Effect of a sustained reduction in plasma free fatty acid concentration on intramuscular long-chain fatty acyl-CoAs and insulin action in type 2 diabetic patients
Effect of a sustained reduction in plasma free fatty acid concentration on intramuscular long-chain fatty acyl-CoAs and insulin action in type 2 diabetic patients
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DOI：
10.2337/diabetes.54.11.3148
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发表时间：
2005-11-01
期刊：
影响因子：
7.7
通讯作者：
DeFronzo, RA
中科院分区：
文献类型：
--
作者：
Bajaj, M;Suraamornkul, S;DeFronzo, RA
研究血浆游离脂肪酸（FFA）浓度持续（7天）降低对胰岛素作用和细胞内长链脂肪酰辅酶A的影响。我们研究了阿昔莫司（一种有效的脂解抑制剂）对7例2型糖尿病患者的作用（年龄53 ± 3岁，BMI 30.2 ± 2.0 kg/m2，空腹血糖8.5 ± 0.8 mmol/l，HbA（1c）7.5 ± 0.4%）。受试者接受口服葡萄糖耐量试验（OGTT）和120分钟正常血糖胰岛素（80 mU/m（2）/min）钳夹，并进行3-[H-3]葡萄糖/股外侧肌活检，以定量胰岛素介导的全身葡萄糖处置率（R-d）和阿昔莫司（250 mg，每6小时一次，持续7天）前后的肌内LCFA-CoA。阿昔莫司显著降低空腹血浆游离脂肪酸（从563 ± 74 μ mol/l降至230 ± 33 μ mol/l; P < 0.01）和OGTT期间的平均血浆游离脂肪酸（从409 ± 44 μ mol/l降至184 ± 22 μ mol/l; P < 0.01）。阿昔莫司治疗后，空腹血浆胰岛素（从78 +/- 18到42 +/- 6 pmol/l; P < 0.05），空腹血糖（从8.5 +/- 0.8到7.0 +/- 0.5 mmol/l; P < 0.02），和OGTT期间的平均血糖（从14.5 +/- 0.8到13.0 +/- 0.8 mmol/l; P < 0.05）。阿昔莫司给药后，胰岛素刺激的R-d从3.3 +/- 0.4增加到4.4 +/- 0.4 mg/kg（-1）中心点/min（-1）（P < 0.03），而内源性葡萄糖生成（EGP）的抑制作用在两项胰岛素钳夹研究中相似，几乎完全（0.16 +/- 0.10 vs. 0.14 +/- 0.10 mg中心点kg（-1）中心点min（-1）; P > 0.05）。基础EGP在阿昔莫司治疗后没有变化（1.9 +/- 0.2 vs. 1.9 +/- 0.2 mg中心点kg（-1）min（-1））。阿昔莫司治疗后，肌肉总LCFA-CoA含量降低（从7.26 +/- 0.58至5.64 +/- 0.79 nmol/g; P < 0.05）。肌肉中棕榈酰辅酶A也减少，（16：0;从1.06 +/- 0.10至0.75 +/- 0.11 nmol/g; P < 0.05），棕榈油酸CoA（16：1;从0.48 +/- 0.05至0.33 +/- 0.05 nmol/g; P = 0.07），油酸CoA（18：1;从2.60 +/- 0.11至1.95 +/- 0.31 nmol/g; P < 0.05），亚油酸CoA（18：2;从1.81 +/- 0.26到1.38 +/- 0.18 nmol/g; P = 0.13）和亚麻酸CoA（18：3;从0.27 +/- 0.03到0.19 +/- 0.02 nmol/g; P < 0.03）水平。阿昔莫司治疗后，肌肉硬脂酸CoA（18：0）未降低。R1的增加与肌肉棕榈酰辅酶A（r = 0.75，P < 0.05）、油酸辅酶A（r = 0.76，P < 0.05）和总肌肉LCFA-CoA（r = 0.74，P < 0.05）水平的降低密切相关。阿昔莫司治疗后血浆脂联素没有显著变化（7.9 +/- 1.8 vs. 7.5 +/- 1.5 μ g/ml）。这些数据表明，肌内LCFA-CoA含量的减少与2型糖尿病患者血浆FFA浓度慢性降低后肌肉中胰岛素敏感性的增强密切相关，尽管对血浆脂联素浓度缺乏影响。
To investigate the effect of a sustained (7-day) decrease in plasma free fatty acid (FFA) concentrations on insulin action and intrainyocellular long-chain fatty acyl-CoAs (LCFA-CoAs), we studied the effect of acipimox, a potent inhibitor of lipolysis, in seven type 2 diabetic patients (age 53 3 years, BMI 30.2 +/- 2.0 kg/m(2), fasting plasma glucose 8.5 +/- 0.8 mmol/l, HbA(1c) 7.5 +/- 0.4%). Subjects received an