Integration of energy metabolism (Homo sapiens)

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Description

Many hormones that affect individual physiological processes including the regulation of appetite, absorption, transport, and oxidation of foodstuffs influence energy metabolism pathways. While insulin mediates the storage of excess nutrients, glucagon is involved in the mobilization of energy resources in response to low blood glucose levels, principally by stimulating hepatic glucose output. Small doses of glucagon are sufficient to induce significant glucose elevations. These hormone-driven regulatory pathways enable the body to sense and respond to changed amounts of nutrients in the blood and demands for energy.
Glucagon and Insulin act through various metabolites and enzymes that target specific steps in metabolic pathways for sugar and fatty acids. The processes responsible for the long-term control of fat synthesis and short term control of glycolysis by key metabolic products and enzymes are annotated in this module as six specific pathways:
Pathway 1. Glucagon signalling in metabolic pathways: In response to low blood glucose, pancreatic alpha-cells release glucagon. The binding of glucagon to its receptor results in increased cAMP synthesis, and Protein Kinase A (PKA) activation.
Pathway 2. PKA mediated phosphorylation:PKA phosphorylates key enzymes, e.g., 6-Phosphofructo-2-kinase /Fructose-2,6-bisphosphatase (PF2K-Pase) at serine 36, and regulatory proteins, e.g., Carbohydrate Response Element Binding Protein (ChREBP) at serine 196 and threonine 666.
Insulin mediated responses to high blood glucose will be annotated in future versions of Reactome. In brief, the binding of insulin to its receptor leads to increased protein phosphatase activity and to hydrolysis of cAMP by cAMP phosphodiesterase. These events counteract the regulatory effects of glucagon.
Pathway 3: Insulin stimulates increased synthesis of Xylulose-5-phosphate (Xy-5-P). Activation of the insulin receptor results indirectly in increased Xy-5-P synthesis from Glyceraldehyde-3-phosphate and Fructose-6-phosphate. Xy-5-P, a metabolite of the pentose phosphate pathway, stimulates protein phosphatase PP2A.
Pathway 4: AMP Kinase (AMPK) mediated response to high AMP:ATP ratio: In response to diet with high fat content or low energy levels, the cytosolic AMP:ATP ratio is increased. AMP triggers a complicated cascade of events. In this module we have annotated only the phosphorylation of ChREBP by AMPK at serine 568, which inactivates this transcription factor.
Pathway 5: Dephosphorylation of key metabolic factors by PP2A: Xy-5-P activated PP2A efficiently dephosphorylates phosphorylated PF2K-Pase resulting in the higher output of F-2,6-P2 that enhances PFK activity in the glycolytic pathway. PP2A also dephosphorylates (and thus activates) cytosolic and nuclear ChREBP.
Pathway 6: Transcriptional activation of metabolic genes by ChREBP: Dephosphorylated ChREBP activates the transcription of genes involved in glucose metabolism such as pyruvate kinase, and lipogenic genes such as acetyl-CoA carboxylase, fatty acid synthetase, acyl CoA synthase and glycerol phosphate acyl transferase.
The illustration below summarizes this network of events. Black lines are metabolic reactions, red lines are negative regulatory events, and green lines are positive regulatory events (figure reused with permission from Veech (2003) - Copyright (2003) National Academy of Sciences, U.S.A.). View original pathway at:Reactome.

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Reactome-Converter 
Pathway is converted from Reactome ID: 163685
Reactome-version 
Reactome version: 61
Reactome Author 
Reactome Author: Gopinathrao, G, D'Eustachio, Peter

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Bibliography

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  134. Neuwald AF.; ''Galpha Gbetagamma dissociation may be due to retraction of a buried lysine and disruption of an aromatic cluster by a GTP-sensing Arg Trp pair.''; PubMed
  135. Thomsen J, Kristiansen K, Brunfeldt K, Sundby F.; ''The amino acid sequence of human glucagon.''; PubMed
  136. Ellard S, Flanagan SE, Girard CA, Patch AM, Harries LW, Parrish A, Edghill EL, Mackay DJ, Proks P, Shimomura K, Haberland H, Carson DJ, Shield JP, Hattersley AT, Ashcroft FM.; ''Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects.''; PubMed
  137. Leech CA, Castonguay MA, Habener JF.; ''Expression of adenylyl cyclase subtypes in pancreatic beta-cells.''; PubMed
  138. Verghese GM, Johnson JD, Vasulka C, Haupt DM, Stumpo DJ, Blackshear PJ.; ''Protein kinase C-mediated phosphorylation and calmodulin binding of recombinant myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS-related protein.''; PubMed
  139. Yan L, Figueroa DJ, Austin CP, Liu Y, Bugianesi RM, Slaughter RS, Kaczorowski GJ, Kohler MG.; ''Expression of voltage-gated potassium channels in human and rhesus pancreatic islets.''; PubMed
  140. Holz GG, Leech CA, Heller RS, Castonguay M, Habener JF.; ''cAMP-dependent mobilization of intracellular Ca2+ stores by activation of ryanodine receptors in pancreatic beta-cells. A Ca2+ signaling system stimulated by the insulinotropic hormone glucagon-like peptide-1-(7-37).''; PubMed
  141. Siu FY, He M, de Graaf C, Han GW, Yang D, Zhang Z, Zhou C, Xu Q, Wacker D, Joseph JS, Liu W, Lau J, Cherezov V, Katritch V, Wang MW, Stevens RC.; ''Structure of the human glucagon class B G-protein-coupled receptor.''; PubMed
  142. Peltonen JM, Pihlavisto M, Scheinin M.; ''Subtype-specific stimulation of [35S]GTPgammaS binding by recombinant alpha2-adrenoceptors.''; PubMed
  143. Kang G, Joseph JW, Chepurny OG, Monaco M, Wheeler MB, Bos JL, Schwede F, Genieser HG, Holz GG.; ''Epac-selective cAMP analog 8-pCPT-2'-O-Me-cAMP as a stimulus for Ca2+-induced Ca2+ release and exocytosis in pancreatic beta-cells.''; PubMed
  144. Thorens B.; ''GLUT2 in pancreatic and extra-pancreatic gluco-detection (review).''; PubMed
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History

View all...
CompareRevisionActionTimeUserComment
93853view13:41, 16 August 2017ReactomeTeamreactome version 61
93414view11:23, 9 August 2017ReactomeTeamreactome version 61
86502view09:19, 11 July 2016ReactomeTeamreactome version 56
83173view10:17, 18 November 2015ReactomeTeamVersion54
81543view13:05, 21 August 2015ReactomeTeamVersion53
77011view08:30, 17 July 2014ReactomeTeamFixed remaining interactions
76716view12:08, 16 July 2014ReactomeTeamFixed remaining interactions
76042view10:10, 11 June 2014ReactomeTeamRe-fixing comment source
75751view11:24, 10 June 2014ReactomeTeamReactome 48 Update
75101view14:05, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74748view08:49, 30 April 2014ReactomeTeamReactome46
72912view15:20, 14 December 2013EgonwFixed the Uniprot-TrEMBL data sources.
69896view19:21, 11 July 2013MaintBotupdated to 2013 schema
44859view09:54, 6 October 2011MartijnVanIerselOntology Term : 'energy metabolic pathway' added !
42162view23:28, 4 March 2011MaintBotModified categories
42052view21:53, 4 March 2011MaintBotAutomatic update
39857view05:53, 21 January 2011MaintBotNew pathway

External references

Datanodes

View all...
NameTypeDatabase referenceComment
2xHC-INS(25-54) ProteinP01308 (Uniprot-TrEMBL)
4xHC-INS(90-110) ProteinP01308 (Uniprot-TrEMBL)
6xInsulin:2xZn2+:Ca2+ (docked granule)ComplexR-HSA-386977 (Reactome)
ABCC8 A1185E ProteinQ09428 (Uniprot-TrEMBL)
ABCC8 E382K ProteinQ09428 (Uniprot-TrEMBL)
ABCC8 L213R ProteinQ09428 (Uniprot-TrEMBL)
ABCC8 L582V ProteinQ09428 (Uniprot-TrEMBL)
ABCC8 N72S ProteinQ09428 (Uniprot-TrEMBL)
ABCC8 P132L ProteinQ09428 (Uniprot-TrEMBL)
ABCC8 ProteinQ09428 (Uniprot-TrEMBL)
ABCC8 R1379C ProteinQ09428 (Uniprot-TrEMBL)
ABCC8 mutants (PNDM, TNDM2)ComplexR-HSA-5683210 (Reactome)
ACACB ProteinO00763 (Uniprot-TrEMBL)
ACCComplexR-HSA-200563 (Reactome)
ACLYProteinP53396 (Uniprot-TrEMBL)
ADCY1 ProteinQ08828 (Uniprot-TrEMBL)
ADCY2 ProteinQ08462 (Uniprot-TrEMBL)
ADCY3 ProteinO60266 (Uniprot-TrEMBL)
ADCY4 ProteinQ8NFM4 (Uniprot-TrEMBL)
ADCY5 ProteinO95622 (Uniprot-TrEMBL)
ADCY5,6,8:G-alpha(s):GTPComplexR-HSA-422306 (Reactome)
ADCY6 ProteinO43306 (Uniprot-TrEMBL)
ADCY7 ProteinP51828 (Uniprot-TrEMBL)
ADCY8 ProteinP40145 (Uniprot-TrEMBL)
ADCY9 ProteinO60503 (Uniprot-TrEMBL)
ADIPOQ ProteinQ15848 (Uniprot-TrEMBL)
ADIPOQ trimer:ADIPOR dimersComplexR-HSA-8848653 (Reactome)
ADIPOQ trimerComplexR-HSA-8849004 (Reactome)
ADIPOR dimersComplexR-HSA-8848546 (Reactome)
ADIPOR1 ProteinQ96A54 (Uniprot-TrEMBL)
ADIPOR2 ProteinQ86V24 (Uniprot-TrEMBL)
ADP MetaboliteCHEBI:16761 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
ADR MetaboliteCHEBI:28918 (ChEBI)
ADR, NAdComplexR-ALL-390627 (Reactome)
ADRA2A ProteinP08913 (Uniprot-TrEMBL)
ADRA2A,C:ADR,NAdComplexR-HSA-400090 (Reactome)
ADRA2A,CComplexR-HSA-400086 (Reactome)
ADRA2C ProteinP18825 (Uniprot-TrEMBL)
AGPAT1ProteinQ99943 (Uniprot-TrEMBL)
AHCYL1 ProteinO43865 (Uniprot-TrEMBL)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerComplexR-HSA-5226920 (Reactome)
AKAP5 ProteinP24588 (Uniprot-TrEMBL)
AMP MetaboliteCHEBI:16027 (ChEBI)
AMPMetaboliteCHEBI:16027 (ChEBI)
AMPK heterotrimer:AMPComplexR-HSA-163747 (Reactome)
AMPK heterotrimer (inactive)ComplexR-HSA-163679 (Reactome)
ARL2 ProteinP36404 (Uniprot-TrEMBL)
ARL2:GTP:ARL2BP:SLC25A4ComplexR-HSA-5250205 (Reactome)
ARL2:GTP:ARL2BPComplexR-HSA-5250201 (Reactome)
ARL2:GTP:ARL2BPComplexR-HSA-5250221 (Reactome)
ARL2:GTPComplexR-HSA-5250197 (Reactome)
ARL2BP ProteinQ9Y2Y0 (Uniprot-TrEMBL)
ARL2BPProteinQ9Y2Y0 (Uniprot-TrEMBL)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
AcCho MetaboliteCHEBI:15355 (ChEBI)
AcChoMetaboliteCHEBI:15355 (ChEBI)
Activated AMPK heterotrimerComplexR-HSA-163736 (Reactome)
Adenylate Cyclase V or VIComplexR-HSA-446432 (Reactome)
Adenylate cyclase (Mg2+ cofactor)ComplexR-HSA-170665 (Reactome)
Adenylate cyclase

