Pank1 deletion in leptin-deficient mice reduces hyperglycaemia and hyperinsulinaemia and modifies global metabolism without affecting insulin resistance.
Pank1 deletion in leptin-deficient mice reduces hyperglycaemia and hyperinsulinaemia and modifies global metabolism without affecting insulin resistance.
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DOI：
10.1007/s00125-014-3245-5
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发表时间：
2014-07
期刊：
影响因子：
8.2
通讯作者：
Jackowski S
中科院分区：
文献类型：
--
作者：
Leonardi R;Rock CO;Jackowski S
泛酸激酶(Pantothenate Kinase，Pank)是辅酶A(CoA)生物合成的第一个酶。Pank1基因缺陷的小鼠肝脏CoA降低40%，空腹低血糖是由于糖异生减少所致。人类PANK1基因的单核苷酸多态与胰岛素水平相关，提示辅酶A和胰岛素稳态之间存在联系。我们确定了Pank1缺乏是否1)改变了胰岛素水平，2)改善了高血糖和高胰岛素血症，3)改善了瘦素(Lep)缺陷小鼠的急性葡萄糖和胰岛素耐量。测定了Pank1基因缺陷小鼠的血清胰岛素以及对葡萄糖和胰岛素耐量试验的反应。测定Lep基因缺陷小鼠肝脏和骨骼肌中辅酶A和调节酶的水平。对双Pank1/Lep缺陷小鼠的糖尿病相关表型和全球代谢进行了分析。与野生型小鼠相比，Pank1基因缺陷小鼠的血清胰岛素水平较低，糖耐量和胰岛素敏感性有所改善。在Lep缺乏的小鼠中，肝脏和肌肉CoA异常高。Pank1基因缺失降低了肝脏CoA，但不降低了肌肉CoA，降低了血糖和胰岛素，但不能改善Lep缺乏动物的急性糖耐量或蛋白激酶B(Akt)的磷酸化。Pank1/Lep双缺陷小鼠表现出全身脂肪酸和氨基酸代谢减少，并更依赖于碳水化合物的利用来产生能量。结果表明，Pank1缺乏驱动全身代谢适应，改善糖尿病表型的某些方面，并使瘦素缺乏小鼠的高血糖和高胰岛素血症与肥胖脱钩。
Pantothenate kinase (PanK) is the first enzyme in coenzyme A (CoA) biosynthesis. Pank1-deficient mice have 40% lower liver CoA and fasting hypoglycaemia that results from reduced gluconeogenesis. Single-nucleotide polymorphisms in the human PANK1 gene are associated with insulin levels suggesting a link between CoA and insulin homeostasis. We determined whether Pank1 deficiency 1) modified insulin levels, 2) ameliorated hyperglycaemia and hyperinsulinemia, and 3) improved acute glucose and insulin tolerance of leptin (Lep)-deficient mice. Serum insulin and responses to glucose and insulin tolerance tests were determined in Pank1-deficient mice. Levels of CoA and regulating enzymes were measured in liver and skeletal muscle of Lep-deficient mice. Double Pank1/Lep-deficient mice were analysed for the diabetes-related phenotype and global metabolism. Pank1-deficient mice had lower serum insulin and improved glucose tolerance and insulin sensitivity compared to wild-type mice. Hepatic and muscle CoA was abnormally high in Lep-deficient mice. Pank1 deletion reduced hepatic CoA but not muscle CoA, reduced serum glucose and insulin, but did not normalize body weight or improve acute glucose tolerance or protein kinase B (Akt) phosphorylation in Lep-deficient animals. Pank1/Lep double-deficient mice exhibited reduced whole-body metabolism of fatty acids and amino acids and had a greater reliance on carbohydrate utilization for energy production. The results indicate that Pank1 deficiency drives a whole-body metabolic adaptation that improves aspects of the diabetic phenotype and uncouples hyperglycaemiaand hyperinsulinemia from obesity in leptin-deficient mice.