Chronic alcohol exposure induces insulin resistance in mice：the possible mechanism of ceramide

doi:10.3969/j.issn.0529-1356.2013.06.004

Abstract

Abstract:

Objective To investigate the relationship among chronic alcohol exposure, insulin sensitivity and ceramide during the alcohol toxicological effect. Methods Wide type (WT) and sphingomyelin synthetase 2 knockout (SMS₂^-/-) mice (about 3 month old) were used to establish the chronic alcohol exposure model. A total of 90 mice of the two genotypes were divided into the control group, moderate EtOH group and high EtOH group. After alcohol exposure for 5 months, fasting plasma glucose（FPG） and levels of fasting insulin (Fins) were measured. The insulin resistance index (HOMA-IR) was calculated. The expression of insulin receptor substrate 2 (IRS2) in hippocampus was tested with immunofluorescent labeling and Western blotting analysis. Results 1. Alcohol exposure caused WT mice FPG and HOMA-IR index increased with dose-dependency (P<0.05). Comparing with the control group, Fins values increased in the treatment dose group (P<0.05). 2. FPG in SMS₂^-/- mice increased with dosedependency (P<0.05), but HOMA-IR index had little changes, comparing with WT mice. In addition, the immunohistochemical staining showed that, in both WT and SMS₂^-/- mice, the number of IRS2-positive cells reduced in CA1 area after alcohol exposure with dose-dependency (P<0.05). However, comparing with the WT mice, the number of IRS2-positive cells of hippocampus in SMS₂^-/- mice reduced greatly (P<0.05). 3. Immunoblotting evidence of IRS2 supported the results of immunohistochemistry in both WT and SMS-/-2 mice.
Conclusion Chronic alcohol exposure can cause insulin resistance in both WT and SMS₂^-/- mice. IRS2 protein expression decreased with dose-dependency after alcohol exposure. IRS2 loss probably is one of the causes of insulin resistance. Ceramide may be involved in the reduction of IRS2 expression and may promote the formation of insulin resistance after alcohol exposure.

Key words: Ethanol exposure, Insulin resistance, Ceramide, Insulin receptor substrate, Western blotting, Mouse

CLC Number:

R749.6

ZHAO Jing-ya LU Guang-xiu XU Gao-lei DENG Jin-bo*. Chronic alcohol exposure induces insulin resistance in mice：the possible mechanism of ceramide[J]. AAS, 2013, 44(6 ): 748-755.

