{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T12:54:03Z","timestamp":1788353643898,"version":"build-2803163510"},"reference-count":53,"publisher":"The Endocrine Society","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,7,1]]},"abstract":"<jats:p>Tuberous sclerosis complex proteins 1\u20132 (TSC1-TSC2) complex integrates both nutrient and hormonal signaling and is a critical negative regulator of mammalian target of rapamycin (mTOR) complex 1. The use of different \u03b2-cell lines expressing or not the insulin receptor (IR+\/+ and IR\u2212\/\u2212) or with a reconstituted expression of IR isoform A or B (Rec A and Rec B) revealed that both phosphatidylinositol 3-kinase\/Akt\/TSC\/mTOR complex 1 and MAPK kinase\/ERK pathways mediate insulin signaling in IR+\/+-, IRA-, or IRB-expressing cells. However, glucose signaling was mediated by MAPK kinase\/ERK and AMP-activated protein kinase pathways as assessed in IR\u2212\/\u2212 cells. The effect of insulin on Akt phosphorylation was completely inhibited by the use of the phosphatidylinositol 3-kinase inhibitor wortmannin in IR+\/+ and Rec B cells, a partial inhibitory effect being observed in Rec A cell line. The knockdown of TSC2 expression up-regulated the downstream basal phosphorylation of 70-kDa ribosomal protein S6 kinase (p70S6K) and mTOR. More importantly, upregulation of p70S6K signaling impaired insulin-stimulated phosphorylation of Akt Ser473 and p70S6K in IR+\/+ and Rec B but not in Rec A cell lines. In fact, insulin receptor substrate-1 Ser307 phosphorylation signal in Rec B was stronger than in Rec A cell line during insulin action. Rec A cells induced a higher proliferation rate compared with Rec B or IR+\/+ during serum stimulation. Thus, we propose that the regulation of TSC2 phosphorylation by insulin or glucose independently integrates \u03b2-cell proliferation signaling, the relative expression of IRA or IRB isoforms in pancreatic \u03b2 cells playing a major role.<\/jats:p>","DOI":"10.1210\/en.2010-0048","type":"journal-article","created":{"date-parts":[[2010,4,29]],"date-time":"2010-04-29T02:33:22Z","timestamp":1272508402000},"page":"3084-3094","source":"Crossref","is-referenced-by-count":30,"title":["Role of the TSC1-TSC2 Complex in the Integration of Insulin and Glucose Signaling Involved in Pancreatic \u03b2-Cell Proliferation"],"prefix":"10.1210","volume":"151","author":[{"given":"Alberto","family":"Bartolome\u0301","sequence":"first","affiliation":[{"name":"Departamento de Bioqui\u0301mica y Biologi\u0301a Molecular (A.B., C.G., M.B.), Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain"},{"name":"Centro de Investigacio\u0301n Biome\u0301dica en Red de Diabetes y Enfermedades Metabo\u0301licas Asociadas (CIBERDEM) (A.B., C.G., M.B.), Mallorca 183, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Guille\u0301n","sequence":"first","affiliation":[{"name":"Departamento de Bioqui\u0301mica y Biologi\u0301a Molecular (A.B., C.G., M.B.), Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain"},{"name":"Centro de Investigacio\u0301n Biome\u0301dica en Red de Diabetes y Enfermedades Metabo\u0301licas Asociadas (CIBERDEM) (A.B., C.G., M.B.), Mallorca 183, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Benito","sequence":"first","affiliation":[{"name":"Departamento de Bioqui\u0301mica y Biologi\u0301a Molecular (A.B., C.G., M.B.), Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain"},{"name":"Centro de Investigacio\u0301n Biome\u0301dica en Red de Diabetes y Enfermedades Metabo\u0301licas Asociadas (CIBERDEM) (A.B., C.G., M.B.), Mallorca 183, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2010,4,28]]},"reference":[{"key":"2020071612375540400_R1","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1055\/s-2007-979040","article-title":"Adaptation of islets of Langerhans to pregnancy: \u03b2-cell growth, enhanced insulin secretion and the role of lactogenic hormones.","volume":"29","author":"Sorenson","year":"1997","journal-title":"Horm Metab Res"},{"key":"2020071612375540400_R2","doi-asserted-by":"crossref","first-page":"358","DOI":"10.2337\/diabetes.47.3.358","article-title":"Role of apoptosis in failure of \u03b2-cell mass compensation for insulin resistance and \u03b2-cell defects in the male Zucker diabetic fatty rat.","volume":"47","author":"Pick","year":"1998","journal-title":"Diabetes"},{"key":"2020071612375540400_R3","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/nrm2327","article-title":"Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and \u03b2-cell failure in type 2 diabetes.","volume":"9","author":"Muoio","year":"2008","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2020071612375540400_R4","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/S0092-8674(00)81896-6","article-title":"Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles.","volume":"88","author":"Bru\u0308ning","year":"1997","journal-title":"Cell"},{"key":"2020071612375540400_R5","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/ng1787","article-title":"Total insulin and IGF-I resistance in pancreatic \u03b2 cells causes overt