title: Chromium enhances insulin responsiveness via AMPK.
abstract: Trivalent chromium (Cr(3+)) is known to improve glucose homeostasis. Cr(3+) has been shown to improve plasma membrane-based aspects of glucose transporter GLUT4 regulation and increase activity of the cellular energy sensor 5' AMP-activated protein kinase (AMPK). However, the mechanism(s) by which Cr(3+) improves insulin responsiveness and whether AMPK mediates this action is not known. In this study we tested if Cr(3+) protected against physiological hyperinsulinemia-induced plasma membrane cholesterol accumulation, cortical filamentous actin (F-actin) loss and insulin resistance in L6 skeletal muscle myotubes. In addition, we performed mechanistic studies to test our hypothesis that AMPK mediates the effects of Cr(3+) on GLUT4 and glucose transport regulation. Hyperinsulinemia-induced insulin-resistant L6 myotubes displayed excess membrane cholesterol and diminished cortical F-actin essential for effective glucose transport regulation. These membrane and cytoskeletal abnormalities were associated with defects in insulin-stimulated GLUT4 translocation and glucose transport. Supplementing the culture medium with pharmacologically relevant doses of Cr(3+) in the picolinate form (CrPic) protected against membrane cholesterol accumulation, F-actin loss, GLUT4 dysregulation and glucose transport dysfunction. Insulin signaling was neither impaired by hyperinsulinemic conditions nor enhanced by CrPic, whereas CrPic increased AMPK signaling. Mechanistically, siRNA-mediated depletion of AMPK abolished the protective effects of CrPic against GLUT4 and glucose transport dysregulation. Together these findings suggest that the micronutrient Cr(3+), via increasing AMPK activity, positively impacts skeletal muscle cell insulin sensitivity and glucose transport regulation.
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Nolan J
authors.initials: NJ
authors.lastname: Hoffman
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Penque
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Diabetes Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Medicine - Endocrinology, Diabetes & Metabolism University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Habegger
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Whitney
authors.initials: W
authors.lastname: Sealls
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Lixuan
authors.initials: L
authors.lastname: Tackett
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biochemistry and Molecular Biology, Center for Diabetes Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: jelmendo@iupui.edu.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Elmendorf
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D002857:Chromium / Q000494:pharmacology*; D019587:Dietary Supplements; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006946:Hyperinsulinism / Q000188:drug therapy / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology; D010848:Picolinic Acids / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000199:Actins; D051275:Glucose Transporter Type 4; D007328:Insulin; D010848:Picolinic Acids; C495694:Slc2a4 protein, rat; D002857:Chromium; D002784:Cholesterol; D055372:AMP-Activated Protein Kinases; D005947:Glucose; C030614:picolinic acid
keywords: AMP-activated protein kinase; Cholesterol; Chromium; GLUT4; Insulin
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