TITLE

In Vitro Responsiveness of Skeletal Muscle Cell PPAR-delta Reflects In Vivo Insulin Sensitivity of the Muscle Cell Donors

AUTHOR(S)
Staiger, Harald; Machicao, Fausto; Fritsche, Andreas; Stefan, Norbert; Haering, Hans-Ulrich
PUB. DATE
June 2007
SOURCE
Diabetes;Jun2007 Supplement 1, Vol. 56, pA86
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
The transcription factor peroxisome proliferator-activated receptor delta (PPAR-delta) regulates muscular oxidative metabolism, and the oxidative capacity of skeletal muscle is thought to be positively associated with wholebody insulin sensitivity. Therefore, we asked whether human myocellular mRNA expression of PPARD (encoding PPAR-delta) is a determinant of insulin sensitivity. Myotubes were derived from 38 healthy non-diabetic donors. Gene expression was quantified by RT-PCR. Donors' insulin sensitivity was calculated from fasting, OGTT- and hyperinsulinemic-euglycemic clamp-derived plasma insulin and glucose concentrations. In human myotubes, basal mRNA levels of PPARD and its target gene PDK4 were significantly correlated (p=0.0312). Basal PPARD mRNA expression did not correlate with donors' anthropometric data, fasting plasma glucose, insulin, and lipid concentrations, or with insulin sensitivity. Basal PDK4 mRNA levels correlated with fasting plasma fatty acid concentrations only. Treatment with the selective high-affinity PPAR-delta agonist GW501516 did not result in an increase in PPARD mRNA, but enhanced PDK4 mRNA expression 13-fold (p<0.0001). The absolute levels of PDK4 mRNA reached after GW501516 treatment did not correlate with the donors' insulin sensitivity. However, the GW501516-induced fold-changes of PDK4 mRNA expression, reflecting PPAR-delta responsiveness, were correlated with the donors' insulin sensitivity (p=0.0046, clamp data; p=0.0182, OGTT data). We conclude that the individual responsiveness of human myocellular PPAR-delta, but not the absolute PPARD mRNA expression level, represents a major determinant of insulin sensitivity.
ACCESSION #
25820645

 

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