Long-term pioglitazone treatment augments insulin sensitivity and PKC- and PKC- activation in skeletal muscles in sucrose fed rats

Short title: Marková et al., Pioglitazone and muscle nPKC Summary It has been suggested that thiazolidinediones (TZDs) ameliorate insulin resistance in muscle tissue by suppressing muscle lipid storage and the activity of novel protein kinase C (nPKC) isoforms. To test this hypothesis, we analyzed long-term metabolic effects of pioglitazone and the activation of nPKC-and- isoforms in an animal model of the metabolic syndrome, the spontaneously hypertensive rat (a congenic SHR strain with wild type Cd36 gene) fed a diet with 60% sucrose from the age of 4 to 8 months. Compared to untreated controls, pioglitazone treatment was associated with significantly increased basal (809±36 vs 527±47 nmol glucose/g/2h, P<0.005) and insulin stimulated glycogenesis (1321±62 vs 749±60 nmol glucose/g/2h, P<0.0001) in isolated gastrocnemius muscles despite increased concentrations of muscle triglycerides (3.83±0.33 vs 2.25±0.12 mol/g, P<0.005). Pioglitazone treated rats compared to untreated controls exhibited significantly increased membrane/total (cytosolic plus membrane) ratio of both PKC- and PKC- isoforms. These results suggest that amelioration of insulin resistance after long-term pioglitazone treatment is associated with increased activation of PKC- and- isoforms increased lipid concentration in skeletal muscles.