The role of sphingolipids in the pancreatic beta cell

最近的研究表明，鞘脂可能在细胞的存活和功能中具有重要的调节作用。 胰腺β细胞。神经酰胺，其响应于炎性细胞因子（例如肿瘤）而产生 坏死因子-α（TNF-α）、白细胞介素1等），已显示诱导β细胞凋亡， 抑制胰岛素分泌。神经节苷脂是神经酰胺的糖基化形式，是公认的自身抗原 参与诱导胰岛炎和1型糖尿病。鞘氨醇1-磷酸， 由各种生长因子产生的神经酰胺，已显示促进β-细胞存活和生长， 可能是由于其前体神经酰胺的相反作用。尽管有这些孤立的研究， 鞘脂作为β-细胞生长、增殖和功能的调节剂尚未被详细研究， 无论是在分离的细胞中还是在完整的动物中。在此，我们建议开展研究，调查 神经鞘脂在β细胞功能中的作用首先，使用药理学抑制剂和一种新的基因敲除小鼠， 不能制造神经酰胺，我们将确定调节鞘脂水平对神经酰胺的影响。 β细胞功能的研究第二，我们将研究神经酰胺 和鞘氨醇1-磷酸用于分化调节细胞存活，同时评估作为 细胞因子或游离脂肪酸诱导的细胞死亡的调节剂。最终这些研究将有助于揭示 调节β-细胞鞘脂水平是否有利于阻断β-细胞死亡， 移植或预防1型或2型糖尿病的发作。

Recent studies suggest that sphingolipids may have important regulatory roles in the survival and function of pancreatic beta-cells. Ceramides, which are produced in response to inflammatory cytokines (e.g. tumor necrosis factor-alpha (TNF-alpha), interleukin 1, etc.), have been shown to induce beta-cell apoptosis and inhibit insulin secretion. Gangliosides, which are glycosylated forms of ceramide, are putative autoantigens involved in the induction of insulitis and type 1 diabetes. And, sphingosine 1-phosphate, a derivative of ceramide produced by various growth factors, has been shown to promote beta-cell survival and growth, perhaps by opposing effects of its precursor, ceramide. Despite these isolated studies, the importance of sphingolipids as regulators of beta-cell growth, proliferation, and function has not been studied in detail, either in isolated cells or in intact animals. Herein we propose to initiate studies investigating the role of sphingolipids in beta-cell function. First, using pharmacological inhibitors and a novel knockout mouse that is incapable of making ceramides, we will determine the consequence of modulating sphingolipid levels on beta cell function in rodents. Second, we will investigate the molecular mechanisms through which ceramide and sphingosine 1-phosphate serve to divergently regulate cell survival, while evaluating the role of either as a modulator of cytokine or free fatty acid-induced cell death. Ultimately these studies will help reveal whether modulating beta-cell sphingolipid levels is beneficial for either blocking beta-cell death during transplantation or preventing the onset of type 1 or type 2 diabetes.