oral glucose tolerance test (OGTT) and 120-min euglycemic insulin (80 mU/m(2) per min) clamp with 3-[H-3]glucose/vastus lateralis muscle biopsies to quantitate rates of insulin-mediated whole-body glucose disposal (R-d) and intramyocellular LCFA-CoAs before and after acipimox (250 mg every 6 h for 7 days). Acipimox significantly reduced fasting plasma FFAs (from 563 74 to 230 33 mu mol/l; P < 0.01) and mean plasma FFAs during the OGTT (from 409 +/- 44 to 184 +/- 22 mu mol/l; P < 0.01). After acipimox, decreases were seen in fasting plasma insulin (from 78 +/- 18 to 42 +/- 6 pmol/l; P < 0.05), fasting plasma glucose (from 8.5 +/- 0.8 to 7.0 +/- 0.5 mmol/l; P < 0.02), and mean plasma glucose during the OGTT (from 14.5 +/- 0.8 to 13.0 +/- 0.8 mmol/l; P < 0.05). After acipimox, insulinstimulated R-d increased from 3.3 +/- 0.4 to 4.4 +/- 0.4 mg kg(-1)center dot min(-1) (P < 0.03), whereas suppression of endogenous glucose production (EGP) was similar and virtually complete during both insulin clamp studies (0.16 +/- 0.10 vs. 0.14 +/- 0.10 mg center dot kg(-1) center dot min(-1); P > 0.05). Basal EGP did not change after acipimox (1.9 +/- 0.2 vs. 1.9 +/- 0.2 mg center dot kg(-1) min(-1)). Total muscle LCFA-CoA content decreased after acipimox treatment (from 7.26 +/- 0.58 to 5.64 +/- 0.79 nmol/g; P < 0.05). Decreases were also seen in muscle palmityl CoA (16:0; from 1.06 +/- 0.10 to 0.75 +/- 0.11 nmol/g; P < 0.05), palmitoleate CoA (16:1; from 0.48 +/- 0.05 to 0.33 +/- 0.05 nmol/g; P = 0.07), oleate CoA (18:1; from 2.60 +/- 0.11 to 1.95 +/- 0.31 nmol/g; P < 0.05), linoleate CoA (18:2; from 1.81 +/- 0.26 to 1.38 +/- 0.18 nmol/g; P = 0.13), and linolenate CoA (18:3; from 0.27 +/- 0.03 to 0.19 +/- 0.02 nmol/g; P < 0.03) levels after acipimox treatment. Muscle stearate CoA (18:0) did not decrease after acipimox treatment. The increase in R, correlated strongly with the decrease in muscle palmityl CoA (r = 0.75, P < 0.05), oleate CoA (r = 0.76, P < 0.05), and total muscle LCFA-CoA (r = 0.74, P < 0.05) levels. Plasma adiponectin did not change significantly after acipimox treatment (7.9 +/- 1.8 vs. 7.5 +/- 1.5 mu g/ml). These data demonstrate that the reduction in intramuscular LCFA-CoA content is closely associated with enhanced insulin sensitivity in muscle after a chronic reduction in plasma FFA concentrations in type 2 diabetic patients despite the lack of an effect on plasma adiponectin concentration.