内毒素诱发胰岛素抵抗机制的研究进展_West China Medical Journal

Authors：

张伊祎 ,  赵铁耘

四川大学华西医院内分泌代谢科（成都 610041）;

Corresponding author：

赵铁耘, Email: zty112356@126.com

Keywords：

内毒素; 胰岛素抵抗; 代谢性疾病; 炎症; 肠道菌群

DOI：

10.7507/1002-0179.201507039

Video：

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内毒素是革兰阴性菌细胞壁的成分之一，其化学结构为脂多糖。胰岛素抵抗在肥胖、代谢综合征、心血管疾病、2 型糖尿病及其并发症等疾病的病理病程中起了重要的作用。现有研究认为肥胖及相关代谢性疾病是慢性低度炎症性疾病，长期慢性炎症可以削弱胰岛素的生物效应。肠道菌群结构紊乱或肠黏膜屏障受损，机体循环系统中内毒素水平增加，诱发慢性低度炎症可致宿主胰岛素抵抗或肥胖。该文综述了近年来内毒素诱发胰岛素抵抗及相关代谢性疾病机制的研究进展。

Citation： 张伊祎, 赵铁耘. 内毒素诱发胰岛素抵抗机制的研究进展. West China Medical Journal, 2017, 32(11): 1805-1809. doi: 10.7507/1002-0179.201507039 Copy

