糖尿病小鼠模型的常见种类及其构建要素分析

doi:10.12300/j.issn.1674-5817.2023.031

摘要/Abstract

摘要：

糖尿病是一种以胰岛素绝对或相对缺乏导致高血糖为特征的疾病，其高发病率和并发症对患者生活产生极大的影响。动物模型被广泛运用于研究糖尿病及其并发症的发生机制及治疗方案。由于糖尿病类型的不同，其发病机制和发病特征也不同，导致治疗方案不同。动物实验除了考虑动物的遗传因素与生理特征（性别、年龄）外，还需要考虑实验方案及各种应对方案，这些因素对实验数据、实验结果的可重复性和稳定性有着重要影响。因此，糖尿病研究需要选择合适的动物模型进行实验：1型糖尿病以胰岛素绝对缺乏为特征，现有的1型糖尿病小鼠模型包括化学（STZ诱导）诱导型和自发性糖尿病模型（NOD小鼠）等；2型糖尿病以胰岛素抵抗和葡萄糖耐量受损为主，现有的2型糖尿病动物模型包括高脂饮食诱导型、自发性（包括单基因肥胖小鼠和多基因肥胖小鼠）模型和遗传修饰小鼠模型。本综述主要总结了糖尿病小鼠模型的常见种类和构建要素，以及选用时需考虑的关键因素，并探讨了这些因素对糖尿病研究的影响，以期为相关研究提供参考。

关键词: 糖尿病, 动物模型, 建模因素, 小鼠

Abstract:

Diabetes mellitus is a disease characterized by absolute or relative lack of insulin, which leads to hyperglycemia, and its high mobidity and complications have a great impact on the lives of patients. Animal models are widely used to study the pathogenesis and treatment of diabetes and its complications. Different types of diabetes, with different pathogenesis and pathognomonic features, have different treatment options. In animal experimental, in addition to considering the genetic factors and physiological characteristics of the animal (such as sex and age), it is also necessary to consider the experimental protocol and various response options, which have a great impact on the experimental data, the reproducibility and stability of the experimental results. Therefore, it is necessary to select suitable animal models for experiments in the study of diabetes. Type 1 diabetes is characterized by absolute insulin deficiency, and existing mouse models of type 1 diabetes include chemically (STZ-induced) induced and spontaneous diabetes model (NOD mice), etc. Type 2 diabetes, characterized by insulin resistance and impaired glucose tolerance, is established in both obese and non-obese animal models, including diet-induced (high-fat diet induced), spontaneous diabetes (including monogenic and polygenic obese mice) models, and genetically modified mouse models. In this review, we discussed the common types of diabetic mouse models and analyzed the elements of their construction, the key factors that should be considered in the selection of diabetic mouse models, and explore the impact of these factors on the research of diabetes.

Key words: Diabetes mellitus, Animal Model, Modeling factors, Mouse

中图分类号:

R587.1

王雪, 呼永河. 糖尿病小鼠模型的常见种类及其构建要素分析[J]. 实验动物与比较医学, 2023, 43(4): 415-421.

Xue WANG, Yonghe HU. Analysis of Common Types and Construction Elements of Diabetic Mouse Models[J]. Laboratory Animal and Comparative Medicine, 2023, 43(4): 415-421.

