基于信号通路的中药治疗2型糖尿病胰岛素抵抗的研究进展
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摘要
胰岛素抵抗与2型糖尿病的发病密切相关。中药治疗2型糖尿病胰岛素抵抗具有安全、多靶点等优势,已成为目前的研究热点。越来越多的临床和实验研究表明,中药可以有效地改善胰岛素抵抗。其中中药通过胰岛素信号转导通路干预胰岛素抵抗的研究在阐明中药作用机制方面尤为重要,本文基于信号通路对IRS、PI3K/Akt、AMPK、GLUT、GSK-3、NF-κB、p38 MAPK、JNK、Nrf2、PPARs、PTP1B等主要靶标对在中药干预胰岛素抵抗的机制作了总结,以期为以后的相关研究提供基础。
Insulin resistance is closely related to the pathogenesis of type 2 diabetes. Traditional Chinese medicine for the treatment of type 2 diabetes insulin resistance has the advantages of safety, multi-target, etc., and has become a hot research topic. More and more clinical and experimental studies have shown that Chinese medicine can effectively improve insulin resistance. Among them, the study of traditional Chinese medicine intervention in insulin resistance through the insulin signal transduction pathway is particularly important in elucidating the mechanism of action of traditional Chinese medicine. This article summarizes the target mechanisms of traditional Chinese medicine intervention in insulin resistance from IRS, PI3K/Akt, AMPK, GLUT, GSK-3, NF-κB, p38MAPK, JNK, Nrf2, PPARs, PTP1B and other major signaling pathways, in order to summarize relevant research provides the basis.
Insulin resistance is closely related to the pathogenesis of type 2 diabetes. Traditional Chinese medicine for the treatment of type 2 diabetes insulin resistance has the advantages of safety, multi-target, etc., and has become a hot research topic. More and more clinical and experimental studies have shown that Chinese medicine can effectively improve insulin resistance. Among them, the study of traditional Chinese medicine intervention in insulin resistance through the insulin signal transduction pathway is particularly important in elucidating the mechanism of action of traditional Chinese medicine. This article summarizes the target mechanisms of traditional Chinese medicine intervention in insulin resistance from IRS, PI3K/Akt, AMPK, GLUT, GSK-3, NF-κB, p38MAPK, JNK, Nrf2, PPARs, PTP1B and other major signaling pathways, in order to summarize relevant research provides the basis.
引文
1 Lillioja S,Mott D M,Spraul M,et al.Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus.Prospective studies of Pima Indians.N Engl J Med,1993,329(27):1988-1992.
2 Guilherme A,Virbasius J V,Puri V,et al.Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes.Nat Rev Mol Cell Biol,2008,9(5):367-377.
3 Gurzov E N,Tran M,Fernandez-Rojo M A,et al.Hepatic oxidative stress promotes insulin-STAT-5 signaling and obesity by inactivating protein tyrosine phosphatase N2.Cell Metab,2014,20(1):85-102.
4 Zhou B,Lu Y,Bentham J,et al.Worldwide trends in diabetes since1980:a pooled analysis of 751 population-based studies with 4·4million participants.Lancet,2016,387(10027):1513-1530.
5 Cheng K C,Asakawa A,Li Y X,et al.Opioid mu-receptors as new target for insulin resistance.Pharmacol Ther,2013,139(3):334-340.
6 Haeusler R A,Accili D.The double life of Irs.Cell Metab,2008,8(1):7-9.
7 Kido Y,Burks D,Withers D,et al.Tissue-specific insulin resistance in mice with mutations in the insulin receptor,IRS-1,and IRS-2.J Clin Invest,2000,105(2):199-205.
8 Bouzakri K,Zachrisson A,Al-Khalili L,et al.siRNA-based gene silencing reveals specialized roles of IRS-1/Akt2 and IRS-2/Akt1 in glucose and lipid metabolism in human skeletal muscle.Cell Metabolism,2006,4(1):89-96.
9 Taniguchi C,Ueki K,Kahn R.Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism.J Clin Invest,2005,115(3):718-727.
10 Tamemoto H,Kadowaki T,Tobe K,et al.Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1.Nature,1994,372(6502):182-186.
