Kruszynska Y T, Mukherjee R, Jow L, Dana S, Paterniti J R, Olefsky J M
Department of Endocrinology & Metabolism, University of California San Diego, Veterans Administration Center, 3350 La Jolla Village Drive, La Jolla, California 92093, USA.
J Clin Invest. 1998 Feb 1;101(3):543-8. doi: 10.1172/JCI1076.
The two isoforms of peroxisome proliferator-activated receptor-gamma (PPARgamma1 and PPARgamma2), 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 PPARgamma, and possibly by inducing its expression, suggests that PPARgamma expression in skeletal muscle plays a key role in determining tissue sensitivity to insulin, and that PPARgamma 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 PPARgamma1 and PPARgamma2 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. PPARgamma1, but not PPARgamma2 mRNA was detected in skeletal muscle at 10-15% of the level found in adipose tissue. No difference was found in PPARgamma1 levels between the three groups, and there was no change in PPARgamma1 levels after 5 h of hyperinsulinemia. In obese subjects, PPARgamma1 correlated with clamp glucose disposal rates (r = 0.92, P < 0.01). In the lean and NIDDM patients, muscle PPARgamma1 levels correlated with percentage body fat (r = 0.76 and r = 0.82, respectively, both P < 0.05) but not with body mass index.
(a) skeletal muscle PPARgamma1 expression does not differ between normal and diabetic subjects, and is not induced by short-term hyperinsulinemia; (b) skeletal muscle PPARgamma1 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.
过氧化物酶体增殖物激活受体γ的两种亚型（PPARγ1和PPARγ2）是配体激活的转录因子，是一类新型胰岛素增敏剂噻唑烷二酮类的细胞内靶点。噻唑烷二酮类通过激活PPARγ并可能诱导其表达来增强肥胖和非胰岛素依赖型糖尿病（NIDDM）患者骨骼肌的胰岛素敏感性，这一观察结果表明骨骼肌中PPARγ的表达在决定组织对胰岛素的敏感性方面起关键作用，并且在胰岛素抵抗的受试者中PPARγ的表达可能降低。我们使用一种灵敏的核糖核酸酶保护分析法，该方法可同时测量这两种亚型，以研究肥胖和NIDDM以及胰岛素对骨骼肌中PPARγ1和PPARγ2 mRNA水平的影响。我们研究了7例NIDDM患者（体重指数，32±1 kg/m2）、7例瘦人（24±1 kg/m2）和6例肥胖（36±1 kg/m2）正常受试者。在5小时高胰岛素血症（每分钟80 mU/m2）正常血糖钳夹前后，从股外侧肌取活检组织。肥胖对照组和NIDDM患者存在胰岛素抵抗，在钳夹的最后30分钟内葡萄糖处置率分别为瘦对照组的67%和31%。在骨骼肌中检测到PPARγ1 mRNA，但未检测到PPARγ2 mRNA，其水平为脂肪组织中水平的10% - 15%。三组之间PPARγ1水平无差异，高胰岛素血症5小时后PPARγ1水平也无变化。在肥胖受试者中，PPARγ1与钳夹葡萄糖处置率相关（r = 0.92，P < 0.01）。在瘦人和NIDDM患者中，肌肉PPARγ1水平与体脂百分比相关（分别为r = 0.76和r = 0.82，均P < 0.05），但与体重指数无关。
（a）正常和糖尿病受试者骨骼肌PPARγ1表达无差异，且不受短期高胰岛素血症诱导；（b）体脂百分比超过25%的受试者骨骼肌PPARγ1表达较高，这可能是维持正常胰岛素敏感性的一种代偿现象。