图/表 1

参考文献 43

1	HASSANEIN M, AFANDI B, AHMEDANI M Y, et al. Diabetes and Ramadan: practical guidelines 2021[J]. Diabetes Res Clin Pract, 2022, 185:109185. DOI: 10.1016/j.diabres.2021.109185 .
2	RADENKOVIĆ M, STOJANOVIĆ M, PROSTRAN M. Experimental diabetes induced by alloxan and streptozotocin: the current state of the art[J]. J Pharmacol Toxicol Methods, 2016, 78:13-31. DOI: 10.1016/j.vascn. 2015. 11.004 .
3	易承学, 闫曼, 钱欣. 链脲佐菌素联合高脂饮食制备糖尿病小鼠模型研究[J]. 镇江高专学报, 2021, 34(4):67-69. DOI: 10.3969/j.issn.1008-8148.2021.04.016 .
	YI C X, YAN M, QIAN X. A study on the preparation of diabetic mouse model with streptozotocin and high fat diet[J]. J Zhenjiang Coll, 2021, 34(4):67-69. DOI: 10.3969/j.issn.1008-8148.2021.04.016 .
4	FURMAN B L. Streptozotocin-induced diabetic models in mice and rats[J]. Curr Protoc, 2021, 1(4): e78. DOI: 10.1002/cpz1.78 .
5	DIENER J L, MOWBRAY S, HUANG W J, et al. FGF21 normalizes plasma glucose in mouse models of type 1 diabetes and insulin receptor dysfunction[J]. Endocrinology, 2021, 162(9): bqab092. DOI: 10.1210/endocr/bqab092 .
6	LIU S, MA L L, REN X Y, et al. A new mouse model of type 2 diabetes mellitus established through combination of high-fat diet, streptozotocin and glucocorticoid[J]. Life Sci, 2021, 286:120062. DOI: 10.1016/j.lfs.2021.120062 .
7	LAFFERTY R A, MCSHANE L M, FRANKLIN Z J, et al. Sustained glucagon receptor antagonism in insulin-deficient high-fat-fed mice[J]. J Endocrinol, 2022, 255(2):91-101. DOI: 10.1530/JOE-22-0106 .
8	HAYASHI K, KOJIMA R, ITO M. Strain differences in the diabetogenic activity of streptozotocin in mice[J]. Biol Pharm Bull, 2006, 29(6):1110-1119. DOI: 10.1248/bpb.29.1110 .
9	DEEDS M C, ANDERSON J M, ARMSTRONG A S, et al. Single dose streptozotocin-induced diabetes: considerations for study design in islet transplantation models[J]. Lab Anim, 2011, 45(3):131-140. DOI: 10.1258/la.2010.010090 .
10	ANDERSON M S, BLUESTONE J A. THE NOD MOUSE: a model of immune dysregulation[J]. Annu Rev Immunol, 2005, 23:447-485. DOI: 10.1146/annurev.immunol.23.021704.115643 .
11	YU F, ZHOU X, JIN X, et al. Rational construction of controllable autoimmune diabetes model depicting clinical features[J]. PLoS One, 2022, 17(1): e0260100. DOI: 10.1371/journal.pone.0260100 .
12	MCNEILLY A D, MCCRIMMON R J. Impaired hypoglycaemia awareness in type 1 diabetes: lessons from the lab[J]. Diabetologia, 2018, 61(4):743-750. DOI: 10.1007/s00125-018-4548-8 .
13	AUBIN A M, LOMBARD-VADNAIS F, COLLIN R, et al. The NOD mouse beyond autoimmune diabetes[J]. Front Immunol, 2022, 13:874769. DOI: 10.3389/fimmu.2022.874769 .
14	VELD P I. Insulitis in human type 1 diabetes: a comparison between patients and animal models[J]. Semin Immunopathol, 2014, 36(5):569-579. DOI: 10.1007/s00281-014-0438-4 .
15	HARRISON L C. The dark side of insulin: a primary autoantigen and instrument of self-destruction in type 1 diabetes[J]. Mol Metab, 2021, 52:101288. DOI: 10.1016/j.molmet.2021.101288 .
16	TOKUDA K, IKEMOTO T, YAMASHITA S, et al. Syngeneically transplanted insulin producing cells differentiated from adipose derived stem cells undergo delayed damage by autoimmune responses in NOD mice[J]. Sci Rep, 2022, 12(1):5852. DOI: 10.1038/s41598-022-09838-x .
17	ALDRICH V R, HERNANDEZ-ROVIRA B B, CHANDWANI A, et al. NOD mice-good model for T1D but not without limitations[J]. Cell Transplant, 2020, 29:963689720939127. DOI: 10.1177/0963689720939127 .
18	GENCHI V A, D'ORIA R, PALMA G, et al. Impaired leptin signalling in obesity: is leptin a new thermolipokine?[J]. Int J Mol Sci, 2021, 22(12):6445. DOI: 10.3390/ijms22126445 .
19	GAULT V A, KERR B D, HARRIOTT P, et al. Administration of an acylated GLP-1 and GIP preparation provides added beneficial glucose-lowering and insulinotropic actions over single incretins in mice with Type 2 diabetes and obesity[J]. Clin Sci (Lond), 2011, 121(3):107-117. DOI: 10.1042/CS20110006 .
20	DUONG M, UNO K, NANKIVELL V, et al. Induction of obesity impairs reverse cholesterol transport in ob/ob mice[J]. PLoS One, 2018, 13(9): e0202102. DOI: 10.1371/journal.pone.0202102 .
21	MARCHETTI P. Islet inflammation in type 2 diabetes[J]. Diabetologia, 2016, 59(4):668-672. DOI: 10.1007/s00125-016-3875-x .
22	WANG F, ZHANG C, DAI L N, et al. Bafilomycin A1 accelerates chronic refractory wound healing in db/db mice[J]. Biomed Res Int, 2020, 2020:6265701. DOI: 10.1155/2020/6265701 .
