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.).
Seino S, Chen L, Seino M, Blondel O, Takeda J, Johnson JH, Bell GI.; ''Cloning of the alpha 1 subunit of a voltage-dependent calcium channel expressed in pancreatic beta cells.''; PubMedEurope PMCScholia
Rall T, Harris BA.; ''Identification of the lesion in the stimulatory GTP-binding protein of the uncoupled S49 lymphoma.''; PubMedEurope PMCScholia
Ansari IH, Longacre MJ, Stoker SW, Kendrick MA, O'Neill LM, Zitur LJ, Fernandez LA, Ntambi JM, MacDonald MJ.; ''Characterization of Acyl-CoA synthetase isoforms in pancreatic beta cells: Gene silencing shows participation of ACSL3 and ACSL4 in insulin secretion.''; PubMedEurope PMCScholia
Pinney SE, MacMullen C, Becker S, Lin YW, Hanna C, Thornton P, Ganguly A, Shyng SL, Stanley CA.; ''Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations.''; PubMedEurope PMCScholia
Morita H, Yano Y, Niswender KD, May JM, Whitesell RR, Wu L, Printz RL, Granner DK, Magnuson MA, Powers AC.; ''Coexpression of glucose transporters and glucokinase in Xenopus oocytes indicates that both glucose transport and phosphorylation determine glucose utilization.''; PubMedEurope PMCScholia
Bayewitch ML, Avidor-Reiss T, Levy R, Pfeuffer T, Nevo I, Simonds WF, Vogel Z.; ''Inhibition of adenylyl cyclase isoforms V and VI by various Gbetagamma subunits.''; PubMedEurope PMCScholia
Fujise A, Mizuno K, Ueda Y, Osada S, Hirai S, Takayanagi A, Shimizu N, Owada MK, Nakajima H, Ohno S.; ''Specificity of the high affinity interaction of protein kinase C with a physiological substrate, myristoylated alanine-rich protein kinase C substrate.''; PubMedEurope PMCScholia
Offermanns S, Wieland T, Homann D, Sandmann J, Bombien E, Spicher K, Schultz G, Jakobs KH.; ''Transfected muscarinic acetylcholine receptors selectively couple to Gi-type G proteins and Gq/11.''; PubMedEurope PMCScholia
Macfarlane WM, O'Brien RE, Barnes PD, Shepherd RM, Cosgrove KE, Lindley KJ, Aynsley-Green A, James RF, Docherty K, Dunne MJ.; ''Sulfonylurea receptor 1 and Kir6.2 expression in the novel human insulin-secreting cell line NES2Y.''; PubMedEurope PMCScholia
Gibson SK, Gilman AG.; ''Gialpha and Gbeta subunits both define selectivity of G protein activation by alpha2-adrenergic receptors.''; PubMedEurope PMCScholia
Leifert WR, Aloia AL, Bucco O, McMurchie EJ.; ''GPCR-induced dissociation of G-protein subunits in early stage signal transduction.''; PubMedEurope PMCScholia
Miki T, Nagashima K, Seino S.; ''The structure and function of the ATP-sensitive K+ channel in insulin-secreting pancreatic beta-cells.''; PubMedEurope PMCScholia
Nauert JB, Rigas JD, Lester LB.; ''Identification of an IQGAP1/AKAP79 complex in beta-cells.''; PubMedEurope PMCScholia
Hollins B, Kuravi S, Digby GJ, Lambert NA.; ''The c-terminus of GRK3 indicates rapid dissociation of G protein heterotrimers.''; PubMedEurope PMCScholia
Delmeire D, Flamez D, Hinke SA, Cali JJ, Pipeleers D, Schuit F.; ''Type VIII adenylyl cyclase in rat beta cells: coincidence signal detector/generator for glucose and GLP-1.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Tomita T, Masuzaki H, Noguchi M, Iwakura H, Fujikura J, Tanaka T, Ebihara K, Kawamura J, Komoto I, Kawaguchi Y, Fujimoto K, Doi R, Shimada Y, Hosoda K, Imamura M, Nakao K.; ''GPR40 gene expression in human pancreas and insulinoma.''; PubMedEurope PMCScholia
Hruz PW, Mueckler MM.; ''Structural analysis of the GLUT1 facilitative glucose transporter (review).''; PubMedEurope PMCScholia
Gullingsrud J, Kim C, Taylor SS, McCammon JA.; ''Dynamic binding of PKA regulatory subunit RI alpha.''; PubMedEurope PMCScholia
Girard CA, Shimomura K, Proks P, Absalom N, Castano L, Perez de Nanclares G, Ashcroft FM.; ''Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes.''; PubMedEurope PMCScholia
Smrcka AV, Hepler JR, Brown KO, Sternweis PC.; ''Regulation of polyphosphoinositide-specific phospholipase C activity by purified Gq.''; PubMedEurope PMCScholia
Bazarsuren A, Grauschopf U, Wozny M, Reusch D, Hoffmann E, Schaefer W, Panzner S, Rudolph R.; ''In vitro folding, functional characterization, and disulfide pattern of the extracellular domain of human GLP-1 receptor.''; PubMedEurope PMCScholia