References

［1］ Liu YF, Cheng H. Insulin receptor substrate and its gene polymorphism and insulin resistance［J］.Section of Endocrinology Foreign Medical Sciences, 2004, 24（3）：188-190.（in Chinese）
刘云峰，程桦. 胰岛素受体底物及其基因多态性与胰岛素抵抗［J］. 国外医学内分泌学分册, 2004, 24 (3)：188-190.
［2］Vegt F, Dekker JM, Groeneveld WJ, et al. Moderate alcohol consumption is associated with lower risk for incident diabetes and mortality: the Hoorn Study ［J］. Diabetes Res Clin Pract, 2002, 57（1）：53-60.
［3］Carlsson S, Hammar N, Grill V, et al. Alcohol consumption and the incidence of type 2 diabetes: a 20-year follow-up of the Finnish twin cohort study［J］. Diabetes Care, 2003, 26 (10)：2785-2790.
［4］Nakanishi N, Suzuki K, Tatara K. Alcohol consumption and risk for development of impaired fasting glucose or type 2 diabetes in middle-aged Japanese men［J］. Diabetes Care, 2003, 26 (1)：48-54.
［5］de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer’s disease［J］. Alzheimers Dis, 2005, 7(1)：45-61. 
［6］Chesik D, de Keyser J, Wilczak N. Insulin-like growth factor system regulates oligodendroglial cell behavior: therapeutic potential in CNS［J］. J Mol Neurosci, 2008,35 (1)：81-90. 
［7］Gong X, Xie Z, Zuo H.In vivo insulin deficiency as a potential etiology for demyelinating disease［J］. Med Hypotheses, 2008, 71(3)：399-403. 
［8］Liang G, Cline GW, Macica CM. IGF-1 stimulates de novo fatty acid biosynthesis by Schwann cells during myelination［J］. Glia, 2007,55 (6)：632-641. 
［9］Ye P, Kollias G., D’Ercole AJ. Insulin-like growth factor-I ameliorates demyelination induced by tumor necrosis factor-alpha in transgenic mice［J］.J Neurosci Res, 2007, 85(4)：712-722.
［10］Soscia SJ, Tong M, Xu XJ, et al. Chronic gestational exposure to ethanol causes insulin and IGF resistance and impairs acetylcholine homeostasis in the brain［J］. Cell Mol Life Sci, 2006, 63 (17)：2039-2056. 
［11］Withers DJ, Burks DJ, Towery HH, et al. Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signaling［J］. Nat Gene,1999, 23(5)：32-40.
［12］Wellen KE,Hotamisligil GS. Inflammation,st ress,and diabetes［J］.J Clin Invest,2005,115 (5)：1111-1119.
［13］Schatter B, Jin S, Klein J，et al. Cross-talk between phosphatidic acid and ceramide during ethanol-induced apoptosis in astrocytes ［J］. BMC Pharmacol, 2005, 5(3)：1-3.
［14］Summers SA. Ceramides in insulin resistance and lipotoxicity［J］. Prog Lipid Res, 2006, 45（1）：42-72.
［15］Qin R, Chen ML, Zhu K,et al. Sphingomyelin synthase 2 deficiency decreases atherosclerosis and inhibits inflammation in mice ［J］. Acta Physiologica Sinica, 2010, 64(4): 333-338. (in Chinese) 
秦睿，陈明亮，朱珂，等. 神经鞘磷脂合成酶2基因的缺失有抗动脉粥样硬化及抗炎作用［J］. 生理学报，2010，64（4）：333-338.
［16］Zhang JSh, He WY, Deng JB, et al. Prenatal alcohol exposure induces the autophagy in cerebellar Purkinje cells of mice ［J］. Acta Anatomica Sinica, 2010, 41（6）：796-804.（in Chinese）
张俊士，贺维亚，邓锦波,等.孕期酒精暴露诱发仔鼠小脑普肯野细胞的自噬［J］. 解剖学报，2010, 41（6）：796-804.
［17］Sheng ShL. Alzheimer’s: From Molecular Biology To The Clinical Diagnosis And Treatment〔M〕.Beijing：Scientific and Technical Documentation Press, 1998:216-254.（in Chinese）
