Prior thiazolidinedione treatment preserves insulin sensitivity in normal rats during acute fatty acid elevation: role of the liver

Endocrinology. 2002 Dec;143(12):4527-35. doi: 10.1210/en.2002-220387.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl Coenzyme A / analysis
  • Adiponectin
  • Animals
  • Blood Glucose / metabolism
  • Fat Emulsions, Intravenous / administration & dosage
  • Fatty Acids, Nonesterified / blood*
  • Glucose / metabolism
  • Glucose Clamp Technique
  • Heparin / administration & dosage
  • Hyperinsulinism
  • Hypoglycemic Agents / pharmacology*
  • Insulin / pharmacology
  • Insulin Resistance*
  • Intercellular Signaling Peptides and Proteins*
  • Liver / drug effects
  • Liver / physiology*
  • Male
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Phosphorylation
  • Pioglitazone
  • Protein-Serine-Threonine Kinases*
  • Proteins / analysis
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Wistar
  • Thiazoles / pharmacology*
  • Thiazolidinediones*

Substances

  • Acyl Coenzyme A
  • Adiponectin
  • Blood Glucose
  • Fat Emulsions, Intravenous
  • Fatty Acids, Nonesterified
  • Hypoglycemic Agents
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Thiazoles
  • Thiazolidinediones
  • Heparin
  • 2,4-thiazolidinedione
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glucose
  • Pioglitazone