Señalización de la secreción de insulina por las células beta del páncreas. Una revisión
Palabras clave:
Insulina, MCF, estrés oxidativoResumen
Sustancias como la glucosa, ácidos grasos libres y aminoácidos se metabolizan en la célula β cuando sus concentraciones intracelulares alcanzan determinados niveles para proporcionar factores de acoplamiento metabólicos reguladores (R- MCF) y efectores (E-MCF). Los R-MCF (por ejemplo, citrato, NADH/NAD+, malonil-CoA, GTP, compuestos acil CoA de cadena larga, glutamato, nucleótidos de adenina), directa o indirectamente mejoran la producción de E-MCF (por ejemplo, ATP, cAMP, monoacilglicerol, NADPH, ROS, compuestos acilo-CoA de cadena corta), que tienen un impacto directo sobre la exocitosis de los gránulos de insulina. Los E-MCF activan los componentes finales de la maquinaria de la exocitosis, incluyendo el canal K+ATP/SUR1/Ca2+, Munc13-1, entre otros., iniciando así la liberación de insulina. Ahora bien, con el fin de prevenir la secreción excesiva de insulina, las células β también están equipadas con mecanismos que controlan producción excesiva de R-MCF y E-MCF. Estos mecanismos incluyen vías metabólicas que actúan como moduladores negativos (AMPK, la carnitina palmitoiltransferasa I, glucosa-6-fosfatasa, y proteínas de desacoplamiento 2, que disminuyen la generación de R-MCF, y de señales que controlan los niveles de E-MCF. Así pues, actualizar el conocimiento de algunas vías de señalización involucradas en la secreción de insulina, resulta importante para comprender mejor la patogenia de la diabetes mellitus tipo 2, donde además, el estrés oxidativo juega un rol significativo. Finalmente se considera ésta, un área importante de investigación, ya que puede generar nuevos conocimientos en la patogénesis molecular de la hiperglucemia e identifica blancos farmacológicos para el tratamiento y/o prevención de complicaciones diabéticas a largo plazo.
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[6] Matschinsky FM. A lesson in metabolic regulationinspired by the glucokinase glucose sensor paradigm. Diabetes 1996; 45:223-241. (Abstract)
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[10] Schyr-Ben-Haroush R, Hija A, Stolovich-Rain M, Dadon D, Granot Z, Ben-Hur V et al. Control of pancreatic beta cell regeneration by glucose metabolism. Cell Metab 2011; 13:440-449.
[11] Prentki M, Matschinsky FM, Madiraju SR. Metabolic signaling in fuel-induced insulin secretion. Cell Metab 2013; 18:162-185.
[12] Macdonald MJ. Feasibility of a mitochondrial pyruvate malate shuttle in pancreatic islets. Further implication of cytosolic NADPH in insulin secretion. J Biol Chem 1995; 270:20051-20058.
[13] Schuit F, De Vos A, Farfari S, Moens K, Pipeleers D, Brun T M et al. Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in ß-cells. J Biol Chem 1997; 272:18572-18579.
[14] Srinivasan M, Choi CS, Ghoshal P, Pliss L, Pandya JD, Hill D, et al. {beta}-Cell-specific pyruvate dehydrogenase deficiency impairs glucose- stimulated insulin secretion. Am J Physiol Endocrinol Metab 2010; 299:E910-E917.
[15] Cline GW, Lepine RL, Papas KK, Kibbey RG, Shulman GI. 13c Nmr isotopomer analysis of anaplerotic pathways in INS-1 cells. J Biol Chem 2004; 279:44370-44375.
[16] Farfari S, Schulz V, Corkey B, Prentki M. Glucoseregulated anaplerosis and cataplerosis in pancreatic beta-cells: possible implication of a pyruvate/ citrate shuttle in insulin secretion. Diabetes 2000; 49:718-726.
[17] Hasan NM, Longacre MJ, Stoker SW, Boonsaen T, Jitrapakdee S, Kendrick MA et al. Impaired anaplerosis and insulin secretion in insulinoma cells caused by small interfering RNA-mediated suppression of pyruvate carboxylase. J Biol Chem 2008; 283:28048-28059.
[18] Macdonald MJ, Longacre MJ, Langberg EC, Tibell A, Kendrick MA, Fukao T et al. Decreased levels of metabolic enzymes in pancreatic islets of patients with type 2 diabetes. Diabetologia 2009; 52:1087-1091.
[19] Maechler P, Li N, Casimir M, Vetterli L, Frigerio F, Brun T. Role of mitochondria in beta-cell function and dysfunction. Adv Exp Med Biol 2010; 654:193-216.
[20] Stanley CA. Two genetic forms of hyperinsulinemic hypoglycemia caused by dysregulation of glutamate dehydrogenase. Neurochem Int 2011; 59:465-472.
[21] Prentki M, Madiraju SR. Glycerolipid metabolism and signaling in health and disease. Endocr Rev 2008; 29:647-676.
[22] Yaney GC, Corkey BE. Fatty acid metabolism and insulin secretion in pancreatic beta cells. Diabetologia 2003; 46:1297-1312.
[23] Herrero L, Rubi B, Sebastian D, Serra D, Asins G, Maechler P et al. Alteration of the malonyl-CoA/carnitine palmitoyltransferase I interaction in the beta-cell impairs glucose-induced insulin secretion. Diabetes 2005; 54:462-471.
[24] Roduit R, Nolan C, Alarcon C, Moore P, Barbeau A, Delghingaro-Augusto V et al. A role for the malonyl-CoA/long-chain acyl-CoA pathway of lipid signaling in the regulation of insulin secretion in response to both fuel and nonfuel stimuli. Diabetes 2004; 53:1007-1019.
