AMELIORATION OF INSULIN-RESISTANCE IN STREPTOZOTOCIN-DIABETIC MICE BYTRANSGENIC OVEREXPRESSION OF GLUT4 DRIVEN BY AN ADIPOSE-SPECIFIC PROMOTERS

In diabetic rodents and humans, glucose transporter 4 (GLUT4) expressi on is suppressed in adipocytes in association with insulin resistance. Transgenic mice overexpressing GLUT4 selectively in fat have enhanced glucose disposal in vivo and massively increased glucose transport in adipocytes. To determine whether overexpression can be maintained in diabetes and whether it can prevent insulin resistance, we rendered wi ld-type and transgenic mice diabetic with streptozotocin. After 12-14 days, blood glucose was more than 21.4 mM and plasma insulin was 1.06 ng/ml or less in both diabetic groups in the fed state. Body weight wa s reduced and gonadal fat pad weight and adipocyte size were 52-75% sm aller in both nontransgenic and transgenic diabetic mice? compared wit h nondiabetic. Basal and maximally-stimulated rates of lipolysis were similar in adipocytes from nontransgenic and transgenic mice, but the ED(50) for isoproterenol nontransgenic diabetic mice, GLUT4 protein Na s reduced 34%, with a 46% reduction in insulin stimulated glucose tran sport. In contrast, in adipocytes of transgenic diabetic mice, GLUT4 r emained 21-fold overexpressed, resulting in al-fold increased basal an d 10-fold increased insulin stimulated glucose transport. Injection of insulin (0.7 mU/g BW) resulted in a 35% decrease in blood glucose in transgenic diabetic mice (P < 0.05), with no effect in nontransgenic d iabetic mice. Thus, high-level overexpression of GLUT4 driven by a fat specific promoter can be maintained with insulinopenic diabetes, even when fat cell metabolism is markedly altered. Overexpression of GLUT4 in adipocytes prevents insulin resistant glucose transport at the cel lular level and improves insulin action in vivo, even with overt diabe tes.