Natural products for the treatment of type 2 diabetes mellitus: Pharmacology and mechanisms

Pharmacological Research

Volumn 130, Issue , 2018, Pages 451-465

  Xu, Lina ^a   Li, Yue ^a   Dai, Yan ^a   Peng, Jinyong ^a  

^a DALIAN MEDICAL UNIVERSITY   (China)

Author keywords

Anti diabetic drug; Herbal medicine; Mechanism; Natural products; Type 2 diabetes mellitus

Indexed keywords

ALKALOID; ANTHOCYANIN; APIGENIN; AURANTIIN; BAICALEIN; BERBERINE; CAFFEIC ACID; COUMARIC ACID; CURCUMIN; EPIGALLOCATECHIN GALLATE; FERULIC ACID; FLAVANOID; GINSENOSIDE; GLUCOSE; HESPERIDIN; HYDROXYTYROSOL; JATRORRHIZINE; KAEMPFEROL; LUTEOLIN; MYRICETIN; NATURAL PRODUCT; POLYPHENOL; QUERCETIN; QUINONE DERIVATIVE; RESVERATROL; RUTOSIDE; SAPONIN DERIVATIVE; TANGERETIN; TERPENOID; UNINDEXED DRUG; BIOLOGICAL PRODUCT;

ANTIDIABETIC ACTIVITY; APOPTOSIS; CELL SURVIVAL; CYTOKINE PRODUCTION; CYTOKINE RELEASE; DIABETIC NEPHROPATHY; DNA DAMAGE; DRUG EFFICACY; DRUG MECHANISM; DRUG RESPONSE; DRUG STRUCTURE; FATTY ACID OXIDATION; GLUCOSE BLOOD LEVEL; GLUCOSE HOMEOSTASIS; GLUCOSE TOLERANCE; HUMAN; HYPERCHOLESTEROLEMIA; HYPERGLYCEMIA; HYPERTRIGLYCERIDEMIA; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OXIDATIVE STRESS; PANCREAS ISLET BETA CELL; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; REVIEW; STREPTOZOTOCIN-INDUCED DIABETES MELLITUS; TREATMENT OUTCOME; TREATMENT RESPONSE; ANIMAL;

ANIMALS; BIOLOGICAL PRODUCTS; DIABETES MELLITUS, TYPE 2; HUMANS;

EID: 85041218546     PISSN: 10436618     EISSN: 10961186     Source Type: Journal    
DOI: 10.1016/j.phrs.2018.01.015     Document Type: Review

References (243)

