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Agonist) Action
Department of Clinical Biochemistry (J.R.Z., J.W.R.), Karolinska Hospital, Karolinska Institute, S-171 76 Stockholm, Sweden; and Department of Molecular Endocrinology (T.D., J.W., M.W., J.V., Z.L., C.M., J.B., B.Z., D.E.M.) Merck Research Laboratories, Rahway, New Jersey 07065
Address all correspondence and requests for reprints to: David E. Moller, M.D., Director, Molecular Endocrinology, Merck Research Laboratories, RY80T-100, 126 East Lincoln Avenue, Rahway, New Jersey 07065. E-mail: david_moller{at}merck.com
Thiazolidinedione (TZD) insulin sensitizers are specific agonists of
peroxisome proliferator activated receptor (PPAR)
. However, their
mechanism of action and the in vivo target tissue(s)
that mediate insulin sensitization remain poorly defined. Although
PPAR messenger RNA expression has been reported in skeletal muscle,
the expression of PPAR within myocytes in intact muscle tissue has
not been examined. An antipeptide PPAR antibody was generated;
immunohistochemistry was then used to demonstrate that PPAR is
present within nuclei of myocytes [in both skeletal (white and red
fibers) and cardiac tissue (rodent and human)]. The effect of insulin
sensitizer treatment on muscle insulin action was studied using
ob/ob mice after 4 days dosing with a potent (6
nM PPAR Kd) TZD (10 mg/kg·day).
2-deoxyglucose (2-DOG) uptake was then assessed in freshly isolated
soleus muscles from lean vs. ob/ob vs. TZD-treated
ob/ob mice. In lean mouse muscles, 2-DOG uptake was
stimulated by 82%, 95%, 165% (with 25, 100, 2000 µU/ml insulin);
muscles from ob/ob were severely insulin resistant
(<80% stimulation with 2000 µU/ml insulin). Muscles from
TZD-treated ob/ob displayed a normal insulin response
with 100 (71%) or 2000 (158%) µU/ml insulin. Additional studies
were performed using ZDF rats treated with/without TZD for 7 days.
In vivo 2-DOG glucose uptake into soleus, gastrocnemius,
and diaphragm muscles was measured during euglycemic-hyperinsulinemic
clamp. Compared with lean rats, muscle 2-DOG uptake in ZDF was reduced
by 52% (soleus) or 71% (diaphragm). Partial (40–60%) normalization
of the reduced 2-DOG uptake was evident in TZD-treated ZDF rats. In
contrast to the effect of in vivo treatment on muscle
insulin action, preincubation of isolated soleus muscles from naive
lean or ob/ob mice for 5 h with 100 nM TZD did not
affect insulin-stimulated 2-DOG uptake. We conclude: 1) PPAR is
expressed in myocytes within skeletal and cardiac muscle. 2) In
vivo activation of PPAR by treatment of insulin-resistant
mice/rats with a potent TZD corrects impaired muscle insulin action. 3)
The lack of a direct effect on muscle after 5 h in
vitro TZD incubation suggests that changes in insulin action
may require a longer duration of PPAR activation or that improved
muscle insulin sensitivity may result from an indirect in
vivo effect of PPAR activation (e.g. changes
in systemic lipid metabolism).
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