KEGG   PATHWAY: mmma04911
Entry
mmma04911                   Pathway                                
Name
Insulin secretion - Marmota marmota marmota (Alpine marmot)
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
mmma04911  Insulin secretion
mmma04911

Other DBs
GO: 0030073
Organism
Marmota marmota marmota (Alpine marmot) [GN:mmma]
Gene
107141876  Slc2a1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
107149487  Slc2a2; solute carrier family 2, facilitated glucose transporter member 2 isoform X1 [KO:K07593]
107146217  Gck; hexokinase-4 isoform X1 [KO:K12407] [EC:2.7.1.2]
107151258  Trpm4; transient receptor potential cation channel subfamily M member 4 isoform X1 [KO:K04979]
107147262  Atp1a4; sodium/potassium-transporting ATPase subunit alpha-4 isoform X1 [KO:K01539] [EC:7.2.2.13]
107147509  sodium/potassium-transporting ATPase subunit alpha-2 [KO:K01539] [EC:7.2.2.13]
107151623  Atp1a3; sodium/potassium-transporting ATPase subunit alpha-3 [KO:K01539] [EC:7.2.2.13]
107156192  Atp1a1; sodium/potassium-transporting ATPase subunit alpha-1 [KO:K01539] [EC:7.2.2.13]
107143346  Atp1b3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540]
107147406  Atp1b1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540]
107152990  Atp1b4; protein ATP1B4 isoform X1 [KO:K01540]
107153662  sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540]
107158005  Atp1b2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540]
107145819  Fxyd2; sodium/potassium-transporting ATPase subunit gamma isoform X2 [KO:K01538]
107135681  Abcc8; ATP-binding cassette sub-family C member 8 isoform X1 [KO:K05032]
107135680  Kcnj11; ATP-sensitive inward rectifier potassium channel 11 [KO:K05004]
107154890  Cacna1c; voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850]
107149619  Cacna1d; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
107159825  Cacna1f; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
107140653  Cacna1s; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
107141405  Camk2d; calcium/calmodulin-dependent protein kinase type II subunit delta isoform X9 [KO:K04515] [EC:2.7.11.17]
107142680  Camk2a; calcium/calmodulin-dependent protein kinase type II subunit alpha isoform X1 [KO:K04515] [EC:2.7.11.17]
107146068  Camk2b; calcium/calmodulin-dependent protein kinase type II subunit beta isoform X1 [KO:K04515] [EC:2.7.11.17]
107158156  Camk2g; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515] [EC:2.7.11.17]
107158118  Kcnma1; calcium-activated potassium channel subunit alpha-1 isoform X1 [KO:K04936]
107155336  Kcnu1; potassium channel subfamily U member 1 [KO:K05274]
107148043  Kcnmb1; calcium-activated potassium channel subunit beta-1 isoform X3 [KO:K04937]
107149467  Kcnmb2; calcium-activated potassium channel subunit beta-2 [KO:K04938]
107149464  Kcnmb3; calcium-activated potassium channel subunit beta-3 isoform X1 [KO:K04939]
107140061  Kcnmb4; calcium-activated potassium channel subunit beta-4 [KO:K04941]
107145058  Kcnn1; small conductance calcium-activated potassium channel protein 1 [KO:K04942]
107156742  Kcnn3; small conductance calcium-activated potassium channel protein 3 isoform X2 [KO:K04944]
107136698  Gcg; pro-glucagon [KO:K05259]
107143875  Glp1r; LOW QUALITY PROTEIN: glucagon-like peptide 1 receptor [KO:K04581]
107150744  gastric inhibitory polypeptide [KO:K05258]
107153063  Gpr119; glucose-dependent insulinotropic receptor [KO:K08424]
107139608  Adcyap1; pituitary adenylate cyclase-activating polypeptide isoform X1 [KO:K05262]
107146154  Adcyap1r1; pituitary adenylate cyclase-activating polypeptide type I receptor isoform X7 [KO:K04587]
107137583  guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
107137572  Gnas; neuroendocrine secretory protein 55 [KO:K04632]
107146235  Adcy1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
107146314  Adcy2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
107137043  Adcy3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
107147463  Adcy4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
107143106  Adcy5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
107148587  Adcy6; adenylate cyclase type 6 isoform X2 [KO:K08046] [EC:4.6.1.1]
107144878  Adcy7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
107143016  Adcy8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
107146665  Adcy9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
107135580  cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
107158295  Prkacb; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
107144974  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
107138645  Creb1; cyclic AMP-responsive element-binding protein 1 isoform X2 [KO:K05870]
107136939  Atf2; LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
107155865  Atf4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
107147808  Creb3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
107135791  Creb3l1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X3 [KO:K09048]
107149021  Creb3l2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
107156760  Creb3l4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
107146134  Creb5; cyclic AMP-responsive element-binding protein 5 isoform X2 [KO:K09047]
107143753  Atf6b; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
107140768  Pdx1; pancreas/duodenum homeobox protein 1 [KO:K07594]
107157066  Ins; insulin [KO:K04526]
107136927  Rapgef4; rap guanine nucleotide exchange factor 4 isoform X8 [KO:K04351]
107142853  Rims2; regulating synaptic membrane exocytosis protein 2 isoform X32 [KO:K15297]
107144588  Pclo; protein piccolo isoform X2 [KO:K16882]
107145346  Rab3a; ras-related protein Rab-3A [KO:K07882]
107145602  Cck; cholecystokinin [KO:K05226]
107139012  Cckar; cholecystokinin receptor type A [KO:K04194]
107150312  Chrm3; muscarinic acetylcholine receptor M3 [KO:K04131]
107151798  Ffar1; free fatty acid receptor 1 [KO:K04325]
107148216  guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
107157430  Gna11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
107135966  Plcb3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
107138232  Plcb2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X1 [KO:K05858] [EC:3.1.4.11]
107145524  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X3 [KO:K05858] [EC:3.1.4.11]
107145453  Plcb1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
107143606  Itpr3; inositol 1,4,5-trisphosphate receptor type 3 isoform X1 [KO:K04960]
107157936  Ryr2; ryanodine receptor 2 [KO:K04962]
107158070  Vamp2; vesicle-associated membrane protein 2 [KO:K13504]
107147036  Stx1a; syntaxin-1A [KO:K04560]
107139985  Snap25; synaptosomal-associated protein 25 isoform X1 [KO:K18211]
107158309  Prkca; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
107146552  Prkcb; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
107158898  Prkcg; protein kinase C gamma type [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
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
mmma00020  Citrate cycle (TCA cycle)
mmma04020  Calcium signaling pathway
KO pathway
ko04911   
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