1. Mathers, C.D., Loncar, D., Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med., 3, 2006, e442.
2. Thomas, C.C., Philipson, L.H., Update on diabetes classification. Med. Clin. North Am. 99 (2015), 1–16.
3. Chillaron, J.J., Flores Le-Roux, J.A., Benaiges, D., Pedro-Botet, J., Type 1 diabetes, metabolic syndrome and cardiovascular risk. Metabolism 63 (2014), 181–187.
4. DeFronzo, R.A., Pathogenesis of type 2 diabetes mellitus. Med. Clin. North Am. 88 (2004), 787–835.
5. Forbes, J.M., Cooper, M.E., Mechanisms of diabetic complications. Physiol. Rev. 93 (2013), 137–188.
6. Labazi, H., Trask, A.J., Coronary microvascular disease as an early culprit in the pathophysiology of diabetes and metabolic syndrome. Pharmacol. Res. 123 (2017), 114–121.
7. Konig, M., Lamos, E.M., Stein, S.A., Davis, S.N., An insight into the recent diabetes trials: what is the best approach to prevent macrovascular and microvascular complications?. Curr. Diab. Rev. 9 (2013), 371–381.
8. Semenkovich, K., Brown, M.E., Svrakic, D.M., Lustman, P.J., Depression in type 2 diabetes mellitus: prevalence, impact, and treatment. Drugs 75 (2015), 577–587.
9. Tamler, R., Deveney, T., Hypogonadism, erectile dysfunction, and type 2 diabetes mellitus: what the clinician needs to know. Postgrad. Med. 122 (2010), 165–175.
10. Ninomiya, T., Diabetes mellitus and dementia. Curr. Diab. Rep., 14, 2014, 487.
11. Domingueti, C.P., Dusse, L.M., Carvalho, M., de Sousa, L.P., Gomes, K.B., Fernandes, A.P., Diabetes mellitus: the linkage between oxidative stress, inflammation, hypercoagulability and vascular complications. J. Diab. Complications 30 (2016), 738–745.
12. Franz, M.J., Boucher, J.L., Rutten-Ramos, S., VanWormer, J.J., Lifestyle weight-loss intervention outcomes in overweight and obese adults with type 2 diabetes: a systematic review and meta-analysis of randomized clinical trials. J. Acad. Nutr. Diet. 115 (2015), 1447–1463.
13. Ghosh, D., Parida, P., Drug discovery and development of type 2 diabetes mellitus: modern-integrative medicinal approach. Curr. Drug Discov. Technol. 13 (2016), 60–67.
14. Phung, O.J., Scholle, J.M., Talwar, M., Coleman, C.I., Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA 303 (2010), 1410–1418.
15. van Staa, T., Abenhaim, L., Monette, J., Rates of hypoglycemia in users of sulfonylureas. J. Clin. Epidemiol. 50 (1997), 735–741.
16. He, L., Wang, H., Gu, C., He, X., Zhao, L., Tong, X., Administration of traditional chinese blood circulation activating drugs for microvascular complications in patients with type 2 diabetes mellitus. J. Diab. Res., 2016, 2016, 1081657.
17. Pang, B., Zhou, Q., Li, J.L., Zhao, L.H., Tong, X.L., Treatment of refractory diabetic gastroparesis: western medicine and traditional Chinese medicine therapies. World J. Gastroenterol. 20 (2014), 6504–6514.
18. Xie, W., Du, L., Diabetes is an inflammatory disease: evidence from traditional Chinese medicines. Diab. Obes. Metab. 13 (2011), 289–301.
19. Salimifar, M., Fatehi-Hassanabad, Z., Fatehi, M., A review on natural products for controlling type 2 diabetes with an emphasis on their mechanisms of actions. Curr. Diab. Rev. 9 (2013), 402–411.
20. Fletcher, B., Gulanick, M., Lamendola, C., Risk factors for type 2 diabetes mellitus. J. Cardiovasc. Nurs. 16 (2002), 17–23.
21. McCarthy, M.I., Genomics type 2 diabetes, and obesity. N. Engl. J. Med. 363 (2010), 2339–2350.
22. Patel, P., Abate, N., Body fat distribution and insulin resistance. Nutrients 5 (2013), 2019–2027.
23. Olefsky, J.M., Kolterman, O.G., Scarlett, J.A., Insulin action and resistance in obesity and noninsulin-dependent type II diabetes mellitus. Am. J. Physiol. 243 (1982), E15–30.
24. Shao, S., Yang, Y., Yuan, G., Zhang, M., Yu, X., Signaling molecules involved in lipid-induced pancreatic beta-cell dysfunction. DNA Cell Biol. 32 (2013), 41–49.
25. Xu, E., Schwab, M., Marette, A., Role of protein tyrosine phosphatases in the modulation of insulin signaling and their implication in the pathogenesis of obesity-linked insulin resistance. Rev. Endocr. Metab. Disord. 15 (2014), 79–97.