Lacey RJ, Chan SL, Cable HC, James RF, Perrett CW, Scarpello JH, Morgan NG.; ''Expression of alpha 2- and beta-adrenoceptor subtypes in human islets of Langerhans.''; PubMedEurope PMCScholia
Akgoz M, Kalyanaraman V, Gautam N.; ''Receptor-mediated reversible translocation of the G protein betagamma complex from the plasma membrane to the Golgi complex.''; PubMedEurope PMCScholia
Henquin JC.; ''Triggering and amplifying pathways of regulation of insulin secretion by glucose.''; PubMedEurope PMCScholia
Gilon P, Henquin JC.; ''Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell function.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Underwood CR, Garibay P, Knudsen LB, Hastrup S, Peters GH, Rudolph R, Reedtz-Runge S.; ''Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor.''; PubMedEurope PMCScholia
Grabsch H, Pereverzev A, Weiergräber M, Schramm M, Henry M, Vajna R, Beattie RE, Volsen SG, Klöckner U, Hescheler J, Schneider T.; ''Immunohistochemical detection of alpha1E voltage-gated Ca(2+) channel isoforms in cerebellum, INS-1 cells, and neuroendocrine cells of the digestive system.''; PubMedEurope PMCScholia
Cheung PC, Salt IP, Davies SP, Hardie DG, Carling D.; ''Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding.''; PubMedEurope PMCScholia
Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK, Eilert MM, Ellis C, Elshourbagy NA, Goetz AS, Minnick DT, Murdock PR, Sauls HR, Shabon U, Spinage LD, Strum JC, Szekeres PG, Tan KB, Way JM, Ignar DM, Wilson S, Muir AI.; ''The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids.''; PubMedEurope PMCScholia
Lang J.; ''Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion.''; PubMedEurope PMCScholia
Wang JJ, Martin PR, Singleton CK.; ''Aspartate 155 of human transketolase is essential for thiamine diphosphate-magnesium binding, and cofactor binding is required for dimer formation.''; PubMedEurope PMCScholia
Ma L, Tsatsos NG, Towle HC.; ''Direct role of ChREBP.Mlx in regulating hepatic glucose-responsive genes.''; PubMedEurope PMCScholia
Jayakumar A, Tai MH, Huang WY, al-Feel W, Hsu M, Abu-Elheiga L, Chirala SS, Wakil SJ.; ''Human fatty acid synthase: properties and molecular cloning.''; PubMedEurope PMCScholia
Prentki M, Madiraju SR.; ''Glycerolipid metabolism and signaling in health and disease.''; PubMedEurope PMCScholia
Yang SN, Berggren PO.; ''Beta-cell CaV channel regulation in physiology and pathophysiology.''; PubMedEurope PMCScholia
Mueckler M, Kruse M, Strube M, Riggs AC, Chiu KC, Permutt MA.; ''A mutation in the Glut2 glucose transporter gene of a diabetic patient abolishes transport activity.''; PubMedEurope PMCScholia
Jacobson DA, Philipson LH.; ''Action potentials and insulin secretion: new insights into the role of Kv channels.''; PubMedEurope PMCScholia
Dallas-Yang Q, Shen X, Strowski M, Brady E, Saperstein R, Gibson RE, Szalkowski D, Qureshi SA, Candelore MR, Fenyk-Melody JE, Parmee ER, Zhang BB, Jiang G.; ''Hepatic glucagon receptor binding and glucose-lowering in vivo by peptidyl and non-peptidyl glucagon receptor antagonists.''; PubMedEurope PMCScholia
Martin BR, Farndale RW, Wong SK.; ''The role of Gs in activation of adenylate cyclase.''; PubMedEurope PMCScholia
Wojcikiewicz RJ, Luo SG.; ''Phosphorylation of inositol 1,4,5-trisphosphate receptors by cAMP-dependent protein kinase. Type I, II, and III receptors are differentially susceptible to phosphorylation and are phosphorylated in intact cells.''; PubMedEurope PMCScholia
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).''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Naylor RN, Greeley SA, Bell GI, Philipson LH.; ''Genetics and pathophysiology of neonatal diabetes mellitus.''; PubMedEurope PMCScholia
Thomsen J, Kristiansen K, Brunfeldt K, Sundby F.; ''The amino acid sequence of human glucagon.''; PubMedEurope PMCScholia
Bratanova-Tochkova TK, Cheng H, Daniel S, Gunawardana S, Liu YJ, Mulvaney-Musa J, Schermerhorn T, Straub SG, Yajima H, Sharp GW.; ''Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion.''; PubMedEurope PMCScholia
Nagasumi K, Esaki R, Iwachidow K, Yasuhara Y, Ogi K, Tanaka H, Nakata M, Yano T, Shimakawa K, Taketomi S, Takeuchi K, Odaka H, Kaisho Y.; ''Overexpression of GPR40 in pancreatic beta-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice.''; PubMedEurope PMCScholia
