Effect of hyperglycemia on signal transduction in skeletal muscle from diabetic Goto-Kakizaki rats.
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)zeta activity was not altered. Interestingly, basal PKCzeta activity was increased under hyperglycemic conditions in GK and Wistar rats. This finding of increased PKCzeta 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 PKCzeta, because an increase in phosphorylation of PKCalpha/beta and PKCdelta, but not PKCtheta, 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, PKCalpha/beta, PKCdelta, and PKCzeta 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.
Steiler
Tatiana L
TL
Department of Physiology and Pharmacology, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
Galuska
Dana
D
Leng
Ying
Y
Chibalin
Alexander V
AV
Gilbert
Marc
M
Zierath
Juleen R
JR
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D000074121:Protein Kinase C-theta; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000099221:Protein Kinase C zeta
D064413:3-Phosphoinositide-Dependent Protein Kinases; D005947:Glucose; D007328:Insulin; D007527:Isoenzymes; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D019000:Phosphotyrosine; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D000074121:Protein Kinase C-theta; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000099221:Protein Kinase C zeta; C497260:Prkcd protein, rat; C494920:Akt1 protein, rat; C489591:Prkcq protein, rat