Naturally occurring compensated insulin resistance selectively alters glucose transporters in visceral and subcutaneous adipose tissues without change in AS160 activation

• Published in: Biochimica et biophysica acta 2011-09, Vol.1812 (9), p.1098-1103
• Main Authors: Waller, A.P., Kohler, K., Burns, T.A., Mudge, M.C., Belknap, J.K., Lacombe, V.A.
• Format: Article
• Language: English
• Subjects: Animals; Biotinylated photo-affinity label; Glucose Tolerance Test - veterinary; Glucose Transport Proteins, Facilitative - metabolism; Glucose Transporter Type 4 - metabolism; GLUT trafficking; GLUT12; GTPase-Activating Proteins - physiology; Horses; Insulin Resistance - physiology; Intra-Abdominal Fat - metabolism; Intra-Abdominal Fat - pathology; Omental; Subcutaneous Fat - metabolism; Subcutaneous Fat - pathology
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2011.02.007

Although the importance of adipose tissue (AT) glucose transport in regulating whole-body insulin sensitivity is becoming increasingly evident and insulin resistance (IR) has been widely recognized, the underlying mechanisms of IR are still not well understood. The purpose of the present study was to determine the early pathological changes in glucose transport by characterizing the alterations in glucose transporters (GLUT) in multiple visceral and subcutaneous adipose depots in a large animal model of naturally occurring compensated IR. AT biopsies were collected from horses, which were classified as insulin-sensitive (IS) or compensated IR based on the results of an insulin-modified frequently sampled intravenous glucose tolerance test. Protein expression of GLUT4 (major isoform) and GLUT12 (one of the most recently discovered isoforms) were measured by Western blotting in multiple AT depots, as well as AS160 (a potential key player in GLUT trafficking pathway). Using a biotinylated bis-mannose photolabeled technique, active cell surface GLUT content was quantified. Omental AT had the highest total GLUT content compared to other sites during the IS state. IR was associated with a significantly reduced total GLUT4 content in omental AT, without a change in content in other visceral or subcutaneous adipose sites. In addition, active cell surface GLUT-4, but not -12, was significantly lower in AT of IR compared to IS horses, without change in AS160 phosphorylation between groups. Our data suggest that GLUT4, but not GLUT12, is a pathogenic factor in AT during naturally occurring compensated IR, despite normal AS160 activation. ►Study of glucose transporters 4 & 12 in a large animal model of naturally occurring IR. ►Using an innovative methodology, we successfully quantified active cell surface GLUT-4 & -12 in AT. ►Sampling multiple AT depots elucidated key selective impairments in the glucose transport pathway. ►Novel mechanistic insights into AT glucose metabolism and early pathogenesis of IR.