11 Jin X,Zhang H X,Cui W W.Effect of Jinlida on DGAT1 in Skeletal Muscle in Fat-Induced Insulin Resistance ApoE-/-Mice.Zhong Yao Cai,2015,38(6):1237-1241.
12 Rui L,Aguirre V,Kim J,et al.Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways.JClin Invest,2001,107(2):181-189.
13 Zhang L,Xu J,Xu J,et al.Extracts from Salvia-Nelumbinis naturalis alleviate hepatosteatosis via improving hepatic insulin sensitivity.JTransl Med,2014,12:236-247.
14 Hotamisligil G,Peraldi P,Budavari A,et al.IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha-and obesityinduced insulin resistance.Science,1996,271(5249):665-668.
15 Zhang H,Ta N,Chen P,Wang H.Erchen decoction and linguizhugan decoction ameliorate hepatic insulin resistance by inhibiting irs-1ser307 phosphorylation in vivo and in vitro.Evid Based Complement Alternat Med,2017,2017:1589871.
16 Jeong M,Park J,Youn D,et al.Albiflorin ameliorates obesity by inducing thermogenic genes via AMPK and PI3K/AKT in vivo and in vitro.Metab Clin Exp,2017,73:85-99.
17 White M.Insulin signaling in health and disease.Science,2003,302(5651):1710-1711.
18 Dai B,Wu Q,Zeng C,et al.The effect of Liuwei Dihuang decoction on PI3K/Akt signaling pathway in liver of type 2 diabetes mellitus(T2DM)rats with insulin resistance.J Ethnopharmacol,2016,192:382-389.
19 Winnay J,Solheim M,Dirice E,et al.PI3-kinase mutation linked to insulin and growth factor resistance in vivo.J Clin Invest,2016,126(4):1401-1412.
20 Dong H,Wang J H,Lu F E,et al.Jiaotai Pill enhances insulin signaling through phosphatidylinositol 3-kinase pathway in skeletal muscle of diabetic rats.Chin J Integr Med,2013,19(9):668-674.
21 George S,Rochford J,Wolfrum C,et al.A family with severe insulin resistance and diabetes due to a mutation in AKT2.Science,2004,304(5675):1325-1328.
22 Kong P,Chi R,Zhang L,et al.Effects of paeoniflorin on tumor necrosis factor-alpha-induced insulin resistance and changes of adipokines in3T3-L1 adipocytes.Fitoterapia,2013,91:44-50.
23 Leavens K F,Easton R M,Shulman G I,et al.Akt2 is required for hepatic lipid accumulation in models of insulin resistance.Cell Metab,2009,10(5):405-418.
24 Yao L,Wei J,Shi S,et al.Modified lingguizhugan decoction incorporated with dietary restriction and exercise ameliorates hyperglycemia,hyperlipidemia and hypertension in a rat model of the metabolic syndrome.BMC Complement Altern Med,2017,17(1):132.
25 Lage R,Dieguez C,Vidal-Puig A,et al.AMPK:a metabolic gauge regulating whole-body energy homeostasis.Trends Mol Med,2008,14(12):539-549.
26 Zhao L,Fu Z,Wu J,et al.Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses.J Physiol,2015,593(17):4067-4079.
27 Minokoshi Y,Alquier T,Furukawa N,et al.AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus.Nature,2004,428(6982):569-574.
28 Xiao B,Heath R,Saiu P,et al.Structural basis for AMP binding to mammalian AMP-activated protein kinase.Nature,2007,449(7161):496-500.
29 Kubota N,Yano W,Kubota T,et al.Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake.Cell Metab,2007,6(1):55-68.
30万春平,魏雅改,李晓雪,等.胡椒碱对HepG2细胞胰岛素抵抗模型糖代谢AMPK信号通路上游靶点干预机制的研究.中国中药杂志,2017,42(3):542-547.
31 Kishton R,Barnes C,Nichols A,et al.AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival.Cell Metab,2016,23(4):649-662.
32 Yang J L,Wang J L,Huang F,et al.Modified Si-Miao-San inhibits inflammation and promotes glucose disposal in adipocytes through regulation of AMP-kinase.Chin J Nat Med,2014,12(12):911-919.