Sakiyama H, Wynn RM, Lee WR, Fukasawa M, Mizuguchi H, Gardner KH, Repa JJ, Uyeda K.; ''Regulation of nuclear import/export of carbohydrate response element-binding protein (ChREBP): interaction of an alpha-helix of ChREBP with the 14-3-3 proteins and regulation by phosphorylation.''; PubMedEurope PMCScholia
Pilkis SJ, el-Maghrabi MR, Claus TH.; ''Hormonal regulation of hepatic gluconeogenesis and glycolysis.''; PubMedEurope PMCScholia
Raybaud A, Baspinar EE, Dionne F, Dodier Y, Sauvé R, Parent L.; ''The role of distal S6 hydrophobic residues in the voltage-dependent gating of CaV2.3 channels.''; PubMedEurope PMCScholia
Dalman HM, Neubig RR.; ''Two peptides from the alpha 2A-adrenergic receptor alter receptor G protein coupling by distinct mechanisms.''; PubMedEurope PMCScholia
Gautam D, Han SJ, Duttaroy A, Mears D, Hamdan FF, Li JH, Cui Y, Jeon J, Wess J.; ''Role of the M3 muscarinic acetylcholine receptor in beta-cell function and glucose homeostasis.''; PubMedEurope PMCScholia
Leech CA, Castonguay MA, Habener JF.; ''Expression of adenylyl cyclase subtypes in pancreatic beta-cells.''; PubMedEurope PMCScholia
Waki H, Yamauchi T, Kamon J, Ito Y, Uchida S, Kita S, Hara K, Hada Y, Vasseur F, Froguel P, Kimura S, Nagai R, Kadowaki T.; ''Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin.''; PubMedEurope PMCScholia
Winzell MS, Ahrén B.; ''G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes.''; PubMedEurope PMCScholia
Tanimura A, Nezu A, Morita T, Hashimoto N, Tojyo Y.; ''Interplay between calcium, diacylglycerol, and phosphorylation in the spatial and temporal regulation of PKCalpha-GFP.''; PubMedEurope PMCScholia
Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y.; ''Inwardly rectifying potassium channels: their structure, function, and physiological roles.''; PubMedEurope PMCScholia
Rutter GA, Hill EV.; ''Insulin vesicle release: walk, kiss, pause ... then run.''; PubMedEurope PMCScholia
Holz GG, Kang G, Harbeck M, Roe MW, Chepurny OG.; ''Cell physiology of cAMP sensor Epac.''; PubMedEurope PMCScholia
Fujimoto K, Shibasaki T, Yokoi N, Kashima Y, Matsumoto M, Sasaki T, Tajima N, Iwanaga T, Seino S.; ''Piccolo, a Ca2+ sensor in pancreatic beta-cells. Involvement of cAMP-GEFII.Rim2. Piccolo complex in cAMP-dependent exocytosis.''; PubMedEurope PMCScholia
Lacey RJ, Cable HC, James RF, London NJ, Scarpello JH, Morgan NG.; ''Concentration-dependent effects of adrenaline on the profile of insulin secretion from isolated human islets of Langerhans.''; PubMedEurope PMCScholia
Thorens B.; ''GLUT2 in pancreatic and extra-pancreatic gluco-detection (review).''; PubMedEurope PMCScholia
Babenko AP, Gonzalez G, Bryan J.; ''Two regions of sulfonylurea receptor specify the spontaneous bursting and ATP inhibition of KATP channel isoforms.''; PubMedEurope PMCScholia
Peltonen JM, Pihlavisto M, Scheinin M.; ''Subtype-specific stimulation of [35S]GTPgammaS binding by recombinant alpha2-adrenoceptors.''; PubMedEurope PMCScholia
Thorell S, Gergely P, Banki K, Perl A, Schneider G.; ''The three-dimensional structure of human transaldolase.''; PubMedEurope PMCScholia
Richardson CC, Hussain K, Jones PM, Persaud S, Löbner K, Boehm A, Clark A, Christie MR.; ''Low levels of glucose transporters and K+ATP channels in human pancreatic beta cells early in development.''; PubMedEurope PMCScholia
Hirasawa A, Hara T, Katsuma S, Adachi T, Tsujimoto G.; ''Free fatty acid receptors and drug discovery.''; PubMedEurope PMCScholia
Shapiro H, Shachar S, Sekler I, Hershfinkel M, Walker MD.; ''Role of GPR40 in fatty acid action on the beta cell line INS-1E.''; PubMedEurope PMCScholia
Yajima H, Komatsu M, Sato Y, Yamada S, Yamauchi K, Sharp GW, Aizawa T, Hashizume K.; ''Norepinephrine inhibits glucose-stimulated, Ca2+-independent insulin release independently from its action on adenylyl cyclase.''; PubMedEurope PMCScholia
Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, Ogi K, Hosoya M, Tanaka Y, Uejima H, Tanaka H, Maruyama M, Satoh R, Okubo S, Kizawa H, Komatsu H, Matsumura F, Noguchi Y, Shinohara T, Hinuma S, Fujisawa Y, Fujino M.; ''Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40.''; PubMedEurope PMCScholia
