Cell type-specific deletion in mice reveals roles for PAS kinase in insulin and glucagon production
Tóm tắt
Per-Arnt-Sim kinase (PASK) is a nutrient-regulated domain-containing protein kinase previously implicated in the control of insulin gene expression and glucagon secretion. Here, we explore the roles of PASK in the control of islet hormone release, by generating mice with selective deletion of the Pask gene in pancreatic beta or alpha cells. Floxed alleles of Pask were produced by homologous recombination and animals bred with mice bearing beta (Ins1
Cre; PaskBKO) or alpha (Ppg
Cre [also known as Gcg]; PaskAKO) cell-selective Cre recombinase alleles. Glucose homeostasis and hormone secretion in vivo and in vitro, gene expression and islet cell mass were measured using standard techniques.
Ins1
Cre-based recombination led to efficient beta cell-targeted deletion of Pask. Beta cell mass was reduced by 36.5% (p < 0.05) compared with controls in PaskBKO mice, as well as in global Pask-null mice (38%, p < 0.05). PaskBKO mice displayed normal body weight and fasting glycaemia, but slightly impaired glucose tolerance, and beta cell proliferation, after maintenance on a high-fat diet. Whilst glucose tolerance was unaffected in PaskAKO mice, glucose infusion rates were increased, and glucagon secretion tended to be lower, during hypoglycaemic clamps. Although alpha cell mass was increased (21.9%, p < 0.05), glucagon release at low glucose was impaired (p < 0.05) in PaskAKO islets. The findings demonstrate cell-autonomous roles for PASK in the control of pancreatic endocrine hormone secretion. Differences between the glycaemic phenotype of global vs cell type-specific null mice suggest important roles for tissue interactions in the control of glycaemia by PASK.
Tài liệu tham khảo
Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE (2014) Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 103:137–149
Kahn SE, Zraika S, Utzschneider KM, Hull RL (2009) The beta cell lesion in type 2 diabetes: there has to be a primary functional abnormality. Diabetologia 52:1003–1012
Parker VE, Savage DB, O'Rahilly S, Semple RK (2011) Mechanistic insights into insulin resistance in the genetic era. Diabet Med 28:1476–1486
Thorens B, Sarkar HK, Kaback HR, Lodish HF (1988) Cloning and functional expression in bacteria of a novel glucose transporter present in liver intestine kidney and B-pancreatic islet cells. Cell 55:281–290
Rutter GA, Pullen TJ, Hodson DJ, Martinez-Sanchez A (2015) Pancreatic beta cell identity, glucose sensing and the control of insulin secretion. Biochem J 466:202–218
Hutton JC, Sener A, Herchuelz A et al (1980) Similarities in the stimulus-secretion coupling mechanisms of glucose- and 2-keto acid-induced insulin release. Endocrinology 106:203–219
Tarasov AI, Griffiths EJ, Rutter GA (2012) Regulation of ATP production by mitochondrial Ca2+. Cell Calcium 52:28–35
Ashcroft FM, Rorsman P (2013) KATP channels and islet hormone secretion: new insights and controversies. Nat Rev Endocrinol 9:660–669
Rutter GA, Theler J-M, Murta M, Wollheim CB, Pozzan T, Rizzuto R (1993) Stimulated Ca2+ influx raises mitochondrial free Ca2+ to supramicromolar levels in a pancreatic β-cell line: possible role in glucose and agonist-induced insulin secretion. J Biol Chem 268:22385–22390
Rutter GA, Pralong W-F, Wollheim CB (1992) Regulation of mitochondrial glycerol phosphate dehydrogenase by Ca2+ within electropermeabilized insulin secreting cells (INS-1). Biochim Biophys Acta 1175:107–113
Rutter GA (2004) Visualising insulin secretion. The Minkowski lecture 2004. Diabetologia 47:1861–1872
Henquin JC (2009) Regulation of insulin secretion: a matter of phase control and amplitude modulation. Diabetologia 52:739–751
Tarussio D, Metref S, Seyer P et al (2014) Nervous glucose sensing regulates postnatal beta cell proliferation and glucose homeostasis. J Clin Investig 124:413–424
Ravier MA, Rutter GA (2005) Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic α-cells. Diabetes 54:1789–1797
Gopel SO, Kanno T, Barg S, Weng X, Gromada J, Rorsman P (2000) Regulation of glucagon release in mouse-cells by KATP channels and inactivation of TTX-sensitive Na+ channels. J Physiol 528:509–520
Liu YJ, Vieira E, Gylfe E (2004) A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic alpha-cell. Cell Calcium 35:357–365
Rutter GA, Leclerc I (2009) The AMP-regulated kinase family: enigmatic targets for diabetes therapy. Mol Cell Endocrinol 297:41–49
