C. Furnsinn et al., Chronic and acute effects of thiazolidinediones BM13.1258 and BM15.2054 onrat skeletal muscle glucose metabolism, BR J PHARM, 128(6), 1999, pp. 1141-1148
1 New thiazolidinediones BM13.1258 and BM15.2054 were studied with regard t
o their PPAR gamma-agonistic activities and to their acute and chronic effe
cts on glucose metabolism in soleus muscle strips from lean and genetically
obese rats.
2 Both BM13.1258 and BM15.2054 revealed to be potent PPAR gamma-activators
in transient transfection assays in vitro.
3 In insulin-resistant obese rats, but not in lean rats, 10 days of oral tr
eatment with either compound increased the stimulatory effect of insulin on
muscle glycogen synthesis to a similar extent (insulin-induced increment i
n mu mol glucose incorporated into glycogen g(-1) h(-1): control, + 1.19 +/
- 0.28; BM13.1258, + 2.50 +/- 0.20; BM15.2054, + 2.55 +/- 0.46; P < 0.05 vs
control each).
4 In parallel to insulin sensitization, mean glucose oxidation increased in
sulin-independently in response to BM13.1258 (to 191 and 183% of control in
the absence and presence of insulin, respectively; P < 0.01 each), which w
as hardly seen in response to BM15.2054 (to 137 and 124% of control, respec
tively; ns).
5 Comparable effects on PPAR gamma activation and on amelioration of insuli
n resistance by BM13.1258 and BM15.2054 were therefore opposed by different
effects on glucose oxidation.
6 In contrast to chronic oral treatment, acute exposure of muscles to BM13.
1258 or BM15.2054 in vitro elicited a distinct catabolic response of glucos
e metabolism in specimens from both lean and obese rats.
7 The results provide evidence that BM13.1258 and BM15.2054 can affect musc
le glucose metabolism via more than one mechanism of action.
8 Further efforts are required to clarify, to what extent the activation of
PPAR gamma are involved sensitization via thiazolidinediones. other mechan
isms besides insulin in the antidiabetic actions of thiazolidinediones.