Smith NJ, Stoddart LA, Devine NM, Jenkins L, Milligan G.; ''The action and mode of binding of thiazolidinedione ligands at free fatty acid receptor 1.''; PubMedEurope PMCScholia
Lok S, Kuijper JL, Jelinek LJ, Kramer JM, Whitmore TE, Sprecher CA, Mathewes S, Grant FJ, Biggs SH, Rosenberg GB.; ''The human glucagon receptor encoding gene: structure, cDNA sequence and chromosomal localization.''; PubMedEurope PMCScholia
Gromada J, Rorsman P, Dissing S, Wulff BS.; ''Stimulation of cloned human glucagon-like peptide 1 receptor expressed in HEK 293 cells induces cAMP-dependent activation of calcium-induced calcium release.''; PubMedEurope PMCScholia
Ostenson CG, Gaisano H, Sheu L, Tibell A, Bartfai T.; ''Impaired gene and protein expression of exocytotic soluble N-ethylmaleimide attachment protein receptor complex proteins in pancreatic islets of type 2 diabetic patients.''; PubMedEurope PMCScholia
Tesmer JJ, Sunahara RK, Gilman AG, Sprang SR.; ''Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS.''; PubMedEurope PMCScholia
Kurose H, Regan JW, Caron MG, Lefkowitz RJ.; ''Functional interactions of recombinant alpha 2 adrenergic receptor subtypes and G proteins in reconstituted phospholipid vesicles.''; PubMedEurope PMCScholia
Nobles M, Benians A, Tinker A.; ''Heterotrimeric G proteins precouple with G protein-coupled receptors in living cells.''; PubMedEurope PMCScholia
Banno Y, Yada Y, Nozawa Y.; ''Purification and characterization of membrane-bound phospholipase C specific for phosphoinositides from human platelets.''; PubMedEurope PMCScholia
Schnell S, Schaefer M, Schöfl C.; ''Free fatty acids increase cytosolic free calcium and stimulate insulin secretion from beta-cells through activation of GPR40.''; PubMedEurope PMCScholia
Runge S, Schimmer S, Oschmann J, Schiødt CB, Knudsen SM, Jeppesen CB, Madsen K, Lau J, Thøgersen H, Rudolph R.; ''Differential structural properties of GLP-1 and exendin-4 determine their relative affinity for the GLP-1 receptor N-terminal extracellular domain.''; PubMedEurope PMCScholia
Freitas Lima LC, Braga VA, do Socorro de França Silva M, Cruz JC, Sousa Santos SH, de Oliveira Monteiro MM, Balarini CM.; ''Adipokines, diabetes and atherosclerosis: an inflammatory association.''; PubMedEurope PMCScholia
Kang G, Leech CA, Chepurny OG, Coetzee WA, Holz GG.; ''Role of the cAMP sensor Epac as a determinant of KATP channel ATP sensitivity in human pancreatic beta-cells and rat INS-1 cells.''; PubMedEurope PMCScholia
Azpiazu I, Akgoz M, Kalyanaraman V, Gautam N.; ''G protein betagamma11 complex translocation is induced by Gi, Gq and Gs coupling receptors and is regulated by the alpha subunit type.''; PubMedEurope PMCScholia
Wu L, Fritz JD, Powers AC.; ''Different functional domains of GLUT2 glucose transporter are required for glucose affinity and substrate specificity.''; PubMedEurope PMCScholia
Kubota M, Wakamatsu K.; ''Peptide fragment of the m3 muscarinic acetylcholine receptor activates G(q) but not G(i2).''; PubMedEurope PMCScholia
Leech CA, Holz GG, Chepurny O, Habener JF.; ''Expression of cAMP-regulated guanine nucleotide exchange factors in pancreatic beta-cells.''; PubMedEurope PMCScholia
Noushmehr H, D'Amico E, Farilla L, Hui H, Wawrowsky KA, Mlynarski W, Doria A, Abumrad NA, Perfetti R.; ''Fatty acid translocase (FAT/CD36) is localized on insulin-containing granules in human pancreatic beta-cells and mediates fatty acid effects on insulin secretion.''; PubMedEurope PMCScholia
Lambert NA.; ''Dissociation of heterotrimeric g proteins in cells.''; PubMedEurope PMCScholia
Wiederkehr A, Wollheim CB.; ''Minireview: implication of mitochondria in insulin secretion and action.''; PubMedEurope PMCScholia
Del Guerra S, Bugliani M, D'Aleo V, Del Prato S, Boggi U, Mosca F, Filipponi F, Lupi R.; ''G-protein-coupled receptor 40 (GPR40) expression and its regulation in human pancreatic islets: the role of type 2 diabetes and fatty acids.''; PubMedEurope PMCScholia
Barg S, Eliasson L, Renström E, Rorsman P.; ''A subset of 50 secretory granules in close contact with L-type Ca2+ channels accounts for first-phase insulin secretion in mouse beta-cells.''; PubMedEurope PMCScholia
