Pioglitazone stimulates AMP-activated protein kinase signalling and increases the expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation in human skeletal muscle in vivo: a randomised trial.
Pioglitazone stimulates AMP-activated protein kinase signalling and increases the expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation in human skeletal muscle in vivo: a randomised trial.
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DOI：
10.1007/s00125-008-1256-9
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发表时间：
2009-04
期刊：
影响因子：
8.2
通讯作者：
Defronzo RA
中科院分区：
文献类型：
--
作者：
Coletta DK;Sriwijitkamol A;Wajcberg E;Tantiwong P;Li M;Prentki M;Madiraju M;Jenkinson CP;Cersosimo E;Musi N;Defronzo RA
噻唑烷二酮类药物改善2型糖尿病胰岛素敏感性的分子机制尚不完全清楚。我们假设吡格列酮会激活腺苷5′-单磷酸活化蛋白激酶（AMPK）通路，并增加与人骨骼肌中脂联素信号传导、NEFA氧化和线粒体功能相关的基因表达。在26例接受以下治疗的初治2型糖尿病患者中进行了一项随机、双盲、平行研究：（1）吡格列酮（n=14）或（2）积极营养治疗（n=12），以将HbA 1c降至吡格列酮治疗组中观察到的水平。使用随机数字表将参与者随机分配到治疗组。在6个月之前和之后，患者向德克萨斯糖尿病研究所的临床研究中心报告股外侧肌活检，随后进行180分钟的正常血-高胰岛素血症（80 mU m−2 min−1）钳夹。吡格列酮组（n=14）或营养治疗组（n=12）的所有患者均纳入分析。吡格列酮显著增加血浆脂联素浓度79%，降低空腹血浆NEFA 35%（均p<0.01）。服用吡格列酮后，胰岛素刺激的葡萄糖处理增加了30%（p<0.01），肌肉AMPK和乙酰辅酶A羧化酶（ACC）磷酸化分别增加了38%和53%（p<0.05）。吡格列酮增加了脂联素受体1和2基因（ADIPOR 1、ADIPOR 2）、过氧化物酶体增殖物激活受体γ、辅激活因子1基因（PPARGC 1）以及参与线粒体功能和脂肪氧化的多个基因的mRNA水平。尽管与营养治疗相似，HbA 1c降低和胰岛素敏感性改善相似，但肌肉AMPK和ACC磷酸化或ADIPOR 1，ADIPOR 2，PPARGC 1和参与线粒体功能和脂肪氧化的基因表达没有显著变化。本研究未报告不良（或意外）反应或副作用。吡格列酮增加血浆脂联素水平，刺激肌肉AMPK信号传导，并增加参与脂联素信号传导、线粒体功能和脂肪氧化的基因表达。这些变化可能代表了噻唑烷二酮改善骨骼肌胰岛素敏感性的重要细胞机制。
The molecular mechanisms by which thiazolidinediones improve insulin sensitivity in type 2 diabetes are not fully understood. We hypothesised that pioglitazone would activate the adenosine 5′-monophosphate-activated protein kinase (AMPK) pathway and increase the expression of genes involved in adiponectin signalling, NEFA oxidation and mitochondrial function in human skeletal muscle. A randomised, double-blind, parallel study was performed in 26 drug-naive type 2 diabetes patients treated with: (1) pioglitazone (n=14) or (2) aggressive nutritional therapy (n=12) to reduce HbA1c to levels observed in the pioglitazone-treated group. Participants were assigned randomly to treatment using a table of random numbers. Before and after 6 months, patients reported to the Clinical Research Center of the Texas Diabetes Institute for a vastus lateralis muscle biopsy followed by a 180 min euglycaemic–hyperinsulinaemic (80 mU m−2 min−1) clamp. All patients in the pioglitazone (n=14) or nutritional therapy (n=12) group were included in the analysis. Pioglitazone significantly increased plasma adiponectin concentration by 79% and reduced fasting plasma NEFA by 35% (both p<0.01). Following pioglitazone, insulin-stimulated glucose disposal increased by 30% (p<0.01), and muscle AMPK and acetyl-CoA carboxylase (ACC) phosphorylation increased by 38% and 53%, respectively (p<0.05). Pioglitazone increased mRNA levels for adiponectin receptor 1 and 2 genes (ADIPOR1, ADIPOR2), peroxisome proliferator-activated receptor gamma, coactivator 1 gene (PPARGC1) and multiple genes involved in mitochondrial function and fat oxidation. Despite a similar reduction in HbA1c and similar improvement in insulin sensitivity with nutritional therapy, there were no significant changes in muscle AMPK and ACC phosphorylation, or the expression of ADIPOR1, ADIPOR2, PPARGC1 and genes involved in mitochondrial function and fat oxidation. No adverse (or unexpected) effects or side effects were reported from the study. Pioglitazone increases plasma adiponectin levels, stimulates muscle AMPK signalling and increases the expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation. These changes may represent an important cellular mechanism by which thiazolidinediones improve skeletal muscle insulin sensitivity.