AIMS/HYPOTHESIS Sphingolipid metabolism regulates beta cell biology and inflammation and is abnormal at the onset of type 1 diabetes. Fenofibrate, a regulator of sphingolipid metabolism, is known to prevent diabetes in NOD mice. Here, we aimed to investigate the effects of fenofibrate on the pancreatic lipidome, pancreas morphology, pancreatic sympathetic nerves and blood glucose homeostasis in NOD mice. METHODS We treated female NOD mice with fenofibrate from 3 weeks of age. The pancreatic lipidome was analysed using MS. Analysis of pancreas and islet volume was performed by stereology. Islet sympathetic nerve fibre volume was evaluated using tyrosine hydroxylase staining. The effect on blood glucose homeostasis was assessed by measuring non-fasting blood glucose from age 12 to 30 weeks. Furthermore, we measured glucose tolerance, fasting insulin and glucagon levels, and insulin tolerance. RESULTS We found that fenofibrate selectively increases the amount of very-long-chain sphingolipids in the pancreas of NOD mice. In addition, we found that fenofibrate causes a remodelling of the pancreatic lipidome with an increased amount of lysoglycerophospholipids. Fenofibrate did not affect islet or pancreas volume, but led to a higher volume of islet sympathetic nerve fibres and tyrosine hydroxylase-positive cells. Fenofibrate-treated NOD mice had a more stable blood glucose, which was associated with reduced non-fasting and increased fasting blood glucose. Furthermore, fenofibrate improved glucose tolerance, reduced fasting glucagon levels and prevented fasting hyperinsulinaemia. CONCLUSIONS/INTERPRETATION These data indicate that fenofibrate alters the pancreatic lipidome to a more anti-inflammatory and anti-apoptotic state. The beneficial effects on islet sympathetic nerve fibres and blood glucose homeostasis indicate that fenofibrate could be used as a therapeutic approach to improve blood glucose homeostasis and prevent diabetes-associated pathologies.

中文翻译：

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非诺贝特可增加NOD小鼠的超长链鞘脂并改善血糖稳态。

目的/假设鞘脂代谢调节β细胞生物学和炎症，并在1型糖尿病发作时异常。非诺贝特，一种鞘脂代谢的调节剂，可以预防NOD小鼠的糖尿病。在这里，我们旨在研究非诺贝特对NOD小鼠胰腺脂质组，胰腺形态，胰交感神经和血糖稳态的影响。方法我们从3周龄开始用非诺贝特治疗雌性NOD小鼠。使用MS分析胰脂质组。胰腺和胰岛体积的分析是通过体视学进行的。使用酪氨酸羟化酶染色评估胰岛交感神经纤维的体积。通过测量12至30周龄的非禁食血糖来评估其对血糖稳态的影响。此外，我们测量了葡萄糖耐量 空腹胰岛素和胰高血糖素水平，以及胰岛素耐受性。结果我们发现非诺贝特有选择地增加了NOD小鼠胰腺中超长链鞘脂的数量。另外，我们发现非诺贝特引起胰脂质组的重塑，并增加了溶血甘油磷脂的量。非诺贝特不影响胰岛或胰脏的体积，但导致胰岛交感神经纤维和酪氨酸羟化酶阳性细胞的体积更大。用非诺贝特治疗的NOD小鼠血糖更稳定，这与减少空腹血糖和增加空腹血糖有关。此外，非诺贝特改善了葡萄糖耐量，降低了空腹胰高血糖素水平，并防止了空腹高胰岛素血症。结论/解释这些数据表明非诺贝特将胰腺脂质组改变为更抗炎和抗凋亡的状态。对胰岛交感神经纤维和血糖动态平衡的有益影响表明，非诺贝特可以用作改善血糖动态平衡和预防糖尿病相关疾病的治疗方法。