The mitogen-activated protein (MAP) kinases and ribosomal S6 protein kinases in the skeletal muscle of insulin-resistant long-term (2 and 6 months' duration) diabetic rats were investigated to understand further the changes in insulin intracellular signaling pathways that accompany diabetes. The effects of insulin-mimetic vanadium compounds on the activity of these kinases were also examined. In the insulin-resistant 2-month diabetic rats, the basal activities of MAP kinases were relatively unchanged, while the basal activities of S6 kinases were significantly increased. Intravenous injection of insulin moderately activated both the 42-kDa MAP kinase (p42mapk) and a 44-kDa MAP kinase (p44erk1) in the 2-month control rats but not in the 2-month diabetic rats. Insulin treatment markedly stimulated the activity of a novel 31-kDa S6 kinase and the previously described 90-kDa ribosomal S6 kinase encoded by one of the rsk genes (p90rsk) in the 2-month control rats, while the effect was substantially reduced in the diabetic rats. In the 6-month diabetic rats, the basal phosphotransferase activities of both MAP kinases were depressed threefold or greater. This correlated with reductions in the amount of immunoreactive p42mapk and p44erk1 proteins in extracts from the diabetic rats. The basal activity of the 31-kDa S6 kinase activity was also reduced fourfold in the 6-month diabetic rats. Treatment of the 2-month diabetic rats with vanadyl sulfate resulted in euglycemia, prevented the increase in the basal activity of S6 kinase, and improved the activation of S6 kinase by insulin. Treatment of the 6-month diabetic rats with an organic vanadium compound, bis(maltolato)oxovanadium(IV), also produced euglycemia and a restoration of the basal S6 kinase activities in these rats. The present findings indicate that insulin resistance associated with long-term diabetes may be linked with depressed signaling through these kinases and that this can be rectified by vanadium-containing compounds.
Skeletal Muscle Mitogen-Activated Protein Kinases and Ribosomal S6 Kinases: Suppression in Chronic Diabetic Rats and Reversal by Vanadium
S.P. is the president, CEO, and majority stockholder of Kinetic Biotechnology, which produces the MAP kinase and S6 kinase antibodies used in this study.
ANOVA, analysis of variance; BMOV, bis(maltolato)oxovanadium(rV); ERK, extracellular signal–regulated kinases; MAP, mitogen-activated protein; MBP, myelin basic protein; p44crkl, 44-kDa mitogen-activated protein kinase encoded by the ERK1 gene; p42mapk, 42-kDa mitogen-activated protein kinase encoded by the mapk or ERK2 gene; p44mpk, 44-kDa sea star meiosis-activated protein kinase; p70S6K, 70-kDa mitogen-activated S6 protein kinase; p90rsk, 90-kDa ribosomal S6 protein kinase encoded by the rsk gene family; PAGE, polyacrylamide gel electrophoresis; SDS, sodium dodecyl sulfate; STZ, streptozotocin.
Yong-jiang Hei, Xunsheng Chen, Steven L Pelech, Jack Diamond, John H McNeill; Skeletal Muscle Mitogen-Activated Protein Kinases and Ribosomal S6 Kinases: Suppression in Chronic Diabetic Rats and Reversal by Vanadium. Diabetes 1 October 1995; 44 (10): 1147–1155. https://doi.org/10.2337/diab.44.10.1147
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