diabetes.","volume":"38","author":"Ueki","year":"2006","journal-title":"Nat Genet"},{"key":"2020071612375540400_R6","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1038\/36116","article-title":"Disruption of IRS-2 causes type 2 diabetes in mice.","volume":"391","author":"Withers","year":"1998","journal-title":"Nature"},{"key":"2020071612375540400_R7","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1172\/JCI200113785","article-title":"Islet \u03b2 cell expression of constitutively active Akt1\/PKB \u03b1 induces striking hypertrophy, hyperplasia, and hyperinsulinemia.","volume":"108","author":"Bernal-Mizrachi","year":"2001","journal-title":"J Clin Invest"},{"key":"2020071612375540400_R8","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1038\/35050135","article-title":"Hypoinsulinaemia, glucose intolerance and diminished \u03b2-cell size in S6K1-deficient mice.","volume":"408","author":"Pende","year":"2000","journal-title":"Nature"},{"key":"2020071612375540400_R9","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1172\/JCI17645","article-title":"Glucokinase and IRS-2 are required for compensatory \u03b2 cell hyperplasia in response to high-fat diet-induced insulin resistance.","volume":"117","author":"Terauchi","year":"2007","journal-title":"J Clin Invest"},{"key":"2020071612375540400_R10","doi-asserted-by":"crossref","first-page":"7882","DOI":"10.1074\/jbc.270.14.7882","article-title":"Glucose, other secretagogues, and nerve growth factor stimulate mitogen-activated protein kinase in the insulin-secreting \u03b2-cell line, INS-1.","volume":"270","author":"Fro\u0308din","year":"1995","journal-title":"J Biol Chem"},{"key":"2020071612375540400_R11","doi-asserted-by":"crossref","first-page":"974","DOI":"10.2337\/diabetes.52.4.974","article-title":"Differential activation mechanisms of Erk-1\/2 and p70(S6K) by glucose in pancreatic \u03b2-cells.","volume":"52","author":"Briaud","year":"2003","journal-title":"Diabetes"},{"key":"2020071612375540400_R12","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1210\/en.2005-0831","article-title":"Differential mitogenic signaling in insulin receptor-deficient fetal pancreatic \u03b2-cells.","volume":"147","author":"Guillen","year":"2006","journal-title":"Endocrinology"},{"key":"2020071612375540400_R13","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.mce.2008.05.020","article-title":"The AMP-regulated kinase family: enigmatic targets for diabetes therapy.","volume":"297","author":"Rutter","year":"2009","journal-title":"Mol Cell Endocrinol"},{"key":"2020071612375540400_R14","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1042\/BJ20080281","article-title":"The TSC1-TSC2 complex: a molecular switchboard controlling cell growth.","volume":"412","author":"Huang","year":"2008","journal-title":"Biochem J"},{"key":"2020071612375540400_R15","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/ncb839","article-title":"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling.","volume":"4","author":"Inoki","year":"2002","journal-title":"Nat Cell Biol"},{"key":"2020071612375540400_R16","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.cell.2005.02.031","article-title":"Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis.","volume":"121","author":"Ma","year":"2005","journal-title":"Cell"},{"key":"2020071612375540400_R17","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S0092-8674(03)00929-2","article-title":"TSC2 mediates cellular energy response to control cell growth and survival.","volume":"115","author":"Inoki","year":"2003","journal-title":"Cell"},{"key":"2020071612375540400_R18","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.molcel.2008.03.003","article-title":"AMPK phosphorylation of raptor mediates a metabolic checkpoint.","volume":"30","author":"Gwinn","year":"2008","journal-title":"Mol Cell"},{"key":"2020071612375540400_R19","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1016\/j.cub.2004.08.026","article-title":"Inappropriate activation of the TSC\/Rheb\/mTOR\/S6K cassette induces IRS1\/2 depletion, insulin resistance, and cell survival deficiencies.","volume":"14","author":"Shah","year":"2004","journal-title":"Curr Biol"},{"key":"2020071612375540400_R20","doi-asserted-by":"crossref","first-page":"2282","DOI":"10.1074\/jbc.M412179200","article-title":"Insulin receptor substrate-2 proteasomal degradation mediated by a mammalian target of rapamycin (mTOR)-induced negative feedback down-regulates protein kinase B-mediated signaling pathway in \u03b2-cells.","volume":"280","author":"Briaud","year":"2005","journal-title":"J Biol Chem"},{"key":"2020071612375540400_R21","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1083\/jcb.200403069","article-title":"The TSC1\u20132 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins.","volume":"166","author":"Harrington","year":"2004","journal-title":"J Cell Biol"},{"key":"2020071612375540400_R22","doi-asserted-by":"crossref","first-page":"E1013","DOI":"10.1152\/ajpendo.00262.2009","article-title":"Critical roles for the TSC-mTOR pathway in \u03b2-cell