| Summary: | 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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