title: Hyperinsulinemia is Associated with Increased Soluble Insulin Receptors Release from Hepatocytes.
abstract: It has been generally assumed that insulin circulates freely in blood. However it can also interact with plasma proteins. Insulin receptors are located in the membrane of target cells and consist of an alpha and beta subunits with a tyrosine kinase cytoplasmic domain. The ectodomain, called soluble insulin receptor (SIR) has been found elevated in patients with diabetes mellitus. We explored if insulin binds to SIRs in circulation under physiological conditions and hypothesize that this SIR may be released by hepatocytes in response to high insulin concentrations. The presence of SIR in rat and human plasmas and the culture medium of hepatocytes was explored using Western blot analysis. A purification protocol was performed to isolated SIR using affinity, gel filtration, and ion exchange chromatographies. A modified reverse hemolytic plaque assay was used to measure SIR release from cultured hepatocytes. Incubation with 1 nmol l(-1) insulin induces the release of the insulin receptor ectodomains from normal rat hepatocytes. This effect can be partially prevented by blocking protease activity. Furthermore, plasma levels of SIR were higher in a model of metabolic syndrome, where rats are hyperinsulinemic. We also found increased SIR levels in hyperinsulinemic humans. SIR may be an important regulator of the amount of free insulin in circulation. In hyperinsulinemia, the amount of this soluble receptor increases and this could lead to higher amounts of insulin bound to this receptor, rather than free insulin, which is the biologically active form of the hormone. This observation could enlighten the mechanisms of insulin resistance.
authors.affiliation: Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México , Mexico City , Mexico.
authors.forename: Marcia
authors.initials: M
authors.lastname: Hiriart
authors.affiliation: Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México , Mexico City , Mexico.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sanchez-Soto
authors.affiliation: Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México , Mexico City , Mexico.
authors.forename: Carlos Manlio
authors.initials: CM
authors.lastname: Diaz-Garcia
authors.affiliation: Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México , Mexico City , Mexico ; Centro Médico ABC , Mexico City , Mexico.
authors.forename: Diana T
authors.initials: DT
authors.lastname: Castanares
authors.affiliation: Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México , Mexico City , Mexico ; Instituto de Ecología, Universidad Nacional Autónoma de México , Mexico City , Mexico.
authors.forename: Morena
authors.initials: M
authors.lastname: Avitia
authors.affiliation: Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México , Mexico City , Mexico.
authors.forename: Myrian
authors.initials: M
authors.lastname: Velasco
authors.affiliation: Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México , Mexico City , Mexico.
authors.forename: Jaime
authors.initials: J
authors.lastname: Mas-Oliva
authors.affiliation: Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México , Mexico City , Mexico.
authors.forename: Marina
authors.initials: M
authors.lastname: Macias-Silva
authors.affiliation: Unidad de Investigación en Diabetes, Instituto Nacional de Salud Pública , Cuernavaca , Mexico.
authors.forename: Clicerio
authors.initials: C
authors.lastname: González-Villalpando
authors.affiliation: Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México , Mexico City , Mexico.
authors.forename: Blanca
authors.initials: B
authors.lastname: Delgado-Coello
authors.affiliation: Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México , Mexico City , Mexico.
authors.forename: Marcela
authors.initials: M
authors.lastname: Sosa-Garrocho
authors.affiliation: Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México , Mexico City , Mexico ; Departamento de Ciencias Básicas, Universidad de Monterrey , Monterrey , Mexico.
authors.forename: Román
authors.initials: R
authors.lastname: Vidaltamayo
authors.affiliation: Departamento de Biomacromoléculas, Instituto de Química , Universidad Nacional Autónoma de México, Mexico City , Mexico.
authors.forename: Deyanira
authors.initials: D
authors.lastname: Fuentes-Silva
keywords: diabetes mellitus type 2; hyperinsulinism; insulin resistance; metabolic syndrome; protease