23	GOOSSENS G H, BLAAK E E. Unraveling the pathophysiology of obesity-related insulin resistance-a perspective on adipose tissue inflammation is directly linked to obesity-induced insulin resistance, while gut dysbiosis and mitochondrial dysfunction are not required[J]. Function (Oxf), 2020, 1(2): zqaa021. DOI: 10.1093/function/zqaa021 .
24	CHAKRABORTY G, THUMPAYIL S, LAFONTANT D E, et al. Age dependence of glucose tolerance in adult KK-Ay mice, a model of non-insulin dependent diabetes mellitus[J]. Lab Anim (NY), 2009, 38(11):364-368. DOI: 10.1038/laban1109-364 .
25	OHTOMO T, INO K, MIYASHITA R, et al. Chronic high-fat feeding impairs adaptive induction of mitochondrial fatty acid combustion-associated proteins in brown adipose tissue of mice[J]. Biochem Biophys Rep, 2017, 10:32-38. DOI: 10.1016/j.bbrep.2017.02.002 .
26	DENVIR J, BOSKOVIC G, FAN J, et al. Whole genome sequence analysis of the TALLYHO/Jng mouse[J].BMC Genom, 2016, 17(1):1-15. DOI: 10.1186/s12864-016-3245-6 .
27	PARKMAN J K, SKLIOUTOVSKAYA-LOPEZ K, MENIKDIWELA K R, et al. Effects of high fat diets and supplemental tart cherry and fish oil on obesity and type 2 diabetes in male and female C57BL/6J and TALLYHO/Jng mice[J]. J Nutr Biochem, 2021, 94:108644. DOI: 10.1016/j.jnutbio.2021.108644 .
28	SHAO W H, JARGALSAIKHAN O, ICHIMURA-SHIMIZU M, et al. Spontaneous occurrence of various types of hepatocellular adenoma in the livers of metabolic syndrome-associated steatohepatitis model TSOD mice[J]. Int J Mol Sci, 2022, 23(19):11923. DOI: 10.3390/ijms231911923 .
29	ISHIBASHI K, TAKEDA Y, NAKATANI E, et al. Activation of PPARγ at an early stage of differentiation enhances adipocyte differentiation of MEFs derived from type II diabetic TSOD mice and alters lipid droplet morphology[J]. Biol Pharm Bull, 2017, 40(6):852-859. DOI: 10.1248/bpb.b17-00030 .
30	NAGY C, EINWALLNER E. Study of in vivo glucose metabolism in high-fat diet-fed mice using oral glucose tolerance test (OGTT) and insulin tolerance test (ITT)[J]. J Vis Exp, 2018(131):56672. DOI: 10.3791/56672 .
31	INGVORSEN C, KARP N A, LELLIOTT C J. The role of sex and body weight on the metabolic effects of high-fat diet in C57BL/6N mice[J]. Nutr Diabetes, 2017, 7(4): e261. DOI: 10.1038/nutd.2017.6 .
32	GUERRA-CANTERA S, FRAGO L M, COLLADO-PÉREZ R, et al. Sex differences in metabolic recuperation after weight loss in high fat diet-induced obese mice[J]. Front Endocrinol (Lausanne), 2021, 12:796661. DOI: 10.3389/fendo.2021.796661 .
33	DROZ B A, SNEED B L, JACKSON C V, et al. Correlation of disease severity with body weight and high fat diet in the FATZO/Pco mouse[J]. PLoS One, 2017, 12(6): e0179808. DOI: 10.1371/journal.pone.0179808 .
34	SPEAKMAN J R. Use of high-fat diets to study rodent obesity as a model of human obesity[J]. Int J Obes, 2019, 43(8):1491-1492. DOI: 10.1038/s41366-019-0363-7 .
35	CHAIX A, DEOTA S, BHARDWAJ R, et al. Sex- and age-dependent outcomes of 9-hour time-restricted feeding of a Western high-fat high-sucrose diet in C57BL/6J mice[J]. Cell Rep, 2021, 36(7):109543. DOI: 10.1016/j.celrep.2021.109543 .
36	ROHAM P H, SAVE S N, SHARMA S. Human islet amyloid polypeptide: a therapeutic target for the management of type 2 diabetes mellitus[J]. J Pharm Anal, 2022, 12(4):556-569. DOI: 10.1016/j.jpha.2022.04.001 .
37	KING M, PEARSON T, SHULTZ L D, et al. Development of new-generation HU-PBMC-NOD/SCID mice to study human islet alloreactivity[J]. Ann N Y Acad Sci, 2007, 1103:90-93. DOI: 10.1196/annals.1394.011 .
38	RIGOLLI M, WHALLEY G A. Heart failure with preserved ejection fraction[J]. J Geriatr Cardiol, 2013, 10(4):369-376. DOI: 10.3969/j.issn.1671-5411.2013.04.011 .
39	MIYACHI Y, MIYAZAWA T, OGAWA Y. HNF1A mutations and beta cell dysfunction in diabetes[J]. Int J Mol Sci, 2022, 23(6):3222. DOI: 10.3390/ijms23063222 .
40	SMITH L I F, HILL T G, BOWE J E. Generating beta-cell-specific transgenic mice using the cre-lox system[J]. Methods Mol Biol, 2020, 2128:181-205. DOI: 10.1007/978-1-0716-0385-7_13 .
41	MILLERSHIP S J, TUNSTER S J, VAN DE PETTE M, et al. Neuronatin deletion causes postnatal growth restriction and adult obesity in 129S2/Sv mice[J]. Mol Metab, 2018, 18:97-106. DOI: 10.1016/j.molmet.2018.09.001 .
42	SINGHA A, PALAVICINI J P, PAN M X, et al. Leptin receptors in RIP-Cre25Mgn neurons mediate anti-dyslipidemia effects of leptin in insulin-deficient mice[J]. Front Endocrinol (Lausanne), 2020, 11:588447. DOI: 10.3389/fendo.2020.588447 .
43	FEX M, WIERUP N, NITERT M D, et al. Rat insulin promoter 2-Cre recombinase mice bred onto a pure C57BL/6J background exhibit unaltered glucose tolerance[J]. J Endocrinol, 2007, 194(3):551-555. DOI: 10.1677/JOE-07-0161 .