1.	Choukem SP, Gautier JF. How to measure hepatic insulin resistance?. Diabetes Metab, 2008, 34(6 Pt 2): 664-673.
2.	Bäckhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA, 2004, 101(44): 15718-15723.
3.	Milanski M, Degasperi G, Coope A, et al. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci, 2009, 29(2): 359-370.
4.	Ding S, Lund PK. Role of intestinal inflammation as an early event in obesity and insulin resistance. Curr Opin Clin Nutr Metab Care, 2011, 14(4): 328-333.
5.	Carvalho E, Jansson PA, Axelsen M, et al. Low cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM. FASEB J, 1999, 13(15): 2173-2178.
6.	Gual P, Le Marchand-Brustel Y, Tanti JF. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie, 2005, 87(1): 99-109.
7.	彭定琼, 高妍, 陈宇, 等. OLETF 大鼠肝脏、肌肉、脂肪组织中胰岛素受体底物的蛋白表达. 中华内分泌代谢杂志, 2001, 17(5): 288-289.
8.	Aspinwall CA, Qian WJ, Roper MG, et al. Roles of insulin receptor substrate-1, phosphatidylinositol 3-kinase, and release of intracellular Ca²⁺ stores in insulin-stimulated insulin secretion in beta -cells. J Biol Chem, 2000, 275(29): 22331-22338.
9.	Withers DJ, Gutierrez JS, Towery H, et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature, 1998, 391(6670): 900-904.
10.	Hennige AM, Burks DJ, Ozcan U, et al. Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes. J Clin Invest, 2003, 112(10): 1521-1532.
11.	Peri F, Piazza M, Calabrese V, et al. Exploring the LPS/TLR4 signal pathway with small molecules. Biochem Soc Trans, 2010, 38(5): 1390-1395.
12.	Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes, 2007, 56(7): 1761-1772.
13.	Cani PD, Delzenne NM. The gut microbiome as therapeutic target. Pharmacol Ther, 2011, 130(2): 202-212.
14.	Song MJ, Kim KH, Yoon JM, et al. Activation of toll-like receptor 4 is associated with insulin resistance in adipocytes. Biochem Biophys Res Commun, 2006, 346(3): 739-745.
15.	Pan ZK. Toll-like receptors and TLR-mediated signaling: more questions than answers. Am J Physiol Lung Cell Mol Physiol, 2004, 286(5): L918-L920.
16.	Fujishiro M, Gotoh Y, Katagiri H, et al. Three mitogen-activated protein kinases inhibit insulin signaling by different mechanisms in 3T3-L1 adipocytes. Mol Endocrinol, 2003, 17(3): 487-497.
17.	Underhill DM, Ozinsky A. Toll-like receptors: key mediators of microbe detection. Curr Opin Immunol, 2002, 14(1): 103-110.
18.	Shishodia S, Koul D, Aggarwal BB. Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates TNF-induced NF-kappa B activation through inhibition of activation of I kappa B alpha kinase and Akt in human non-small cell lung carcinoma: correlation with suppression of COX-2 synthesis. J Immunol, 2004, 173(3): 2011-2022.
19.	Cani PD, Bibiloni R, Knauf C, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes, 2008, 57(6): 1470-1481.
20.	Ma LJ, Mao SL, Taylor KL, et al. Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes, 2004, 53(2): 336-346.
21.	Shoelson SE, Lee J, Yuan M. Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. Int J Obes Relat Metab Disord, 2003, 27(Suppl 3): S49-S52.
22.	候丽琼, 赵铁耘, 张伊祎. 黄连素对肥胖胰岛素抵抗大鼠骨骼肌胰岛素抵抗的干预研究. 四川大学学报: 医学版, 2015, 46(6): 827-831.
23.	Carvalho-Filho MA, Ueno M, Carvalheira JB, et al. Targeted disruption of iNOS prevents LPS-induced S-nitrosation of IRbeta/IRS-1 and Akt and insulin resistance in muscle of mice. Am J Physiol Endocrinol Metab, 2006, 291(3): E476-E482.
24.	Agwunobi AO, Reid C, Maycock P, et al. Insulin resistance and substrate utilization in human endotoxemia. J Clin Endocrinol Metab, 2000, 85(10): 3770-3778.
25.	Dandona P, Ghanim H, Bandyopadhyay A, et al. Insulin suppresses endotoxin-induced oxidative, nitrosative, and inflammatory stress in humans. Diabetes Care, 2010, 33(11): 2416-2423.
26.	Chang YH, Chang DM, Lin KC, et al. Visfatin in overweight/obesity, type 2 diabetes mellitus, insulin resistance, metabolic syndrome and cardiovascular diseases: a meta-analysis and systemic review. Diabetes Metab Res Rev, 2011, 27(6): 515-527.
27.	Mehta NN, Mcgillicuddy FC, Anderson PD, et al. Experimental endotoxemia induces adipose inflammation and insulin resistance in humans. Diabetes, 2010, 59(1): 172-181.
28.	Pussinen PJ, Havulinna AS, Lehto M, et al. Endotoxemia is associated with an increased risk of incident diabetes. Diabetes Care, 2011, 34(2): 392-397.
29.	刘云慧, 赵铁耘, 侯丽琼. 不同糖代谢及不同体质量指数人群空腹血浆内毒素水平的变化及其相关因素研究. 四川大学学报: 医学版, 2013, 44(5): 769-773, 778.

