Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents.
Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents.
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胰岛素2型糖尿病父母的胰岛素耐药后代的胰岛素刺激的ATP合成和磷酸盐转运减少。
DOI：
10.1371/journal.pmed.0020233
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发表时间：
2005-09
期刊：
影响因子：
15.8
通讯作者：
Shulman, GI
中科院分区：
文献类型：
--
作者：
Petersen, KF;Dufour, S;Shulman, GI
胰岛素抵抗是2型糖尿病发展的最佳预测因素。最近的研究表明，2型糖尿病父母的年轻、消瘦、胰岛素抵抗（IR）后代的肌肉线粒体磷酸化活性基础率降低，这与肌细胞内脂质（IMCL）含量增加有关，进而阻断了肌肉中的胰岛素信号传导和胰岛素作用。为了进一步表征这些个体的线粒体活性，我们在类似的参与者队列中检查了胰岛素刺激的骨骼肌三磷酸腺苷（ATP）合成和磷酸盐转运速率。通过31 P磁共振波谱（MRS）评估了胰岛素刺激的肌肉线粒体ATP合酶通量和胰岛素刺激的肌细胞内无机磷酸盐（Pi）浓度增加的速率，这些研究对象是2型糖尿病父母的健康、瘦型、IR后代和胰岛素敏感性正常的健康、瘦型对照参与者。通过1H MRS评估所有参与者比目鱼肌中的IMCL含量。在高胰岛素-正葡萄糖钳夹期间，与对照参与者相比，IR后代中胰岛素刺激的葡萄糖摄取率降低约50%（与对照组相比p = 0.007），并且与IMCL含量的约2倍增加相关（与对照组相比p < 0.006）。在对照组中，ATP合成率在高胰岛素-正常血糖钳夹期间增加了约90%。相比之下，胰岛素刺激的肌肉线粒体ATP合成率在IR后代中仅增加了5%（p = 0.001 vs对照组），并且与胰岛素刺激的肌细胞内Pi浓度增加的严重减少相关（IR后代：4.7% ± 1.9% vs对照组：19.3% ± 5.7%; p = 0.03）。胰岛素诱导的肌细胞内Pi浓度增加与胰岛素刺激的ATP合成率增加相关（r = 0.67; p = 0.008）。这些数据表明，胰岛素刺激的线粒体ATP合成率降低，在IR后代的父母与2型糖尿病。此外，这些IR后代也有受损的胰岛素刺激的磷酸盐转运在肌肉中，这可能有助于他们的缺陷，在胰岛素刺激的线粒体ATP合成率。
Insulin resistance is the best predictor for the development of type 2 diabetes. Recent studies have shown that young, lean, insulin-resistant (IR) offspring of parents with type 2 diabetes have reduced basal rates of muscle mitochondrial phosphorylation activity associated with increased intramyocellular lipid (IMCL) content, which in turn blocks insulin signaling and insulin action in muscle. In order to further characterize mitochondrial activity in these individuals, we examined insulin-stimulated rates of adenosine triphosphate (ATP) synthesis and phosphate transport in skeletal muscle in a similar cohort of participants. Rates of insulin-stimulated muscle mitochondrial ATP synthase flux and insulin-stimulated increases in concentrations of intramyocellular inorganic phosphate (Pi) were assessed by 31P magnetic resonance spectroscopy (MRS) in healthy, lean, IR offspring of parents with type 2 diabetes and healthy, lean control participants with normal insulin sensitivity. IMCL content in the soleus muscle of all participants was assessed by 1H MRS. During a hyperinsulinemic-euglycemic clamp, rates of insulin-stimulated glucose uptake were decreased by approximately 50% in the IR offspring compared to the control participants (p = 0.007 versus controls) and were associated with an approximately 2-fold increase in IMCL content (p < 0.006 versus controls). In the control participants rates of ATP synthesis increased by approximately 90% during the hyperinsulinemic-euglycemic clamp. In contrast, insulin-stimulated rates of muscle mitochondrial ATP synthesis increased by only 5% in the IR offspring (p = 0.001 versus controls) and was associated with a severe reduction of insulin-stimulated increases in the intramyocellular Pi concentrations (IR offspring: 4.7% ± 1.9% versus controls: 19.3% ± 5.7%; p = 0.03). Insulin-induced increases in intramyocellular Pi concentrations correlated well with insulin-stimulated increases in rates of ATP synthesis (r = 0.67; p = 0.008). These data demonstrate that insulin-stimulated rates of mitochondrial ATP synthesis are reduced in IR offspring of parents with type 2 diabetes. Furthermore, these IR offspring also have impaired insulin-stimulated phosphate transport in muscle, which may contribute to their defects in insulin-stimulated rates of mitochondrial ATP synthesis.
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影响因子：
158.5
作者：
Cline, GW;Petersen, KF;Shulman, GI
通讯作者：
Shulman, GI
影响因子：
5.8
作者：
Gudbjörnsdóttir, S;Sjöstrand, M;Lönnroth, P
通讯作者：
Lönnroth, P
DOI：
10.1073/pnas.1032913100
发表时间：
2003-07-08
影响因子：
11.1
作者：
Patti, ME;Butte, AJ;Mandarino, LJ
通讯作者：
Mandarino, LJ
影响因子：
7.7
作者：
Coggins, M;Lindner, J;Barrett, E
通讯作者：
Barrett, E
影响因子：
7.7
作者：
Griffin, ME;Marcucci, MJ;Shulman, GI
通讯作者：
Shulman, GI