盛树力.老年痴呆：从分子生物学到临床诊治〔M〕.北京：科学技术文献出版社，1998:216-254. 
［18］Broughton SK, Chen H, Back SA. et al. Large-scale generation of highly enriched neural stem-cell-derived oligodendroglial cultures: maturation-dependent differences in insulin-like growth factor-mediated signal transduction ［J］. J Neurochem, 2007, 100 (3): 628-638. 
［19］Freude S, Leeser U, Schubert M, et al. IRS-2 branch of IGF-1 receptor signaling is essential for appropriate timing of myelination ［J］. J Neurochem, 2008, 107(4): 907-917.
［20］Joseph D,Ercole A, Ye P. Expanding the mind: insulin-like growth factor I and brain development ［J］.Endocrinology, 2008,149 (12): 5958-5962.
［21］Shao J, Yamashita H, Qiao L, et al. Phosphatidylinositol3-Kinase redistribution is associated with skeletal muscle insulin resistance in gestational diabetes mellitus ［J］.Diabetes, 2002, 51 (1):19-29.
［22］Zhang YW, Hong J. Inflammatory factors and insulin resistance ［J］. Diagn Concepts Pract, 2010, 9(1) : 90-94.（in Chinese）
张豫文，洪洁. 炎症因子与胰岛素抵抗［J］. Diagn Concepts Pract, 2010, 9(1) : 90-94. 
［23］Li LF, Li J. Molecular mechanism of oxidative stress induced insulin resistance ［J］. Chinese Journal of Diabetes, 2008, 16(11): 697-698.（in Chinese）
李兰芳，黎健. 氧化应激诱导胰岛素抵抗的分子机制［J］. 中国糖尿病杂志,2008, 16(11) : 697-698. 
［24］Fu YH, Sun XF, Qu W. Effort of chronic ethanol administration on pancreatic islets and oxidative stress of rats ［J］.Journal of Hygiene Research，2004, 33(4): 440-443.（in Chinese）
付元华，孙秀发，曲巍.长期酒精摄入对大鼠胰岛的影响及与氧化应激关系的探讨［J］.卫生研究, 2004, 33(4): 440-443. 
［25］de la Monte SM, Longato L, Tong M, et al. The liver-brain axis of alcohol-mediated neurodegeneration: role of toxic lipids［J］.
Int J Environ Res Public Health, 2009, 6(7): 2055-2075.
［26］Matthew J. Brady IRS2 takes center stage in the development of type 2 diabetes ［J］. J Clin Invest,2004,114(7): 886-888.
［27］Zhao HY, Wang Y, Ma YP, et al. Insulin signal transduction and insulin resistance［J］.New Chinese Medicine,2010, 41(4): 267-271.（in Chinese）
赵海燕，王勇，马永平，等.胰岛素信号转导障碍与胰岛素抵抗［J］.新医学，2010，41(4): 267-271.
［28］Deng TX,Wang ZhX, Gao XQ, et al. Alcohol-induced proliferation of neurons in mouse hippocampal dentate gyrus: a possible role of ceramide［J］. Acta Physiologica Sinica, 2011, 63(6): 479-490
［29］Liu J, Huan C, Chakraborty M, et al.Macrophage sphingomyelin synthase 2 deficiency decreases atherosclerosis in mice［J］. Circ Res, 2009,105(3): 295-303. 
［30］Adibhatla RM, Hatcher JF. Altered lipid metabolism in brain injury and disorders ［J］. Subcell Biochem, 2008, 49(2): 241-268.
［31］Daigo M, Arai Y, Yamashiro Y, et al. Effect of hypoxic-ischemic injury on serine palmitoyltransferase activity in the developing rat brain ［J］. Pathobiology, 2008, 75(6): 330-334. 
［32］Soeda S, Tsuji Y, Shimeno H, et al. Inhibition of sphingomyeli-nase activity helps to prevent neuron death caused by ischemic stress ［J］.Neurochem Int, 2004, 45 (5): 619-626.
［33］Soriano JM, Gonzalez L, Catala AI. Mechanism of action of sphin-golipids and their metabolites in the toxicity of fumonisin B1 ［J］. Prog Lipid Res, 2005, 44 (6): 345-356.

