title: Insulin receptor isoform A ameliorates long-term glucose intolerance in diabetic mice.
abstract: Type 2 diabetes mellitus is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion. Previous in vitro data showed that insulin receptor isoform A, but not B, favours basal glucose uptake through its specific association with endogenous GLUT1/2 in murine hepatocytes and beta cells. With this background, we hypothesized that hepatic expression of insulin receptor isoform A in a mouse model of type 2 diabetes could potentially increase the glucose uptake of these cells, decreasing the hyperglycaemia and therefore ameliorating the diabetic phenotype. To assure this hypothesis, we have developed recombinant adeno-associated viral vectors expressing insulin receptor isoform A (IRA) or isoform B (IRB) under the control of a hepatocyte--specific promoter. Our results demonstrate that in the long term, hepatic expression of IRA in diabetic mice is more efficient than IRB in ameliorating glucose intolerance. Consequently, it impairs the induction of compensatory mechanisms through beta cell hyperplasia and/or hypertrophy that finally lead to beta cell failure, reverting the diabetic phenotype in about 8 weeks. Our data suggest that long-term hepatic expression of IRA could be a promising therapeutic approach for the treatment of type 2 diabetes mellitus.
authors: Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid 28040, Spain.|CIBER of Diabetes and Related Diseases (CIBERDEM), Health Institute Carlos III (ISCIII), Madrid 28029, Spain.|Mechanisms of Insulin Resistance Consortium (MOIR), Madrid 28040, Spain.
authors: Sabela
authors: S
authors: Diaz-Castroverde
authors: Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid 28040, Spain.|CIBER of Diabetes and Related Diseases (CIBERDEM), Health Institute Carlos III (ISCIII), Madrid 28029, Spain.
authors: Almudena
authors: A
authors: Gómez-Hernández
authors: Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid 28040, Spain.|CIBER of Diabetes and Related Diseases (CIBERDEM), Health Institute Carlos III (ISCIII), Madrid 28029, Spain.
authors: Silvia
authors: S
authors: Fernández
authors: Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid 28040, Spain.|CIBER of Diabetes and Related Diseases (CIBERDEM), Health Institute Carlos III (ISCIII), Madrid 28029, Spain.
authors: Gema
authors: G
authors: García-Gómez
authors: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra 31008, Spain.
authors: Marianna
authors: M
authors: Di Scala
authors: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, Navarra 31008, Spain.
authors: Gloria
authors: G
authors: González-Aseguinolaza
authors: Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid 28040, Spain.|CIBER of Diabetes and Related Diseases (CIBERDEM), Health Institute Carlos III (ISCIII), Madrid 28029, Spain.|Mechanisms of Insulin Resistance Consortium (MOIR), Madrid 28040, Spain.
authors: Elisa
authors: E
authors: Fernández-Millán
authors: Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Amadeo Vives 2, Madrid 28009, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Health Institute Carlos III (ISCIII), Madrid 28029, Spain.
authors: Águeda
authors: Á
authors: González-Rodríguez
authors: Differentiation and Cytometry Unit, Hematopoietic Innovative Therapies Division, CIEMAT-CIBER of Rare Diseases (CIBERER)-Institute of Health Investigation Jiménez Díaz Foundation (IIS-FJD), Madrid 28040, Spain.
authors: María
authors: M
authors: García-Bravo
authors: Institute of Genetic and Molecular and Cellular Biology (CNRS UMR7104; INSERM U596; ULP, Collége de France) and Mouse Clinical Institute, Illkirch, Strasbourg 67400, France.
authors: Pierre
authors: P
authors: Chambon
authors: Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid 28040, Spain.|CIBER of Diabetes and Related Diseases (CIBERDEM), Health Institute Carlos III (ISCIII), Madrid 28029, Spain.|Mechanisms of Insulin Resistance Consortium (MOIR), Madrid 28040, Spain.
authors: Carmen
authors: C
authors: Álvarez
authors: Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid 28040, Spain.
authors: Liliana
authors: L
authors: Perdomo
authors: Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid 28040, Spain.
authors: Nuria
authors: N
authors: Beneit
authors: Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid 28040, Spain oescriba@ucm.es.|CIBER of Diabetes and Related Diseases (CIBERDEM), Health Institute Carlos III (ISCIII), Madrid 28029, Spain.|Mechanisms of Insulin Resistance Consortium (MOIR), Madrid 28040, Spain.
authors: Oscar
authors: 0000-0002-8249-1645
authors: O
authors: Escribano
authors: Department of Biochemistry and Molecular Biology II, School of Pharmacy, Complutense University of Madrid, Madrid 28040, Spain.|CIBER of Diabetes and Related Diseases (CIBERDEM), Health Institute Carlos III (ISCIII), Madrid 28029, Spain.|Mechanisms of Insulin Resistance Consortium (MOIR), Madrid 28040, Spain.
authors: Manuel
authors: M
authors: Benito
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D000229:Dependovirus / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000378:metabolism* / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006706:Homeostasis; D006965:Hyperplasia; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*
chemical_list: D007328:Insulin; D020033:Protein Isoforms; D049452:Green Fluorescent Proteins; D011972:Receptor, Insulin; D005947:Glucose
keywords: Adeno-associated virus (AAVs); Glucose homeostasis; Insulin receptor isoforms; Liver