Havula E, Hietakangas V.; ''Glucose sensing by ChREBP/MondoA-Mlx transcription factors.''; PubMedEurope PMCScholia
Nolan CJ, Madiraju MS, Delghingaro-Augusto V, Peyot ML, Prentki M.; ''Fatty acid signaling in the beta-cell and insulin secretion.''; PubMedEurope PMCScholia
Eason MG, Liggett SB.; ''Chimeric mutagenesis of putative G-protein coupling domains of the alpha2A-adrenergic receptor. Localization of two redundant and fully competent gi coupling domains.''; PubMedEurope PMCScholia
Tsuboi T, da Silva Xavier G, Holz GG, Jouaville LS, Thomas AP, Rutter GA.; ''Glucagon-like peptide-1 mobilizes intracellular Ca2+ and stimulates mitochondrial ATP synthesis in pancreatic MIN6 beta-cells.''; PubMedEurope PMCScholia
Lin YW, MacMullen C, Ganguly A, Stanley CA, Shyng SL.; ''A novel KCNJ11 mutation associated with congenital hyperinsulinism reduces the intrinsic open probability of beta-cell ATP-sensitive potassium channels.''; PubMedEurope PMCScholia
Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T.; ''Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.''; PubMedEurope PMCScholia
Latour MG, Alquier T, Oseid E, Tremblay C, Jetton TL, Luo J, Lin DC, Poitout V.; ''GPR40 is necessary but not sufficient for fatty acid stimulation of insulin secretion in vivo.''; PubMedEurope PMCScholia
Ma L, Robinson LN, Towle HC.; ''ChREBP*Mlx is the principal mediator of glucose-induced gene expression in the liver.''; PubMedEurope PMCScholia
Thorens B, Porret A, Bühler L, Deng SP, Morel P, Widmann C.; ''Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor.''; PubMedEurope PMCScholia
Colville CA, Seatter MJ, Jess TJ, Gould GW, Thomas HM.; ''Kinetic analysis of the liver-type (GLUT2) and brain-type (GLUT3) glucose transporters in Xenopus oocytes: substrate specificities and effects of transport inhibitors.''; PubMedEurope PMCScholia
Banki K, Halladay D, Perl A.; ''Cloning and expression of the human gene for transaldolase. A novel highly repetitive element constitutes an integral part of the coding sequence.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Sher E, Giovannini F, Codignola A, Passafaro M, Giorgi-Rossi P, Volsen S, Craig P, Davalli A, Carrera P.; ''Voltage-operated calcium channel heterogeneity in pancreatic beta cells: physiopathological implications.''; PubMedEurope PMCScholia
Lang J, Nishimoto I, Okamoto T, Regazzi R, Kiraly C, Weller U, Wollheim CB.; ''Direct control of exocytosis by receptor-mediated activation of the heterotrimeric GTPases Gi and G(o) or by the expression of their active G alpha subunits.''; PubMedEurope PMCScholia
Dessauer CW, Chen-Goodspeed M, Chen J.; ''Mechanism of Galpha i-mediated inhibition of type V adenylyl cyclase.''; PubMedEurope PMCScholia
Bavec A, Licar A.; ''Functional characterization of N-terminally GFP-tagged GLP-1 receptor.''; PubMedEurope PMCScholia
McIntire WE.; ''Structural determinants involved in the formation and activation of G protein betagamma dimers.''; PubMedEurope PMCScholia
Gao Z, Young RA, Trucco MM, Greene SR, Hewlett EL, Matschinsky FM, Wolf BA.; ''Protein kinase A translocation and insulin secretion in pancreatic beta-cells: studies with adenylate cyclase toxin from Bordetella pertussis.''; PubMedEurope PMCScholia
Proks P, Arnold AL, Bruining J, Girard C, Flanagan SE, Larkin B, Colclough K, Hattersley AT, Ashcroft FM, Ellard S.; ''A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes.''; PubMedEurope PMCScholia
Luvisetto S, Fellin T, Spagnolo M, Hivert B, Brust PF, Harpold MM, Stauderman KA, Williams ME, Pietrobon D.; ''Modal gating of human CaV2.1 (P/Q-type) calcium channels: I. The slow and the fast gating modes and their modulation by beta subunits.''; PubMedEurope PMCScholia
MacDonald PE, Wang G, Tsuk S, Dodo C, Kang Y, Tang L, Wheeler MB, Cattral MS, Lakey JR, Salapatek AM, Lotan I, Gaisano HY.; ''Synaptosome-associated protein of 25 kilodaltons modulates Kv2.1 voltage-dependent K(+) channels in neuroendocrine islet beta-cells through an interaction with the channel N terminus.''; PubMedEurope PMCScholia
Vignali S, Leiss V, Karl R, Hofmann F, Welling A.; ''Characterization of voltage-dependent sodium and calcium channels in mouse pancreatic A- and B-cells.''; PubMedEurope PMCScholia