type V or VI: G-protein beta

gamma Complex
ComplexR-HSA-400038 (Reactome)
Adenylyl cyclase

(pancreatic beta

cell)
ComplexR-HSA-446658 (Reactome)
ArgN-GCG(98-127) ProteinP01275 (Uniprot-TrEMBL) The amide group at the C-terminus is not necessary for biological activity.
Btn-ACACA ProteinQ13085 (Uniprot-TrEMBL)
CACNA1A ProteinO00555 (Uniprot-TrEMBL)
CACNA1C ProteinQ13936 (Uniprot-TrEMBL)
CACNA1D ProteinQ01668 (Uniprot-TrEMBL)
CACNA1E ProteinQ15878 (Uniprot-TrEMBL)
CACNA2D2(19-1150) ProteinQ9NY47 (Uniprot-TrEMBL)
CACNB2 ProteinQ08289 (Uniprot-TrEMBL)
CACNB3 ProteinP54284 (Uniprot-TrEMBL)
CHRM3 ProteinP20309 (Uniprot-TrEMBL)
CHRM3ProteinP20309 (Uniprot-TrEMBL)
Ca-channel (closed)ComplexR-HSA-111877 (Reactome)
Ca-channel (open)ComplexR-HSA-111873 (Reactome)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
ChREBP:MLXComplexR-HSA-163700 (Reactome)
Core SNARE ComplexComplexR-HSA-387383 (Reactome)
DAG MetaboliteCHEBI:17815 (ChEBI)
DAGMetaboliteCHEBI:17815 (ChEBI)
DDCX MetaboliteCHEBI:30805 (ChEBI)
E4PMetaboliteCHEBI:16897 (ChEBI)
FASNProteinP49327 (Uniprot-TrEMBL)
FFAR1 ProteinO14842 (Uniprot-TrEMBL)
FFAR1 ligandsComplexR-ALL-400427 (Reactome)
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.
FFAR1ProteinO14842 (Uniprot-TrEMBL)
Fatty acidsR-NUL-163730 (Reactome)
Fru(6)PMetaboliteCHEBI:15946 (ChEBI)
G-alpha(i,o):GDP:G beta:G gammaComplexR-HSA-400088 (Reactome)
G-alpha(i,o):GTP:G-beta:G-gammaComplexR-HSA-400031 (Reactome)
G-alpha(i,o):GTPComplexR-HSA-400076 (Reactome)
G-alpha(q) 11,14,15,Q:GTPComplexR-HSA-400008 (Reactome)
G-alpha(q)11,14,15,Q:G-beta:G-gammaComplexR-HSA-399987 (Reactome)
G-alpha(q)11,14,15,Q:GDP:G-beta:G-gammaComplexR-HSA-399992 (Reactome)
G-alpha(s):GTP:G-beta:G-gammaComplexR-HSA-422322 (Reactome)
G-beta:G-gamma (candidates)ComplexR-HSA-400034 (Reactome)
G-beta:G-gamma dimerComplexR-HSA-164386 (Reactome)
G-beta:G-gammaComplexR-HSA-399993 (Reactome)
G-protein alpha (s):GTPComplexR-HSA-164358 (Reactome)
G-protein with G(s) alpha:GDPComplexR-HSA-164384 (Reactome)
GA3PMetaboliteCHEBI:29052 (ChEBI)
GCG(53-81) ProteinP01275 (Uniprot-TrEMBL)
GCG(53-81)ProteinP01275 (Uniprot-TrEMBL)
GCGR ProteinP47871 (Uniprot-TrEMBL)
GCGR:GCG(53-81)ComplexR-HSA-163627 (Reactome)
GCGRProteinP47871 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GLP-1 (7-37) ProteinP01275 (Uniprot-TrEMBL)
GLP-1:GLP-1R:Heterotrimeric G(s):GDPComplexR-HSA-422310 (Reactome)
GLP-1:GLP-1R:Heterotrimeric G(s):GTPComplexR-HSA-422311 (Reactome)
GLP-1R:Heterotrimeric G(s):GDPComplexR-HSA-422314 (Reactome)
GLP1R ProteinP43220 (Uniprot-TrEMBL)
GLUT1,2ComplexR-HSA-500048 (Reactome) Human pancreatic beta cells contain GLUT1 and GLUT2 transporters, with GLUT1 predominant. Rodent beta cells predominantly contain GLUT2, which may account for differences observed in the toxicity of streptozotocin.
GNA11 ProteinP29992 (Uniprot-TrEMBL)
GNA14 ProteinO95837 (Uniprot-TrEMBL)
GNA15 ProteinP30679 (Uniprot-TrEMBL)
GNAI1 ProteinP63096 (Uniprot-TrEMBL)
GNAI2 ProteinP04899 (Uniprot-TrEMBL)
GNAQ ProteinP50148 (Uniprot-TrEMBL)
GNAS1 ProteinQ5JWF2 (Uniprot-TrEMBL)
GNAS2 ProteinP63092 (Uniprot-TrEMBL)
GNB1 ProteinP62873 (Uniprot-TrEMBL)
GNB2 ProteinP62879 (Uniprot-TrEMBL)
GNB3 ProteinP16520 (Uniprot-TrEMBL)
GNB4 ProteinQ9HAV0 (Uniprot-TrEMBL)
GNB5 ProteinO14775 (Uniprot-TrEMBL)
GNG10 ProteinP50151 (Uniprot-TrEMBL)
GNG11 ProteinP61952 (Uniprot-TrEMBL)
GNG12 ProteinQ9UBI6 (Uniprot-TrEMBL)
GNG13 ProteinQ9P2W3 (Uniprot-TrEMBL)
GNG2 ProteinP59768 (Uniprot-TrEMBL)
GNG3 ProteinP63215 (Uniprot-TrEMBL)
GNG4 ProteinP50150 (Uniprot-TrEMBL)
GNG5 ProteinP63218 (Uniprot-TrEMBL)
GNG7 ProteinO60262 (Uniprot-TrEMBL)
GNG8 ProteinQ9UK08 (Uniprot-TrEMBL)
GNGT1 ProteinP63211 (Uniprot-TrEMBL)
GNGT2 ProteinO14610 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
GlcMetaboliteCHEBI:17925 (ChEBI)
Gs-activated adenylate cyclaseComplexR-HSA-163622 (Reactome)
Guanine nucleotide-binding protein beta subunit R-HSA-114545 (Reactome)
Guanine nucleotide-binding protein gamma subunit R-HSA-114546 (Reactome)
H2OMetaboliteCHEBI:15377 (ChEBI)
I(1,4,5)P3 MetaboliteCHEBI:16595 (ChEBI)
I(1,4,5)P3MetaboliteCHEBI:16595 (ChEBI)
INS(57-87)ProteinP01308 (Uniprot-TrEMBL)
IP3 receptor homotetramerComplexR-HSA-169686 (Reactome)
IQGAP1 ProteinP46940 (Uniprot-TrEMBL)
ITPR1 ProteinQ14643 (Uniprot-TrEMBL)
ITPR2 ProteinQ14571 (Uniprot-TrEMBL)
ITPR3 ProteinQ14573 (Uniprot-TrEMBL)
ITPR:I(1,4,5)P3 tetramerComplexR-HSA-169696 (Reactome)
Inactive

