Browsing by Author "Hoffman, Nolan J."

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    Chromium Enhances Insulin Responsiveness via AMPK
    (Elsevier, 2014-05) Hoffman, Nolan J.; Penque, Brent A.; Habegger, Kirk M.; Sealls, Whitney; Tackett, Lixuan; Elmendorf, Jeffrey S.; Department of Cellular & Integrative Physiology, IU School of Medicine
    Trivalent chromium (Cr3+) is known to improve glucose homeostasis. Cr3+ 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 Cr3+ improves insulin responsiveness and whether AMPK mediates this action is not known. In this study we tested if Cr3+ 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 Cr3+ 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 Cr3+ 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 Cr3+, via increasing AMPK activity, positively impacts skeletal muscle cell insulin sensitivity and glucose transport regulation.
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    Identification of an Actin-Based Antidiabetic Action of Chromium in Skeletal Muscle
    (Office of the Vice Chancellor for Research, 2010-04-09) Hoffman, Nolan J.; Habegger, Kirk M.; Elmendorf, Jeffrey S.
    We recently demonstrated that cortical filamentous actin (F-actin) loss contributes to cellular insulin resistance induced by hyperinsulinemia. New animal and human analyses suggest a similar loss of F-actin is present in insulin-resistant skeletal muscle and results from cellular cholesterol accrual. Interestingly, we found that chromium picolinate (CrPic), a dietary supplement recognized to improve insulin action, lowers plasma membrane cholesterol in cultured adipocytes. Understanding whether CrPic can improve F-actin structure in insulinresistant skeletal muscle via lowering membrane cholesterol is not known, yet significant, as skeletal muscle is responsible for a large majority of insulin-stimulated glucose transport. In L6 myotubes stably expressing the insulin-responsive glucose transporter GLUT4 carrying an exofacial myc-epitope tag, acute insulin stimulation (20 min, 100 nM) increased myc-epitope labeling at the surface of intact cells by ~2-fold (P<0.05). In contrast, the ability of insulin to stimulate this process was inhibited 25% (P<0.05) by sustained exposure of L6 myotubes to insulin (12 h, 5 nM). Defects in insulin signaling did not readily account for the observed disruption. However, we found that insulin-induced insulin-resistant myotubes displayed a 28% elevation (P<0.05) in membrane cholesterol with a reciprocal 14% loss (P<0.05) in F-actin. This cholesterol/actin imbalance and insulin/GLUT4 dysfunction was corrected by the cholesterollowering action of CrPic. Mechanistically, CrPic increased the activity of the AMP-activated protein kinase (AMPK). Tests also revealed that other well-recognized activators of AMPK (e.g., AICAR, DNP) lowered membrane cholesterol and that, in a fashion similar to that witnessed for CrPic, improved regulation of GLUT4 in insulin-induced insulin-resistant myotubes. These data, as well as findings from ongoing siRNA-mediated AMPK knockdown experiments, are consistent with AMPK mediating its antidiabetic action by lowering cellular cholesterol. We predict that chromium, via AMPK activation, protects against cholesterol accrual that induces skeletal muscle F-actin loss and insulin resistance.