Peterhoff M, Sieg A, Brede M, Chao CM, Hein L, Ullrich S.; ''Inhibition of insulin secretion via distinct signaling pathways in alpha2-adrenoceptor knockout mice.''; PubMedEurope PMCScholia
Digby GJ, Lober RM, Sethi PR, Lambert NA.; ''Some G protein heterotrimers physically dissociate in living cells.''; PubMedEurope PMCScholia
Babenko AP, Polak M, Cavé H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P.; ''Activating mutations in the ABCC8 gene in neonatal diabetes mellitus.''; PubMedEurope PMCScholia
Ferrer J, Benito C, Gomis R.; ''Pancreatic islet GLUT2 glucose transporter mRNA and protein expression in humans with and without NIDDM.''; PubMedEurope PMCScholia
Remaury A, Larrouy D, Daviaud D, Rouot B, Paris H.; ''Coupling of the alpha 2-adrenergic receptor to the inhibitory G-protein Gi and adenylate cyclase in HT29 cells.''; PubMedEurope PMCScholia
Veech RL.; ''A humble hexose monophosphate pathway metabolite regulates short- and long-term control of lipogenesis.''; PubMedEurope PMCScholia
Arbuckle MI, Kane S, Porter LM, Seatter MJ, Gould GW.; ''Structure-function analysis of liver-type (GLUT2) and brain-type (GLUT3) glucose transporters: expression of chimeric transporters in Xenopus oocytes suggests an important role for putative transmembrane helix 7 in determining substrate selectivity.''; PubMedEurope PMCScholia
Nakayama T, Penheiter AR, Penheiter SG, Chini EN, Thompson M, Warner DO, Jones KA.; ''Differential effects of volatile anesthetics on M3 muscarinic receptor coupling to the Galphaq heterotrimeric G protein.''; PubMedEurope PMCScholia
Kang G, Chepurny OG, Malester B, Rindler MJ, Rehmann H, Bos JL, Schwede F, Coetzee WA, Holz GG.; ''cAMP sensor Epac as a determinant of ATP-sensitive potassium channel activity in human pancreatic beta cells and rat INS-1 cells.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Ross D, Joyner WL.; ''Resting distribution and stimulated translocation of protein kinase C isoforms alpha, epsilon and zeta in response to bradykinin and TNF in human endothelial cells.''; PubMedEurope PMCScholia
Tesmer VM, Kawano T, Shankaranarayanan A, Kozasa T, Tesmer JJ.; ''Snapshot of activated G proteins at the membrane: the Galphaq-GRK2-Gbetagamma complex.''; PubMedEurope PMCScholia
Fujiwara K, Maekawa F, Yada T.; ''Oleic acid interacts with GPR40 to induce Ca2+ signaling in rat islet beta-cells: mediation by PLC and L-type Ca2+ channel and link to insulin release.''; PubMedEurope PMCScholia
Gromada J, Brock B, Schmitz O, Rorsman P.; ''Glucagon-like peptide-1: regulation of insulin secretion and therapeutic potential.''; PubMedEurope PMCScholia
Kim SJ, Choi WS, Han JS, Warnock G, Fedida D, McIntosh CH.; ''A novel mechanism for the suppression of a voltage-gated potassium channel by glucose-dependent insulinotropic polypeptide: protein kinase A-dependent endocytosis.''; PubMedEurope PMCScholia
De Vos A, Heimberg H, Quartier E, Huypens P, Bouwens L, Pipeleers D, Schuit F.; ''Human and rat beta cells differ in glucose transporter but not in glucokinase gene expression.''; PubMedEurope PMCScholia
Tsuboi T, Rutter GA.; ''Insulin secretion by 'kiss-and-run' exocytosis in clonal pancreatic islet beta-cells.''; PubMedEurope PMCScholia
Cummins MM, O'Mullane LM, Barden JA, Cook DI, Poronnik P.; ''Antisense co-suppression of G(alpha)(q) and G(alpha)(11) demonstrates that both isoforms mediate M(3)-receptor-activated Ca(2+) signalling in intact epithelial cells.''; PubMedEurope PMCScholia
Calle R, Ganesan S, Smallwood JI, Rasmussen H.; ''Glucose-induced phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) in isolated rat pancreatic islets.''; PubMedEurope PMCScholia
Henquin JC, Ishiyama N, Nenquin M, Ravier MA, Jonas JC.; ''Signals and pools underlying biphasic insulin secretion.''; PubMedEurope PMCScholia
Yamamoto H, Matsumura T, Kugiyama K, Oishi Y, Ogata N, Yasue H, Miyamoto E.; ''The antibody specific for myristoylated alanine-rich C kinase substrate phosphorylated by protein kinase C: activation of protein kinase C in smooth muscle cells in human coronary arteries.''; PubMedEurope PMCScholia
Runge S, Thøgersen H, Madsen K, Lau J, Rudolph R.; ''Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain.''; PubMedEurope PMCScholia