PP2A-ABdeltaC

complex
ComplexR-HSA-165992 (Reactome)
InsulinComplexR-HSA-74674 (Reactome)
K+MetaboliteCHEBI:29103 (ChEBI)
KCNB1 ProteinQ14721 (Uniprot-TrEMBL)
KCNC2 ProteinQ96PR1 (Uniprot-TrEMBL)
KCNG2 ProteinQ9UJ96 (Uniprot-TrEMBL)
KCNJ11 tetramer:ABCC8:Mg2+:ADP tetramerComplexR-HSA-265734 (Reactome)
KCNJ11 ProteinQ14654 (Uniprot-TrEMBL)
KCNJ11:ATP

tetramer:ABCC8

tetramer
ComplexR-HSA-265746 (Reactome)
KCNS3 ProteinQ9BQ31 (Uniprot-TrEMBL)
MARCKSProteinP29966 (Uniprot-TrEMBL)
MLX ProteinQ9UH92 (Uniprot-TrEMBL)
MLXIPL ProteinQ9NP71 (Uniprot-TrEMBL)
MLXIPLProteinQ9NP71 (Uniprot-TrEMBL)
MLXProteinQ9UH92 (Uniprot-TrEMBL)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
Mg2+:ADPComplexR-ALL-6790050 (Reactome)
Muscarinic

Acetylcholine Receptor M3:Acetylcholine

Complex
ComplexR-HSA-400013 (Reactome)
NAD+ MetaboliteCHEBI:15846 (ChEBI)
NAd MetaboliteCHEBI:18357 (ChEBI)
OLEA MetaboliteCHEBI:16196 (ChEBI)
PALM MetaboliteCHEBI:15756 (ChEBI)
PFKFB1 ProteinP16118 (Uniprot-TrEMBL)
PFKFB1 dimerComplexR-HSA-71786 (Reactome)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PKA catalytic subunitComplexR-HSA-111920 (Reactome)
PKA tetramerComplexR-HSA-111922 (Reactome)
PKA:AKAP79:IQGAP1 ComplexComplexR-HSA-381635 (Reactome)
PKLR-1ProteinP30613-1 (Uniprot-TrEMBL)
PLC beta1,2,3:G-alpha(q):GTPComplexR-HSA-400011 (Reactome)
PLC beta1,2,3ComplexR-HSA-400005 (Reactome) Pancreatic beta cells contain PLC Beta 1, PLC Beta 2, and PLC Beta 3. It is unknown which PLC or combination of PLC's are activated in response to G(q).
PLCB1 ProteinQ9NQ66 (Uniprot-TrEMBL)
PLCB2 ProteinQ00722 (Uniprot-TrEMBL)
PLCB3 ProteinQ01970 (Uniprot-TrEMBL)
PP2A-ABdeltaC complexComplexR-HSA-165961 (Reactome)
PP2A-ABdeltaC complexComplexR-HSA-165970 (Reactome)
PPP2CA ProteinP67775 (Uniprot-TrEMBL)
PPP2CB ProteinP62714 (Uniprot-TrEMBL)
PPP2R1A ProteinP30153 (Uniprot-TrEMBL)
PPP2R1B ProteinP30154 (Uniprot-TrEMBL)
PPP2R5D ProteinQ14738 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKAA2 ProteinP54646 (Uniprot-TrEMBL)
PRKAB2 ProteinO43741 (Uniprot-TrEMBL)
PRKACA ProteinP17612 (Uniprot-TrEMBL)
PRKACB ProteinP22694 (Uniprot-TrEMBL)
PRKACG ProteinP22612 (Uniprot-TrEMBL)
PRKAG2 ProteinQ9UGJ0 (Uniprot-TrEMBL)
PRKAR1A ProteinP10644 (Uniprot-TrEMBL)
PRKAR1B ProteinP31321 (Uniprot-TrEMBL)
PRKAR2A ProteinP13861 (Uniprot-TrEMBL)
PRKAR2B ProteinP31323 (Uniprot-TrEMBL)
PRKCA ProteinP17252 (Uniprot-TrEMBL)
PRKCAProteinP17252 (Uniprot-TrEMBL)
Pentadecanoic acid MetaboliteCHEBI:42504 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
Potassium

voltage-gated channels (beta

cell, closed)
ComplexR-HSA-381655 (Reactome) Human pancreatic beta cells contain Kv2.1, Kv3.2, Kv6.2, and Kv9.3 voltage gated potassium channels. The channels are closed in a resting beta and channels open in response to depolarization. Open channels counteract the effect of closed ATP-gated potassium channels and thereby end stimulation of insulin secretion .
Potassium

voltage-gated channels (beta

cell, open)
ComplexR-HSA-381640 (Reactome) Human pancreatic beta cells contain Kv2.1, Kv3.2, Kv6.2, and Kv9.3 voltage gated potassium channels. The channels are closed in a resting beta and channels open in response to depolarization. Open channels counteract the effect of closed ATP-gated potassium channels and thereby end stimulation of insulin secretion .
Potassium Channel,

closed (pancreatic

beta cell)
R-HSA-446513 (Reactome)
Potassium Channel,

open (pancreatic

beta cell)
R-HSA-446505 (Reactome)
Protein Kinase A, catalytic subunitsComplexR-HSA-111917 (Reactome)
Protein Kinase C, alpha type: DAGComplexR-HSA-422275 (Reactome)
R5PMetaboliteCHEBI:78679 (ChEBI)
RAP1A ProteinP62834 (Uniprot-TrEMBL)
RAP1A:GDPComplexR-HSA-5252143 (Reactome)
RAP1A:GTPComplexR-HSA-5252145 (Reactome)
RAPGEF3 ProteinO95398 (Uniprot-TrEMBL)
RAPGEF3:cAMP complexComplexR-HSA-381702 (Reactome)
RAPGEF3ProteinO95398 (Uniprot-TrEMBL)
RAPGEF4 ProteinQ8WZA2 (Uniprot-TrEMBL)
RAPGEF4:cAMP ComplexComplexR-HSA-381680 (Reactome)
RAPGEF4ProteinQ8WZA2 (Uniprot-TrEMBL)
RGZ MetaboliteCHEBI:50122 (ChEBI)
SH7PMetaboliteCHEBI:15721 (ChEBI)
SLC25A4 ProteinP12235 (Uniprot-TrEMBL)
SLC25A4ProteinP12235 (Uniprot-TrEMBL)
SLC25A5 ProteinP05141 (Uniprot-TrEMBL)
SLC25A5,6 dimersComplexR-HSA-187453 (Reactome)
SLC25A6 ProteinP12236 (Uniprot-TrEMBL)
SLC2A1 ProteinP11166 (Uniprot-TrEMBL)
SLC2A2 ProteinP11168 (Uniprot-TrEMBL)
SNAP25 ProteinP60880 (Uniprot-TrEMBL)
SNAP25ProteinP60880 (Uniprot-TrEMBL)
SNARE ComplexComplexR-HSA-265202 (Reactome)
STK11ProteinQ15831 (Uniprot-TrEMBL)
STX1A ProteinQ16623 (Uniprot-TrEMBL)
STX1A:STXBP1ComplexR-HSA-265191 (Reactome)
STXBP1 ProteinP61764 (Uniprot-TrEMBL)
STXBP1ProteinP61764 (Uniprot-TrEMBL)
SYT5 ProteinO00445 (Uniprot-TrEMBL)
SYT5ProteinO00445 (Uniprot-TrEMBL)
TALDO1 ProteinP37837 (Uniprot-TrEMBL)
TALDO1 dimerComplexR-HSA-5659970 (Reactome)
TALDO1ProteinP37837 (Uniprot-TrEMBL)
TKT ProteinP29401 (Uniprot-TrEMBL)
TKT dimerComplexR-HSA-71322 (Reactome)
ThDP MetaboliteCHEBI:9532 (ChEBI)
VAMP2 ProteinP63027 (Uniprot-TrEMBL)
VAMP2ProteinP63027 (Uniprot-TrEMBL)
Voltage-gated

