title: Prior thiazolidinedione treatment preserves insulin sensitivity in normal rats during acute fatty acid elevation: role of the liver.
abstract: Thiazolidinediones lower lipids, but it is unclear whether this is essential for their insulin-sensitizing action. We investigated relationships between lipid-lowering and insulin-sensitizing actions of a thiazolidinedione. Normal rats were pretreated with or without Pioglitazone (Pio, 3 mg/kg.d) for 2 wk. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp with elevation of free fatty acids (FFA) by Intralipid/heparin infusion over 6 h. In untreated rats insulin sensitivity decreased by 46% over 3-6 h of elevated FFA, whereas it remained normal but with a 50% increase in FFA clearance in Pio-treated rats. After matching plasma FFA, insulin sensitivity was still partially (30%) protected in Pio-treated rats, substantially by maintaining insulin suppressibility of hepatic glucose output. This was associated with lower hepatic long-chain acyl-coenzyme A. Plasma adiponectin was increased 2-fold in Pio-treated rats and was negatively correlated with hepatic glucose output (r2 = 0.70, P < 0.001) and liver long-chain acyl-coenzyme A (r2 = 0.39, P < 0.005). Pio-induced muscle insulin sensitization was largely diminished after matching plasma FFA elevation, but insulin-stimulated protein kinase B phosphorylation was protected. We conclude that thiazolidinediones can protect against lipid-induced insulin resistance with a significant component (mainly liver) of the protective effect not requiring lipid lowering. This may be related to chronic elevation of adiponectin by thiazolidinediones.
authors.affiliation: Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales 2010, Australia. j.ye@garvan.org.au
authors.forename: Ji-Ming
authors.initials: JM
authors.lastname: Ye
authors.forename: Georgia
authors.initials: G
authors.lastname: Frangioudakis
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Iglesias
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Furler
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Ellis
authors.forename: Nicholas
authors.initials: N
authors.lastname: Dzamko
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cooney
authors.forename: Edward W
authors.initials: EW
authors.lastname: Kraegen
mesh_terms: D000214:Acyl Coenzyme A / Q000032:analysis; D052242:Adiponectin; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005217:Fat Emulsions, Intravenous / Q000008:administration & dosage; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006493:Heparin / Q000008:administration & dosage; D006946:Hyperinsulinism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D000077205:Pioglitazone; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones
chemical_list: D000214:Acyl Coenzyme A; D052242:Adiponectin; D001786:Blood Glucose; D005217:Fat Emulsions, Intravenous; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D006493:Heparin; C089946:2,4-thiazolidinedione; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; D000077205:Pioglitazone