26. Maiese, K., New insights for oxidative stress and diabetes mellitus. Oxid. Med. Cell Longev., 2015, 2015, 875961.
27. Kim, K.A., Shin, Y.J., Akram, M., Kim, E.S., Choi, K.W., Suh, H., Lee, C.H., et al. High glucose condition induces autophagy in endothelial progenitor cells contributing to angiogenic impairment. Biol. Pharm. Bull. 37 (2014), 1248–1252.
28. Girgis, C.M., Cheng, K., Scott, C.H., Gunton, J.E., Novel links between HIFs type 2 diabetes, and metabolic syndrome. Trends Endocrinol. Metab. 23 (2012), 372–380.
29. He, Q., Gao, Z., Yin, J., Zhang, J., Yun, Z., Ye, J., Regulation of HIF-1{alpha} activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia. Am. J. Physiol. Endocrinol. Metab. 300 (2011), E877–885.
30. Feng, Y.M., Zhao, D., Zhang, N., Yu, C.G., Zhang, Q., Thijs, L., Staessen, J.A., Insulin resistance in relation to lipids and inflammation in type-2 diabetic patients and non-diabetic people. PLoS One, 11, 2016, e0153171.
31. Nieto-Vazquez, I., Fernandez-Veledo, S., Kramer, D.K., Vila-Bedmar, R., Garcia-Guerra, L., Lorenzo, M., Insulin resistance associated to obesity: the link TNF-alpha. Arch. Physiol. Biochem. 114 (2008), 183–194.
32. Li, Z.Y., Song, J., Zheng, S.L., Fan, M.B., Guan, Y.F., Qu, Y., Xu, J., et al. Adipocyte metrnl antagonizes insulin resistance through PPARgamma signaling. Diabetes 64 (2015), 4011–4022.
33. Sears, B., Perry, M., The role of fatty acids in insulin resistance. Lipids Health Dis., 14, 2015, 121.
34. Jiao, P., Ma, J., Feng, B., Zhang, H., Diehl, J.A., Chin, Y.E., Yan, W., et al. FFA-induced adipocyte inflammation and insulin resistance: involvement of ER stress and IKKbeta pathways. Obesity 19 (2011), 483–491.
35. Samuel, V.T., Shulman, G.I., Mechanisms for insulin resistance: common threads and missing links. Cell 148 (2012), 852–871.
36. Yao, H., Qiao, Y.J., Zhao, Y.L., Tao, X.F., Xu, L.N., Yin, L.H., Qi, Y., et al. Herbal medicines and nonalcoholic fatty liver disease. World J. Gastroenterol. 22 (2016), 6890–6905.
37. Wenfeng, Z., Yakun, W., Di, M., Jianping, G., Chuanxin, W., Chun, H., Kupffer cells: increasingly significant role in nonalcoholic fatty liver disease. Ann. Hepatol. 13 (2014), 489–495.
38. Amati, F., Revisiting the diacylglycerol-induced insulin resistance hypothesis. Obes. Rev. 13:Suppl 2 (2012), 40–50.
39. Turban, S., Hajduch, E., Protein kinase C isoforms: mediators of reactive lipid metabolites in the development of insulin resistance. FEBS Lett. 585 (2011), 269–274.
40. Copps, K.D., White, M.F., Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 55 (2012), 2565–2582.
41. Kuzmenko, D.I., Klimentyeva, T.K., Role of ceramide in apoptosis and development of insulin resistance. Biochemistry 81 (2016), 913–927.
42. Martins, A.R., Nachbar, R.T., Gorjao, R., Vinolo, M.A., Festuccia, W.T., Lambertucci, R.H., Cury-Boaventura, M.F., et al. Mechanisms underlying skeletal muscle insulin resistance induced by fatty acids: importance of the mitochondrial function. Lipids Health Dis., 11, 2012, 30.
43. Wu, H., Ballantyne, C.M., Skeletal muscle inflammation and insulin resistance in obesity. J. Clin. Invest. 127 (2017), 43–54.
44. Kahn, S.E., The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia 46 (2003), 3–19.
45. Barlow, A.D., Thomas, D.C., Autophagy in diabetes: beta-cell dysfunction, insulin resistance, and complications. DNA Cell Biol. 34 (2015), 252–260.
46. Jeschke, M.G., Boehning, D., Endoplasmic reticulum stress and insulin resistance post-trauma: similarities to type 2 diabetes. J. Cell Mol. Med. 16 (2012), 437–444.
47. Mukherjee, A., Morales-Scheihing, D., Butler, P.C., Soto, C., Type 2 diabetes as a protein misfolding disease. Trends Mol. Med. 21 (2015), 439–449.
48. Zheng, H., Wu, J., Jin, Z., Yan, L.J., Protein modifications as manifestations of hyperglycemic glucotoxicity in diabetes and its complications. Biochem. Insights 9 (2016), 1–9.
49. Muka, T., Nano, J., Voortman, T., Braun, K.V.E., Ligthart, S., Stranges, S., Bramer, W.M., et al. The role of global and regional DNA methylation and histone modifications in glycemic traits and type 2 diabetes: a systematic review. Nutr. Metab. Cardiovasc. Dis. 26 (2016), 553–566.