1. Choukem SP, Gautier JF. How to measure hepatic insulin resistance?. Diabetes Metab, 2008, 34(6 Pt 2): 664-673.
2. Bäckhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA, 2004, 101(44): 15718-15723.
3. Milanski M, Degasperi G, Coope A, et al. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci, 2009, 29(2): 359-370.
4. Ding S, Lund PK. Role of intestinal inflammation as an early event in obesity and insulin resistance. Curr Opin Clin Nutr Metab Care, 2011, 14(4): 328-333.
5. Carvalho E, Jansson PA, Axelsen M, et al. Low cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM. FASEB J, 1999, 13(15): 2173-2178.
6. Gual P, Le Marchand-Brustel Y, Tanti JF. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie, 2005, 87(1): 99-109.
7. 彭定琼, 高妍, 陈宇, 等. OLETF 大鼠肝脏、肌肉、脂肪组织中胰岛素受体底物的蛋白表达. 中华内分泌代谢杂志, 2001, 17(5): 288-289.
8. Aspinwall CA, Qian WJ, Roper MG, et al. Roles of insulin receptor substrate-1, phosphatidylinositol 3-kinase, and release of intracellular Ca²⁺ stores in insulin-stimulated insulin secretion in beta -cells. J Biol Chem, 2000, 275(29): 22331-22338.
9. Withers DJ, Gutierrez JS, Towery H, et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature, 1998, 391(6670): 900-904.
10. Hennige AM, Burks DJ, Ozcan U, et al. Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes. J Clin Invest, 2003, 112(10): 1521-1532.
11. Peri F, Piazza M, Calabrese V, et al. Exploring the LPS/TLR4 signal pathway with small molecules. Biochem Soc Trans, 2010, 38(5): 1390-1395.
12. Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes, 2007, 56(7): 1761-1772.
13. Cani PD, Delzenne NM. The gut microbiome as therapeutic target. Pharmacol Ther, 2011, 130(2): 202-212.
14. Song MJ, Kim KH, Yoon JM, et al. Activation of toll-like receptor 4 is associated with insulin resistance in adipocytes. Biochem Biophys Res Commun, 2006, 346(3): 739-745.
15. Pan ZK. Toll-like receptors and TLR-mediated signaling: more questions than answers. Am J Physiol Lung Cell Mol Physiol, 2004, 286(5): L918-L920.
16. Fujishiro M, Gotoh Y, Katagiri H, et al. Three mitogen-activated protein kinases inhibit insulin signaling by different mechanisms in 3T3-L1 adipocytes. Mol Endocrinol, 2003, 17(3): 487-497.
17. Underhill DM, Ozinsky A. Toll-like receptors: key mediators of microbe detection. Curr Opin Immunol, 2002, 14(1): 103-110.
18. Shishodia S, Koul D, Aggarwal BB. Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates TNF-induced NF-kappa B activation through inhibition of activation of I kappa B alpha kinase and Akt in human non-small cell lung carcinoma: correlation with suppression of COX-2 synthesis. J Immunol, 2004, 173(3): 2011-2022.
19. Cani PD, Bibiloni R, Knauf C, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes, 2008, 57(6): 1470-1481.
20. Ma LJ, Mao SL, Taylor KL, et al. Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes, 2004, 53(2): 336-346.
21. Shoelson SE, Lee J, Yuan M. Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. Int J Obes Relat Metab Disord, 2003, 27(Suppl 3): S49-S52.
22. 候丽琼, 赵铁耘, 张伊祎. 黄连素对肥胖胰岛素抵抗大鼠骨骼肌胰岛素抵抗的干预研究. 四川大学学报: 医学版, 2015, 46(6): 827-831.
23. Carvalho-Filho MA, Ueno M, Carvalheira JB, et al. Targeted disruption of iNOS prevents LPS-induced S-nitrosation of IRbeta/IRS-1 and Akt and insulin resistance in muscle of mice. Am J Physiol Endocrinol Metab, 2006, 291(3): E476-E482.
24. Agwunobi AO, Reid C, Maycock P, et al. Insulin resistance and substrate utilization in human endotoxemia. J Clin Endocrinol Metab, 2000, 85(10): 3770-3778.
25. Dandona P, Ghanim H, Bandyopadhyay A, et al. Insulin suppresses endotoxin-induced oxidative, nitrosative, and inflammatory stress in humans. Diabetes Care, 2010, 33(11): 2416-2423.
26. Chang YH, Chang DM, Lin KC, et al. Visfatin in overweight/obesity, type 2 diabetes mellitus, insulin resistance, metabolic syndrome and cardiovascular diseases: a meta-analysis and systemic review. Diabetes Metab Res Rev, 2011, 27(6): 515-527.
27. Mehta NN, Mcgillicuddy FC, Anderson PD, et al. Experimental endotoxemia induces adipose inflammation and insulin resistance in humans. Diabetes, 2010, 59(1): 172-181.
28. Pussinen PJ, Havulinna AS, Lehto M, et al. Endotoxemia is associated with an increased risk of incident diabetes. Diabetes Care, 2011, 34(2): 392-397.
29. 刘云慧, 赵铁耘, 侯丽琼. 不同糖代谢及不同体质量指数人群空腹血浆内毒素水平的变化及其相关因素研究. 四川大学学报: 医学版, 2013, 44(5): 769-773, 778.

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