Chronic and acute effects of thiazolidinediones BM13.1258 and BM15.2054 on rat skeletal muscle glucose metabolism.
1 New thiazolidinediones BM13.1258 and BM15.2054 were studied with regard to their PPARgamma-agonistic activities and to their acute and chronic effects on glucose metabolism in soleus muscle strips from lean and genetically obese rats. 2 Both BM13.1258 and BM15.2054 revealed to be potent PPARgamma-activators in transient transfection assays in vitro. 3 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 micromol 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 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). 5 Comparable effects on PPARgamma activation and on amelioration of insulin 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 glucose metabolism in specimens from both lean and obese rats. 7 The results provide evidence that BM13.1258 and BM15.2054 can affect muscle glucose metabolism via more than one mechanism of action. 8 Further efforts are required to clarify, to what extent other mechanisms besides insulin sensitization via the activation of PPARgamma are involved in the antidiabetic actions of thiazolidinediones.
Fürnsinn
C
C
Department of Medicine III, Division of Endocrinology & Metabolism, Währinger Gürtel 18-20, A-1090 Vienna, Austria. clemens.fuernsinn@akh-wien.ac.at
Brunmair
B
B
Meyer
M
M
Neschen
S
S
Furtmüller
R
R
Roden
M
M
Kühnle
H F
HF
Nowotny
P
P
Schneider
B
B
Waldhäusl
W
W
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D003847:Deoxyglucose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D008024:Ligands; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
C403085:BM 15.2054; D007328:Insulin; D008024:Ligands; D010080:Oxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C403084:BM 13.1258; D003847:Deoxyglucose; C089946:2,4-thiazolidinedione; D005947:Glucose