SKELETAL-MUSCLE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA EXPRESSION IN OBESITY AND NON-INSULIN-DEPENDENT DIABETES-MELLITUS

The two isoforms of peroxisome proliferator-activated receptor-gamma ( PPAR gamma 1 and PPAR gamma 2), are ligand-activated transcription fac tors that are the intracellular targets of a new class of insulin sens itizing agents, the thiazolidinediones. The observation that thiazolid inediones enhance skeletal muscle insulin sensitivity in obesity and i n patients with non-insulin-dependent diabetes mellitus (NIDDM), by ac tivating PPAR gamma, and possibly by inducing its expression, suggests that PPAR gamma expression in skeletal muscle plays a key role in det ermining tissue sensitivity to insulin, and that PPAR gamma expression may be decreased in insulin resistant subjects, We used a sensitive r ibonuclease protection assay, that permits simultaneous measurement of the two isoforms, to examine the effects of obesity and NIDDM, and th e effects of insulin, on skeletal muscle levels of PPAR gamma 1 and PP AR gamma 2 mRNA. We studied seven patients with NIDDM (body mass index , 32 +/- kg/m(2)), seven lean (24 +/- 1 kg/m(2)), and six obese (36 +/ - kg/m(2)) normal subjects. Biopsies from the vastus lateralis muscle were taken before and after a 5-h hyperinsulinemic (80 mU/m(2) per min ute) euglycemic clamp, The obese controls and NIDDM patients were insu lin resistant with glucose disposal rates during the last 30 min of th e clamp that were 67 and 31%, respectively, of those found in the lean controls. PPAR gamma 1, but not PPAR gamma 2 mRNA was detected in ske letal muscle at 10-15% of the level found in adipose tissue. No differ ence was found in PPAR gamma 1 levels between the three groups, and th ere was no change in PPAR gamma 1 levels after 5 h of hyperinsulinemia . In obese subjects, PPAR gamma 1 correlated with clamp glucose dispos al rates (r = 0.92, P < 0.01). In the lean and NIDDM patients, muscle PPAR gamma 1 levels correlated with percentage body fat (r = 0.76 and r = 0.82, respectively, both P < 0.05) but not with body mass index. I n conclusion: (a) skeletal muscle PPAR gamma 1 expression does not dif fer between normal and diabetic subjects, and is not induced by short- term hyperinsulinemia; (b) skeletal muscle PPAR gamma 1 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.