酮替芬对链脲佐菌素诱导的糖尿病模型大鼠胰岛功能的影响

中国临床药理学与治疗学 ›› 2013, Vol. 18 ›› Issue (6): 627-632.

酮替芬对链脲佐菌素诱导的糖尿病模型大鼠胰岛功能的影响

陈咨苗¹, 陈肖俊¹, 王美荣¹, 潘亮亮², 胡万里², 倪连松¹

¹温州医学院附属第一医院内分泌科,
²温州医学院电镜中心,温州 325000,浙江

收稿日期:2012-09-17 修回日期:2013-01-02 发布日期:2013-06-19
作者简介:陈咨苗,男,硕士,主治医师,主要从事糖尿病与胰岛素抵抗发病机制及治疗研究。Tel: 13506528878 E-mail: zimiaochen@163.com
基金资助:
温州市科技局基金资助(Y20100063)

Effect of Ketotifen on pancreatic function of streptozotocin-induced type 2 diabetic rats

CHEN Zi-miao¹, CHEN Xiao-jun¹, WANG Mei-rong¹, PAN Liang-liang², HU Wan-li², NI Lian-song¹

¹Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical College,
²Electron Microscopy Center of Wenzhou Medical College, Wenzhou 325000, Zhejiang, China

Received:2012-09-17 Revised:2013-01-02 Published:2013-06-19

摘要/Abstract

摘要： 目的: 探讨酮替芬对链脲佐菌素诱导的糖尿病模型大鼠胰岛功能的影响及其作用机制。方法: 以高糖高脂饲料对SD大鼠饮食诱导6周,随后一次性i.p.给予链脲佐菌素(STZ)制备糖尿病大鼠模型。模型建立后,实验组给予酮替芬 0.09 mg·kg^-1·d^-1,分别在第0、4、8周宰杀实验大鼠,检测空腹血糖(FBG)、空腹胰岛素(FINS),计算胰岛素敏感指数(ISI)、胰岛素抵抗指数(HOMA-IR),检测炎症因子IL-6、TNF-α,并留取胰腺组织,制片染色进行光镜、电镜观察。分离胰岛细胞线粒体,检测细胞色素C氧化酶(Cytochrome C oxidase, CCO)、琥珀酸脱氢酶(Succinate dehydrogenase, SDH)活性。结果: 酮替芬降低糖尿病大鼠的血糖水平(P<0.05), 增加ISI和降低HOMA-IR(P<0.01),降低IL-6和TNF-α水平,增加胰腺组织中 CCO和SDH活性(P<0.01),还可以改善胰岛细胞形态结构。结论: 酮替芬能改善糖尿病大鼠的胰岛功能,其作用机制可能是通过抑制NF-κB激活实现抗炎及改善β细胞线粒体的能量代谢。

关键词: 酮替芬, 糖尿病, 胰岛功能, 血糖

Abstract: AIM: To investigate the effect and mechanism of Ketotifen on pancreatic function of streptozotocin-induced type 2 diabetic rats.METHODS: Male SD rats were fed with high-carbon hydrate-fat diet 6 weeks and ip given STZ to induce a type 2 diabetes model. Rats of Ketotifen group were fed with Ketotifen 0.09 mg·kg^-1·d^-1, and killed in batches in different time (0, 4^th, 8^th week) to test the fasting blood glucose (FBG), fasting plasma insulin (FINS), the insulin sensitivity index (ISI) and homeostasis model assessment insulin resistance index (HOMA-IR) were calculated, the levels of Interleukin-6 (IL-6), tumor nectosis factor-alpha (TNF-α) were tested, and the pancreatic tissue were excised and observed by light microscope (LM) and transmission electron microscope, islet cell mitochondria were separated to test the activity of cytochrome C oxidase (CCO) and succinate dehydrogenase (SDH).RESULTS: Ketotifen suppressed serum glucose in diabetic rats (P<0.05), increased ISI and reduced HOMA-IR (P<0.01). Ketotifen reduced serum IL-6,TNF-α, increased the activity of CCO and SDH. Furthermore, Ketotifen can improve the morphological structure of islet cell.CONCLUSION: Ketotifen can improve the pancreatic function of streptozotocin-induced type 2 diabetic rats possibly by inhibition of activation of NF-κB to anti-inflammatory and improve the energy metabolism of βcell mitochondria.