function","volume":"297","author":"Mori","year":"2009","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2020071612375540400_R23","doi-asserted-by":"crossref","first-page":"9250","DOI":"10.1073\/pnas.0803047105","article-title":"Disruption of Tsc2 in pancreatic \u03b2 cells induces \u03b2 cell mass expansion and improved glucose tolerance in a TORC1-dependent manner.","volume":"105","author":"Rachdi","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612375540400_R24","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.1128\/MCB.01695-07","article-title":"Biphasic response of pancreatic \u03b2-cell mass to ablation of tuberous sclerosis complex 2 in mice.","volume":"28","author":"Shigeyama","year":"2008","journal-title":"Mol Cell Biol"},{"key":"2020071612375540400_R25","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.2337\/db08-0519","article-title":"Upregulation of the mTOR complex 1 pathway by Rheb in pancreatic \u03b2 cells leads to increased \u03b2 cell mass and prevention of hyperglycemia.","volume":"58","author":"Hamada","year":"2009","journal-title":"Diabetes"},{"key":"2020071612375540400_R26","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/0006-291X(89)92439-X","article-title":"Alternative splicing of human insulin receptor messenger RNA.","volume":"159","author":"Seino","year":"1989","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071612375540400_R27","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1210\/endo.132.3.8440175","article-title":"Ligand-binding properties of the two isoforms of the human insulin receptor.","volume":"132","author":"Yamaguchi","year":"1993","journal-title":"Endocrinology"},{"key":"2020071612375540400_R28","doi-asserted-by":"crossref","first-page":"47380","DOI":"10.1074\/jbc.M208371200","article-title":"Comparison of the functional insulin binding epitopes of the A and B isoforms of the insulin receptor.","volume":"277","author":"Whittaker","year":"2002","journal-title":"J Biol Chem"},{"key":"2020071612375540400_R29","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1210\/mend-5-5-734","article-title":"Different ligand affinities of the two human insulin receptor splice variants are reflected in parallel changes in sensitivity for insulin action.","volume":"5","author":"McClain","year":"1991","journal-title":"Mol Endocrinol"},{"key":"2020071612375540400_R30","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1055\/s-2004-814157","article-title":"The insulin receptor isoform exon 11- (IR-A) in cancer and other diseases: a review.","volume":"35","author":"Denley","year":"2003","journal-title":"Horm Metab Res"},{"key":"2020071612375540400_R31","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/S1097-2765(01)00203-9","article-title":"Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic \u03b2 cells.","volume":"7","author":"Leibiger","year":"2001","journal-title":"Mol Cell"},{"key":"2020071612375540400_R32","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1096\/fj.02-0685fje","article-title":"Chronic hyperglycemia impairs insulin secretion by affecting insulin receptor expression, splicing, and signaling in RIN \u03b2 cell line and human islets of Langerhans.","volume":"17","author":"Hribal","year":"2003","journal-title":"FASEB J"},{"key":"2020071612375540400_R33","doi-asserted-by":"crossref","first-page":"820","DOI":"10.2337\/db08-0551","article-title":"\u03b2-Cell hyperplasia induced by hepatic insulin resistance: role of a liver-pancreas endocrine axis through insulin receptor A isoform.","volume":"58","author":"Escribano","year":"2009","journal-title":"Diabetes"},{"key":"2020071612375540400_R34","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1091\/mbc.e07-05-0473","article-title":"Role of insulin receptor and balance in insulin receptor isoforms A and B in regulation of apoptosis in simian virus 40-immortalized neonatal hepatocytes.","volume":"19","author":"Nevado","year":"2008","journal-title":"Mol Biol Cell"},{"key":"2020071612375540400_R35","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1016\/0006-291X(89)91346-6","article-title":"Precocious induction of malic enzyme by nutritional and hormonal factors in rat foetal hepatocyte primary cultures.","volume":"161","author":"Fabregat","year":"1989","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071612375540400_R36","doi-asserted-by":"crossref","first-page":"3855","DOI":"10.1016\/j.febslet.2008.10.020","article-title":"Biphasic effect of insulin on \u03b2 cell apoptosis depending on glucose deprivation.","volume":"582","author":"Guillen","year":"2008","journal-title":"FEBS Lett"},{"key":"2020071612375540400_R37","doi-asserted-by":"crossref","first-page":"7106","DOI":"10.1158\/0008-5472.CAN-06-4798","article-title":"Identification of S664 TSC2 phosphorylation as a marker for extracellular signal-regulated kinase mediated mTOR activation in tuberous sclerosis and human cancer.","volume":"67","author":"Ma","year":"2007","journal-title":"Cancer Res"},{"key":"2020071612375540400_R38","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1161\/01.RES.0000256090.42690.05","article-title":"AMP-activated protein kinase in