Skeletal muscle peroxisome proliferator-activated receptor-γ expression in obesity and non-insulin-dependent diabetes mellitus

Abstract

The two isoforms of peroxisome proliferator-activated receptor-γ (PPARγ1 and PPARγ2), are ligand-activated transcription factors that are the intracellular targets of a new class of insulin sensitizing agents, the thiazolidinediones. The observation that thiazolidinediones enhance skeletal muscle insulin sensitivity in obesity and in patients with non-insulin- dependent diabetes mellitus (NIDDM), by activating PPARγ, and possibly by inducing its expression, suggests that PPARγ expression in skeletal muscle plays a key role in determining tissue sensitivity to insulin, and that PPARγ expression may be decreased in insulin resistant subjects. We used a sensitive ribonuclease protection assay, that permits simultaneous measurement of the two isoforms, to examine the effects of obesity and NIDDM, and the effects of insulin, on skeletal muscle levels of PPARγ1 and PPARγ2 mRNA. We studied seven patients with NIDDM (body mass index, 32±1 kg/m2), seven lean (24±1 kg/m2), and six obese (36+1 kg/m2) normal subjects. Biopsies from the vastus lateralis muscle were taken before and after a 5-h hyperinsulinemic (80 mU/m2 per minute) euglycemic clamp. The obese controls and NIDDM patients were insulin resistant with glucose disposal rates during the last 30 min of the clamp that were 67 and 31%, respectively, of those found in the lean controls. PPARγ1, but not PPARγ2 mRNA was detected in skeletal muscle at 10-15% of the level found in adipose tissue. No difference was found in PPARγ1 levels between the three groups, and there was no change in PPARγ1 levels after 5 h of hyperinsulinemia. In obese subjects, PPARγ1 correlated with clamp glucose disposal rates (r = 0.92, P < 0.01). In the lean and NIDDM patients, muscle PPARγ1 levels correlated with percentage body fat (r = 0.76 and r = 0.82, respectively, both P < 0.05) but not with body mass index. In conclusion: (a) skeletal muscle PPARγ1 expression does not differ between normal and diabetic subjects, and is not induced by short- term hyperinsulinemia; (b) skeletal muscle PPARγ1 expression was higher in subjects whose percent body fat exceeded 25%, and this may be a compensatory phenomenon in an attempt to maintain normal insulin sensitivity.