Calcium Channels (pancreatic beta

cell)
ComplexR-HSA-265569 (Reactome)
Voltage-gated

Calcium Channels

Type Cav1 (closed)
ComplexR-HSA-400095 (Reactome)
Voltage-gated

Calcium Channels

Type Cav1 (open)
ComplexR-HSA-400055 (Reactome)
XY5PMetaboliteCHEBI:57737 (ChEBI)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
Zn2+MetaboliteCHEBI:29105 (ChEBI)
cAMP MetaboliteCHEBI:17489 (ChEBI)
cAMP:PKA regulatory subunitComplexR-HSA-111923 (Reactome)
cAMP:PKA:AKAP79:IQGAP1 ComplexComplexR-HSA-381615 (Reactome)
cAMPMetaboliteCHEBI:17489 (ChEBI)
mature GLP-1ComplexR-HSA-381662 (Reactome)
p-4S-MARCKSProteinP29966 (Uniprot-TrEMBL)
p-S196,T666-MLXIPLProteinQ9NP71 (Uniprot-TrEMBL)
p-S33-PFKFB1 ProteinP16118 (Uniprot-TrEMBL)
p-S568-MLXIPLProteinQ9NP71 (Uniprot-TrEMBL)
p-T172-PRKAA2 ProteinP54646 (Uniprot-TrEMBL)
p-T666-MLXIPLProteinQ9NP71 (Uniprot-TrEMBL)
phosphoPFKFB1 dimerComplexR-HSA-163745 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
6xInsulin:2xZn2+:Ca2+ (docked granule)R-HSA-265166 (Reactome)
ABCC8 mutants (PNDM, TNDM2)mim-catalysisR-HSA-5683209 (Reactome)
ACCArrowR-HSA-163743 (Reactome)
ACLYArrowR-HSA-163770 (Reactome)
ADCY5,6,8:G-alpha(s):GTPArrowR-HSA-381704 (Reactome)
ADCY5,6,8:G-alpha(s):GTPmim-catalysisR-HSA-381607 (Reactome)
ADIPOQ trimer:ADIPOR dimersArrowR-HSA-8848663 (Reactome)
ADIPOQ trimerR-HSA-8848663 (Reactome)
ADIPOR dimersR-HSA-8848663 (Reactome)
ADPArrowR-HSA-163215 (Reactome)
ADPArrowR-HSA-163672 (Reactome)
ADPArrowR-HSA-163676 (Reactome)
ADPArrowR-HSA-163691 (Reactome)
ADPArrowR-HSA-163773 (Reactome)
ADPArrowR-HSA-164151 (Reactome)
ADPArrowR-HSA-399978 (Reactome)
ADPArrowR-HSA-5672027 (Reactome)
ADPR-HSA-163215 (Reactome)
ADPR-HSA-5672027 (Reactome)
ADR, NAdR-HSA-400071 (Reactome)
ADRA2A,C:ADR,NAdArrowR-HSA-400071 (Reactome)
ADRA2A,C:ADR,NAdArrowR-HSA-400092 (Reactome)
ADRA2A,CR-HSA-400071 (Reactome)
AGPAT1ArrowR-HSA-163748 (Reactome)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerTBarR-HSA-169683 (Reactome)
AMPK heterotrimer:AMPArrowR-HSA-163664 (Reactome)
AMPK heterotrimer:AMPR-HSA-164151 (Reactome)
AMPK heterotrimer (inactive)R-HSA-163664 (Reactome)
AMPR-HSA-163664 (Reactome)
AMPTBarR-HSA-163691 (Reactome)
ARL2:GTP:ARL2BP:SLC25A4ArrowR-HSA-5250209 (Reactome)
ARL2:GTP:ARL2BP:SLC25A4mim-catalysisR-HSA-5672027 (Reactome)
ARL2:GTP:ARL2BPArrowR-HSA-5250210 (Reactome)
ARL2:GTP:ARL2BPArrowR-HSA-5250217 (Reactome)
ARL2:GTP:ARL2BPR-HSA-5250209 (Reactome)
ARL2:GTP:ARL2BPR-HSA-5250210 (Reactome)
ARL2:GTPR-HSA-5250217 (Reactome)
ARL2BPR-HSA-5250217 (Reactome)
ATPArrowR-HSA-163215 (Reactome)
ATPArrowR-HSA-5672027 (Reactome)
ATPR-HSA-163215 (Reactome)
ATPR-HSA-163672 (Reactome)
ATPR-HSA-163676 (Reactome)
ATPR-HSA-163691 (Reactome)
ATPR-HSA-163773 (Reactome)
ATPR-HSA-164151 (Reactome)
ATPR-HSA-164377 (Reactome)
ATPR-HSA-265682 (Reactome)
ATPR-HSA-381607 (Reactome)
ATPR-HSA-399978 (Reactome)
ATPR-HSA-5672027 (Reactome)
AcChoR-HSA-400012 (Reactome)
Activated AMPK heterotrimerArrowR-HSA-164151 (Reactome)
Activated AMPK heterotrimermim-catalysisR-HSA-163691 (Reactome)
Adenylate Cyclase V or VIR-HSA-400097 (Reactome)
Adenylate cyclase (Mg2+ cofactor)R-HSA-163617 (Reactome)
Adenylate cyclase

type V or VI: G-protein beta

gamma Complex
ArrowR-HSA-400097 (Reactome)
Adenylyl cyclase

(pancreatic beta

cell)
R-HSA-381704 (Reactome)
ArrowR-HSA-163691 (Reactome)
ArrowR-HSA-265682 (Reactome)
CHRM3R-HSA-400012 (Reactome)
Ca-channel (closed)R-HSA-381644 (Reactome)
Ca-channel (open)ArrowR-HSA-381644 (Reactome)
Ca2+ArrowR-HSA-169683 (Reactome)
Ca2+ArrowR-HSA-265166 (Reactome)
Ca2+ArrowR-HSA-265645 (Reactome)
Ca2+R-HSA-169683 (Reactome)
Ca2+R-HSA-265166 (Reactome)
Ca2+R-HSA-265645 (Reactome)
ChREBP:MLXArrowR-HSA-163666 (Reactome)
ChREBP:MLXArrowR-HSA-163669 (Reactome)
ChREBP:MLXArrowR-HSA-163733 (Reactome)
ChREBP:MLXArrowR-HSA-163743 (Reactome)
ChREBP:MLXArrowR-HSA-163748 (Reactome)
ChREBP:MLXArrowR-HSA-163770 (Reactome)
Core SNARE Complexmim-catalysisR-HSA-265166 (Reactome)
DAGArrowR-HSA-399998 (Reactome)
DAGR-HSA-400015 (Reactome)
E4PArrowR-HSA-163751 (Reactome)
E4PR-HSA-163764 (Reactome)
FASNArrowR-HSA-163733 (Reactome)
FFAR1 ligandsR-HSA-400434 (Reactome)
FFAR1:FFAR1 ligandsArrowR-HSA-400434 (Reactome)
FFAR1:FFAR1 ligandsmim-catalysisR-HSA-416530 (Reactome)
FFAR1R-HSA-400434 (Reactome)
Fatty acidsArrowR-HSA-163691 (Reactome)
Fru(6)PR-HSA-163751 (Reactome)
Fru(6)PR-HSA-163764 (Reactome)
G-alpha(i,o):GDP:G beta:G gammaR-HSA-400092 (Reactome)
G-alpha(i,o):GTP:G-beta:G-gammaArrowR-HSA-400092 (Reactome)
G-alpha(i,o):GTP:G-beta:G-gammaR-HSA-400037 (Reactome)
G-alpha(i,o):GTPArrowR-HSA-400037 (Reactome)
G-alpha(i,o):GTPArrowR-HSA-400063 (Reactome)
G-alpha(i,o):GTPTBarR-HSA-265166 (Reactome)
G-alpha(q) 11,14,15,Q:GTPArrowR-HSA-400027 (Reactome)
G-alpha(q) 11,14,15,Q:GTPR-HSA-400023 (Reactome)
G-alpha(q)11,14,15,Q:G-beta:G-gammaArrowR-HSA-399995 (Reactome)
G-alpha(q)11,14,15,Q:G-beta:G-gammaArrowR-HSA-416530 (Reactome)
G-alpha(q)11,14,15,Q:G-beta:G-gammaR-HSA-400027 (Reactome)
G-alpha(q)11,14,15,Q:GDP:G-beta:G-gammaR-HSA-399995 (Reactome)
G-alpha(q)11,14,15,Q:GDP:G-beta:G-gammaR-HSA-416530 (Reactome)
G-alpha(s):GTP:G-beta:G-gammaR-HSA-422320 (Reactome)
G-beta:G-gamma (candidates)ArrowR-HSA-400037 (Reactome)
G-beta:G-gamma (candidates)ArrowR-HSA-400046 (Reactome)
G-beta:G-gamma (candidates)ArrowR-HSA-422320 (Reactome)
G-beta:G-gamma (candidates)R-HSA-400097 (Reactome)
G-beta:G-gamma dimerArrowR-HSA-825631 (Reactome)
G-beta:G-gammaArrowR-HSA-400027 (Reactome)
G-protein alpha (s):GTPArrowR-HSA-422320 (Reactome)
G-protein alpha (s):GTPArrowR-HSA-825631 (Reactome)
G-protein alpha (s):GTPR-HSA-163617 (Reactome)
G-protein alpha (s):GTPR-HSA-381704 (Reactome)
G-protein with G(s) alpha:GDPR-HSA-825631 (Reactome)
GA3PArrowR-HSA-163764 (Reactome)
GA3PR-HSA-163741 (Reactome)
GA3PR-HSA-163751 (Reactome)
GCG(53-81)R-HSA-163625 (Reactome)
GCGR:GCG(53-81)ArrowR-HSA-163625 (Reactome)
GCGR:GCG(53-81)mim-catalysisR-HSA-825631 (Reactome)
GCGRR-HSA-163625 (Reactome)
GDPArrowR-HSA-381706 (Reactome)
GDPArrowR-HSA-381727 (Reactome)
GDPArrowR-HSA-399995 (Reactome)
GDPArrowR-HSA-400092 (Reactome)
GDPArrowR-HSA-416530 (Reactome)
GDPArrowR-HSA-825631 (Reactome)
GLP-1:GLP-1R:Heterotrimeric G(s):GDPArrowR-HSA-381612 (Reactome)
GLP-1:GLP-1R:Heterotrimeric G(s):GDPR-HSA-381706 (Reactome)
GLP-1:GLP-1R:Heterotrimeric G(s):GTPArrowR-HSA-381706 (Reactome)
GLP-1R:Heterotrimeric G(s):GDPR-HSA-381612 (Reactome)
GLUT1,2mim-catalysisR-HSA-499981 (Reactome)
GTPR-HSA-381706 (Reactome)
GTPR-HSA-381727 (Reactome)
GTPR-HSA-399995 (Reactome)
GTPR-HSA-400092 (Reactome)
GTPR-HSA-416530 (Reactome)
GTPR-HSA-825631 (Reactome)
GlcArrowR-HSA-499981 (Reactome)
GlcR-HSA-499981 (Reactome)
Gs-activated adenylate cyclaseArrowR-HSA-163617 (Reactome)
Gs-activated adenylate cyclasemim-catalysisR-HSA-164377 (Reactome)
H2OR-HSA-163750 (Reactome)
H2OR-HSA-399998 (Reactome)
I(1,4,5)P3ArrowR-HSA-169683 (Reactome)
I(1,4,5)P3ArrowR-HSA-399998 (Reactome)
I(1,4,5)P3R-HSA-169680 (Reactome)
INS(57-87)ArrowR-HSA-265166 (Reactome)
INS(57-87)R-HSA-265166 (Reactome)
IP3 receptor homotetramerR-HSA-169680 (Reactome)
ITPR:I(1,4,5)P3 tetramerArrowR-HSA-169680 (Reactome)
ITPR:I(1,4,5)P3 tetramermim-catalysisR-HSA-169683 (Reactome)
Inactive

