Age and muscle-type modulated role of intramyocellular lipids in the progression of insulin resistance in nondiabetic Zucker rats

The effect of muscle fiber type and maturation on intramyocellular lipid (IMCL) content and its relationship to insulin resistance was investigated. Intramyocellular lipid content in slow-twitch (soleus) and fast-twitch (tibialis anterior, TA) muscles of fa/fa (Zucker fatty rat, ZFR) and age-matched lean (Zucker lean rat, ZLR) Zucker rats were repeatedly measured over 3 months. Intramyocellular lipid levels in both the soleus and the TA were significantly higher in the ZFR relative to the ZLR. For the ZFR, IMCLTA increased by ~2-fold from 5.3 to 8.4 weeks of age. No subsequent accumulation of IMCLTA occurred in ZFR from 8.4 up to 13.1 weeks of age. For ZLR, IMCLTA contents steadily decreased from 6.6 to 13.1 weeks of age (−77%, P < .05). In contrast, IMCL levels in the soleus were not significantly altered in either rat strain over the course of the study. Maximum impairment in whole-body insulin sensitivity in ZFR was observed at 9-weeks of age, concomitant with peak IMCLTA accumulation. Insulin-stimulated 2-deoxy-d-glucose (2DG) transport in the TA muscle of 10.2- and 14.1-week-old ZFR was significantly impaired relative to age-matched ZLR. Insulin-stimulated glucose uptake in the soleus of ZFR and ZLR decreased (P < .05) as the animals matured (ZFR, −49%; ZLR, −69%). Overall, these results support the hypothesis that fast-twitch glycolytic muscles play a major role during the onset of insulin resistance. In addition, proper timing may govern the success of a pharmacological studies aimed at measuring the impact of insulin-sensitizing drugs on IMCL.