疾病模型种类 Disease model type	构建小鼠 Modeling mice	主要特征 Main characteristic	适用范围 Scope of application
化学诱导1型糖尿病模型 Chemically induced T1DM	单次高剂量STZ诱导小鼠	单纯性高血糖	开发新型治疗1型糖尿病胰岛素
	多次低剂量STZ诱导小鼠	诱导性胰腺炎，高血糖	β细胞功能受损的1型糖尿病的治疗
自发性1型糖尿病模型 Spontaneous T1DM	NOD小鼠	胰岛被白细胞浸润，β细胞受损	自身免疫系统受损所致1型糖尿病的治疗
自发性2型糖尿病模型 Spontaneous T2DM	ob/ob小鼠	一过性高血糖（4周龄～20周龄），低代谢，食欲旺盛	肥胖为主、高血糖不严重的2型糖尿病及Ⅰ、Ⅱ期肥胖症的治疗
	db/db小鼠	严重的高胰岛素血症、高血糖和肥胖	β细胞功能受损的2型糖尿病及其并发症的治疗
	KK小鼠	2～3月龄开始肥胖，食欲旺盛，高胰岛素血症	非胰岛素依赖型2型糖尿病的治疗
	KK-Ay小鼠	8周龄开始肥胖，30周龄出现高血糖	肥胖为主非胰岛素依赖型2型糖尿病，糖尿病肾病及脑病等并发症的治疗
	Tallyho/Jng小鼠	高血糖，胰岛肥大，葡萄糖耐受不良，高胰岛素血症较轻微	基因所致肥胖型2型糖尿病的治疗
	TSOD小鼠	严重的高胰岛素血症、高血糖和肥胖	自发性肥胖型2型糖尿病的治疗
饮食诱导2型糖尿病模型 Diet-induced T2DM	高脂饮食所致肥胖小鼠	高血糖不明显，喂养持续时间久	改善胰岛素的治疗方法

疾病模型种类 Disease model type	构建小鼠 Modeling mice	主要特征 Main characteristic	适用范围 Scope of application
化学诱导1型糖尿病模型 Chemically induced T1DM	单次高剂量STZ诱导小鼠	单纯性高血糖	开发新型治疗1型糖尿病胰岛素
	多次低剂量STZ诱导小鼠	诱导性胰腺炎，高血糖	β细胞功能受损的1型糖尿病的治疗
自发性1型糖尿病模型 Spontaneous T1DM	NOD小鼠	胰岛被白细胞浸润，β细胞受损	自身免疫系统受损所致1型糖尿病的治疗
自发性2型糖尿病模型 Spontaneous T2DM	ob/ob小鼠	一过性高血糖（4周龄～20周龄），低代谢，食欲旺盛	肥胖为主、高血糖不严重的2型糖尿病及Ⅰ、Ⅱ期肥胖症的治疗
	db/db小鼠	严重的高胰岛素血症、高血糖和肥胖	β细胞功能受损的2型糖尿病及其并发症的治疗
	KK小鼠	2～3月龄开始肥胖，食欲旺盛，高胰岛素血症	非胰岛素依赖型2型糖尿病的治疗
	KK-Ay小鼠	8周龄开始肥胖，30周龄出现高血糖	肥胖为主非胰岛素依赖型2型糖尿病，糖尿病肾病及脑病等并发症的治疗
	Tallyho/Jng小鼠	高血糖，胰岛肥大，葡萄糖耐受不良，高胰岛素血症较轻微	基因所致肥胖型2型糖尿病的治疗
	TSOD小鼠	严重的高胰岛素血症、高血糖和肥胖	自发性肥胖型2型糖尿病的治疗
饮食诱导2型糖尿病模型 Diet-induced T2DM	高脂饮食所致肥胖小鼠	高血糖不明显，喂养持续时间久	改善胰岛素的治疗方法

