KEGG   PATHWAY: ko04911
Entry
ko04911                     Pathway                                
Name
Insulin secretion
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
Pathway map
ko04911  Insulin secretion
ko04911

Other DBs
GO: 0030073
Orthology
K01538  FXYD2, ATP1G1; sodium/potassium-transporting ATPase subunit gamma (FXYD domain-containing ion transport regulator 2)
K01539  ATP1A; sodium/potassium-transporting ATPase subunit alpha [EC:7.2.2.13]
K01540  ATP1B, CD298; sodium/potassium-transporting ATPase subunit beta
K02677  PRKCA; classical protein kinase C alpha type [EC:2.7.11.13]
K04131  CHRM3; muscarinic acetylcholine receptor M3
K04194  CCKAR; cholecystokinin A receptor
K04325  FFAR1, GPR40; free fatty acid receptor 1
K04345  PKA; protein kinase A [EC:2.7.11.11]
K04351  RAPGEF4, EPAC2; Rap guanine nucleotide exchange factor 4
K04374  ATF4, CREB2; cyclic AMP-dependent transcription factor ATF-4
K04450  ATF2, CREBP1; cyclic AMP-dependent transcription factor ATF-2
K04515  CAMK2; calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:2.7.11.17]
K04526  INS; insulin
K04560  STX1A; syntaxin 1A
K04581  GLP1R; glucagon-like peptide 1 receptor
K04587  ADCYAP1R1, PACAPRI; pituitary adenylate cyclase-activating polypeptide type I receptor
K04632  GNAS; guanine nucleotide-binding protein G(s) subunit alpha
K04634  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha
K04635  GNA11; guanine nucleotide-binding protein subunit alpha-11
K04850  CACNA1C, CAV1.2; voltage-dependent calcium channel L type alpha-1C
K04851  CACNA1D, CAV1.3; voltage-dependent calcium channel L type alpha-1D
K04853  CACNA1F, CAV1.4; voltage-dependent calcium channel L type alpha-1F
K04857  CACNA1S, CAV1.1; voltage-dependent calcium channel L type alpha-1S
K04936  KCNMA1, KCA1.1; potassium large conductance calcium-activated channel subfamily M alpha member 1
K04937  KCNMB1; potassium large conductance calcium-activated channel subfamily M beta member 1
K04938  KCNMB2; potassium large conductance calcium-activated channel subfamily M beta member 2
K04939  KCNMB3; potassium large conductance calcium-activated channel subfamily M beta member 3
K04941  KCNMB4; potassium large conductance calcium-activated channel subfamily M beta member 4
K04942  KCNN1, KCA2.1; potassium intermediate/small conductance calcium-activated channel subfamily N member 1
K04943  KCNN2, KCA2.2; potassium intermediate/small conductance calcium-activated channel subfamily N member 2
K04944  KCNN3, KCA2.3; potassium intermediate/small conductance calcium-activated channel subfamily N member 3
K04945  KCNN4, KCA3.1; potassium intermediate/small conductance calcium-activated channel subfamily N member 4
K04960  ITPR3; inositol 1,4,5-triphosphate receptor type 3
K04962  RYR2; ryanodine receptor 2
K04979  TRPM4; transient receptor potential cation channel subfamily M member 4
K05004  KCNJ11, KIR6.2; potassium inwardly-rectifying channel subfamily J member 11
K05032  ABCC8, SUR1; ATP-binding cassette subfamily C (CFTR/MRP) member 8
K05226  CCK; cholecystokinin
K05258  GIP; gastric inhibitory polypeptide
K05259  GCG; glucagon
K05262  ADCYAP; pituitary adenylate cyclase-activating polypeptide
K05274  KCNMA3, KCNU1, KCA5.1; potassium large conductance calcium-activated channel subfamily M alpha member 3
K05858  PLCB; phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]
K05870  CREB1; cyclic AMP-responsive element-binding protein 1
K07299  SLC2A1, GLUT1; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 1
K07593  SLC2A2, GLUT2; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 2
K07594  IPF1, PDX1; insulin promoter factor 1
K07882  RAB3A; Ras-related protein Rab-3A
K08041  ADCY1; adenylate cyclase 1 [EC:4.6.1.1]
K08042  ADCY2; adenylate cyclase 2 [EC:4.6.1.1]
K08043  ADCY3; adenylate cyclase 3 [EC:4.6.1.1]
K08044  ADCY4; adenylate cyclase 4 [EC:4.6.1.1]
K08045  ADCY5; adenylate cyclase 5 [EC:4.6.1.1]
K08046  ADCY6; adenylate cyclase 6 [EC:4.6.1.1]
K08047  ADCY7; adenylate cyclase 7 [EC:4.6.1.1]
K08048  ADCY8; adenylate cyclase 8 [EC:4.6.1.1]
K08049  ADCY9; adenylate cyclase 9 [EC:4.6.1.1]
K08424  GPR119; glucose-dependent insulinotropic receptor
K09047  CREB5, CREBPA; cyclic AMP-responsive element-binding protein 5
K09048  CREB3; cyclic AMP-responsive element-binding protein 3
K09049  ATF6B, CREBL1; cyclic AMP-dependent transcription factor ATF-6 beta
K12407  GCK; glucokinase [EC:2.7.1.2]
K13504  VAMP2; vesicle-associated membrane protein 2
K15297  RIMS2, RIM2; regulating synaptic membrane exocytosis protein 2
K16882  PCLO; protein piccolo
K18211  SNAP25; synaptosomal-associated protein 25
K19662  PRKCB; classical protein kinase C beta type [EC:2.7.11.13]
K19663  PRKCG; classical protein kinase C gamma type [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
PMID:20551594
  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
PMID:20225132
  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
PMID:22974438
  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
PMID:21934040
  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
PMID:10605628
  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
PMID:19036624
  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
PMID:15655710
  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
PMID:15271645
  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
PMID:17306374
  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
PMID:19074620
  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
PMID:19817800
  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
PMID:22970724
  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
PMID:14693691
  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
PMID:20055708
  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
PMID:17084085
  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
PMID:11522660
  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
PMID:19817784
  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
PMID:19660440
  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
Related
pathway
ko00020  Citrate cycle (TCA cycle)
ko04020  Calcium signaling pathway

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