[1]	HONG Xiao-min LI San-qiang CUI Qin-yi ZHENG Run-yue YANG Meng-li LUO Ren-li LI Qian-hui. Nuclear factor-κB signaling pathway and gender differences in alcoholic liver fibrosis [J]. Acta Anatomica Sinica, 2024, 55(1): 55-61.
[2]	WEI Xi-xi LI Chao-hong ZHAO Chen-lu TANG Jia-ping LIU Yu-zhen. Characterization of group Ⅰ metabotropic glutamate receptors in rat superior cervical ganglion and their changes following chronic intermittent hypoxia [J]. Acta Anatomica Sinica, 2024, 55(1): 3-9.
[3]	YUAN Lei YANG Zhi-wei YANG Hui LIU Zheng-hai HE Jie WAN Wei. Panax notoginseng saponin relieving the inflammatory pain caused by complete Freund’s adjuvant by inhibiting the activation of astrocytes in mice [J]. Acta Anatomica Sinica, 2024, 55(1): 25-31.
[4]	MA Ting-ting CHEN Jian-hong LIU Ai-cui LI Hai-ning. Role of inhibiting lncRNA TUG1 to down-regulate nucleotide binding oligomerization domain like receptor protein 1 inflammasome in delaying the progression of Alzheimer’s disease [J]. Acta Anatomica Sinica, 2024, 55(1): 32-42.
[5]	ZOU Cheng-gong FENG Hao CHEN Bing TANG Hui SHAO Chuan SUN Mou YANG Rong HE Jia-quan . Research on the dynamic changes of neurological dysfunction and cognitive function impairment in traumatic brain injury [J]. Acta Anatomica Sinica, 2024, 55(1): 43-48.
[6]	LÜ Hai-yan SHEN Xi-ya ZHAO Fu-sheng ZHU Mei . Effects of tricholoma matsutake polysaccharides on 1-methy-4-pehnyl-pyridine ion-induced PC12 cell damage [J]. Acta Anatomica Sinica, 2024, 55(1): 49-54.
[7]	ZHENG Li-ping LIU Xia DU Xiao-hua WU Ya-juan LIU Shan-shan . Expression and distribution of brain-derived neurotrophic factor in different cerebrum regions of yak and cattle [J]. Acta Anatomica Sinica, 2024, 55(1): 10-16.
[8]	HAO Yong-ming GUO Lei ZHOU Cheng-hui PEI Han-jun LI Li ZHAO Zhe . Establishment of a rat model of myocardial hypertrophy by a modified abdominal aortic coarctation method [J]. Acta Anatomica Sinica, 2024, 55(1): 120-124.
[9]	XU Ya-ping YU Yue-xin CHEN Jin-fu WANG Ke-ke GUO Zhikun . Structural distribution and mechanism of elastic fibers and collagen fibers in ventricular interstitium of aged rats [J]. Acta Anatomica Sinica, 2023, 54(6): 716-721.
[10]	WANG Wen-juan DING Yu-tong SU Hao REN Jie SUN Yan-rong WANG Han-fei LU Jia-li ZHANG Lin-qian BAI Yu QIN Li-hua. Changes of Nogo-A expression in hippocampus and striatum of rats under low estrogen condition [J]. Acta Anatomica Sinica, 2023, 54(6): 620-627.
[11]	ZHANG Qin YANG Jun-xia JIANG Qing-song. Effect of fosinopril on angiotensin converting enzyme 2 and vascular endothelial growth factor in diabetic retinopathy mice [J]. Acta Anatomica Sinica, 2023, 54(6): 628-634.
[12]	CHEN Zi-xuan SI Li-na SHU Wei-han ZHANG Xin WEI Chen-yang CHENG Lu-yang YANG Song-he QIAO Yue-bing. Mechanism of melatonin regulation of PI3K/Akt/mTOR signaling in hypothalamus delaying the initiation of puberty in female mice mice [J]. Acta Anatomica Sinica, 2023, 54(6): 644-651.
[13]	LIANG Pan-pan YU Ai-mei DU Jing KOU Wen-hui WANG Huan-huan SONG Ai-xia. Inhibitory effect of sodium ferulate on inflammatory response in migraine rats based on c-Jun N-terminal kinase/p38 mitogen-activated protein kinase signaling pathway [J]. Acta Anatomica Sinica, 2023, 54(6): 652-659.
[14]	XU Ying LIU Bin ZHENG Xing HE Zong-zhao. Role and mechanism of complement C3a receptor in the cognitive impairment of septic rats induced by cecal ligation and perforation [J]. Acta Anatomica Sinica, 2023, 54(6): 668-675.
[15]	LIU Zhe-chuan LI Kun MA Shuai-nan MENG Jia-qi WANG Yan-qin. Effects of liraglutide on inflammation and mitochondrial fusion/division in Parkinson’s disease model of mice induced by paraquat [J]. Acta Anatomica Sinica, 2023, 54(6): 676-681.