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      Peripheral insulin resistance in ILK-depleted mice by reduction of GLUT4 expression.

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          Abstract

          The development of insulin resistance is characterized by the impairment of glucose uptake mediated by glucose transporter 4 (GLUT4). Extracellular matrix changes are induced when the metabolic dysregulation is sustained. The present work was devoted to analyze the possible link between the extracellular-to-intracellular mediator integrin linked kinase (ILK) and the peripheral tissue modification that leads to glucose homeostasis impairment. Mice with general depletion of ILK in adulthood (cKD-ILK) maintained in a chow diet exhibited increased glycaemia and insulinemia concurrently with a reduction of the expression and membranes presence of GLUT4 in the insulin-sensitive peripheral tissues compared with their wildtype littermates (WT). Tolerance tests and insulin sensitivity indexes confirmed the insulin resistance in cKD-ILK, suggesting a similar stage to prediabetes in humans. Under randomly fed conditions, no differences between cKD-ILK and WT were observed in the expression of insulin receptor (IR-B) and its substrate IRS-1expressions. The IR-B isoform phosphorylated at tyrosines 1150/1151 was increased but the AKT phosphorylation in serine 473 was reduced in cKD-ILK tissues. Similarly, ILK-blocked myotubes reduced their GLUT4 promoter activity and GLUT4 expression levels. On the other hand, the glucose uptake capacity in response to exogenous insulin was impaired when ILK was blocked in vivo and in vitro, although IR/IRS/AKT phosphorylation states were increased but not different between groups. We conclude that ILK depletion modifies the transcription of GLUT4 which results in reduced peripheral insulin sensitivity and glucose uptake, suggesting ILK as a molecular target and a prognostic biomarker of insulin resistance.

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          Author and article information

          Journal
          J. Endocrinol.
          The Journal of endocrinology
          BioScientifica
          1479-6805
          0022-0795
          May 10 2017
          Affiliations
          [1 ] M Hatem-Vaquero, Department of Systems Biology, Physiology Unit, Universidad de Alcala de Henares, Madrid, Spain.
          [2 ] M Griera, Department of Systems Biology, Physiology Unit, Universidad de Alcala de Henares, Madrid, Spain.
          [3 ] A Garcia-Jerez, Department of Systems Biology, Physiology Unit, Universidad de Alcala de Henares, Madrid, Spain.
          [4 ] A Luengo, Department of Systems Biology, Physiology Unit, Universidad de Alcala de Henares, Madrid, Spain.
          [5 ] J Alvarez-Hernandez, Endocrinology and Nutrition Department, Hospital Universitario Principe de Asturias, Alcala de Henares, Spain.
          [6 ] J Rubio-Garcia, Endocrinology and Nutrition Department, Hospital Universitario Principe de Asturias, Alcala de Henares, Spain.
          [7 ] L Calleros, Department of Systems Biology, Physiology Unit, Universidad de Alcala de Henares, Madrid, Spain.
          [8 ] D Rodriguez-Puyol, Biomedical Research Foundation and Nephrology Department, Hospital Universitario Principe de Asturias, Alcala de Henares, Spain.
          [9 ] M Rodriguez-Puyol, Department of Systems Biology, Physiology Unit, Universidad de Alcala de Henares, Madrid, Spain.
          [10 ] S de Frutos, Department of Systems Biology, Physiology Unit, Universidad de Alcala de Henares, Madrid, Spain sergio.frutos@uah.es.
          Article
          JOE-16-0662
          10.1530/JOE-16-0662
          28490443
          f085b2cd-0c91-4e11-be55-f1b6a3cf802f
          History

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