33 Huang S,Czech M P.The GLUT4 glucose transporter.Cell Metab,2007,5(4):237-252.
34 Boden G,Homko C,Barrero C,et al.Excessive caloric intake acutely causes oxidative stress,GLUT4 carbonylation,and insulin resistance in healthy men.Sci Transl Med,2015,7(304):304re7.
35戚琛晔,席守民,马灵筠,等.栀子苷对胰岛素抵抗HepG-2细胞葡糖转运体4表达的影响.中国临床药理学杂志,2014,30(6):537-539.
36 Sano H,Eguez L,Teruel M N,et al.Rab10,a target of the AS160 Rab GAP,is required for insulin-stimulated translocation of GLUT4 to the adipocyte plasma membrane.Cell Metab,2007,5(4):293-303.
37 Singh J,Kakkar P.Modulation of liver function,antioxidant responses,insulin resistance and glucose transport by Oroxylum indicum stem bark in STZ induced diabetic rats.Food Chem Toxicol,2013,62:722-731.
38 Kaidanovich O,Eldar-Finkelman H.The role of glycogen synthase kinase-3 in insulin resistance and type 2 diabetes.Expert Opin Ther Targets,2002,6(5):555-561.
39 Saltiel A,Kahn C.Insulin signalling and the regulation of glucose and lipid metabolism.Nature,2001,414(6865):799-806.
40金鑫,赵海燕,马永平.甘草黄酮对2型糖尿病大鼠肝脏中GSK-3β蛋白表达的影响.天然产物研究与开发,2014,26(3):419-422.
41 Hao J,Chen C,Huang K,et al.Polydatin improves glucose and lipid metabolism in experimental diabetes through activating the Akt signaling pathway.Eur J Pharmacol,2014,745:152-165.
42 Chiang S H,Bazuine M,Lumeng C N,et al.The protein kinase IKKepsilon regulates energy balance in obese mice.Cell,2009,138(5):961-975.
43 Cai D,Yuan M,Frantz D,et al.Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.Nat Med,2005,11(2):183-190.
44 Zou X,Huang W,Lu F,et al.The effects of Jiao-Tai-Wan on sleep,inflammation and insulin resistance in obesity-resistant rats with chronic partial sleep deprivation.BMC Complement Altern Med,2017,17(1):165.
45苏卓,郭诚,梁韬.杜仲多糖对链脲佐菌素致糖尿病小鼠的作用.中国实验方剂学杂志,2016,22(14):159-162.
46 Lawan A,Bennett A M.Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism.Trends in endocrinology and metabolism:TEM,2017,28(12):868-878.
47 Hotamisligil G S,Davis R J.Cell Signaling and Stress Responses.Cold Spring Harb Perspect Biol,2016,8(10):a006072.
48 Fang P,Yu M,Min W,et al.Beneficial effect of baicalin on insulin sensitivity in adipocytes of diet-induced obese mice.Diabetes Res Clin Pract,2018,139:262-271.
49 Liu Y,Song A,Zang S,et al.Jinlida reduces insulin resistance and ameliorates liver oxidative stress in high-fat fed rats.J Ethnopharmacol,2015,162:244-252.
50 Vallerie S,Hotamisligil G.The role of JNK proteins in metabolism.Sci Transl Med,2010,2(60):60rv5.
51 Yang Y,Li W,Li Y,et al.Dietary Lycium barbarum polysaccharide induces Nrf2/ARE pathway and ameliorates insulin resistance induced by high-fat via activation of PI3K/AKT signaling.Oxid Med Cell Longev,2014,2014:145641.
52 Gao W,Du X,Lei L,et al.NEFA-induced ROS impaired insulin signalling through the JNK and p38MAPK pathways in non-alcoholic steatohepatitis.J Cell Mol Med,2018,22(7):3408-3422.
53 Liu Y,Li X,Xie C,et al.Prevention Effects and Possible Molecular Mechanism of Mulberry Leaf Extract and its Formulation on Rats with Insulin-Insensitivity.PloS One,2016,11(4):e0152728.
54 Zhang Z,Zhou S,Jiang X,et al.The role of the Nrf2/Keap1 pathway in obesity and metabolic syndrome.Rev Endocr Metab Disord,2015,16(1):35-45.