PP2A-ABdeltaC

complex
R-HSA-163769 (Reactome)
InsulinArrowR-HSA-265166 (Reactome)
K+ArrowR-HSA-5683209 (Reactome)
K+R-HSA-5683209 (Reactome)
KCNJ11 tetramer:ABCC8:Mg2+:ADP tetramerR-HSA-265682 (Reactome)
KCNJ11 tetramer:ABCC8:Mg2+:ADP tetramermim-catalysisR-HSA-265682 (Reactome)
KCNJ11:ATP

tetramer:ABCC8

tetramer
ArrowR-HSA-265682 (Reactome)
MARCKSR-HSA-399978 (Reactome)
MLXIPLArrowR-HSA-163688 (Reactome)
MLXIPLArrowR-HSA-164056 (Reactome)
MLXIPLR-HSA-163666 (Reactome)
MLXIPLR-HSA-163672 (Reactome)
MLXIPLR-HSA-163691 (Reactome)
MLXR-HSA-163666 (Reactome)
Mg2+:ADPArrowR-HSA-265682 (Reactome)
Muscarinic

Acetylcholine Receptor M3:Acetylcholine

Complex
ArrowR-HSA-400012 (Reactome)
Muscarinic

Acetylcholine Receptor M3:Acetylcholine

Complex
mim-catalysisR-HSA-399995 (Reactome)
PFKFB1 dimerArrowR-HSA-163750 (Reactome)
PFKFB1 dimerR-HSA-163773 (Reactome)
PI(4,5)P2R-HSA-399998 (Reactome)
PKA catalytic subunitArrowR-HSA-111925 (Reactome)
PKA catalytic subunitArrowR-HSA-381644 (Reactome)
PKA catalytic subunitArrowR-HSA-381707 (Reactome)
PKA catalytic subunitArrowR-HSA-381713 (Reactome)
PKA catalytic subunitmim-catalysisR-HSA-163676 (Reactome)
PKA catalytic subunitmim-catalysisR-HSA-163773 (Reactome)
PKA tetramerR-HSA-111925 (Reactome)
PKA:AKAP79:IQGAP1 ComplexR-HSA-381707 (Reactome)
PKLR-1ArrowR-HSA-163669 (Reactome)
PLC beta1,2,3:G-alpha(q):GTPArrowR-HSA-400023 (Reactome)
PLC beta1,2,3:G-alpha(q):GTPmim-catalysisR-HSA-399998 (Reactome)
PLC beta1,2,3R-HSA-400023 (Reactome)
PP2A-ABdeltaC complexArrowR-HSA-163769 (Reactome)
PP2A-ABdeltaC complexmim-catalysisR-HSA-163688 (Reactome)
PP2A-ABdeltaC complexmim-catalysisR-HSA-163689 (Reactome)
PP2A-ABdeltaC complexmim-catalysisR-HSA-163750 (Reactome)
PP2A-ABdeltaC complexmim-catalysisR-HSA-164056 (Reactome)
PPiArrowR-HSA-164377 (Reactome)
PPiArrowR-HSA-381607 (Reactome)
PRKCAR-HSA-400015 (Reactome)
PiArrowR-HSA-163688 (Reactome)
PiArrowR-HSA-163689 (Reactome)
PiArrowR-HSA-163750 (Reactome)
PiArrowR-HSA-164056 (Reactome)
Potassium

voltage-gated channels (beta

cell, closed)
ArrowR-HSA-381713 (Reactome)
Potassium

voltage-gated channels (beta

cell, open)
R-HSA-381713 (Reactome)
Potassium Channel,

closed (pancreatic

beta cell)
R-HSA-400063 (Reactome)
Potassium Channel,

open (pancreatic

beta cell)
ArrowR-HSA-400063 (Reactome)
Protein Kinase A, catalytic subunitsmim-catalysisR-HSA-163672 (Reactome)
Protein Kinase C, alpha type: DAGArrowR-HSA-400015 (Reactome)
Protein Kinase C, alpha type: DAGmim-catalysisR-HSA-399978 (Reactome)
R-HSA-111925 (Reactome) The four protein kinase A (PKA) regulatory subunit isoforms differ in their tissue specificity and functional characteristics. The specific isoform activated in response to glucagon signalling is not known. The PKA kinase is a tetramer of two regulatory and two catalytic. The regulatory subunits block the catalytic subunits. Binding of cAMP to the regulatory subunit leads to the dissociation of the tetramer into two active dimers made up of a regulatory and a catalytic subunit.
R-HSA-163215 (Reactome) A family of antiport, ATP-ADP translocases (SLC25A4,5,6), preferentially export ATP from the matrix while importing ADP from the cytosol, thereby maintaining a high ADP:ATP ratio in the matrix. When there are increased energy demands on the body, such as under heavy exercise, cytosolic ADP rises and is exchanged with mitochondrial matrix ATP via the transmembrane ADP:ATP translocase. Increased ADP causes the proton-motive force to be discharged and protons enter via ATPase, thereby regenerating the ATP pool.
There are 3 isoforms of translocases in humans; isoform 1 (SLC25A4) is the heart/skeletal muscle form, isoform 2 (SLC25A5) is the fibroblast form and isoform 3 (SLC25A6) is the liver form. All isoforms exist as homodimers.
R-HSA-163617 (Reactome) G(s)-alpha:GTP binds to inactive adenylate cyclase, causing a conformational transition in adenylate cyclase exposing the catalytic site and activating it.
R-HSA-163625 (Reactome) Glucagon (Thomsen J et al, 1972) is an important peptide hormone produced by the pancreas. It is released when the glucose level in the blood is low (hypoglycemia), causing the liver to convert stored glycogen into glucose and release it into the bloodstream. The action of glucagon is thus opposite to that of insulin. Glucagon, together with glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2), are peptide hormones encoded by a single common prohormone precursor, proglucagon.The glucagon receptor (Lok S et al, 1994) plays a central role in regulating the level of blood glucose by controlling the rate of hepatic glucose production and insulin secretion. The activity of this receptor is mediated by coupling to Gs and q, which stimulate adenylyl cyclase and a phosphatidylinositol-calcium second messenger system respectively.
R-HSA-163664 (Reactome) At the beginning of this reaction, 1 molecule of 'AMPK heterotrimer (inactive)', and 1 molecule of 'AMP' are present. At the end of this reaction, 1 molecule of 'AMPK heterotrimer:AMP' is present.

This reaction takes place in the 'nucleus'.

R-HSA-163666 (Reactome) At the beginning of this reaction, 1 molecule of 'ChREBP protein', and 1 molecule of 'MLX protein' are present. At the end of this reaction, 1 molecule of 'ChREBP:MLX' is present.

This reaction takes place in the 'nucleus'.

R-HSA-163669 (Reactome) At the end of this reaction, 1 molecule of 'pyruvate kinase, liver and RBC' is present.

This reaction takes place in the 'nucleus'.

R-HSA-163670 (Reactome) ChREBP (Carbohydrate Response Element Binding Protein) doubly phosphorylated at threonine 666 and serine 196 is inactive and is localized to the cytosol. Removal of the phosphate residue at serine 196 allows ChREBP to translocate between the cytosol and the nucleoplasm (Sakiyama et al. 2008).
R-HSA-163672 (Reactome) In its active (unphosphorylated) form, ChREBP (Carbohydrate Response Element Binding Protein) binds so-called ChRE (Carbohydrate Response Element) DNA sequence motifs found upstream of several genes involved in glucose utilization and lipid synthesis, activating transcription of these genes. Phosphorylation of ChREBP at threonine residue 666 by PKA (protein kinase A) blocks this binding activity, and thus has the effect of down-regulating expression of the target genes. ChREBP phosphorylation can be reversed by the action of protein phosphatase 2A (PP2A).
R-HSA-163676 (Reactome) Phosphorylation of ChREBP (Carbohydrate Response Element Binding Protein) at serine 196 by PKA inhibits its nuclear translocation. This reaction has been studied in detail using mouse proteins (Kawaguchi et al. 2001); the human version of the reaction is inferred from these studies.
R-HSA-163688 (Reactome) At the beginning of this reaction, 1 molecule of 'pChREBP (Thr 666)' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'ChREBP protein' are present.

This reaction takes place in the 'nucleus' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.

R-HSA-163689 (Reactome) At the beginning of this reaction, 1 molecule of 'pChREBP (Ser 196, Thr 666)' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'pChREBP (Thr 666)' are present.

This reaction takes place in the 'cytosol' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.

R-HSA-163691 (Reactome) In the nucleus, activated AMPK phosphorylates serine residue 568 of ChREBP (Carbohydrate Response Element Binding Protein). Phosphorylated ChREBP does not bind to ChRE chromosomal DNA sequence elements and thus loses its ability to promote transcription of genes involved in glycolysis and lipogenesis.
R-HSA-163733 (Reactome) At the end of this reaction, 1 molecule of 'Fatty acid synthase ' is present.

This reaction takes place in the 'nucleus' (Ma et al. 2005, Havula et al. 2012).

R-HSA-163741 (Reactome) Cytosolic transketolase (TKT) catalyzes the reversible reaction of D-glyceraldehyde 3-phosphate and sedoheptulose 7-phosphate to form D-xylulose 5-phosphate and D-ribose 5-phosphate. The active transketolase enzyme is a homodimer with one molecule of thiamine pyrophosphate and magnesium bound to each monomer (Wang et al. 1997).
R-HSA-163743 (Reactome) At the end of this reaction, 1 molecule of 'Acetyl-CoA carboxylase 2 ' is present.

This reaction takes place in the 'nucleus' (Ma et al. 2006).

R-HSA-163748 (Reactome) At the end of this reaction, 1 molecule of '1-acyl-sn-glycerol-3-phosphate acyltransferase alpha ' is present.

