title: Insulin receptor isoform A confers a higher proliferative capability to pancreatic beta cells enabling glucose availability and IGF-I signaling.
abstract: The main compensatory response to insulin resistance is the pancreatic beta cell hyperplasia to account for increased insulin secretion. In fact, in a previous work we proposed a liver-pancreas endocrine axis with IGF-I (insulin-like growth factor type I) secreted by the liver acting on IRA insulin receptor in beta cells from iLIRKO mice (inducible Liver Insulin Receptor KnockOut) that showed a high IRA/IRB ratio. However, the role of insulin receptor isoforms in the IGF-I-induced beta cell proliferation as well as the underlying molecular mechanisms remain poorly understood. For this purpose, we have used four immortalized mouse beta cell lines: bearing IR (IRLoxP), lacking IR (IRKO), expressing exclusively IRA (IRA), or alternatively expressing IRB (IRB). Pancreatic beta cell proliferation studies showed that IRA cells are more sensitive than those expressing IRB to the mitogenic response induced by IGF-I, acting through the pathway IRA/IRS-1/2/αp85/Akt/mTORC1/p70S6K. More importantly, IRA beta cells, but not IRB, showed an increased glucose uptake as compared with IRLoxP cells, this effect being likely owing to an enhanced association between Glut-1 and Glut-2 with IRA. Overall, our results strongly suggest a prevalent role of IRA in glucose availability and IGF-I-induced beta cell proliferation mainly through mTORC1. These results could explain, at least partially, the role played by the liver-secreted IGF-I in the compensatory beta cell hyperplasia observed in response to severe hepatic insulin resistance in iLIRKO mice.
authors: Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain. Electronic address: oescriba@ucm.es.
authors: Oscar
authors: O
authors: Escribano
authors: Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
authors: Almudena
authors: A
authors: Gómez-Hernández
authors: Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
authors: Sabela
authors: S
authors: Díaz-Castroverde
authors: Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
authors: Carmen
authors: C
authors: Nevado
authors: Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
authors: Gema
authors: G
authors: García
authors: Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
authors: Yolanda F
authors: YF
authors: Otero
authors: Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
authors: Liliana
authors: L
authors: Perdomo
authors: Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
authors: Nuria
authors: N
authors: Beneit
authors: Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain; Health Research Institute of San Carlos Clinic Hospital (IdISSC), Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
authors: Manuel
authors: M
authors: Benito
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D005947:Glucose / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D020033:Protein Isoforms; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
keywords: Beta cell hyperplasia; Glucose transport; IGF-I; Insulin receptor isoforms