Hyperpolarized NMR study of the impact of pyruvate dehydrogenase kinase inhibition on the pyruvate dehydrogenase and TCA flux in type 2 diabetic rat muscle.
Hyperpolarized NMR study of the impact of pyruvate dehydrogenase kinase inhibition on the pyruvate dehydrogenase and TCA flux in type 2 diabetic rat muscle.
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DOI：
10.1007/s00424-021-02613-3
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发表时间：
2021-11
影响因子：
4.5
通讯作者：
Jue, Thomas
中科院分区：
文献类型：
--
作者：
Park, Jae Mo;Josan, Sonal;Hurd, Ralph E.;Graham, James;Havel, Peter J.;Bendahan, David;Mayer, Dirk;Chung, Youngran;Spielman, Daniel M.;Jue, Thomas
丙酮酸脱氢酶在介导脂质诱导的胰岛素抵抗中的作用是2型糖尿病发病机制的核心问题。许多研究人员援引兰德尔假说来解释骨骼肌中葡萄糖处置减少，设想脂肪酸氧化增加引起乙酰辅酶A池升高。多年来，体内核磁共振研究已经挑战了这种单一的观点。溶解动态核极化核磁共振技术的出现和独特的2型糖尿病大鼠模型提供了一个澄清的机会。动态核极化显著提高了NMR信号的灵敏度，并允许测量体内代谢动力学。糖尿病肌肉的丙酮酸脱氢酶活性比对照肌肉低得多，如[1- 13 C]乳酸和[2- 13 C]丙酮酸转化为HCO 3 −和乙酰肉毒碱所证明的。丙酮酸脱氢酶激酶抑制剂二氯醋酸盐可使糖尿病患者丙酮酸脱氢酶活性迅速恢复至对照水平。然而，糖尿病患者丙酮酸脱氢酶通量的动态变化比对照组大得多。二氯乙酸诱导的丙酮酸脱氢酶活性激增产生不同量的乙酰肉毒碱，但不影响三羧酸通量。进一步的研究现在可以继续与动态核极化的方法和独特的大鼠模型，密切询问的生化机制接口氧化代谢与胰岛素抵抗和代谢耐受性。
The role of pyruvate dehydrogenase in mediating lipid-induced insulin resistance stands as a central question in the pathogenesis of type 2 diabetes mellitus. Many researchers have invoked the Randle hypothesis to explain the reduced glucose disposal in skeletal muscle by envisioning an elevated acetyl CoA pool arising from increased oxidation of fatty acids. Over the years, in vivo NMR studies have challenged that monolithic view. The advent of the dissolution dynamic nuclear polarization NMR technique and a unique type 2 diabetic rat model provides an opportunity to clarify. Dynamic nuclear polarization enhances dramatically the NMR signal sensitivity and allows the measurement of metabolic kinetics in vivo. Diabetic muscle has much lower pyruvate dehydrogenase activity than control muscle, as evidenced in the conversion of [1-13C]lactate and [2-13C]pyruvate to HCO3− and acetyl carnitine. The pyruvate dehydrogenase kinase inhibitor, dichloroacetate, restores rapidly the diabetic pyruvate dehydrogenase activity to control level. However, diabetic much has a much larger dynamic change in pyruvate dehydrogenase flux than control. The dichloroacetate induced surge in pyruvate dehydrogenase activity produces a differential amount of acetyl carnitine but does not affect the tricarboxylic acid flux. Further studies can now proceed with the dynamic nuclear polarization approach and a unique rat model to interrogate closely the biochemical mechanism interfacing oxidative metabolism with insulin resistance and metabolic inflexibility.
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DOI：
10.1073/pnas.1107163108
发表时间：
2011-08-30
影响因子：
11.1
作者：
Cummings, Bethany P.;Bettaieb, Ahmed;Havel, Peter J.
通讯作者：
Havel, Peter J.
影响因子：
7.7
作者：
Kelley, DE;Mandarino, LJ
通讯作者：
Mandarino, LJ
影响因子：
82.9
作者：
Day, Sam E.;Kettunen, Mikko I.;Brindle, Kevin M.
通讯作者：
Brindle, Kevin M.
影响因子：
7.7
作者：
Holness, MJ;Kraus, A;Sugden, MC
通讯作者：
Sugden, MC
影响因子：
5.5
作者：
Brooks, George A.
通讯作者：
Brooks, George A.