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.
Highlights
Experimental studies have demonstrated the importance of sphingolipids in regulating beta cell biology and inflammation [1, 2]
We have previously shown that sphingolipid metabolism is abnormal at the onset of type 1 diabetes, as evidenced by a reduced islet level of sulfatide and reduced expression of several enzymes involved in sphingolipid metabolism [16]
Fenofibrate promotes the formation of very-long-chain sphingolipids We previously showed how fenofibrate prevented diabetes in NOD mice and how this was associated with increased islet sulfatide levels, as evaluated by immunohistochemistry [16]
Summary
Experimental studies have demonstrated the importance of sphingolipids in regulating beta cell biology and inflammation [1, 2]. The central sphingolipid metabolite is ceramide, which is generally considered to induce apoptosis and insulin. Adding a phosphocholine generates sphingomyelin, which is a major component of myelin sheaths [5]. The addition of galactose and sulfate to ceramide forms sulfatide, which is an insulin chaperone and regulator of insulin secretion [6, 7]. Sphingolipids are of interest as a major component of the myelin sheath surrounding sympathetic nerves [9]. Sympathetic neurons inhibit insulin and stimulate glucagon secretion to prevent hypoglycaemia [12, 13]. The loss of pancreatic sympathetic nerve fibres is, a contributing factor to the early loss of glucagon secretion observed in adolescents with type 1 diabetes and NOD mice [11, 14]
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