Trümper J, Ross D, Jahr H, Brendel MD, Göke R, Hörsch D.; ''The Rap-B-Raf signalling pathway is activated by glucose and glucagon-like peptide-1 in human islet cells.''; PubMedEurope PMCScholia
Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M.; ''Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.''; PubMedEurope PMCScholia
Tarasov AI, Nicolson TJ, Riveline JP, Taneja TK, Baldwin SA, Baldwin JM, Charpentier G, Gautier JF, Froguel P, Vaxillaire M, Rutter GA.; ''A rare mutation in ABCC8/SUR1 leading to altered ATP-sensitive K+ channel activity and beta-cell glucose sensing is associated with type 2 diabetes in adults.''; PubMedEurope PMCScholia
Orskov C, Rabenhøj L, Wettergren A, Kofod H, Holst JJ.; ''Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans.''; PubMedEurope PMCScholia
MacDonald PE, El-Kholy W, Riedel MJ, Salapatek AM, Light PE, Wheeler MB.; ''The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion.''; PubMedEurope PMCScholia
Cheng H, Straub SG, Sharp GW.; ''Protein acylation in the inhibition of insulin secretion by norepinephrine, somatostatin, galanin, and PGE2.''; PubMedEurope PMCScholia
Wittpoth C, Scholich K, Yigzaw Y, Stringfield TM, Patel TB.; ''Regions on adenylyl cyclase that are necessary for inhibition of activity by beta gamma and G(ialpha) subunits of heterotrimeric G proteins.''; PubMedEurope PMCScholia
Barg S, Rorsman P.; ''Insulin secretion: a high-affinity Ca2+ sensor after all?''; PubMedEurope PMCScholia
Verhoeven NM, Huck JH, Roos B, Struys EA, Salomons GS, Douwes AC, van der Knaap MS, Jakobs C.; ''Transaldolase deficiency: liver cirrhosis associated with a new inborn error in the pentose phosphate pathway.''; PubMedEurope PMCScholia
Zhao Y, Fang Q, Straub SG, Sharp GW.; ''Both G i and G o heterotrimeric G proteins are required to exert the full effect of norepinephrine on the beta-cell K ATP channel.''; PubMedEurope PMCScholia
Yang SN, Berggren PO.; ''The role of voltage-gated calcium channels in pancreatic beta-cell physiology and pathophysiology.''; PubMedEurope PMCScholia
Ma L, Sham YY, Walters KJ, Towle HC.; ''A critical role for the loop region of the basic helix-loop-helix/leucine zipper protein Mlx in DNA binding and glucose-regulated transcription.''; PubMedEurope PMCScholia
Jiang G, Zhang BB.; ''Glucagon and regulation of glucose metabolism.''; PubMedEurope PMCScholia
Kotarsky K, Nilsson NE, Flodgren E, Owman C, Olde B.; ''A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs.''; PubMedEurope PMCScholia
Hamming KS, Soliman D, Matemisz LC, Niazi O, Lang Y, Gloyn AL, Light PE.; ''Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K(+) channel.''; PubMedEurope PMCScholia
Gautam D, Han SJ, Hamdan FF, Jeon J, Li B, Li JH, Cui Y, Mears D, Lu H, Deng C, Heard T, Wess J.; ''A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo.''; PubMedEurope PMCScholia
Doyle ME, Egan JM.; ''Mechanisms of action of glucagon-like peptide 1 in the pancreas.''; PubMedEurope PMCScholia
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.
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.
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).
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 .
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 .
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.
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 (Banki et al. 1994) and transaldolase deficiency in a patient has been correlated with a mutation in the TALDO1 gene (Verhoeven et al. 2001).
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.
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.
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).
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'.
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'.
Cytosolic transketolase 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).
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.
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.
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.
ATP-sensitive potassium channels (KATP channels) bind ATP and close. The KATP channels in the beta cell are inward rectifying (allowing potassium ions to pass out 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.
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.