55 Yagishita Y,Uruno A,Fukutomi T,et al.Nrf2 Improves Leptin and Insulin Resistance Provoked by Hypothalamic Oxidative Stress.Cell Rep,2017,18(8):2030-2044.
56 Haluzík M,Haluzík M.Peroxisome proliferator activated receptors(PPAR)and insulin sensitivity:experimental studies.Cesk Fysiol,2006,55(4):163-168.
57 Koo S H,Satoh H,Herzig S,et al.PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3.Nat Med,2004,10(5):530-534.
58 Li L,Yoshitomi H,Wei Y,et al.Tang-Nai-Kang alleviates prediabetes and metabolic disorders and induces a gene expression switch toward fatty acid oxidation in SHR.Cg-Leprcp/NDmcr rats.PloS One,2015,10(4):e0122024.
59 Johnson T O,Ermolieff J,Jirousek M R.Protein tyrosine phosphatase1B inhibitors for diabetes.Nat Rev Drug Discov,2002,1(9):696-709.
60 Bhakta H K,Paudel P,Fujii H,et al.Oligonol promotes glucose uptake by modulating the insulin signaling pathway in insulin-resistant HepG2cells via inhibiting protein tyrosine phosphatase 1B.Arch Pharm Res,2017,40(11):1314-1327.
2 Guilherme A,Virbasius J V,Puri V,et al.Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes.Nat Rev Mol Cell Biol,2008,9(5):367-377.
3 Gurzov E N,Tran M,Fernandez-Rojo M A,et al.Hepatic oxidative stress promotes insulin-STAT-5 signaling and obesity by inactivating protein tyrosine phosphatase N2.Cell Metab,2014,20(1):85-102.
4 Zhou B,Lu Y,Bentham J,et al.Worldwide trends in diabetes since1980:a pooled analysis of 751 population-based studies with 4·4million participants.Lancet,2016,387(10027):1513-1530.
5 Cheng K C,Asakawa A,Li Y X,et al.Opioid mu-receptors as new target for insulin resistance.Pharmacol Ther,2013,139(3):334-340.
6 Haeusler R A,Accili D.The double life of Irs.Cell Metab,2008,8(1):7-9.
7 Kido Y,Burks D,Withers D,et al.Tissue-specific insulin resistance in mice with mutations in the insulin receptor,IRS-1,and IRS-2.J Clin Invest,2000,105(2):199-205.
8 Bouzakri K,Zachrisson A,Al-Khalili L,et al.siRNA-based gene silencing reveals specialized roles of IRS-1/Akt2 and IRS-2/Akt1 in glucose and lipid metabolism in human skeletal muscle.Cell Metabolism,2006,4(1):89-96.
9 Taniguchi C,Ueki K,Kahn R.Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism.J Clin Invest,2005,115(3):718-727.
10 Tamemoto H,Kadowaki T,Tobe K,et al.Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1.Nature,1994,372(6502):182-186.
11 Jin X,Zhang H X,Cui W W.Effect of Jinlida on DGAT1 in Skeletal Muscle in Fat-Induced Insulin Resistance ApoE-/-Mice.Zhong Yao Cai,2015,38(6):1237-1241.
12 Rui L,Aguirre V,Kim J,et al.Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways.JClin Invest,2001,107(2):181-189.
13 Zhang L,Xu J,Xu J,et al.Extracts from Salvia-Nelumbinis naturalis alleviate hepatosteatosis via improving hepatic insulin sensitivity.JTransl Med,2014,12:236-247.
14 Hotamisligil G,Peraldi P,Budavari A,et al.IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha-and obesityinduced insulin resistance.Science,1996,271(5249):665-668.
15 Zhang H,Ta N,Chen P,Wang H.Erchen decoction and linguizhugan decoction ameliorate hepatic insulin resistance by inhibiting irs-1ser307 phosphorylation in vivo and in vitro.Evid Based Complement Alternat Med,2017,2017:1589871.
16 Jeong M,Park J,Youn D,et al.Albiflorin ameliorates obesity by inducing thermogenic genes via AMPK and PI3K/AKT in vivo and in vitro.Metab Clin Exp,2017,73:85-99.
