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1 Diabetes and Metabolism Unit and 2 Obesity Research Center, Department of Medicine, and 3 Department of Physiology, Boston University Medical Center, Boston, Massachusetts 02118
Numerous studies have shown a
correlation between changes in protein kinase C (PKC) distribution
and/or activity and insulin resistance in skeletal muscle. To
investigate which PKC isoforms might be involved and how they affect
insulin action and signaling, studies were carried out in rat soleus
muscle incubated with phorbol esters. Muscles preincubated for 1 h
with 1 µM phorbol 12,13-dibutyrate (PDBu) showed an impaired ability
of insulin to stimulate glucose incorporation into glycogen and a
translocation of PKC-
, -
I, -
, and -
, and probably -II,
from the cytosol to membranes. Preincubation with 1 µM PDBu decreased
activation of the insulin receptor tyrosine kinase by insulin and to an
even greater extent the phosphorylation of Akt/protein kinase B and
glycogen synthase kinase-3. However, it failed to diminish the
activation of phosphatidylinositol 3'-kinase by insulin. Despite these
changes in signaling, the stimulation by insulin of glucose transport
(2-deoxyglucose uptake) and glucose incorporation into lipid and
oxidation to CO2 was unaffected. The results indicate that
preincubation of skeletal muscle with phorbol ester leads to a
translocation of multiple conventional and novel PKC isoforms and to an
impairment of several, but not all, events in the insulin-signaling
cascade. They also demonstrate that these changes are associated with
an inhibition of insulin-stimulated glycogen synthesis but that, at the
concentration of PDBu used here, glucose transport, its incorporation
into lipid, and its oxidation to CO2 are unaffected.
protein kinase C; phorbol dibutyrate; Akt/protein kinase B; glycogen synthase kinase-3; soleus muscle
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