Peroxisome proliferator-activated receptor-γ coactivator-1 and insulin resistance: acute effect of fatty acids

• Published in: Diabetologia 2006-10, Vol.49 (10), p.2419-2426
• Main Authors: Hoeks, J, Hesselink, M. K. C, Russell, A. P, Mensink, M, Saris, W. H. M, Mensink, R. P, Schrauwen, P
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Blood Glucose - metabolism; Body Mass Index; Carrier Proteins - genetics; Diabetes. Impaired glucose tolerance; Emulsions; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; fatty acids; Fatty Acids, Nonesterified - administration & dosage; Fatty Acids, Nonesterified - blood; Fatty Acids, Nonesterified - pharmacology; Glucose Clamp Technique; Heat-Shock Proteins - genetics; Humans; insulin resistance; Insulin Resistance - physiology; lipid metabolism; Male; Medical sciences; Muscle, Skeletal - drug effects; Muscle, Skeletal - physiology; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PGC1; PPAR alpha - genetics; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors - genetics; Transcription Factors - physiology; Type 2 diabetes mellitus
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-006-0369-2

Aims/hypothesis Peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1 (PPARGC1), a coactivator regulating the transcription of genes involved in oxidative metabolism, is downregulated in patients with type 2 diabetes and in their first-degree relatives. Whether this downregulation is a cause or effect of early aberrations in the development of insulin resistance, such as disturbances in fat metabolism, is unknown. We examined whether lipid-induced insulin resistance was associated with downregulation of expression of skeletal muscle genes involved in oxidative metabolism and mitochondrial biogenesis in humans. Materials and methods Nine healthy lean male subjects underwent a 6-h hyperinsulinaemic-euglycaemic clamp with simultaneous infusion of either a lipid emulsion or glycerol as a control. Blood was sampled at regular time points and muscle biopsies were taken before and after every test. Intramuscular triacylglycerol (IMTG) content was determined by Oil Red O staining and gene expression was measured by quantitative PCR. Results Lipid infusion resulted in a ~2.7-fold increase in plasma NEFA levels and a 31±6% decrease in insulin sensitivity (p=0.001). The infusion of lipids resulted in a ~1.6-fold increase in IMTG (p=0.02), whereas during the clamp with glycerol infusion IMTG tended to decrease to ~53% of preinfusion levels (p=0.065). Lipid infusion decreased PPARGC1A, PPARGC1B and PPARA expression to ~61, 77 and ~52% of basal values respectively, whereas expression of uncoupling protein 3 was upregulated 1.8-fold (all p