da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK, Rutter GA (2003) Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression. Biochem J 371:761–774
da Silva Xavier G, Leclerc I, Salt IP et al (2000) Role of AMP-activated protein kinase in the regulation by glucose of islet beta-cell gene expression. Proc Natl Acad Sci U S A 97:4023–4028
Kuznetsov JN, Leclerc GJ, Leclerc GM, Barredo JC (2011) AMPK and Akt determine apoptotic cell death following perturbations of one-carbon metabolism by regulating ER stress in acute lymphoblastic leukemia. Mol Cancer Ther 10:437–447
Sun G, da Silva Xavier G, Gorman T et al (2015) LKB1 and AMPKalpha1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia. Mol Metab 4:277–286
Hofer T, Spielmann P, Stengel P et al (2001) Mammalian PASKIN, a PAS-serine/threonine kinase related to bacterial oxygen sensors. Biochem Biophys Res Commun 288:757–764
Rutter J, Michnoff CH, Harper SM, Gardner KH, McKnight SL (2001) PAS kinase: an evolutionarily conserved PAS domain-regulated serine/threonine kinase. Proc Natl Acad Sci U S A 98:8991–8996
Sabatini PV, Lynn FC (2015) All-encomPASsing regulation of beta-cells: PAS domain proteins in beta-cell dysfunction and diabetes. Trends Endocrinol Metab 26:49–57
Grose JH, Smith TL, Sabic H, Rutter J (2007) Yeast PAS kinase coordinates glucose partitioning in response to metabolic and cell integrity signaling. EMBO J 26:4824–4830
da Silva Xavier G, Rutter J, Rutter GA (2004) Involvement of Per-Arnt-Sim (PAS) kinase in the stimulation of preproinsulin and pancreatic duodenum homeobox 1 gene expression by glucose. Proc Natl Acad Sci U S A 101:8319–8324
Hao HX, Cardon CM, Swiatek W et al (2007) PAS kinase is required for normal cellular energy balance. Proc Natl Acad Sci U S A 104:15466–15471
Semplici F, Vaxillaire M, Fogarty S et al (2011) A human mutation within the per-ARNT-sim (PAS) domain-containing protein kinase (PASK) causes basal insulin hypersecretion. J Biol Chem 286:44005–44014
da Silva Xavier G, Farhan H, Kim H et al (2011) Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion. Diabetologia 54:819–827
Fontes G, Semache M, Hagman DK et al (2009) Involvement of Per-Arnt-Sim kinase and extracellular-regulated kinases-1/2 in palmitate inhibition of insulin gene expression in pancreatic beta-cells. Diabetes 58:2048–2058
Semache M, Zarrouki B, Fontes G et al (2013) Per-Arnt-Sim kinase regulates pancreatic duodenal homeobox-1 protein stability via phosphorylation of glycogen synthase kinase 3beta in pancreatic beta-cells. J Biol Chem 288:24825–24833
Thorens B, Tarussio D, Maestro MA, Rovira M, Heikkila E, Ferrer J (2015) Ins1 knock-in mice for beta cell-specific gene recombination. Diabetologia 58:558–656
Herrera PL (2000) Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 127:2317–2322
Katschinski DM, Marti HH, Wagner KF et al (2003) Targeted disruption of the mouse PAS domain serine/threonine kinase PASKIN. Mol Cell Biol 23:6780–6789
Elayat AA, el-Naggar MM, Tahir M (1995) An immunocytochemical and morphometric study of the rat pancreatic islets. J Anat 186:629–637
Kone M, Pullen TJ, Sun G et al (2014) LKB1 and AMPK differentially regulate pancreatic beta-cell identity. FASEB J 28:4972–4985
Solomou A, Meur G, Bellomo E et al (2015) The zinc transporter Slc30a8/ZnT8 is required in a subpopulation of pancreatic α-cells for hypoglycemia-induced glucagon secretion. J Biol Chem 290:21432–21442
Patel D, Ythier D, Brozzi F, Eizirik DL, Thorens B (2015) Clic4, a novel protein that sensitizes β-cells to apoptosis. Mol Metab 4:253–264
Hurtado-Carneiro V, Roncero I, Egger SS et al (2014) PAS kinase is a nutrient and energy sensor in hypothalamic areas required for the normal function of AMPK and mTOR/S6K1. Mol Neurobiol 50:314–326
Melloul D, Marshak S, Cerasi E (2002) Regulation of insulin gene transcription. Diabetologia 45:309–326
Vinet L, Lamprianou S, Babic A et al (2015) Targeting GLP-1 receptors for repeated magnetic resonance imaging differentiates graded losses of pancreatic beta cells in mice. Diabetologia 58:304–312
Hauge-Evans AC, King AJ, Carmignac D et al (2009) Somatostatin secreted by islet delta-cells fulfills multiple roles as a paracrine regulator of islet function. Diabetes 58:403–411
Kikani CK, Antonysamy SA, Bonanno JB et al (2010) Structural bases of PAS domain-regulated kinase (PASK) activation in the absence of activation loop phosphorylation. J Biol Chem 285:41034–41043