School of Medicine, Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Dis Model Mech. 2014 Jun;7(6):625-33. doi: 10.1242/dmm.015750. Epub 2014 Apr 24.
One of the tissues or organs affected by diabetes is the nervous system, predominantly the peripheral system (peripheral polyneuropathy and/or painful peripheral neuropathy) but also the central system with impaired learning, memory and mental flexibility. The aim of this study was to test the hypothesis that the pre-diabetic or diabetic condition caused by a high-fat diet (HFD) can damage both the peripheral and central nervous systems. Groups of C57BL6 and Swiss Webster mice were fed a diet containing 60% fat for 8 months and compared to control and streptozotocin (STZ)-induced diabetic groups that were fed a standard diet containing 10% fat. Aspects of peripheral nerve function (conduction velocity, thermal sensitivity) and central nervous system function (learning ability, memory) were measured at assorted times during the study. Both strains of mice on HFD developed impaired glucose tolerance, indicative of insulin resistance, but only the C57BL6 mice showed statistically significant hyperglycemia. STZ-diabetic C57BL6 mice developed learning deficits in the Barnes maze after 8 weeks of diabetes, whereas neither C57BL6 nor Swiss Webster mice fed a HFD showed signs of defects at that time point. By 6 months on HFD, Swiss Webster mice developed learning and memory deficits in the Barnes maze test, whereas their peripheral nervous system remained normal. In contrast, C57BL6 mice fed the HFD developed peripheral nerve dysfunction, as indicated by nerve conduction slowing and thermal hyperalgesia, but showed normal learning and memory functions. Our data indicate that STZ-induced diabetes or a HFD can damage both peripheral and central nervous systems, but learning deficits develop more rapidly in insulin-deficient than in insulin-resistant conditions and only in Swiss Webster mice. In addition to insulin impairment, dyslipidemia or adiponectinemia might determine the neuropathy phenotype.
糖尿病影响的组织或器官之一是神经系统，主要是外周系统（周围多发性神经病和/或痛性周围神经病），但也包括中枢系统，表现为学习、记忆和思维灵活性受损。本研究旨在验证以下假说，即高脂肪饮食（HFD）引起的糖尿病前期或糖尿病状态可损害外周和中枢神经系统。将 C57BL6 和瑞士 Webster 小鼠分组，喂食含 60%脂肪的饮食 8 个月，并与喂食含 10%脂肪的标准饮食的对照组和链脲佐菌素（STZ）诱导的糖尿病组进行比较。在研究过程中的不同时间点测量外周神经功能（传导速度、热敏感性）和中枢神经系统功能（学习能力、记忆能力）。两种品系的 HFD 小鼠均出现葡萄糖耐量受损，表明存在胰岛素抵抗，但仅 C57BL6 小鼠出现统计学上的显著高血糖。STZ 诱导的 C57BL6 糖尿病小鼠在糖尿病 8 周后在 Barnes 迷宫中出现学习能力缺陷，而喂食 HFD 的 C57BL6 或瑞士 Webster 小鼠在该时间点均未出现缺陷迹象。在 HFD 喂养 6 个月时，瑞士 Webster 小鼠在 Barnes 迷宫测试中出现学习和记忆缺陷，而其外周神经系统仍正常。相比之下，喂食 HFD 的 C57BL6 小鼠出现周围神经功能障碍，表现为神经传导速度减慢和热痛觉过敏，但学习和记忆功能正常。我们的数据表明，STZ 诱导的糖尿病或 HFD 均可损害外周和中枢神经系统，但在胰岛素缺乏而非胰岛素抵抗的情况下，学习缺陷的发展更快，且仅在瑞士 Webster 小鼠中出现。除了胰岛素受损外，血脂异常或脂联素血症也可能决定神经病变表型。
