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Effect of Hyperglycemia on Signal Transduction in Skeletal Muscle from Diabetic Goto-Kakizaki Rats

Departments of Physiology and Pharmacology (T.L.S., D.G.) and Surgical Sciences (Y.L., A.V.C., J.R.Z.), Section for Integrative Physiology, Karolinska Institutet, SE-17177 Stockholm, Sweden; and Laboratoire de Physiopathologie de la Nutrition (M.G.), Universite Paris 7, 75251 Paris, France

Address all correspondence and requests for reprints to: Juleen R. Zierath, Ph.D., Professor of Physiology, Department of Surgical Sciences, Section for Integrative Physiology, Karolinska Institutet, von Eulers väg 4, II, SE-171 77 Stockholm, Sweden. E-mail: Juleen.Zierath{at}fyfa.ki.se.

We determined basal and insulin-stimulated responses on signaling intermediates in soleus skeletal muscle from male Wistar and diabetic Goto-Kakizaki (GK) rats. Rats were infused with glucose (5 or 20 mM) for 3 h, followed by a continuous infusion of saline or insulin (3 U/kg·h) for 20 min. Under euglycemic and hyperglycemic conditions, basal and insulin-stimulated action on phosphatidylinositol (PI) 3-kinase, protein kinase B/Akt, and ERK were reduced in GK rats, whereas insulin-stimulated protein kinase C (PKC) activity was not altered. Interestingly, basal PKC activity was increased under hyperglycemic conditions in GK and Wistar rats. This finding of increased PKC activity was confirmed in vitro in isolated soleus muscle exposed to high extracellular glucose, and occurred concomitant with an increase in PI-dependent kinase 1 (PDK-1) activity. The glucose effects were not specific to PKC, because an increase in phosphorylation of PKC/ß and PKC, but not PKC, in isolated soleus muscle exposed to 25 mM glucose was observed. In conclusion, insulin signaling defects in diabetic GK rats are not corrected by an acute normalization of glycemia. Interestingly, acute hyperglycemia leads to a parallel increase in PDK-1, PKC/ß, PKC, and PKC phosphorylation/activity via a PI 3-kinase-protein kinase B/Akt-independent mechanism. The long-term consequence of elevated PDK-1 and PKC phosphorylation/activity should be considered in the context of diabetes mellitus, as hyperglycemia is a clinical feature of this disease.

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