Discordance between intramuscular triglyceride and insulin sensitivity in skeletal muscle of Zucker diabetic rats after treatment with fenofibrate and rosiglitazone.
OBJECTIVE
Intramyocellular triglyceride (IMTG) correlates with insulin resistance, but there is no clear causal relationship. Insulin resistance and associated hyperinsulinaemia may increase IMTG, via the insulin-regulated transcription factor, sterol regulatory element-binding protein 1 (SREBP-1). PPAR agonists may also affect IMTG via changes in insulin sensitivity, SREBP-1 or other factors.


METHODS
We examined skeletal muscle IMTG and SREBP-1 expression, and metabolic parameters in Zucker diabetic fatty rats (ZDF) after 25 weeks of PPAR-gamma or PPAR-alpha administration.


RESULTS
Compared with Zucker lean rats (ZL), untreated ZDF had significantly higher weights, serum glucose, insulin, free fatty acids, total cholesterol and triglycerides. IMTG and SREBP-1c messenger RNA (mRNA) were also higher in untreated ZDF; both were decreased by fenofibrate (FF). Rosiglitazone (Rosi), despite marked improvement in glycaemia, hyperinsulinaemia and hyperlipidaemia, failed to affect SREBP-1 expression, and increased body weight and IMTG. Rosi/FF combination caused less weight gain and no IMTG increase, despite metabolic effects similar to Rosi alone.


CONCLUSIONS
IMTG and SREBP-1c mRNA are high in the ZDF. FF and Rosi both improved insulin sensitivity but had opposite effects on IMTG. Thus, there was a clear discordance between insulin sensitivity and IMTG with PPAR agonists, indicating that IMTG and insulin sensitivity do not share a simple relationship.
Nadeau
K J
KJ
Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO, USA. nadeaukj@hotmail.com
Ehlers
L B
LB
Aguirre
L E
LE
Reusch
J E B
JE
Draznin
B
B
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D011345:Fenofibrate / Q000494:pharmacology / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D047493:PPAR alpha; D051381:Rats; D011924:Rats, Zucker / Q000033:anatomy & histology / Q000378:metabolism; D000077154:Rosiglitazone; D051780:Sterol Regulatory Element Binding Protein 1; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use; D014280:Triglycerides / Q000378:metabolism*
D001786:Blood Glucose; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007328:Insulin; D047493:PPAR alpha; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone; D011345:Fenofibrate