metabolic control and insulin signaling.","volume":"100","author":"Towler","year":"2007","journal-title":"Circ Res"},{"key":"2020071612375540400_R39","doi-asserted-by":"crossref","first-page":"9769","DOI":"10.1074\/jbc.C400557200","article-title":"The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway.","volume":"280","author":"Corradetti","year":"2005","journal-title":"J Biol Chem"},{"key":"2020071612375540400_R40","doi-asserted-by":"crossref","first-page":"4104","DOI":"10.1128\/MCB.00289-08","article-title":"The TSC1-TSC2 complex is required for proper activation of mTOR complex 2.","volume":"28","author":"Huang","year":"2008","journal-title":"Mol Cell Biol"},{"key":"2020071612375540400_R41","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1101\/gad.1256804","article-title":"Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1\/TSC2 tumor suppressor complex.","volume":"18","author":"Brugarolas","year":"2004","journal-title":"Genes Dev"},{"key":"2020071612375540400_R42","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1097\/01.TP.0000081043.23751.81","article-title":"Elevated portal vein drug levels of sirolimus and tacrolimus in islet transplant recipients: local immunosuppression or islet toxicity?","volume":"76","author":"Desai","year":"2003","journal-title":"Transplantation"},{"key":"2020071612375540400_R43","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S1097-2765(02)00568-3","article-title":"Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase\/akt pathway.","volume":"10","author":"Manning","year":"2002","journal-title":"Mol Cell"},{"key":"2020071612375540400_R44","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1096\/fj.06-7589com","article-title":"Selective gene activation by spatial segregation of insulin receptor B signaling.","volume":"21","author":"Uhles","year":"2007","journal-title":"FASEB J"},{"key":"2020071612375540400_R45","doi-asserted-by":"crossref","first-page":"3219","DOI":"10.1128\/MCB.01489-08","article-title":"Glucose effects on \u03b2-cell growth and survival require activation of insulin receptors and insulin receptor substrate-2.","volume":"29","author":"Assmann","year":"2009","journal-title":"Mol Cell Biol"},{"key":"2020071612375540400_R46","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1042\/bj3350533","article-title":"AMP-activated protein kinase is activated by low glucose in cell lines derived from pancreatic \u03b2 cells, and may regulate insulin release.","volume":"335","author":"Salt","year":"1998","journal-title":"Biochem J"},{"key":"2020071612375540400_R47","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1007\/s00125-002-1030-3","article-title":"AICA-riboside induces apoptosis of pancreatic \u03b2 cells through stimulation of AMP-activated protein kinase.","volume":"46","author":"Kefas","year":"2003","journal-title":"Diabetologia"},{"key":"2020071612375540400_R48","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1677\/joe.1.06413","article-title":"Over-expression of AMP-activated protein kinase impairs pancreatic \u03b2-cell function in vivo.","volume":"187","author":"Richards","year":"2005","journal-title":"J Endocrinol"},{"key":"2020071612375540400_R49","doi-asserted-by":"crossref","first-page":"e6189","DOI":"10.1371\/journal.pone.0006189","article-title":"Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway","volume":"4","author":"Zhang","year":"2009","journal-title":"PLoS ONE"},{"key":"2020071612375540400_R50","doi-asserted-by":"crossref","first-page":"945","DOI":"10.2337\/db07-0922","article-title":"mTOR inhibition by rapamycin prevents \u03b2-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes.","volume":"57","author":"Fraenkel","year":"2008","journal-title":"Diabetes"},{"key":"2020071612375540400_R51","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1097\/01.tp.0000296035.48728.28","article-title":"Rapamycin impairs in vivo proliferation of islet \u03b2-cells.","volume":"84","author":"Zahr","year":"2007","journal-title":"Transplantation"},{"key":"2020071612375540400_R52","first-page":"3065","article-title":"Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer.","volume":"118","author":"Carracedo","year":"2008","journal-title":"J Clin Invest"},{"key":"2020071612375540400_R53","doi-asserted-by":"crossref","first-page":"46","DOI":"10.4161\/cc.4.1.1343","article-title":"Tuberous sclerosis and insulin resistance. Unlikely bedfellows reveal a TORrid affair.","volume":"4","author":"Shah","year":"2005","journal-title":"Cell Cycle"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/151\/7\/3084\/7411736\/endo3084.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/151\/7\/3084\/7411736\/endo3084.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T21:10:36Z","timestamp":1594933836000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/151\/7\/3084\/2456755"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,4,28]]},"references-count":53,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2010,7,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2010-0048","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,4,28]]}}}