Effects of pioglitazone on intramyocellular fat metabolism in patients with type 2 diabetes mellitus

J Clin Endocrinol Metab. 2010 Apr;95(4):1916-23. doi: 10.1210/jc.2009-0911. Epub 2010 Feb 15.

Abstract

Context: Lipotoxicity (increased tissue fat content) has been implicated in the development of muscle insulin resistance and type 2 diabetes mellitus (T2DM).

Objective: The aim was to study the effect of pioglitazone on intramyocellular fat metabolism.

Research design: Twenty-four T2DM subjects (glycosylated hemoglobin = 8.3 +/- 0.4%) participated in three similar study protocols before and after 4 months of 45 mg/d pioglitazone treatment: 1) 3-h euglycemic insulin (80 mU/m(2) . min) clamp with measurement of intramyocellular fat with proton nuclear magnetic resonance; 2) vastus lateralis muscle biopsy for measurement of LC-FACoAs 60 min before start of the insulin clamp; and 3) muscle biopsy for measurement of diacylglycerol 60 min before start of the insulin clamp.

Results: In all three protocols, pioglitazone similarly reduced (all P < 0.05) the glycosylated hemoglobin (Delta = 0.8-1.2%), fasting plasma glucose (39-76 mg/dl), fasting free fatty acid (132-236 mumol/liter), and increased insulin-stimulated glucose disposal (by 25-56%). Intramyocellular fat (protocol I) declined from 1.5 to 0.9% (P < 0.05) and correlated with the increase in glucose disposal rate (r = 0.65; P < 0.05). Long chain-fatty acyl-coenzyme A decreased from 12.5 to 8.1 nmol/g (P < 0.05) and correlated with the increase in disposal rate (r = 0.76; P < 0.05). Pioglitazone therapy had no effect on muscle diacylglycerol content.

Conclusions: Pioglitazone improves insulin resistance in T2DM in association with mobilization of fat and toxic lipid metabolites out of muscle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acyl Coenzyme A / metabolism
  • Adult
  • Aged
  • Chromatography, High Pressure Liquid
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diglycerides / metabolism
  • Fatty Acids, Nonesterified / blood
  • Female
  • Glucose Clamp Technique
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Insulin Resistance / physiology
  • Lipid Metabolism / drug effects*
  • Magnetic Resonance Spectroscopy
  • Male
  • Middle Aged
  • Muscle Cells / drug effects
  • Muscle Cells / metabolism*
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Pioglitazone
  • Tandem Mass Spectrometry
  • Thiazolidinediones / therapeutic use*
  • Triglycerides / metabolism

Substances

  • Acyl Coenzyme A
  • Diglycerides
  • Fatty Acids, Nonesterified
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Thiazolidinediones
  • Triglycerides
  • Pioglitazone