S26948, a new specific peroxisome proliferator activated receptor gamma modulator improved in vivo hepatic insulin sensitivity in 48 h lipid infused rats.
We examined whether S26948, a new specific peroxisome proliferator activated receptor gamma modulator prevented insulin-resistance induced by a 48 h intralipid-infusion in normal rat (IL rats). The effect of S26948 (30 mg/kg) was compared to rosiglitazone (10 mg/kg). Rats were catheterized in the right jugular vein 4 days before the beginning of the 48 h lipid or saline infusions. Animals were intraperitoneally injected once daily with vehicle, S26948 or rosiglitazone. At the end of the infusion the rats underwent either a glucose tolerance test or a euglycemic-hyperinsulinemic clamp. Finally isolation and incubation of hepatocytes in another series of rats were performed. Intralipid infusion leads to a 4-fold increase in plasma free fatty acid concentration compared to controls (C). Both S26948 and rosiglitazone decreased plasma free fatty acid concentration in IL rats compared to vehicle treated IL rats. Glucose-induced insulin secretion was significantly increased in IL compared to C and was associated with insulin resistance. Both S26948 and rosiglitazone treatments normalized glucose-induced insulin secretion and improved insulin action in IL rats. However, S26948 specifically improved hepatic insulin sensitivity whereas rosiglitazone improved both hepatic insulin sensitivity and insulin-stimulated glucose utilization. Finally, studies on isolated hepatocytes showed differential effect of both compounds on gene expression of key enzymes of glucose metabolism. Our data show that non thiazolidinedione S26948 may represent an alternative way for the management of dysregulated hepatic insulin sensitivity.
Sohn
Kyung-Ah Kim
KA
University Paris Diderot, CNRS, Paris, France.
Cruciani-Guglielmacci
Céline
C
Kassis
Nadim
N
Clément
Laurence
L
Ouali
Fetta
F
Caüzac
Michèle
M
Lebègue
Nicolas
N
Berthelot
Pascal
P
Caignard
Daniel-Henri
DH
Pégorier
Jean-Paul
JP
Renard
Pierre
P
Dacquet
Catherine
C
Ktorza
Alain
A
Magnan
Christophe
C
D052242:Adiponectin / Q000097:blood / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000037:antagonists & inhibitors; D015309:Glucose Clamp Technique; D006493:Heparin / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D007262:Infusions, Intravenous; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000819:agonists / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D000077154:Rosiglitazone; D012501:Saphenous Vein; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors
D052242:Adiponectin; D052160:Benzothiazoles; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; C541482:S26948; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D006493:Heparin; D005947:Glucose