4 [KO:K05858] [EC:3.1.4.11]
3710  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
6262  RYR2; ryanodine receptor 2 [KO:K04962]
6844  VAMP2; vesicle associated membrane protein 2 [KO:K13504]
6804  STX1A; syntaxin 1A [KO:K04560]
6616  SNAP25; synaptosome associated protein 25 [KO:K18211]
5578  PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
5579  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
5582  PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
Compound
C00002  ATP
C00022  Pyruvate
C00031  D-Glucose
C00076  Calcium cation
C00092  D-Glucose 6-phosphate
C00162  Fatty acid
C00165  Diacylglycerol
C00238  Potassium cation
C00575  3',5'-Cyclic AMP
C01245  D-myo-Inositol 1,4,5-trisphosphate
C01330  Sodium cation
C01996  Acetylcholine
Reference
  Authors
Seino S, Shibasaki T, Minami K
  Title
Pancreatic beta-cell signaling: toward better understanding of diabetes and its treatment.
  Journal
Proc Jpn Acad Ser B Phys Biol Sci 86:563-77 (2010)
DOI:10.2183/pjab.86.563
Reference
  Authors
Jitrapakdee S, Wutthisathapornchai A, Wallace JC, MacDonald MJ
  Title
Regulation of insulin secretion: role of mitochondrial signalling.
  Journal
Diabetologia 53:1019-32 (2010)
DOI:10.1007/s00125-010-1685-0
Reference
  Authors
Rorsman P, Braun M
  Title
Regulation of insulin secretion in human pancreatic islets.
  Journal
Annu Rev Physiol 75:155-79 (2013)
DOI:10.1146/annurev-physiol-030212-183754
Reference
PMID:9715374
  Authors
Jones PM, Persaud SJ
  Title
Protein kinases, protein phosphorylation, and the regulation of insulin secretion from pancreatic beta-cells.
  Journal
Endocr Rev 19:429-61 (1998)
DOI:10.1210/edrv.19.4.0339
Reference
  Authors
MacDonald PE
  Title
Signal integration at the level of ion channel and exocytotic function in pancreatic beta-cells.
  Journal
Am J Physiol Endocrinol Metab 301:E1065-9 (2011)
DOI:10.1152/ajpendo.00426.2011
Reference
PMID:9914469
  Authors
Lang J
  Title
Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion.
  Journal
Eur J Biochem 259:3-17 (1999)
DOI:10.1046/j.1432-1327.1999.00043.x
Reference
  Authors
Kieffer TJ, Habener JF
  Title
The glucagon-like peptides.
  Journal
Endocr Rev 20:876-913 (1999)
DOI:10.1210/edrv.20.6.0385
Reference
  Authors
Girard J
  Title
The incretins: from the concept to their use in the treatment of type 2 diabetes. Part A: incretins: concept and physiological functions.
  Journal
Diabetes Metab 34:550-9 (2008)
DOI:10.1016/j.diabet.2008.09.001
Reference
  Authors
Holz GG
  Title
New insights concerning the glucose-dependent insulin secretagogue action of glucagon-like peptide-1 in pancreatic beta-cells.
  Journal
Horm Metab Res 36:787-94 (2004)
DOI:10.1055/s-2004-826165
Reference
  Authors
Holst JJ, Gromada J
  Title
Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans.
  Journal
Am J Physiol Endocrinol Metab 287:E199-206 (2004)
DOI:10.1152/ajpendo.00545.2003
Reference
  Authors
Doyle ME, Egan JM
  Title
Mechanisms of action of glucagon-like peptide 1 in the pancreas.
  Journal
Pharmacol Ther 113:546-93 (2007)
DOI:10.1016/j.pharmthera.2006.11.007
Reference
  Authors
Kim W, Egan JM
  Title
The role of incretins in glucose homeostasis and diabetes treatment.
  Journal
Pharmacol Rev 60:470-512 (2008)
DOI:10.1124/pr.108.000604
Reference
  Authors
Seino S, Takahashi H, Fujimoto W, Shibasaki T
  Title
Roles of cAMP signalling in insulin granule exocytosis.
  Journal
Diabetes Obes Metab 11 Suppl 4:180-8 (2009)
DOI:10.1111/j.1463-1326.2009.01108.x
Reference
  Authors
Tengholm A
  Title
Cyclic AMP dynamics in the pancreatic beta-cell.
  Journal
Ups J Med Sci 117:355-69 (2012)
DOI:10.3109/03009734.2012.724732
Reference
  Authors
Holz GG
  Title
Epac: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell.
  Journal
Diabetes 53:5-13 (2004)
DOI:10.2337/diabetes.53.1.5
Reference
  Authors
Gloerich M, Bos JL
  Title
Epac: defining a new mechanism for cAMP action.
  Journal
Annu Rev Pharmacol Toxicol 50:355-75 (2010)
DOI:10.1146/annurev.pharmtox.010909.105714
Reference
  Authors
Bos JL
  Title
Epac proteins: multi-purpose cAMP targets.
  Journal
Trends Biochem Sci 31:680-6 (2006)
DOI:10.1016/j.tibs.2006.10.002
Reference
  Authors
Filipsson K, Kvist-Reimer M, Ahren B
  Title
The neuropeptide pituitary adenylate cyclase-activating polypeptide and islet function.
  Journal
Diabetes 50:1959-69 (2001)
DOI:10.2337/diabetes.50.9.1959
Reference
  Authors
Kebede MA, Alquier T, Latour MG, Poitout V
  Title
Lipid receptors and islet function: therapeutic implications?
  Journal
Diabetes Obes Metab 11 Suppl 4:10-20 (2009)
DOI:10.1111/j.1463-1326.2009.01114.x
Reference
  Authors
Morgan NG, Dhayal S
  Title
G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell.
  Journal
Biochem Pharmacol 78:1419-27 (2009)
DOI:10.1016/j.bcp.2009.07.020
KO pathway
ko04911   

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