This reaction takes place in the 'nucleus' (Ma et al.2007).

R-HSA-163750 (Reactome) At the beginning of this reaction, 1 molecule of 'pPF2K-Pase complex' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'PF2K-Pase1 homodimer' are present.

This reaction takes place in the 'cytosol' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.

R-HSA-163751 (Reactome) Cytosolic transketolase (TKT) catalyzes the reaction of D-glyceraldehyde 3-phosphate and D-fructose 6-phosphate to form D-erythrose 4-phosphate and D-xylulose 5-phosphate. The active transketolase enzyme is a homodimer with one molecule of thiamine pyrophosphate and magnesium bound to each monomer (Wang et al. 1997).
R-HSA-163764 (Reactome) Dimeric cytosolic transaldolase (TALDO1) catalyzes the reversible reaction of D-erythrose 4-phosphate and D-fructose 6-phosphate to form D-glyceraldehyde 3-phosphate and sedoheptulose 7-phosphate. Protein expressed from the cloned gene has been characterized biochemically and crystallographically (Banki et al. 1994; Thorell et al. 2000) and transaldolase deficiency in a patient has been correlated with a mutation in the TALDO1 gene (Verhoeven et al. 2001).
R-HSA-163769 (Reactome) Xylulose-5-phosphate binds to Protein phosphatase 2A (PP2A), activating it. This regulatory step may be the crucial physiological link explaining the coordinately increased rates of glycolysis and lipogenesis generally observed in individuals consuming high-carbohydrate diets.
R-HSA-163770 (Reactome) At the end of this reaction, 1 molecule of 'citrate lyase monomer' is present.

This reaction takes place in the 'nucleus'.

R-HSA-163773 (Reactome) Activated PKA (protein kinase A) phosphorylates serine 36 of the bifunctional 6-Phosphofructo-2-kinase /Fructose-2,6-bisphosphatase (PFKFB1) enzyme. This phosphorylation inhibits the enzyme's phosphofructokinase (PFK-2) activity while activating its phosphatase activity. As a result, cytosolic levels of Fructose-2,6-bisphosphate (F-2,6-P2) are reduced. F-2,6-P2 in turn is a key positive regulator of the committed step of glycolysis, so the net effect of this phosphorylation event is a reduced rate of glycolysis.
R-HSA-164056 (Reactome) At the beginning of this reaction, 1 molecule of 'pChREBP(Ser 568)' is present. At the end of this reaction, 1 molecule of 'Orthophosphate', and 1 molecule of 'ChREBP protein' are present.

This reaction takes place in the 'nucleus' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.

R-HSA-164151 (Reactome) LKB1 phosphorylates threonine residue 172 of the alpha subunit of the AMPK heterotrimer, activating it. LKB1, a serine/threonine kinase, was first identified as the gene whose mutation is associated with the Peutz-Jeghers familial cancer syndrome. This disease phenotype is consistent with the hypothesis that the interaction between LKB1 and AMPK normally plays a key role in the negative regulation of cell growth (Hardie 2004).
R-HSA-164377 (Reactome) Activated adenylate cyclase associated with the plasma membrane catalyzes the reaction of cytosolic ATP to form 3',5'-cyclicAMP and pyrophosphate ().
R-HSA-164423 (Reactome) ChREBP (Carbohydrate Response Element Binding Protein) doubly phosphorylated at threonine 666 and serine 196 is inactive and is localized to the cytosol. Removal of the phosphate residue at serine 196 allows ChREBP to translocate between the cytosol and the nucleoplasm (Sakiyama et al. 2008).
R-HSA-169680 (Reactome) The IP3 receptor (IP3R) is an IP3-gated calcium channel. It is a large, homotetrameric protein, similar to other calcium channel proteins such as ryanodine. The four subunits form a 'four-leafed clover' structure arranged around the central calcium channel. Binding of ligands such as IP3 results in conformational changes in the receptor's structure that leads to channel opening.
R-HSA-169683 (Reactome) IP3 promotes the release of intracellular calcium.
R-HSA-265166 (Reactome) Exocytosis of insulin-zinc granules occurs by the calcium-dependent fusion of the membrane of the secretory granule with the plasma membrane. In general, exocytosis proceeds by formation of a "SNARE pair", a complex between a SNARE-type protein on the granule and a SNARE-type protein on the plasma membrane. (The interaction is between coiled coil domains on each SNARE-type protein.)

In the particular case of insulin granules in beta cells, the SNARE protein on the granule is Synaptobrevin2/VAMP2 and the SNARE protein on the plasma membrane is Syntaxin1A in a complex with SNAP-25. Unc18-1 binds Syntaxin1A and thereby prevents association with Synaptobrevin2 until dissociation of Unc18-1. Syntaxin 4 is also involved and binds filamentous actin but its exact role is unknown.
Insulin exocytosis occurs in two phases: 1) a rapid release of about 100 of the 1000 docked granules within the first 5 minutes of glucose stimulation and 2) a subsequent slow release over 30 minutes or more due to migration of internal granules to the plasma membrane. Data from knockout mice show that Syntaxin 1A is involved in rapid release but not slow release, whereas Syntaxin 4 is involved in both types of release.

Calcium dependence of membrane fusion is conferred by Synaptotagmin V, which binds calcium ions and associates with the Syntaxin1A-Synaptobrevin2 pair. The exact mechanism of Synaptotagmin's action is unknown. The migration of internal granules to the plasma membrane during slow release is also calcium dependent.

Microscopically, exocytosis is seen to occur as a "kiss and run" process in which the membrane of the secretory granule fuses transiently with the plasma membrane to form a small pore of about 4 nm between the interior of the granule and the exterior of the cell. Only a portion of the insulin in a granule is secreted after which the pore closes and the vesicle is recaptured back into the cell. Dynamin-1 and NSF may play a role in recapture but the mechanism is not fully known.

The major effect of adrenaline and noradrenaline on insulin secretion is the inhibition of exocytosis of pre-existing insulin secretory granules. The inhibition occurs at a "distal site", that is, the effect is most pronounced on granules already near the cytosolic face of the plasma membrane. The effect is caused by the Gi/o alpha:GTP complex but the exact mechanism by which Gi/o alpha:GTP inhibits exocytosis is unknown. On release, the higher pH in the extracellular region favours dissociation of Zn2+ from insulin. The insulin hexamer becomes unstable at this higher pH and it dissociates into the active insulin monomer.

