Objective

Acute administration of the main protein component of high-density lipoprotein, apolipoprotein A-I (ApoA-1), improves glucose uptake in skeletal muscle. The molecular mechanisms mediating this are not known, but in muscle cell cultures, ApoA-1 failed to increase glucose uptake when infected with a dominant-negative AMP-activated protein kinase (AMPK) virus. We therefore investigated whether AMPK is necessary for ApoA-1-stimulated glucose uptake in intact heart and skeletal muscle in vivo.

Methods

The effect of injection with recombinant human ApoA-1 (rApoA-1) on glucose tolerance, glucose-stimulated insulin secretion, and glucose uptake into skeletal and heart muscle with and without block of insulin secretion by injection of epinephrine (0.1 mg/kg) and propranolol (5 mg/kg), were investigated in 8 weeks high-fat diet-fed (60E%) wild-type and AMPKα₂ kinase-dead mice in the overnight-fasted state. In addition, the effect of rApoA-1 on glucose uptake in isolated skeletal muscle ex vivo was studied.

Results

rApoA-1 lowered plasma glucose concentration by 1.7 mmol/l within 3 h (6.1 vs 4.4 mmol/l; p < 0.001). Three hours after rApoA-1 injection, glucose tolerance during a 40-min glucose tolerance test (GTT) was improved compared to control (area under the curve (AUC) reduced by 45%, p < 0.001). This was accompanied by an increased glucose clearance into skeletal (+110%; p < 0.001) and heart muscle (+100%; p < 0.001) and an increase in glucose-stimulated insulin secretion 20 min after glucose injection (+180%; p < 0.001). When insulin secretion was blocked during a GTT, rApoA-1 still enhanced glucose tolerance (AUC lowered by 20% compared to control; p < 0.001) and increased glucose clearance into skeletal (+50%; p < 0.05) and heart muscle (+270%; p < 0.001). These improvements occurred to a similar extent in both wild-type and AMPKα₂ kinase-dead mice and thus independently of AMPKα₂ activity in skeletal- and heart muscle. Interestingly, rApoA-1 failed to increase glucose uptake in isolated skeletal muscles ex vivo.

Conclusions

In conclusion, ApoA-1 stimulates in vivo glucose disposal into skeletal and heart muscle independently of AMPKα₂. The observation that ApoA-1 fails to increase glucose uptake in isolated muscle ex vivo suggests that additional systemic effects are required.

中文翻译：

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ApoA-1通过增加葡萄糖对心脏和骨骼肌的摄取而独立于AMPKα2，从而改善了葡萄糖耐量。

目的

急性施用高密度脂蛋白的主要蛋白成分载脂蛋白AI（ApoA-1）可改善骨骼肌的葡萄糖摄取。介导此作用的分子机制尚不清楚，但是在肌肉细胞培养中，ApoA-1感染显性阴性AMP激活的蛋白激酶（AMPK）病毒后未能增加葡萄糖摄取。因此，我们调查了在体内完整心脏和骨骼肌中AMPK是否对ApoA-1刺激的葡萄糖摄取 至关重要。

方法

注射肾上腺素（0.1 mg / kg）注射重组人ApoA-1（rApoA-1）对葡萄糖耐受性，葡萄糖刺激的胰岛素分泌以及骨骼肌和心肌中葡萄糖摄取的影响和普萘洛尔（5毫克/千克），8周高脂肪饮食喂养的（60E％）野生型和AMPKα进行了研究₂ 在过夜禁食的状态激酶死亡的小鼠。另外，研究了rApoA-1对离体骨骼肌离体葡萄糖摄取的影响。

结果

rApoA-1在3小时内使血糖浓度降低了1.7 mmol / l（6.1对4.4 mmol / l； p <0.001）。注射rApoA-1后三小时，与对照组相比，在40分钟葡萄糖耐量测试（GTT）中的葡萄糖耐量得到了改善（曲线下面积（AUC）降低了45％，p <0.001）。这伴随着注射葡萄糖20分钟后，骨骼中的葡萄糖清除率增加（+ 110％; p <0.001）和心肌（+ 100％; p <0.001），葡萄糖刺激的胰岛素分泌增加（+ 180％; p <0.001）。当GTT期间胰岛素分泌受阻时，rApoA-1仍能增强葡萄糖耐量（AUC与对照组相比降低20％； p <0.001），并增加对骨骼和骨骼肌（+ 50％； p <0.05）的葡萄糖清除率270％； p <0.001）。₂ 激酶死亡的小鼠，因此独立于AMPKα ₂ 在skeletal-和心脏肌肉的活动。有趣的是，rApoA-1无法增加离体骨骼肌的葡萄糖摄取 。

结论

最后，载脂蛋白A-1能刺激 体内 葡萄糖处置成骨骼肌和心脏肌肉独立地AMPKα的₂。ApoA-1无法增加离体肌肉离体葡萄糖摄取的观察结果  表明，还需要其他全身作用。