In vitro responsiveness of human muscle cell peroxisome proliferator-activated receptor δ reflects donors' insulin sensitivity in vivo

Eur J Clin Invest 2011; 41 (12): 1323–1329 Background Peroxisome proliferator‐activated receptor δ (PPARδ) activation enhances muscular fatty acid oxidation and oxidative phosphorylation, and muscle’s oxidative capacity positively associates with whole‐body insulin sensitivity. Therefore, we asked here whether human muscle cell PPARD expression is a determinant of donors’ insulin sensitivity. Materials and methods Skeletal muscle cells derived from 38 nondiabetic donors were differentiated in vitro to myotubes, and gene (mRNA) expression was quantified by real‐time RT–PCR. Donors’ insulin sensitivity was calculated from plasma insulin and glucose levels during oral glucose tolerance test (OGTT) and hyperinsulinemic‐euglycemic clamp. Results Basal myotube PPARD expression was closely related to the expression of its target genes PDK4 and ANGPTL4 (P = 0·0312 and P = 0·0003, respectively). Basal PPARD, PDK4 and ANGPTL4 expression levels were not associated with donors’ insulin sensitivity (P > 0·2, all). Treatment of myotubes with a selective high‐affinity PPARδ agonist (GW501516) did not change mean PPARD, but enhanced mean PDK4 and ANGPTL4 expression 13‐ and 16‐fold, respectively (P 0·2, both). However, GW501516‐mediated fold increments in PDK4 and ANGPTL4 expression, reflecting PPARδ responsiveness, were positively associated with donors’ insulin sensitivity derived from OGTT (P = 0·0182 and P = 0·0231, respectively) and hyperinsulinemic‐euglycemic clamp (P = 0·0046 and P = 0·0258, respectively). Conclusions Using a highly selective pharmacological tool, we show here that the individual responsiveness of human muscle cell PPARδ, rather than the absolute PPARD expression level, represents a major determinant of insulin sensitivity.