Abstract：
OBJECTIVE: Sulfatide is a chaperone for insulin manufacturing in beta cells. Here we explore whether the blood glucose values normally could be associated with this sphingolipid and especially two of its building enzymes CERS2 and CERS6. Both T1D and T2D have low blood sulfatide levels, and insulin resistance on beta cells at clinical diagnosis. Furthermore, we examined islet pericytes for sulfatide, and beta-cell receptors for GLP-1, both of which are related to the insulin production.
METHODS: We examined mRNA levels in islets from the DiViD and nPOD studies, performed genetic association analyses, and histologically investigated pericytes in the islets for sulfatide.
RESULTS: Polymorphisms of the gene encoding the CERS6 enzyme responsible for synthesising dihydroceramide, a precursor to sulfatide, are associated with random blood glucose values in non-diabetic persons. This fits well with our finding of sulfatide in pericytes in the islets, which regulates the capillary blood flow in the islets of Langerhans, which is important for oxygen supply to insulin production. In the islets of newly diagnosed T1D patients, we observed low levels of GLP-1 receptors; this may explain the insulin resistance in their beta cells and their low insulin production. In T2D patients, we identified associated polymorphisms in both CERS2 and CERS6.
CONCLUSIONS: Here, we describe several polymorphisms in sulfatide enzymes related to blood glucose levels and HbA1c in non-diabetic individuals. Islet pericytes from such persons contain sulfatide. Furthermore, low insulin secretion in newly diagnosed T1D may be explained by beta-cell insulin resistance due to low levels of GLP-1 receptors.
METHODS: We examined mRNA levels in islets from the DiViD and nPOD studies, performed genetic association analyses, and histologically investigated pericytes in the islets for sulfatide.
RESULTS: Polymorphisms of the gene encoding the CERS6 enzyme responsible for synthesising dihydroceramide, a precursor to sulfatide, are associated with random blood glucose values in non-diabetic persons. This fits well with our finding of sulfatide in pericytes in the islets, which regulates the capillary blood flow in the islets of Langerhans, which is important for oxygen supply to insulin production. In the islets of newly diagnosed T1D patients, we observed low levels of GLP-1 receptors; this may explain the insulin resistance in their beta cells and their low insulin production. In T2D patients, we identified associated polymorphisms in both CERS2 and CERS6.
CONCLUSIONS: Here, we describe several polymorphisms in sulfatide enzymes related to blood glucose levels and HbA1c in non-diabetic individuals. Islet pericytes from such persons contain sulfatide. Furthermore, low insulin secretion in newly diagnosed T1D may be explained by beta-cell insulin resistance due to low levels of GLP-1 receptors.
摘要：
目的：硫肽是β细胞制造胰岛素的伴侣。在这里，我们探讨了血糖值是否通常与这种鞘脂有关，尤其是其两种构建酶CERS2和CERS6。T1D和T2D都有低血硫酸盐水平，和临床诊断时β细胞的胰岛素抵抗。此外，我们检查了胰岛周细胞的硫酸脂，和GLP-1的β细胞受体，两者都与胰岛素的产生有关。
方法：我们从DiViD和nPOD研究中检测了胰岛中的mRNA水平，进行遗传关联分析，并对胰岛中的周细胞进行了组织学研究。
结果：编码负责合成二氢神经酰胺的CERS6酶的基因多态性，硫酸脂的前体,与非糖尿病患者的随机血糖值相关。这与我们在胰岛周细胞中发现的硫酸盐非常吻合，调节胰岛的毛细血管血流，这对胰岛素生产的氧气供应很重要。在新诊断的T1D患者的胰岛中，我们观察到低水平的GLP-1受体;这可能解释了其β细胞的胰岛素抵抗和胰岛素产量低.在T2D患者中，我们鉴定了CERS2和CERS6的相关多态性.
结论：这里，我们描述了非糖尿病个体中与血糖水平和HbA1c相关的硫酸盐酶的几种多态性.来自这些人的胰岛周细胞含有硫苷脂。此外，新诊断的T1D中胰岛素分泌低可能是由于GLP-1受体水平低导致β细胞胰岛素抵抗。
方法：我们从DiViD和nPOD研究中检测了胰岛中的mRNA水平，进行遗传关联分析，并对胰岛中的周细胞进行了组织学研究。
结果：编码负责合成二氢神经酰胺的CERS6酶的基因多态性，硫酸脂的前体,与非糖尿病患者的随机血糖值相关。这与我们在胰岛周细胞中发现的硫酸盐非常吻合，调节胰岛的毛细血管血流，这对胰岛素生产的氧气供应很重要。在新诊断的T1D患者的胰岛中，我们观察到低水平的GLP-1受体;这可能解释了其β细胞的胰岛素抵抗和胰岛素产量低.在T2D患者中，我们鉴定了CERS2和CERS6的相关多态性.
结论：这里，我们描述了非糖尿病个体中与血糖水平和HbA1c相关的硫酸盐酶的几种多态性.来自这些人的胰岛周细胞含有硫苷脂。此外，新诊断的T1D中胰岛素分泌低可能是由于GLP-1受体水平低导致β细胞胰岛素抵抗。
