Previous studies have shown that T3 coordinately stimulates GLUT4-glucose transporter messenger RNA (mRNA) and protein expression in mixed fiber-type skeletal muscle of the rat and produces a concomitant elevation in basal (noninsulin mediated) glucose uptake. The aim of the present study was to 1) determine the precise mechanism(s) for the T3-induced expression of GLUT4 in skeletal muscle, and 2) investigate the potential benefits of T3 on noninsulin dependent diabetes mellitus (NIDDM). Ten daily ip injections of T3 (100 micrograms/100 g BW) administered to hypothyroid male Sprague-Dawley rats, increased both GLUT4 mRNA and transcription approximately 70% (P < 0.05) in mixed fiber-type hindlimb skeletal muscle. Transcriptional induction was subsequently defined to be restricted to red (oxidative) muscle fibers (2.5-fold; P < 0.05), whereas GLUT4 protein was increased in both red and white (glycolytic) skeletal muscle. GLUT4 mRNA and protein expression were similarly inducible in the skeletal muscle of insulin-resistant Zucker rats. More importantly, T3 treatment totally ameliorated hyperinsulinemia in obese animals (P < 0.001), although their moderately elevated plasma glucose levels were not significantly altered. In conclusion, regulation of GLUT4 expression by T3 was shown to lie at the transcriptional level in red skeletal muscle, whereas in white muscle fiber types, it appears to operate via an alternative posttranscriptional mechanism. These data also support the potential of hormonally inducing glucose transporter expression in insulin-resistant muscle. However, high levels of T3 are associated with a number of adverse side-effects, in particular the stimulation of hepatic gluconeogenesis. Nevertheless, future studies may demonstrate, e.g. subthyrotoxic levels, to be similarly effective but without side effects, and thus perhaps find a clinical application in reducing both hyperinsulinemia and hyperglycemia in NIDDM.