17 White M.Insulin signaling in health and disease.Science,2003,302(5651):1710-1711.
18 Dai B,Wu Q,Zeng C,et al.The effect of Liuwei Dihuang decoction on PI3K/Akt signaling pathway in liver of type 2 diabetes mellitus(T2DM)rats with insulin resistance.J Ethnopharmacol,2016,192:382-389.
19 Winnay J,Solheim M,Dirice E,et al.PI3-kinase mutation linked to insulin and growth factor resistance in vivo.J Clin Invest,2016,126(4):1401-1412.
20 Dong H,Wang J H,Lu F E,et al.Jiaotai Pill enhances insulin signaling through phosphatidylinositol 3-kinase pathway in skeletal muscle of diabetic rats.Chin J Integr Med,2013,19(9):668-674.
21 George S,Rochford J,Wolfrum C,et al.A family with severe insulin resistance and diabetes due to a mutation in AKT2.Science,2004,304(5675):1325-1328.
22 Kong P,Chi R,Zhang L,et al.Effects of paeoniflorin on tumor necrosis factor-alpha-induced insulin resistance and changes of adipokines in3T3-L1 adipocytes.Fitoterapia,2013,91:44-50.
23 Leavens K F,Easton R M,Shulman G I,et al.Akt2 is required for hepatic lipid accumulation in models of insulin resistance.Cell Metab,2009,10(5):405-418.
24 Yao L,Wei J,Shi S,et al.Modified lingguizhugan decoction incorporated with dietary restriction and exercise ameliorates hyperglycemia,hyperlipidemia and hypertension in a rat model of the metabolic syndrome.BMC Complement Altern Med,2017,17(1):132.
25 Lage R,Dieguez C,Vidal-Puig A,et al.AMPK:a metabolic gauge regulating whole-body energy homeostasis.Trends Mol Med,2008,14(12):539-549.
26 Zhao L,Fu Z,Wu J,et al.Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses.J Physiol,2015,593(17):4067-4079.
27 Minokoshi Y,Alquier T,Furukawa N,et al.AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus.Nature,2004,428(6982):569-574.
28 Xiao B,Heath R,Saiu P,et al.Structural basis for AMP binding to mammalian AMP-activated protein kinase.Nature,2007,449(7161):496-500.
29 Kubota N,Yano W,Kubota T,et al.Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake.Cell Metab,2007,6(1):55-68.
30万春平,魏雅改,李晓雪,等.胡椒碱对HepG2细胞胰岛素抵抗模型糖代谢AMPK信号通路上游靶点干预机制的研究.中国中药杂志,2017,42(3):542-547.
31 Kishton R,Barnes C,Nichols A,et al.AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival.Cell Metab,2016,23(4):649-662.
32 Yang J L,Wang J L,Huang F,et al.Modified Si-Miao-San inhibits inflammation and promotes glucose disposal in adipocytes through regulation of AMP-kinase.Chin J Nat Med,2014,12(12):911-919.
33 Huang S,Czech M P.The GLUT4 glucose transporter.Cell Metab,2007,5(4):237-252.
34 Boden G,Homko C,Barrero C,et al.Excessive caloric intake acutely causes oxidative stress,GLUT4 carbonylation,and insulin resistance in healthy men.Sci Transl Med,2015,7(304):304re7.
35戚琛晔,席守民,马灵筠,等.栀子苷对胰岛素抵抗HepG-2细胞葡糖转运体4表达的影响.中国临床药理学杂志,2014,30(6):537-539.
36 Sano H,Eguez L,Teruel M N,et al.Rab10,a target of the AS160 Rab GAP,is required for insulin-stimulated translocation of GLUT4 to the adipocyte plasma membrane.Cell Metab,2007,5(4):293-303.
37 Singh J,Kakkar P.Modulation of liver function,antioxidant responses,insulin resistance and glucose transport by Oroxylum indicum stem bark in STZ induced diabetic rats.Food Chem Toxicol,2013,62:722-731.
38 Kaidanovich O,Eldar-Finkelman H.The role of glycogen synthase kinase-3 in insulin resistance and type 2 diabetes.Expert Opin Ther Targets,2002,6(5):555-561.
