Fenofibrate increases very-long-chain sphingolipids and improves blood glucose homeostasis in NOD mice

Abstract

Aims/hypothesisSphingolipid 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.MethodsWe 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.ResultsWe 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/interpretationThese 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.Electronic supplementary materialThe online version of this article (10.1007/s00125-019-04973-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

PPARs and the Development of Type 1 Diabetes

“…Another sphingolipid with a suspected role in T1D pathology is the proapoptotic ceramide of which C16 promotes apoptosis, mitochondrial dysfunction, and insulin resistance [139][140][141][142], while C24 has beneficial roles in regulating metabolic health [141,143]. Recently, we demonstrated that fenofibrate altered ceramide composition in the pancreas of NOD mice increasing C24 and decreasing C16, hence creating a more beneficial ceramide composition [138]. WY14643 was otherwise found to increase ceramide levels in rat hearts [134], suggesting organ-specific regulation 4 PPAR Research of ceramide synthesis.…”

“…PPARα is similarly involved in regulating the composition of sulfatide species with C16 (insulin folding and secretion) and C24 (immune regulation) having different functions [136,137]. In the pancreas, fenofibrate especially increased the amount of C24 sulfatide thereby creating an anti-inflammatory sulfatide composition [138].…”

Sphingolipids in Type 1 Diabetes: Focus on Beta-Cells

“…Using fenofibrate, which activates the sulfatide biosynthesis, Holm and colleagues were able to completely prevent diabetes development in NOD mice [14]. In the follow-up study they demonstrated that fenofibrate selectively elevates the pancreatic content of very-long-chain SLs in NOD mice and reduces the incidence of diabetes by around 50% [184]. Moreover they showed that fenofibrate treatment leads to remodeling of pancreatic lipidome with increased amount of lysoglycerophospholipids [184].…”

“…In the follow-up study they demonstrated that fenofibrate selectively elevates the pancreatic content of very-long-chain SLs in NOD mice and reduces the incidence of diabetes by around 50% [184]. Moreover they showed that fenofibrate treatment leads to remodeling of pancreatic lipidome with increased amount of lysoglycerophospholipids [184]. NOD mice treated with fenofibrate were characterized by more stable blood glucose and improved glucose tolerance [184].…”

“…Moreover they showed that fenofibrate treatment leads to remodeling of pancreatic lipidome with increased amount of lysoglycerophospholipids [184]. NOD mice treated with fenofibrate were characterized by more stable blood glucose and improved glucose tolerance [184]. Sulfatide was additionally shown to inhibit insulitis and to prevent diabetes in NOD mice by blockage of L-selectin [185].…”