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Pharmacological activation of PDC flux reverses lipid-induced inhibition of insulin action in muscle during recovery from exercise
Diabetes ( IF 7.7 ) Pub Date : 2024-04-12 , DOI: 10.2337/db23-0879
Christian S. Carl 1 , Marie M. Jensen 2 , Kim A. Sjøberg 1 , Dumitru Constantin-Teodosiu 3 , Ian R. Hill 3 , Rasmus Kjøbsted 1 , Paul L. Greenhaff 3 , Jørgen F.P. Wojtaszewski 1 , Erik A. Richter 1 , Andreas M. Fritzen 1, 4 , Bente Kiens 1
Affiliation  

Insulin resistance is a risk factor for type 2 diabetes and exercise can improve insulin sensitivity. However, following exercise high circulating fatty acid (FA) levels might counteract this. We hypothesized that such inhibition would be reduced by forcibly increasing carbohydrate oxidation through pharmacological activation of the pyruvate dehydrogenase complex (PDC). Insulin-stimulated glucose uptake was examined with a cross-over design in healthy young men (n = 8) in a previously exercised and a rested leg during a hyperinsulinemiceuglycemic clamp five hours after one-legged exercise with: 1) infusion of saline, 2) infusion of intralipid imitating circulating FA levels during recovery from whole-body exercise, and 3) infusion of intralipid + oral PDC-activator, dichloroacetate (DCA). Intralipid infusion reduced insulin-stimulated glucose uptake by 19% in the previously exercised leg, which was not observed in the contralateral rested leg. Interestingly, this effect of intralipid in the exercised leg was abolished by DCA, which increased muscle PDC activity (130%) and flux (acetylcarnitine 130%) and decreased inhibitory phosphorylation of PDC on Ser293 (∼40%) and Ser300 (∼80%). Novel insight is provided into the regulatory interaction between glucose and lipid metabolism during exercise recovery. Coupling exercise and PDC flux activation upregulated the capacity for both glucose transport (exercise) and oxidation (DCA), which seems necessary to fully stimulate insulin-stimulated glucose uptake during recovery.

中文翻译:

PDC通量的药理激活可逆转运动恢复过程中脂质诱导的肌肉胰岛素作用抑制

胰岛素抵抗是 2 型糖尿病的危险因素,运动可以提高胰岛素敏感性。然而,运动后高循环脂肪酸 (FA) 水平可能会抵消这一点。我们假设,通过丙酮酸脱氢酶复合物(PDC)的药理学激活,强制增加碳水化合物氧化,可以减少这种抑制。在健康年轻男性(n = 8)中,在单腿运动后 5 小时进行高胰岛素正常血糖钳夹时,通过交叉设计检查了健康年轻男性 (n = 8) 之前运动过的腿和休息过的腿的胰岛素刺激葡萄糖摄取:1) 输注生理盐水,2 ) 在全身运动恢复期间输注模拟循环 FA 水平的脂肪乳,以及 3) 输注脂肪乳 + 口服 PDC 激活剂二氯乙酸盐 (DCA)。输注脂肪乳可使先前锻炼的腿中胰岛素刺激的葡萄糖摄取量减少 19%,而在对侧休息的腿中未观察到这种情况。有趣的是,运动腿中脂肪乳的这种作用被 DCA 消除,增加了肌肉 PDC 活性 (130%) 和流量(乙酰肉碱 130%),并减少了 PDC 对 Ser293 (∼40%) 和 Ser300 (∼80%) 的抑制性磷酸化)。为运动恢复过程中葡萄糖和脂质代谢之间的调节相互作用提供了新的见解。耦合运动和 PDC 通量激活上调了葡萄糖转运(运动)和氧化(DCA)的能力,这似乎是恢复期间充分刺激胰岛素刺激的葡萄糖摄取所必需的。
更新日期:2024-04-12
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