维生素D3对2型糖尿病小鼠轻度认知障碍的改善作用及机制研究

doi:10.19723/j.issn.1671-167X.2023.04.003

摘要/Abstract

摘要：

目的: 探讨维生素D3对2型糖尿病小鼠轻度认知障碍的改善作用，并进一步探讨其可能的作用机制。方法: 将雄性db/db小鼠随机分为4组: 糖尿病(diabetes mellitus, DM)模型组、维生素D3低剂量组[250 IU/(kg·d)]、中剂量组[500 IU/(kg·d)]和高剂量组[1 000 IU/(kg·d)]，将与其匹配的db/m小鼠作为正常对照组。维生素D3各剂量组每天灌胃相应浓度的维生素D3玉米油溶液，正常对照组和DM模型组灌胃玉米油，连续饲养16周。分别于实验第0、4、8和16周检测各组小鼠空腹血糖，实验第16周进行新物体识别实验，实验结束后留取各组小鼠的海马和皮质，分别检测各组小鼠海马组织中5-羟色胺(5-hydroxytryptamine, 5-HT)浓度、皮质组织中白细胞介素-18(interleukin-18, IL-18)的含量及海马组织中核苷酸结合寡聚化结构域样受体蛋白3(nucleotide binding oligomerization domain-like receptor family pyrin domain-containing protein 3, NLRP3)的蛋白表达情况。结果: 与正常对照组相比，DM模型组小鼠空腹血糖值显著升高(P < 0.01)，新物体探索次数、探索时间和辨别指数均显著下降(P < 0.05)，海马组织中5-HT浓度显著下降(P < 0.01)，皮质组织中IL-18浓度显著升高(P < 0.01)，海马组织中NLRP3的阳性表达明显增加。与DM模型组相比，第8周和第16周的维生素D3中剂量和高剂量组小鼠血糖显著下降(P < 0.05或P < 0.01)，维生素D3高剂量组小鼠新物体探索次数、探索时间和辨别指数均显著升高(P < 0.05)，中剂量和高剂量组小鼠海马组织中5-HT浓度显著升高(P < 0.01)且皮质组织中IL-18浓度显著降低(P < 0.01)，各剂量组小鼠海马组织中NLRP3的阳性表达明显降低。结论: 维生素D3可能通过抑制NLRP3活性降低炎症反应，进而改善2型糖尿病小鼠轻度认知障碍。

关键词: 维生素D3, 2型糖尿病, 认知功能障碍

Abstract:

Objective: To investigate the effect of vitamin D3 on mild cognitive impairment in type 2 diabetic mice and explore its possible mechanism. Methods: Male db/db mice were randomly divided into 4 groups: the diabetes mellitus (DM) group, the low dose [250 IU/(kg·d)], medium dose [500 IU/ (kg·d)] and high dose [1 000 IU/(kg·d)] vitamin D3 intervention groups. The db/m mice were enrolled as the normal control group. The mice in vitamin D3 groups were gavaged with corresponding concentration of vitamin D3 in corn oil, and the mice in the normal control group and the DM group were gavaged with corn oil. After being fed for 16 weeks, fasting blood glucose of mice in each group was measured at the end of 0, 4, 8 and 16 weeks, and the new object recognition experiment was conducted at the end of 16 weeks. At the end of the experiment, the hippocampi and cortices of mice in each group were collected, and the concentration of 5-hydroxytryptamine (5-HT) and interleukin-18 (IL-18) in the hippocampal tissues of mice in each group were determined by enzyme linked immunosorbent assay (ELISA). Immunohistochemical staining was used to observe the expression of nucleotide binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) in the hippocampal tissues of the mice. Results: Compared with the normal control group, the fasting blood glucose of mice in DM group was significantly increased (P < 0.01). The exploration and discrimination index (DI) in the new object recognition experiment were significantly decreased (P < 0.05). The concentrations of 5-HT in the hippocampal tissues of mice were significantly decreased (P < 0.01). The concentrations of IL-18 in cortical tissues of mice were significantly increased (P < 0.01) and the positive expression of NLRP3 in the hippocampal tissues was higher. However, compared with the DM group, the fasting blood glucose of mice was significantly decreased in the medium and high dose vitamin D3 groups at the end of 8 and 16 weeks (P < 0.05 or P < 0.01). The exploration and DI of mice in the new object recognition experiment were significantly increased in high dose vitamin D3 group (P < 0.05). The concentrations of 5-HT in hippocampal tissues were significantly increased (P < 0.01) and the concentrations of IL-18 in cortical tissues were significantly decreased in the medium and high dose vitamin D3 groups (P < 0.01). The positive expression of NLRP3 in hippocampal tissues was reduced in all the vitamin D3 groups. Conclusion: Vitamin D3 might reduce the inflammatory response by inhibiting the activity of NLRP3, and thus ameliorating mild cognitive impairment in type 2 diabetic mice.

Key words: Vitamin D3, Type 2 diabetes mellitus, Cognitive dysfunction

中图分类号:

R591.44

鲍雷,蔡夏夏,张明远,任磊磊. 维生素D3对2型糖尿病小鼠轻度认知障碍的改善作用及机制研究[J]. 北京大学学报（医学版）, 2023, 55(4): 587-592.

Lei BAO,Xia-xia CAI,Ming-yuan ZHANG,Lei-lei REN. Effect of vitamin D3 on mild cognitive impairment in type 2 diabetic mice and its possible mechanism[J]. Journal of Peking University (Health Sciences), 2023, 55(4): 587-592.

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Group	n	Number of exploration times, n	Exploration time/s	DI/%
N	12	7.80±0.85	10.52±1.11	69.34±6.12
DM	12	1.50±0.60^*	1.16±0.45^*	19.51±7.02^*
LVD3	12	2.90±0.92	3.39±1.29	21.36±11.02
MVD3	12	3.20±0.84	3.24±0.87	29.37±10.04
HVD3	12	3.90±0.69^#	4.70±1.08^#	54.27±8.11^#

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