Key words: Ketotifen, Diabetes mellitus, Pancreatic function, Blood glucose

中图分类号:

R285.5
965.2

陈咨苗, 陈肖俊, 王美荣, 潘亮亮, 胡万里, 倪连松. 酮替芬对链脲佐菌素诱导的糖尿病模型大鼠胰岛功能的影响[J]. 中国临床药理学与治疗学, 2013, 18(6): 627-632.

CHEN Zi-miao, CHEN Xiao-jun, WANG Mei-rong, PAN Liang-liang, HU Wan-li, NI Lian-song. Effect of Ketotifen on pancreatic function of streptozotocin-induced type 2 diabetic rats[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2013, 18(6): 627-632.

参考文献

[1] Pedotti R, Devoss JJ, Youssef S, et al. Multiple elements of the allergic arm of the immune response modulate autoimmune demyelination [J]. Proc Natl Acad Sci USA, 2003, 100(4): 1867-1872.
[2] Simons FE, Simons KJ. Histamine and H1-antihistamines: celebrating a century of progress [J]. J Allergy Clin Immunol, 2011, 128(6): 1139-1150.
[3] Oguri S, Motegi K, Endo Y. Augmented lipopolysaccharide-induction of the histamine-forming enzyme in streptozotocin-induced diabetic mice[J]. Biochim Biophys Acta, 2003, 1637(1): 83-90.
[4] Hsiao SH, Chung HH, Inui A, et al. Inhibitory effect of 5-hydroxytryptamine on hyperphagia in mice with genetic overexpression of neuropeptide Y[J]. Neurosci Lett,2006, 394(3): 256-258.
[5] Heimes K, Feistel B, Verspohl EJ. Impact of the 5-HT₃ receptor channel system for insulin secretion and interaction of ginger extracts [J]. Eur J Pharmacol, 2009, 624(1/2/3):5 8-65.
[6] Karin M, Lawrence T, Nizet V. Innate immunity gone awry: linking microbial infections to chronic inflamm ation and cancer[J]. Cell, 2006, 124(4):823-835.
[7] Liu J, Divoux A, Sun J, et al. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice[J]. Nat Med, 2009, 15(8): 940-945.
[8] Wang J, Shi GP. Mast cell stabilization: novel medication for obesity and diabetes[J]. Diabetes Metab Res Rev, 2011, 27(8): 919-924.
[9] 何银辉,徐海燕,孙霞,等. 2型糖尿病合理用药策略[J]. 中国临床药理学与治疗学,2011, 16(7): 837-840.
[10]Simmons RA, Suponit sky-Kroyter I, Selak MA. Progressive acaccumulation of mitochondrial DNA mutations and decline in mitochondrial function lead to beta-cell failure[J]. J Bio Chem, 2005, 280(31): 28785-28791.
[11]Deng Y, Scherer PE. Adipokines as novel biomarkers and regulators of the metabolic syndrome [J]. Ann N Y Acad Sci, 2011, 1226(1): 50.
[12]Siepe M, Goebel U, Mecklenburg A, et al. Pulsatile pulmonary perfusion during cardio-pulmonary bypass reduces the pulmonary inflammatory response[J]. Ann Thorac Surg, 2008, 86(1): 115-122.
[13]Kim BC, Kim HT, Mamura M, et al. Tumor necrosis factor induces apoptosis in hepatoma cells by increasing Ca(2+) release from the endoplasmic reticulum and suppressing Bcl-2 expression [J]. J Biol Chem, 2002, 277(35): 31381-31389.
[14]Kelley DE, He J, Menshikova EV, et al. Dysfunct ion of mitochondria in human skeletal muscle in type 2 diabetes [J]. Diabetes, 2002, 51(10) : 2944- 2950.
[15]Choo HJ, Kim JH, Kwon OB, et al. Mitochondria are impaired in the adipocytes of type 2 diabetic mice [J]. Diabetologia, 2006, 49(4):784-791.
[16]Chen N, Leng YP, Xu WJ, et al. Contribution of endogenous inhibitor of nitric oxide synthase to hepatic mitochondrial dysfunction in streptozotocin-induced diabetic rats[J]. Cell Physiol Biochem, 2011, 27(3/4): 341-352.
[17]Wu RL, Anthes JC, Kreutner W, et al. Desloratadine inhibits constitutive and histamine stimulated nuclear factor-kappaB activity consistent with inverse agonism at the histamine H1 Receptor [J]. Int Arch Allergy Immunol, 2004, 135(4): 313-318.