39 Saltiel A,Kahn C.Insulin signalling and the regulation of glucose and lipid metabolism.Nature,2001,414(6865):799-806.
40金鑫,赵海燕,马永平.甘草黄酮对2型糖尿病大鼠肝脏中GSK-3β蛋白表达的影响.天然产物研究与开发,2014,26(3):419-422.
41 Hao J,Chen C,Huang K,et al.Polydatin improves glucose and lipid metabolism in experimental diabetes through activating the Akt signaling pathway.Eur J Pharmacol,2014,745:152-165.
42 Chiang S H,Bazuine M,Lumeng C N,et al.The protein kinase IKKepsilon regulates energy balance in obese mice.Cell,2009,138(5):961-975.
43 Cai D,Yuan M,Frantz D,et al.Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.Nat Med,2005,11(2):183-190.
44 Zou X,Huang W,Lu F,et al.The effects of Jiao-Tai-Wan on sleep,inflammation and insulin resistance in obesity-resistant rats with chronic partial sleep deprivation.BMC Complement Altern Med,2017,17(1):165.
45苏卓,郭诚,梁韬.杜仲多糖对链脲佐菌素致糖尿病小鼠的作用.中国实验方剂学杂志,2016,22(14):159-162.
46 Lawan A,Bennett A M.Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism.Trends in endocrinology and metabolism:TEM,2017,28(12):868-878.
47 Hotamisligil G S,Davis R J.Cell Signaling and Stress Responses.Cold Spring Harb Perspect Biol,2016,8(10):a006072.
48 Fang P,Yu M,Min W,et al.Beneficial effect of baicalin on insulin sensitivity in adipocytes of diet-induced obese mice.Diabetes Res Clin Pract,2018,139:262-271.
49 Liu Y,Song A,Zang S,et al.Jinlida reduces insulin resistance and ameliorates liver oxidative stress in high-fat fed rats.J Ethnopharmacol,2015,162:244-252.
50 Vallerie S,Hotamisligil G.The role of JNK proteins in metabolism.Sci Transl Med,2010,2(60):60rv5.
51 Yang Y,Li W,Li Y,et al.Dietary Lycium barbarum polysaccharide induces Nrf2/ARE pathway and ameliorates insulin resistance induced by high-fat via activation of PI3K/AKT signaling.Oxid Med Cell Longev,2014,2014:145641.
52 Gao W,Du X,Lei L,et al.NEFA-induced ROS impaired insulin signalling through the JNK and p38MAPK pathways in non-alcoholic steatohepatitis.J Cell Mol Med,2018,22(7):3408-3422.
53 Liu Y,Li X,Xie C,et al.Prevention Effects and Possible Molecular Mechanism of Mulberry Leaf Extract and its Formulation on Rats with Insulin-Insensitivity.PloS One,2016,11(4):e0152728.
54 Zhang Z,Zhou S,Jiang X,et al.The role of the Nrf2/Keap1 pathway in obesity and metabolic syndrome.Rev Endocr Metab Disord,2015,16(1):35-45.
55 Yagishita Y,Uruno A,Fukutomi T,et al.Nrf2 Improves Leptin and Insulin Resistance Provoked by Hypothalamic Oxidative Stress.Cell Rep,2017,18(8):2030-2044.
56 Haluzík M,Haluzík M.Peroxisome proliferator activated receptors(PPAR)and insulin sensitivity:experimental studies.Cesk Fysiol,2006,55(4):163-168.
57 Koo S H,Satoh H,Herzig S,et al.PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3.Nat Med,2004,10(5):530-534.
58 Li L,Yoshitomi H,Wei Y,et al.Tang-Nai-Kang alleviates prediabetes and metabolic disorders and induces a gene expression switch toward fatty acid oxidation in SHR.Cg-Leprcp/NDmcr rats.PloS One,2015,10(4):e0122024.
59 Johnson T O,Ermolieff J,Jirousek M R.Protein tyrosine phosphatase1B inhibitors for diabetes.Nat Rev Drug Discov,2002,1(9):696-709.
60 Bhakta H K,Paudel P,Fujii H,et al.Oligonol promotes glucose uptake by modulating the insulin signaling pathway in insulin-resistant HepG2cells via inhibiting protein tyrosine phosphatase 1B.Arch Pharm Res,2017,40(11):1314-1327.