Direct Thiazolidinedione Action on Isolated Rat Skeletal Muscle Fuel Handling Is Independent of Peroxisome Proliferator–Activated Receptor-γ−Mediated Changes in Gene Expression

Q1 · MEDICINE

Article

Author: Gras, Florian ; Wagner, Ludwig ; Roden, Michael ; Fürnsinn, Clemens ; Neschen, Susanne ; Brunmair, Barbara ; Waldhäusl, Werner

Thiazolidinediones (TZDs) are believed to induce insulin sensitization by modulating gene expression via agonistic stimulation of the nuclear peroxisome proliferator–activated receptor-γ (PPAR-γ). We have shown earlier that the TZD troglitazone inhibits mitochondrial fuel oxidation in isolated rat skeletal muscle. In the present study, rat soleus muscle strips were exposed to TZDs to examine whether the inhibition of fuel oxidation is mediated by PPAR-γ activation. Our findings consistently indicated direct, acute, and PPAR-γ−independent TZD action on skeletal muscle fuel metabolism. Rapid stimulation of lactate release by 20 μmol/l troglitazone within 30 min suggested that direct TZD action on skeletal muscle in vitro does not rely on changes in gene expression rates (12.6 ± 0.6 [control] vs. 16.0 ± 0.8 μmol · g−1 · h−1 [troglitazone]; P < 0.01). This conclusion was supported by the failure of actinomycin D and cycloheximide to block the effects of troglitazone. Mitochondrial fuel oxidation was consistently inhibited by six different TZDs (percent inhibition of CO2 production from palmitate after 25 h: troglitazone, −61 ± 2%; pioglitazone, −43 ± 7% ; rosiglitazone, −22 ± 6%; BM13.1258, −47 ± 9%; BM15.2054, −51 ± 4%; and T-174, −59 ± 4% [P < 0.005 each]), but not by PPAR-γ agonistic compounds not belonging to the TZD class (JTT-501, −5 ± 7% [NS]; prostaglandin J2, 17 ± 7% [P < 0.05]), which further argues against dependence on PPAR-γ activation. In summary, our findings provided good evidence that direct inhibition of mitochondrial fuel oxidation in isolated skeletal muscle is a group-specific effect of TZDs and is independent of PPAR-γ−mediated gene expression.

01 Nov 1999·British Journal of Pharmacology

Chronic and acute effects of thiazolidinediones BM13.1258 and BM15.2054 on rat skeletal muscle glucose metabolism

Article

Author: C Fürnsinn ; S Neschen ; W Waldhäusl ; M Meyer ; H F Kühnle ; B Schneider ; P Nowotny ; M Roden ; B Brunmair ; R Furtmüller

New thiazolidinediones BM13.1258 and BM15.2054 were studied with regard to their PPARγ‐agonistic activities and to their acute and chronic effects on glucose metabolism in soleus muscle strips from lean and genetically obese rats.

Both BM13.1258 and BM15.2054 revealed to be potent PPARγ‐activators in transient transfection assays in vitro.

In insulin‐resistant obese rats, but not in lean rats, 10 days of oral treatment with either compound increased the stimulatory effect of insulin on muscle glycogen synthesis to a similar extent (insulin‐induced increment in μmol 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).

In parallel to insulin sensitization, mean glucose oxidation increased insulin‐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 was hardly seen in response to BM15.2054 (to 137 and 124% of control, respectively; ns).

Comparable effects on PPARγ activation and on amelioration of insulin resistance by BM13.1258 and BM15.2054 were therefore opposed by different effects on glucose oxidation.

In contrast to chronic oral treatment, acute exposure of muscles to BM13.1258 or BM15.2054 in vitro elicited a distinct catabolic response of glucose metabolism in specimens from both lean and obese rats.

The results provide evidence that BM13.1258 and BM15.2054 can affect muscle glucose metabolism via more than one mechanism of action.

Further efforts are required to clarify, to what extent other mechanisms besides insulin sensitization via the activation of PPARγ are involved in the antidiabetic actions of thiazolidinediones.

British Journal of Pharmacology (1999) 128, 1141–1148; doi:10.1038/sj.bjp.0702886

100 Deals associated with BM-152054

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Preclinical	United States	Roche Holding AG	-
Obesity	Preclinical	United States	Roche Holding AG	-

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