R-HSA-265645 (Reactome) Voltage-gated calcium channels respond to a change in voltage across the plasma membrane by opening and allowing free movement of calcium ions. In an unstimulated cell the concentration of calcium ions outside the cells is higher than inside due to calcium transporters so channel opening results in an influx of calcium into the cytosol. In the cytosol the calcium ions cause an immediate exocytosis of the readily releasable pool of docked insulin granules as well as a migration of reserve granules toward the plasma membrane where they will be released during the second, sustained phase of insulin secretion.
Mouse and human beta cells are known to contain L type channels Cav1.2 and Cav1.3, both of which have been shown to physically associate with docked insulin granules via Syntaxin1A. Cav1.2 and Cav1.3 predominate in the initial rapid release of insulin. Human beta cells also contain the P/Q type channel Cav2.1 and the R type channel Cav2.3. Cav2.3 is involved in regulating the second, sustained phase of insulin release but signaling and regulatory differences between the two phases of secretion are not fully characterized. Human cells also exhibit T-type (brief burst) calcium currents but the responsible channel has not been identified.
R-HSA-265682 (Reactome) The beta-cell ATP-sensitive potassium channel (KATP channel) comprise the tetrameric ATP-sensitive inward rectifier potassium channel 11 (KCNJ11, Kir6.2) and the tetrameric channel regulator ATP-binding cassette sub-family C member 8 (ABCC8). When the ATP/ADP ratio is high, the KCNJ11 (Kir6.2) subunit binds ATP and the channel closes. Conversely, when the ADP:ATP ratio is high, the ABCC8 (SUR1) subunit binds magnesium-ADP and the channel is open.
The KATP channels in the beta cell are inwardly rectifying (allowing potassium ions to pass out of the cell) and are partially responsible for maintaining the resting potential of the cell, about -70 mV. Closure of the KATP channels causes a depolarization (a reduction in the voltage differential) across the plasma membrane.
The antidiabetic activity of sulfonylurea drugs such as acetohexamide, tolbutamide, glipzide, glibenclamide, and glimepiride is due to their binding ABCC8 (SUR1) subunits and inhibiting potassium efflux.
R-HSA-381607 (Reactome) Activated adenylyl cyclase catalyzes the conversion of one molecule of ATP to one molecule of 3',5'-cyclic AMP (cAMP) and one molecule of pyrophosphate.
R-HSA-381608 (Reactome) Each molecule of Epac2 binds 2 molecules of cAMP. Epac2 binds cAMP less tightly than PKA binds cAMP so it is believed that Epac2 binds cAMP after PKA is saturated. The binding of cAMP by Epac2 activates the guanyl nucleotide exchange activity of Epac2. Epac2 has also been shown to directly bind the SUR1 subunits of ATP-gated potassium channels (KATP channels) in beta cells so Epac2 may regulate potassium transport.
Epac2 interacts with the calcium sensor Piccolo in a complex with Rim2 at the cell membrane. This may influence exocytosis of insulin. Epac2 also interacts with the ryanodine-sensitive calcium channel on the ER membrane and may cause release of calcium from the ER into the cytosol.
R-HSA-381612 (Reactome) Glucagon-like Peptide-1 is synthesized in intestinal L-cells in response to the presence of glucose and fatty acids absorbed from the intestine. Most GLP-1 is the GLP-1 (7-36) amidated form; some GLP-1 is the GLP-1 (7-37) form. GLP-1 circulates to the pancreas where it binds the Glucagon-like Peptide-1 Receptor (GLP-1R), a G-protein coupled receptor located on the plasma membrane of beta cells. GLP-1R is a seven-pass transmembrane protein and a member of the B family of GPCRs, which have N-terminal extracellular domains of 100-150 amino acids. GLP-1 interacts with the extracellular N-terminal region of GLP-1R.
R-HSA-381644 (Reactome) Activated Protein Kinase A promotes the release of calcium from the endoplasmic reticulum into the cytosol. This may be due to phosphorylation of ER calcium channels by PKA, however this has not been demonstrated.
R-HSA-381668 (Reactome) Each molecule of Epac1 binds 1 molecule of cAMP. Epac1 binds cAMP less tightly than PKA binds cAMP so it is believed that Epac1 binds cAMP after PKA is saturated. The binding of cAMP by Epac1 activates the guanyl nucleotide exchange activity of Epac1. Epac1 has also been shown to bind the SUR1 subunit of ATP-gated potassium channels (KATP channels) in beta cells so Epac1 may participate in direct regulation of potassium transport.
Epac1 also interacts with the calcium sensor Piccolo in a complex with Rim2 at the cell membrane. This may influence exocytosis of insulin.
R-HSA-381704 (Reactome) By analogy with adenylyl cyclases I and II, adenylyl cyclase VIII is activated by G(s) alpha:GTP by protein-protein interaction between G(s) alpha and the C2 region of adenylyl cyclase VIII, forming a complex. Adenylyl cyclase VIII is present in beta cells of rat and is activated by both G(s) alpha:GTP and calcium:calmodulin, thus integrating signals from both GLP-1 via G(s) alpha and glucose via calcium. Human beta cells contain adenylyl cyclases V and VI, which are also activated by G(s) alpha:GTP, and may contain additional adenylyl cyclases.
R-HSA-381706 (Reactome) GLP-1R that has bound GLP-1 activates the alpha subunit of the heterotrimeric G-protein G(s) by protein-protein interaction between intracellular loop 3 of GLP-1R and G(s). The activation causes exchange of GDP for GTP by the alpha subunit of G(s).
R-HSA-381707 (Reactome) The inactive Protein Kinase A (PKA) complex contains 2 regulatory subunits and 2 catalytic subunits. Binding of the regulatory subunits to the catalytic subunits maintains inactivity. In humans there are 3 different catalytic subunits and 4 different regulatory subunits. The particular subunits present in the beta cells of the pancreas are unknown. In beta cells PKA is associated with AKAP79 and IQGAP1, which are believed to tether PKA to the inner surface of the plasma membrane.
Activation by cAMP occurs when each regulatory subunit binds 2 molecules of cAMP, causing dissociation of the catalytic subunits. The active catalytic subunits are thereby released to phosphorylate their target proteins.
Prolonged exposure to increased cAMP levels results in translocation of the active catalytic subunits to the nucleus, where they regulate the PDX-1 and CREB transcription factors and cause increased transcription of the insulin gene.
R-HSA-381713 (Reactome) Protein kinase A acts to antagonize voltage-gated potassium channels (Kv channels) by increasing the polarizing voltage required to open them. Maintenance of the Kv channels in the closed state prolongs depolarization and insulin secretion. The exact mechanism of the interaction between PKA and the Kv channels is unknown.
R-HSA-381727 (Reactome) EPAC1 and EPAC2 are activated by binding cAMP and positively regulate the exchange of GDP for GTP by the small GTPase RAP1A. The downstream effects of RAP1A:GTP in beta cells are uncertain but may involve increasing the number of "restless newcomer" secretory granules near the plasma membrane and thereby increasing secretion of insulin.
Other effects of RAP1A :GTP may include regulating beta cell proliferation through activation of the Raf/MEK/ERK mitogenic cascade and activation of the PI3 Kinase/PDK/PKC cell growth pathway.
R-HSA-399978 (Reactome) One of the known targets of PKC-alpha is the Myristoylated Alanine-rich C Kinase Substrate (MARCKS). MARCKS is phosphorylated at 4 serine residues and is believed to affect trafficking of insulin granules, increasing insulin secretion.
R-HSA-399995 (Reactome) The binding of acetylcholine to the Muscarinic Acetylcholine Receptor M3 activates the heterotrimeric G protein, Gq, associated with the M3 receptor. Activation occurs through protein-protein interaction and results in the alpha subunit of Gq exchanging GDP for GTP (i.e releasing GDP and binding GTP). The 3 subunits of the G protein then dissociate into an alpha:GTP complex and a beta:gamma complex.
R-HSA-399998 (Reactome) Phospholipase C beta-1 associated with the G(q) complex in the plasma membrane catalyzes the hydrolysis of 1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate to yield D-myo-Inositol 1,4,5-trisphosphate and 1,2-Diacylglycerol.
R-HSA-400012 (Reactome) Intrapancreatic parasympathetic (vagal) nerve endings release acetylcholine during preabsorptive and absorptive phases of feeding. The acetylcholine binds Muscarinic Acetylcholine Receptor M3 on pancreatic islet beta cells (inferred from experiments with knockout mice).
R-HSA-400015 (Reactome) Diacylglycerol, produced by PLC beta-mediated PIP2 hydrolysis in G alpha (q) signalling, remains in the plasma membrane and binds Protein Kinase C alpha (PKC-alpha), causing PKC-alpha to translocate from the cytosol to the plasma membrane. PKC-alpha is thereby activated and phosphorylates target proteins.
R-HSA-400023 (Reactome) The Gq alpha:GTP complex activates Phospholipase C beta-1 through protein interaction (inferred from homologues in Bos taurus). The activation by Gq alpha is insensitive to pertussis toxin whilst activation of PLC beta by the G beta-gamma complex is sensitive to pertussis toxin.
R-HSA-400027 (Reactome) In the non-activated state heterotrimeric G proteins exist at membranes as heterotrimeric complexes of alpha, beta, and gamma subunits, with the alpha subunit bound to GDP. Upon activation by a receptor coupled to the heterotrimer, exchange of GDP for GTP by the Gq alpha subunit causes the alpha subunit to lose affinity for the beta and gamma subunits. The alpha subunit with bound GTP then dissociates from the beta and gamma subunits.
R-HSA-400037 (Reactome) Exchange of GDP for GTP by the alpha subunit of the heterotrimeric G-protein complex causes the complex to dissociate into the G alpha:GTP complex and the beta-gamma complex. Both complexes have effector functions.
R-HSA-400046 (Reactome) Closing (inhibition) of the L-type calcium channels in the plasma membrane prevents the flow of calcium ions across the membrane.
R-HSA-400063 (Reactome) ATP-sensitive Potassium channels open and allow an inward rectifying current of potassium ions to flow, reestablishing the resting potential of the cell.
R-HSA-400071 (Reactome) The pancreatic beta cell contains Alpha2A and Alpha2C Adrenergic Receptors. These are G-protein coupled receptors that can bind either adrenaline or noradrenaline.
R-HSA-400092 (Reactome) In the pancreatic beta cell, alpha2 adrenergic receptors are coupled to Gi and Go heterotrimeric G-proteins. Binding of adrenaline or noradrenaline by the alpha2 adrenergic receptor acts through protein-protein interaction to stimulate the Gi alpha subunit or Go alpha subunit in heterotrimeric G-protein complexes to exchange GDP for GTP. The particular G alpha subunits have been identified in mice as Gi alpha1, Gi alpha 2, and Go alpha2.
R-HSA-400097 (Reactome) Adenylyl cyclases V and VI are the particular adenylyl cyclases present in beta cells of the human pancreas. The G-protein beta-gamma complex interacts with adenylyl cyclases via protein-protein interactions with the C1 and C2 cytoplasmic loops of adenylyl cyclase. The interaction may produce either stimulation or inhibition of the adenylyl cyclase depending on the particular adenylyl cyclase. In the case of adenylyl cyclases V and VI the interaction inhibits cyclase activity.
R-HSA-400434 (Reactome) Free fatty acid receptor 1 (FFAR1), also known as GPR40, is a G-protein coupled receptor located in the plasma membrane of pancreatic beta cells. FFAR1/GPR40 binds medium and long chain free fatty acids (free fatty acids having more than 12 carbon groups).
R-HSA-416530 (Reactome) FFAR1 (GPR40) is a G-protein coupled receptor. Based on studies with inhibitors of G proteins such as pertussis toxin FFAR1 is believed to signal through Gq/11. Binding of free fatty acids by FFAR1 activates the heterotrimeric Gq complex, which then activates Phospholipase C. From experiments in knockout mice it is estimated that signaling through FFAR1 is responsible for about 50% of the augmentation of insulin secretion produced by free fatty acids. The rest of the augmentation is due to metabolism of the free fatty acids within the pancreatic beta cell.
R-HSA-422320 (Reactome) The binding of GTP by G(s) alpha causes the heterotrimeric G-protein complex to reorientate, exposing previously bound faces of the G(s) alpha:GTP complex and the G-beta: G-gamma complex. Unlike the case with Gi/o heterotrimers, Gs heterotrimers are not observed to significantly dissociate in living cells.
R-HSA-499981 (Reactome) Human pancreatic beta cells express glucose transporters 1 and (GLUT1, GLUT2), which are responsible for uptake of glucose from the extracellular medium into the cytosol. (Rodent pancreatic beta cells express only Glut2.)
R-HSA-5250209 (Reactome) The complex between ADP-ribosylation factor-like protein 2-binding protein (ARL2BP aka BART) and GTP-bound ADP-ribosylation factor-like protein 2 (ARL2:GTP) is able to bind the ADP/ATP translocase 1 protein (SLC25A4 aka ANT1) at the mitochondrial inner membrane (Zhang et al. 2009, Bailey et al. 2009). ARL2 is essential for a number of mitochondrial functions, including mitochondrial morphology, motility and maintenance of ATP levels.
R-HSA-5250210 (Reactome) When ADP-ribosylation factor-like protein 2-binding protein (ARL2BP aka BART) binds GTP-bound ADP-ribosylation factor-like protein 2 (ARL2:GTP), the resultant complex can enter the mitochondrion via an unknown mechanism (Zhang et al. 2009, Bailey et al. 2009). Although ARL2 is a member of the ARF family of G proteins, it lacks the myristoylation at glycine-2 characteristic of that family and thus can move across the mitochondrial membrane into the intermembrane space (Sharer et al. 2002).
R-HSA-5250217 (Reactome) ADP-ribosylation factor-like protein 2 (ARL2) is a small (21kDa) GTPase protein that is able to bind GDP or GTP. It is implicated in a range of processes from trafficking processes to regulation of microtuble dynamics. ADP-ribosylation factor-like protein 2-binding protein (ARL2BP aka BART) is an effector protein that binds ARL2 (Zhang et al. 2009, Bailey et al. 2009). This binding is dependent on ARL2 being in its GTP-bound form.
R-HSA-5672027 (Reactome) A family of antiport, dimeric ATP-ADP translocases (SLC25A4,5,6), preferentially export ATP from the matrix while importing ADP from the cytosol, thereby maintaining a high ADP:ATP ratio in the matrix. When there are increased energy demands on the body, such as under heavy exercise, cytosolic ADP rises and is exchanged with mitochondrial matrix ATP via the transmembrane ADP:ATP translocase. Increased ADP causes the proton-motive force to be discharged and protons enter via ATPase, thereby regenerating the ATP pool. There are 3 isoforms of translocases in humans with isoform 1 (SLC25A4, NAT1) being the heart/skeletal muscle form.
R-HSA-5683209 (Reactome) Neonatal diabetes mellitus (NDM) is a rare condition defined as insulin-requiring hyperglycemia within the first month of life. About half of the neonates have a transient form that resolves at a median age of 3 months whereas the rest have a permanent form of diabetes.