[25] Antinozzi PA, Segall L, Prentki M, Mcgarry JD, Newgard CB. Molecular or pharmacologic perturbation of the link between glucose and lipid metabolism is without effect on glucose-stimulated insulin secretion. J Biol Chem 1998; 273:16146-16154.
[26] Schulze Du, Dufer M, Wieringa B, Krippeit-Drews P, Drews G. An adenylate kinase is involved in KATP channel regulation of mouse pancreatic beta cells. Diabetologia 2007; 50:2126-2134.
[27] Drews G, Krippeit-Drews P, Dufer M. Electrophysiology of islet cells. Adv Exp Med Biol 2010; 654:115-163.
[28] Ruderman N, Prentki M. AMP kinase and malonyl- CoA: targets for therapy of the metabolic syndrome. Nat Rev Drug Discov 2004; 3:340-351.
[29] Prentki M, Madiraju SR. Glycerolipid/free fatty acid cycle and islet beta-cell function in health, obesity and diabetes. Mol Cell Endocrinol 2012; 353:88-100.
[30] Lamontagne J, Pepin E, Peyot ML, Joly E, Ruderman NB, Poitout V et al. Pioglitazone acutely reduces insulin secretion and causes metabolic deceleration of the pancreatic beta-cell at submaximal glucose concentrations. Endocrinology 2009; 150:3465-3474.
[31] Fu A, Eberhard CE, Screaton RA. Role of AMPK in pancreatic beta cell function. Mol Cell Endocrinol 2013; 366:127-134
[32] Nolan CJ, Leahy JL, Delghingaro-Augusto V, Moibi J, Soni K, Peyot ML et al. Beta-cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling. Diabetologia 2006 49:2120-2130.
[33] Peyot ML, Nolan CJ, Soni K, Joly E, Lussier R, Corkey BE et al. Hormone-sensitive lipase has a role in lipid signaling for insulin secretion but is nonessential for the incretin action of glucagon-like peptide 1. Diabetes 2004; 53:1733-1742.
[34] Mulder H, Yang S, Winzell MS, Holm C, Ahren B. Inhibition of lipase activity and lipolysis in rat islets reduces insulin secretion. Diabetes 2004; 53:122-128.
[35] Bratanova-Tochkova TK, Cheng H, Daniel S, Gunawardana S, Liu YJ, Mulvaney-Musa J. et al. Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion. Diabetes 2002; 51 (Suppl. 1):S83-S90.
[36] Gonzalo S, Linder ME. SNAP-25 palmitoylation and plasma membrane targeting require a functional secretory pathway. Mol Biol Cell 1998; 9:585-597.
[37] Chapman ER, Blasi J, An S, Brose N, Johnston PA, Sudhof TC, Jahn R. Fatty acylation of synaptotagmin in PC12 cells and synaptosomes. Biochem Biophys Res Commun 1996; 225:326-332.
[38] Rhee JS, Betz A, Pyott S, Reim K, Varoqueaux F, Augustin I. Beta phorbol ester- and diacylglycerol-induced augmentation of transmitter release is mediated by Munc13s and not by PKCs. Cell 2002; 108:121-133.
[39] Kwan EP, Xie L, Sheu L, Nolan CJ, Prentki M, Betz A et al. Munc13-1 deficiency reduces insulin secretion and causes abnormal glucose tolerance. Diabetes 2006; 55:1421-1429.
[40] Brownlee M. A radical explanation for glucose-induced beta cell dysfunction. J Clin Invest 2003; 112:1788-1790.
[41] Krauss S, Zhang CY, Scorrano L, Dalgaard LT, St-Pierre J, Grey ST et al. Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction. J Clin Invest 2003; 112:1831-1842.
[42 ]Seino S, Shibasaki T. PKA-dependent and PKAindependent pathways for cAMP-regulated exocytosis. Physiol Rev 2005; 85:1303-1342.
[43] Safayhi H, Haase H, Kramer U. L-type calcium channels in insulin-secreting cells: biochemical characterization and phosphorylation in RINm5F cells. Mol Endocrinol 1997; 11:619-629.
[44] Thorens B, Deriaz N, Bosco D. Protein kinase Adependent phosphorylation of GLUT2 in pancreatic β cells. J Biol Chem 1996; 271:8075-8081.
[45] Sugawara K, Shibasaki T, Mizoguchi A, Saito T, Seino S. Rab11 and its effector Rip11 participate in regulation of insulin granule exocytosis. Genes Cells 2009; 14:445-456.
[46] Seino S. Cell signalling in insulin secretion: the molecular targets of ATP, cAMP and sulfonylurea. Diabetología 2012; 55:2096-2108.
[47] De Rooij J, Rehmann H, Van Triest M, Cool RH, Wittinghofer A, Bos JL. Mechanism of regulation of the Epac family of cAMP-dependent RapGEFs. J Biol Chem 2000; 275:20829-20836.
[48]De Rooij J, Zwartkruis FJ, Verheijen MH. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 1998; 396:474-477.
[49] Kawasaki H, Springett GM, Mochizuki N. A family of cAMP-binding proteins that directly activate Rap1. Science 1998; 282:2275-2279.
[50] Gloerich M, Bos JL. Epac: defining a new mechanism for cAMP action. Annu Rev Pharmacol Toxicol 2010; 50:355-375.
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Publicado
2018-05-29
Cómo citar
Corro, A., Medina, I., & Matheus, N. (2018). Señalización de la secreción de insulina por las células beta del páncreas. Una revisión. Gaceta De Ciencias Veterinarias, 22(2), 53-62. Recuperado a partir de https://revistas.uclave.org/index.php/gcv/article/view/531
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