UBC Theses and Dissertations
Effects of BMOV on protein-serine kinase activities in skeletal muscle of diabetic rats Girn, Jaspal S.
The in vivo effects of bis (maltolato) oxovanadium (IV) (BMOV) on the activity of various protein kinases in two cascades that are implicated as upstream mediators of the biological effects of insulin were investigated. The integrity of the MAP kinase pathway was evaluated by studying the activation of ERK1, ERK2 and p90[sup rsk]. The activity of p70[sup s6k] was also evaluated as a possible downstream enzyme in insulin action . The intact rat served as a convenient animal model system to study the mechanism of insulin action. Hind limb muscle extracts were prepared and subjected to specific immunoprecipitation experiments for the kinases mentioned above. The first part of the study examined the effects of BMOV on protein-serine kinases in Zucker Diabetic Fatty (ZDF) rats. The Zucker Diabetic Fatty (ZDF) provided an ideal model to study the activity of protein kinases in noninsulindependent diabetes mellitus (N1DDM), as the development of the disease in these rats closely parallels NIDDM in humans. BMOV treatment for 8 weeks significantly (p < 0.05) decreased the basal activity of p70[sup s6k] by 30% when compared to the untreated group. Furthermore, following BMOV treatment the basal kinase activity of ERK-1 and ERK-2 significantly decreased by 40% and 35%, respectively, when compared to the untreated group. p90[sup rsk] is postulated to be downstream of ERK-2 and any changes in ERK-2 could be reflected in the activity of p90[sup rsk]. BMOV treatment decreased p90[sup rsk] activity by approximately 75% when compared to the untreated group. The activity of protein kinases was also investigated in the Streptozotocin (STZ) Diabetic Wistar rat. This model is representative of insulindependent diabetes melliuts (IDDM), because the chemical, STZ destroys the pancreatic (3-cells. p70[sup s6k] activity was altered basally and following 5 U/kg insulin stimulation in STZ-diabetic rats and BMOV treatment for 8 weeks was unable to restore the activity to control values. In addition, ERK-1 and ERK-2 are markedly active in the diabetic state following stimulation with 5 U/kg insulin when compared to control. The activity of both ERK-1 and ERK-2 was 5 fold greater than basal control. Chronic BMOV treatment was able to restore the activity of ERK-2 in the diabetic treated animals to normal, whereas the activity of ERK-1 was unaffected. Finally, there appears to be a dissociation between ERK-2 and p90[sup rsk]. 5 U/kg insulin was required to activate ERK-2 to its maximal level, whereas 10 U/kg was required to achieve maximal activity of p90[sup rsk]. In the diabetic state, ERK-2 activity was markedly active in response to insulin stimulation, whereas p90[sup rsk] showed no change. Finally, BMOV treatment decreased the activity of ERK-2, whereas p90[sup rsk] activity was increased with BMOV treatment.
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