ATP-binding cassette sub-family C member 8 (ABCC8) is a subunit of the beta-cell ATP-sensitive potassium channel (KATP). KATP channels play an important role in the control of insulin release. Elevation of the ATP:ADP ratio closes KATP channels leading to cellular depolarisation, calcium influx and exocytosis of insulin from its storage granules. Defects in ABCC8 can cause dysregulation of insulin secretion resulting in hyperglycemias or hypoglycemias.

Defects in ABCC8 can cause permanent neonatal diabetes mellitus (PNDM; MIM:606176). Wild-type ABCC8 confers a lower open-channel probability (Po) than activating mutations of ABCC8, where overactive KATP channels reduce insulin secretion, resulting in hyperglycemia, diagnosed within the first months of life. PNDM requires lifelong therapy. Mutations causing PNDM include P132L, L213R, N72S, A1185E and E382K (Proks et al. 2006, Babenko et al. 2006, Ellard et al. 2007).

Defects in ABCC8 can also cause transient noenatal diabetes mellitus 2 (TNDM2; MIM:610374). Babies are born with intrauterine growth retardation and present within the first 6 weeks of life with severe failure to thrive, hyperglycemia, and dehydration. The condition usually resolves within the first 6 months after birth but there is a predisposition to type 2 diabetes later in life (Naylor et al. 2011). Activating mutations causing TNDM2 are R1379C and L582V (Babenko et al. 2006). These mutations confer a higher open-channel probability (Po) than wild-type ABCC8, keeping the KATP channel open thus not allow cellular depolarisation to occur with the end result of reduced insulin secretion and hyperglycemia.
R-HSA-825631 (Reactome) The G(s)alpha G-beta G-gamma complex bound to glucagon, in the plasma membrane, releases a molecule of bound GDP, binds a molecule of GTP, and dissociates to yield a G(s)alpha:GTP complex and a G-beta:G-gamma dimer (Siu et al. 2013).
R-HSA-8848663 (Reactome) Adipokines are a group of over 600 bioactive molecules produced by adipose tissue that acts as paracrine and endocrine hormones. These molecules are important in the regulation of diverse processes including appetite control, fat distribution, inflammation, blood pressure, hemostasis and endothelial function. Adipokines may present anti and proinflammatory effects. Cardiovascular diseases (CVDs) can be one of the most important causes of death in diabetics and diabetes can in turn increase the risk of cardiovascular events. Obesity is a chronic condition and is characterised by overproduction of inflammatory adipokines by adipose tissue and this may be the link between obesity, CVD and diabetes (Freitas Lima et al. 2015).

Adiponectin (ADIPOQ, also known as 30-kDa adipocyte complement-related protein ACRP30) is an adipocyte-derived hormone that acts as an antidiabetic and anti-atherogenic adipokine. ADIPOQ blood levels are decreased under conditions of obesity, insulin resistance and type 2 diabetes. ADIPOQ can form a wide range of multimers from trimers to high molecular weight (HMW) multimers (Waki et al. 2003). The trimeric form is shown here. Through binding adiponectin receptor proteins 1 and 2 (ADIPOR1 and 2), ADIPOQ trimer stimulates AMPK phosphorylation and activation in the liver and the skeletal muscle, enhancing glucose and fatty-acid utilisation. ADIPOR1 is abundantly expressed in skeletal muscle, whereas ADIPOR2 is predominantly expressed in the liver (Yamauchi et al. 2003). ADIPORs are thought to function as homo- or hetero-multimers. For simplicity, the combinations annotated here are shown as homodimers. Although ADIPOR1 and 2 are predicted to contain seven transmembrane domains, they are structurally, topologically and functionally distinct from GPCRs.
R5PArrowR-HSA-163741 (Reactome)
RAP1A:GDPR-HSA-381727 (Reactome)
RAP1A:GTPArrowR-HSA-381727 (Reactome)
RAPGEF3:cAMP complexArrowR-HSA-265682 (Reactome)
RAPGEF3:cAMP complexArrowR-HSA-381668 (Reactome)
RAPGEF3:cAMP complexArrowR-HSA-381727 (Reactome)
RAPGEF3R-HSA-381668 (Reactome)
RAPGEF4:cAMP ComplexArrowR-HSA-265682 (Reactome)
RAPGEF4:cAMP ComplexArrowR-HSA-381608 (Reactome)
RAPGEF4:cAMP ComplexArrowR-HSA-381727 (Reactome)
RAPGEF4R-HSA-381608 (Reactome)
SH7PArrowR-HSA-163764 (Reactome)
SH7PR-HSA-163741 (Reactome)
SLC25A4R-HSA-5250209 (Reactome)
SLC25A5,6 dimersmim-catalysisR-HSA-163215 (Reactome)
SNAP25R-HSA-265166 (Reactome)
SNARE ComplexArrowR-HSA-265166 (Reactome)
STK11mim-catalysisR-HSA-164151 (Reactome)
STX1A:STXBP1R-HSA-265166 (Reactome)
STXBP1ArrowR-HSA-265166 (Reactome)
SYT5R-HSA-265166 (Reactome)
TALDO1 dimermim-catalysisR-HSA-163764 (Reactome)
TBarR-HSA-265166 (Reactome)
TKT dimermim-catalysisR-HSA-163741 (Reactome)
TKT dimermim-catalysisR-HSA-163751 (Reactome)
VAMP2R-HSA-265166 (Reactome)
Voltage-gated

Calcium Channels (pancreatic beta

cell)
mim-catalysisR-HSA-265645 (Reactome)
Voltage-gated

Calcium Channels

Type Cav1 (closed)
ArrowR-HSA-400046 (Reactome)
Voltage-gated

Calcium Channels

Type Cav1 (closed)
TBarR-HSA-265166 (Reactome)
Voltage-gated

Calcium Channels

Type Cav1 (open)
R-HSA-400046 (Reactome)
XY5PArrowR-HSA-163741 (Reactome)
XY5PArrowR-HSA-163751 (Reactome)
XY5PArrowR-HSA-163769 (Reactome)
Zn2+ArrowR-HSA-265166 (Reactome)
Zn2+TBarR-HSA-265682 (Reactome)
cAMP:PKA regulatory subunitArrowR-HSA-111925 (Reactome)
cAMP:PKA:AKAP79:IQGAP1 ComplexArrowR-HSA-381707 (Reactome)
cAMPArrowR-HSA-164377 (Reactome)
cAMPArrowR-HSA-381607 (Reactome)
cAMPR-HSA-111925 (Reactome)
cAMPR-HSA-381608 (Reactome)
cAMPR-HSA-381668 (Reactome)
cAMPR-HSA-381707 (Reactome)
mature GLP-1R-HSA-381612 (Reactome)
p-4S-MARCKSArrowR-HSA-399978 (Reactome)
p-S196,T666-MLXIPLArrowR-HSA-163676 (Reactome)
p-S196,T666-MLXIPLR-HSA-163689 (Reactome)
p-S568-MLXIPLArrowR-HSA-163691 (Reactome)
p-S568-MLXIPLR-HSA-164056 (Reactome)
p-T666-MLXIPLArrowR-HSA-163670 (Reactome)
p-T666-MLXIPLArrowR-HSA-163672 (Reactome)
p-T666-MLXIPLArrowR-HSA-163689 (Reactome)
p-T666-MLXIPLArrowR-HSA-164423 (Reactome)
p-T666-MLXIPLR-HSA-163670 (Reactome)
p-T666-MLXIPLR-HSA-163676 (Reactome)
p-T666-MLXIPLR-HSA-163688 (Reactome)
p-T666-MLXIPLR-HSA-164423 (Reactome)
phosphoPFKFB1 dimerArrowR-HSA-163773 (Reactome)
phosphoPFKFB1 dimerR-HSA-163750 (Reactome)
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