Department of Histology and Embryology, University of Campinas (UNICAMP), Campinas, SP, Brazil.
Int J Exp Pathol. 2014 Aug;95(4):296-308. doi: 10.1111/iep.12084. Epub 2014 May 23.
In this study, we investigated the effect of low density lipoprotein receptor (LDLr) deficiency on gap junctional connexin 36 (Cx36) islet content and on the functional and growth response of pancreatic beta-cells in C57BL/6 mice fed a high-fat (HF) diet. After 60 days on regular or HF diet, the metabolic state and morphometric islet parameters of wild-type (WT) and LDLr-/- mice were assessed. HF diet-fed WT animals became obese and hypercholesterolaemic as well as hyperglycaemic, hyperinsulinaemic, glucose intolerant and insulin resistant, characterizing them as prediabetic. Also they showed a significant decrease in beta-cell secretory response to glucose. Overall, LDLr-/- mice displayed greater susceptibility to HF diet as judged by their marked cholesterolaemia, intolerance to glucose and pronounced decrease in glucose-stimulated insulin secretion. HF diet induced similarly in WT and LDLr-/- mice, a significant decrease in Cx36 beta-cell content as revealed by immunoblotting. Prediabetic WT mice displayed marked increase in beta-cell mass mainly due to beta-cell hypertrophy/replication. Nevertheless, HF diet-fed LDLr-/- mice showed no significant changes in beta-cell mass, but lower islet-duct association (neogenesis) and higher beta-cell apoptosis index were seen as compared to controls. The higher metabolic susceptibility to HF diet of LDLr-/- mice may be explained by a deficiency in insulin secretory response to glucose associated with lack of compensatory beta-cell expansion.
在这项研究中，我们研究了低密度脂蛋白受体 (LDLr) 缺乏对缝隙连接连接蛋白 36 (Cx36) 胰岛含量的影响，以及高脂 (HF) 饮食喂养的 C57BL/6 小鼠胰岛β细胞的功能和生长反应。在正常饮食或 HF 饮食 60 天后，评估野生型 (WT) 和 LDLr-/- 小鼠的代谢状态和胰岛形态参数。HF 饮食喂养的 WT 动物变得肥胖、高胆固醇血症以及高血糖、高胰岛素血症、葡萄糖不耐受和胰岛素抵抗，表现出糖尿病前期特征。它们的胰岛β细胞对葡萄糖的分泌反应也显著降低。总体而言，LDLr-/- 小鼠对 HF 饮食的敏感性更高，表现在它们的胆固醇水平显著升高、对葡萄糖不耐受以及葡萄糖刺激的胰岛素分泌明显下降。HF 饮食同样诱导 WT 和 LDLr-/- 小鼠的 Cx36 胰岛β细胞含量显著降低，这通过免疫印迹得到证实。糖尿病前期 WT 小鼠的胰岛β细胞质量显著增加，主要归因于β细胞肥大/复制。然而，与对照组相比，HF 饮食喂养的 LDLr-/- 小鼠的胰岛β细胞质量没有显著变化，但胰岛-导管关联（新生）较低，β细胞凋亡指数较高。LDLr-/- 小鼠对 HF 饮食的代谢敏感性较高，可能与缺乏对葡萄糖的胰岛素分泌反应代偿性β细胞扩张有关。