Cytosolic transketolase 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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
The pancreatic beta cell contains Alpha2A and Alpha2C Adrenergic Receptors. These are G-protein coupled receptors that can bind either adrenaline or noradrenaline.
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.
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.
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.
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.
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).
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.
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).
ATP-sensitive Potassium channels open and allow an inward rectifying current of potassium ions to flow, reestablishing the resting potential of the cell.
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.
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.
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).
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.
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.)
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.
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.
G(s)-alpha:GTP binds to inactive adenylate cyclase, causing a conformational transition in adenylate cyclase exposing the catalytic site and activating it.
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).
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.
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'.
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.
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.
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.
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'.
A family of antiport, ATP-ADP translocases, 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 is the heart/skeletal muscle form, isoform 2 is the fibroblast form and isoform 3 is the liver form. All isoforms exist as homodimers. The translocase can adopt 2 different conformations, called the CATR (carboxyatractyloside) and BA (bongkrekic acid) conformations. Amongst the endogenous nucleotides, only ADP and ATP can trigger the rapid conversion between the CATR and BA conformations. The reaction can be summed as below: ADPout + ATPin <-> ADPin + ATPout
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.).
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=163685
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
GDP G-protein beta
G-protein gamma ComplexGTP G-protein beta
G-protein gamma ComplexZinc
Calcium Complex in docked granuleAKAP79
IQGAP1 ComplexPKA AKAP79
IQGAP1 ComplexAnnotated Interactions
GDP G-protein beta
G-protein gamma ComplexGTP G-protein beta
G-protein gamma ComplexZinc
Calcium Complex in docked granuleAKAP79
IQGAP1 ComplexThis reaction takes place in the 'nucleus'.
This reaction takes place in the 'cytosol' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.
This reaction takes place in the 'cytosol' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.
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.
This reaction takes place in the 'nucleus'.
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.
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.
Epac1 also interacts with the calcium sensor Piccolo in a complex with Rim2 at the cell membrane. This may influence exocytosis 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.
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.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus' and is mediated by the 'phosphatidate phosphatase activity' of 'PP2A-ABdeltaC complex'.
There are 3 isoforms of translocases in humans; isoform 1 is the heart/skeletal muscle form, isoform 2 is the fibroblast form and isoform 3 is the liver form. All isoforms exist as homodimers. The translocase can adopt 2 different conformations, called the CATR (carboxyatractyloside) and BA (bongkrekic acid) conformations. Amongst the endogenous nucleotides, only ADP and ATP can trigger the rapid conversion between the CATR and BA conformations.
The reaction can be summed as below:
ADPout + ATPin <-> ADPin + ATPout
PKA AKAP79
IQGAP1 Complex