[1]	梁天薇, 邓亚胜, 黄慧, 荣娜, 刘鑫, 王玉洁, 林江. 围绝经期综合征动物模型的制备方法及评价指标分析[J]. 实验动物与比较医学, 2024, 44(1): 74-84.
[2]	梁敏, 郭洋, 王津津, 朱梦妍, 池骏, 陈艳娟, 王成稷, 喻智澜, 沈如凌. Dmd基因突变小鼠构建及在肌肉及免疫系统的表型验证[J]. 实验动物与比较医学, 2024, 44(1): 42-51.
[3]	郑建华, 法云智, 董巧燕, 邱业峰, 陈菁青. 高原急性缺氧肠道应激损伤小鼠模型的构建与评价[J]. 实验动物与比较医学, 2024, 44(1): 31-41.
[4]	唐倩倩, 张秀莉, 常在. 清华大学实验动物中心小鼠自动饮水系统漏水情况统计分析[J]. 实验动物与比较医学, 2024, 44(1): 85-91.
[5]	中国研究型医院学会医学动物实验专家委员会. 自发性脑出血动物模型选择及临床前药物试验指南（2024年版）[J]. 实验动物与比较医学, 2024, 44(1): 3-30.
[6]	刘欣, 石少波, 张翠, 杨波, 曲川. 小鼠自体动静脉内瘘端侧吻合模型的建立与评价[J]. 实验动物与比较医学, 2023, 43(6): 595-603.
[7]	王丹, 张晓璐, 王妍, 傅博, 王文栋, 刘京, 张甦寅, 武怡荷, 吴德国, 杜小燕, 战大伟, 章秀林, 李长龙. Big-BALB/c小鼠亚系选育前后的抗体制备效率比较研究[J]. 实验动物与比较医学, 2023, 43(6): 612-618.
[8]	聂永强, 王朝霞. 濒危基因编辑小鼠品系拯救技术及其应用探讨[J]. 实验动物与比较医学, 2023, 43(6): 636-640.
[9]	万颖寒, 顾也欣, 袁雨浓, 汤忞, 鲁立. FDA现代化法案2.0给疾病动物模型发展带来的启示和思考[J]. 实验动物与比较医学, 2023, 43(5): 472-481.
[10]	谢淑武, 沈如凌, 林金杏, 范春. 雄性不育药物研发相关实验动物模型建立和应用进展[J]. 实验动物与比较医学, 2023, 43(5): 504-511.
[11]	陈艳娟, 沈如凌. 模式动物疾病模型在结直肠癌医学研究中的应用进展[J]. 实验动物与比较医学, 2023, 43(5): 512-523.
[12]	于灵芝, 谢建芸, 冯丽萍, 魏晓锋. 金黄色葡萄球菌荧光定量PCR检测方法的建立及其在大鼠、小鼠粪便检测中的应用[J]. 实验动物与比较医学, 2023, 43(5): 566-573.
[13]	王成稷, 王珏, 王海杰, 陆炜晟, 史岩, 顾正页, 万鸣秋, 沈如凌. 乳胶血管灌注技术制作小鼠头面部静脉血管模型方法初探[J]. 实验动物与比较医学, 2023, 43(5): 574-578.
[14]	翟珊珊, 梁亮, 曹颖颖, 李竹欣, 王青, 陶俊宇, 运晨霞, 冷静, 唐海波. 一例树鼩毛发上皮瘤的诊断及细胞生物学特性观察[J]. 实验动物与比较医学, 2023, 43(4): 440-445.
[15]	张睿, 吕美豫, 张建军, 刘金莲, 陈彦, 黄志强, 刘尧, 周澜华. 痤疮动物模型建立及评价研究进展[J]. 实验动物与比较医学, 2023, 43(4): 398-405.