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J. Biol. Chem., Vol. 265, Issue 28, 16880-16885, 10, 1990
J Turinsky, DM O'Sullivan and BP Bayly
Phorbol esters have been reported to decrease sensitivity or responsiveness
to insulin in cells in vitro. Since phorbol esters are analogues of
endogenously produced 1,2-diacylglycerol, the present study investigated
whether 1,2-diacylglycerol concentration is elevated in insulin-resistant
tissues of the rat in vivo. Studies were done on 11-12-week-old genetically
obese Zucker rats, which are insulin- resistant. Lean Zucker rats served as
controls. Levels of 1,2- diacylglycerol in obese rats were increased 82% in
liver, 136% in calf muscles, 72% in soleus muscle, a slow-twitch muscle,
and 40% in plantaris muscle, a fast-twitch muscle. Ceramide levels in the
same tissues were increased 26, 52, 69, and 13%, respectively. Studies were
also done on normal, non-obese Sprague-Dawley rats 3 h, 1, 3, 8, and 15
days after interrupting the nerve supply to hindlimb muscles. We have
previously shown that 3-17 days after denervation, soleus muscles are
completely unresponsive to insulin and do not increase glucose uptake in
response to insulin stimulation in vivo, whereas plantaris muscles show a
normal glucose uptake when stimulated by insulin; however, the
insulin-induced increment in glucose uptake is reduced 68% because it is
superimposed on already elevated basal glucose uptake (Turinsky, J. (1987)
Am. J. Physiol. 252, R531-R537). In the present study, the denervated
soleus muscles exhibited a sustained increase of 23-56% in
1,2-diacylglycerol concentration between 3 h and 15 days after interruption
of nerve supply. The denervated soleus muscles also showed 34 and 42%
increases in ceramide concentration at 3 and 8 days after denervation,
respectively. In contrast, no increases in 1,2- diacylglycerol
concentration were observed in plantaris muscles at shorter intervals than
15 days after denervation. Ceramide concentrations in plantaris muscles
were increased 43 and 75% at 8 and 15 days after denervation, respectively.
These observations demonstrate that tissue insulin resistance is frequently
associated with a long term increase in tissue 1,2-diacylglycerol
concentration. This suggests the possibility that augmented
1,2-diacylglycerol levels contribute to the development of some types of
tissue insulin resistance.
1,2-Diacylglycerol and ceramide levels in insulin-resistant tissues of the rat in vivo
Department of Physiology and Cell Biology, Albany Medical College, New York 12208.
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