KEGG   PATHWAY: rno04911
Entry
rno04911                    Pathway                                
Name
Insulin secretion - Rattus norvegicus (rat)
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
rno04911  Insulin secretion
rno04911

Other DBs
GO: 0030073
Organism
Rattus norvegicus (rat) [GN:rno]
Gene
114493  Cacna1f; voltage-dependent L-type calcium channel subunit alpha-1F [KO:K04853]
116470  Stx1a; syntaxin-1A [KO:K04560]
116839  Rims2; regulating synaptic membrane exocytosis protein 2 isoform 1 [KO:K15297]
171140  Camk2g; calcium/calmodulin-dependent protein kinase type II subunit gamma [KO:K04515] [EC:2.7.11.17]
171143  Trpm4; transient receptor potential cation channel subfamily M member 4 [KO:K04979]
24166  Adcyap1; pituitary adenylate cyclase-activating polypeptide precursor [KO:K05262]
24167  Adcyap1r1; pituitary adenylate cyclase-activating polypeptide type I receptor isoform a precursor [KO:K04587]
24211  Atp1a1; sodium/potassium-transporting ATPase subunit alpha-1 precursor [KO:K01539] [EC:7.2.2.13]
24212  Atp1a2; sodium/potassium-transporting ATPase subunit alpha-2 precursor [KO:K01539] [EC:7.2.2.13]
24213  Atp1a3; sodium/potassium-transporting ATPase subunit alpha-3 [KO:K01539] [EC:7.2.2.13]
24214  Atp1b2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540]
24239  Cacna1c; voltage-dependent L-type calcium channel subunit alpha-1C [KO:K04850]
24245  Camk2b; calcium/calmodulin-dependent protein kinase type II subunit beta isoform 2 [KO:K04515] [EC:2.7.11.17]
24246  Camk2d; calcium/calmodulin-dependent protein kinase type II subunit delta [KO:K04515] [EC:2.7.11.17]
24260  Chrm3; muscarinic acetylcholine receptor M3 [KO:K04131]
24385  Gck; hexokinase-4 isoform 2 [KO:K12407] [EC:2.7.1.2]
24505  Ins1; insulin-1 preproprotein [KO:K04526]
24506  Ins2; insulin-2 preproprotein [KO:K04526]
24654  Plcb1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
24680  Prkca; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
24681  Prkcg; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
24778  Slc2a1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
24803  Vamp2; vesicle-associated membrane protein 2 [KO:K13504]
24889  Cckar; cholecystokinin receptor type A [KO:K04194]
24896  Gnas; SCG6 (secretogranin VI) isoform SCG6 precursor [KO:K04632]
24952  Gcg; pro-glucagon preproprotein [KO:K05259]
25012  Snap25; synaptosomal-associated protein 25 isoform a [KO:K18211]
25023  Prkcb; protein kinase C beta type isoform 2 [KO:K19662] [EC:2.7.11.13]
25031  Plcb4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
25040  Gip; gastric inhibitory polypeptide precursor [KO:K05258]
25051  Glp1r; glucagon-like peptide 1 receptor precursor [KO:K04581]
252857  Rapgef4; rap guanine nucleotide exchange factor 4 [KO:K04351]
25289  Adcy6; adenylate cyclase type 6 isoform 2 [KO:K08046] [EC:4.6.1.1]
25298  Cck; cholecystokinin preproprotein [KO:K05226]
25351  Slc2a2; solute carrier family 2, facilitated glucose transporter member 2 [KO:K07593]
25390  Atp1b3; sodium/potassium-transporting ATPase subunit beta-3 [KO:K01540]
25400  Camk2a; calcium/calmodulin-dependent protein kinase type II subunit alpha [KO:K04515] [EC:2.7.11.17]
25531  Rab3a; ras-related protein Rab-3A [KO:K07882]
25559  Abcc8; ATP-binding cassette sub-family C member 8 isoform 1 [KO:K05032]
25636  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
25650  Atp1b1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540]
25679  Itpr3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
266607  Ffar1; free fatty acid receptor 1 [KO:K04325]
29132  Atp1a4; sodium/potassium-transporting ATPase subunit alpha-4 [KO:K01539] [EC:7.2.2.13]
29241  Adcy8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
29322  Plcb3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
293508  Prkacb; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
294961  Kcnmb2; calcium-activated potassium channel subunit beta-2 [KO:K04938]
29535  Pdx1; pancreas/duodenum homeobox protein 1 [KO:K07594]
29639  Fxyd2; sodium/potassium-transporting ATPase subunit gamma isoform a [KO:K01538]
29716  Cacna1d; voltage-dependent L-type calcium channel subunit alpha-1D [KO:K04851]
29747  Kcnmb1; calcium-activated potassium channel subunit beta-1 [KO:K04937]
298400  Creb3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
302813  Gpr119; glucose-dependent insulinotropic receptor [KO:K08424]
302950  Adcy9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
305509  Adcy1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
310303  Kcnmb3; calcium-activated potassium channel subunit beta-3 [KO:K04939]
310616  Creb3l4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform 1 [KO:K09048]
314638  Creb3l3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
362165  Creb3l1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
362339  Creb3l2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
406169  Atf6b; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
500131  Creb5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
54223  Adcy4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
54261  Kcnn1; small conductance calcium-activated potassium channel protein 1 [KO:K04942]
54262  Kcnn2; small conductance calcium-activated potassium channel protein 2 isoform 2 [KO:K04943]
54263  Kcnn3; small conductance calcium-activated potassium channel protein 3 [KO:K04944]
56768  Pclo; protein piccolo isoform 1 [KO:K16882]
64508  Adcy3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
64532  Adcy5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
65206  Kcnn4; intermediate conductance calcium-activated potassium channel protein 4 isoform a [KO:K04945]
66016  Kcnmb4; calcium-activated potassium channel subunit beta-4 [KO:K04941]
680912  Kcnu1; potassium channel subfamily U member 1 isoform X6 [KO:K05274]
682930  Cacna1s; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
689560  Ryr2; ryanodine receptor 2 isoform 1 [KO:K04962]
79255  Atf4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
81636  Adcy2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
81646  Creb1; cyclic AMP-responsive element-binding protein 1 isoform A [KO:K05870]
81647  Atf2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
81662  Gna11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
81666  Gnaq; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
83535  Kcnj11; ATP-sensitive inward rectifier potassium channel 11 [KO:K05004]
83731  Kcnma1; calcium-activated potassium channel subunit alpha-1 isoform 1 [KO:K04936]
84396  Atp1b4; protein ATP1B4 [KO:K01540]
84420  Adcy7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
85240  Plcb2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
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
rno00020  Citrate cycle (TCA cycle)
rno04020  Calcium signaling pathway
KO pathway
ko04911   

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