50. Sharma, S., Taliyan, R., Histone deacetylase inhibitors: future therapeutics for insulin resistance and type 2 diabetes. Pharmacol. Res. 113 (2016), 320–326.
51. Mao, Y., Mohan, R., Zhang, S., Tang, X., MicroRNAs as pharmacological targets in diabetes. Pharmacol. Res. 75 (2013), 37–47.
52. Beccuti, G., Monagheddu, C., Evangelista, A., Ciccone, G., Broglio, F., Soldati, L., Bo, S., Timing of food intake: sounding the alarm about metabolic impairments? A systematic review. Pharmacol. Res. 125 (2017), 132–141.
53. Heim, K.E., Tagliaferro, A.R., Bobilya, D.J., Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J. Nutr. Biochem. 13 (2002), 572–584.
54. Sak, K., Everaus, H., Role of flavonoids in future anticancer therapy by eliminating the cancer stem cells. Curr. Stem Cell Res. Ther. 10 (2015), 271–282.
55. Vezza, T., Rodriguez-Nogales, A., Algieri, F., Utrilla, M.P., Rodriguez-Cabezas, M.E., Galvez, J., Flavonoids in inflammatory bowel disease: a review. Nutrients, 8, 2016, 211.
56. Chirumbolo, S., Flavonoids in coronary heart disease. Thromb. Res. 135 (2015), 1040–1041.
57. Kumar, S., Pandey, A.K., Chemistry and biological activities of flavonoids: an overview. Sci. World J., 2013, 2013, 162750.
58. Chen, S., Jiang, H., Wu, X., Fang, J., Therapeutic effects of quercetin on inflammation, obesity, and type 2 diabetes. Mediators Inflamm., 2016, 2016, 9340637.
59. Maciel, R.M., Costa, M.M., Martins, D.B., Franca, R.T., Schmatz, R., Graca, D.L., Duarte, M.M., et al. Antioxidant and anti-inflammatory effects of quercetin in functional and morphological alterations in streptozotocin-induced diabetic rats. Res. Vet. Sci 95 (2013), 389–397.
60. Chis, I.C., Coseriu, A., Simedrea, R., Oros, A., Nagy, A.L., Clichici, S., In vivo effects of quercetin in association with moderate exercise training in improving streptozotocin-induced aortic tissue injuries. Molecules 20 (2015), 21770–21786.
61. Alam, M.M., Meerza, D., Naseem, I., Protective effect of quercetin on hyperglycemia, oxidative stress and DNA damage in alloxan induced type 2 diabetic mice. Life Sci. 109 (2014), 8–14.
62. Wang, W., Wang, C., Ding, X.Q., Pan, Y., Gu, T.T., Wang, M.X., Liu, Y.L., et al. Quercetin and allopurinol reduce liver thioredoxin-interacting protein to alleviate inflammation and lipid accumulation in diabetic rats. Br. J. Pharmacol. 169 (2013), 1352–1371.
63. Eid, H.M., Nachar, A., Thong, F., Sweeney, G., Haddad, P.S., The molecular basis of the antidiabetic action of quercetin in cultured skeletal muscle cells and hepatocytes. Pharmacogn. Mag. 11 (2015), 74–81.
64. Lai, P.B., Zhang, L., Yang, L.Y., Quercetin ameliorates diabetic nephropathy by reducing the expressions of transforming growth factor-beta1 and connective tissue growth factor in streptozotocin-induced diabetic rats. Ren. Fail. 34 (2012), 83–87.
65. Sharma, S., Ali, A., Ali, J., Sahni, J.K., Baboota, S., Rutin: therapeutic potential and recent advances in drug delivery. Expert Opin. Investig. Drugs. 22 (2013), 1063–1079.
66. Ghorbani, A., Mechanisms of antidiabetic effects of flavonoid rutin. Biomed. Pharmacother. 96 (2017), 305–312.
67. Hunyadi, A., Martins, A., Hsieh, T.J., Seres, A., Zupko, I., Chlorogenic acid and rutin play a major role in the in vivo anti-diabetic activity of Morus alba leaf extract on type II diabetic rats. PLoS One, 7, 2012, e50619.
68. Hsu, C.Y., Shih, H.Y., Chia, Y.C., Lee, C.H., Ashida, H., Lai, Y.K., Weng, C.F., Rutin potentiates insulin receptor kinase to enhance insulin-dependent glucose transporter 4 translocation. Mol. Nutr. Food Res. 58 (2014), 1168–1176.
69. Stanely Mainzen Prince, P., Kannan, N.K., Protective effect of rutin on lipids, lipoproteins, lipid metabolizing enzymes and glycoproteins in streptozotocin-induced diabetic rats. J. Pharm. Pharmacol. 58 (2006), 1373–1383.
70. Fernandes, A.A., Novelli, E.L., Okoshi, K., Okoshi, M.P., Di Muzio, B.P., Guimaraes, J.F., Fernandes Junior, A., Influence of rutin treatment on biochemical alterations in experimental diabetes. Biomed. Pharmacother. 64 (2010), 214–219.
71. Wang, Y.B., Ge, Z.M., Kang, W.Q., Lian, Z.X., Yao, J., Zhou, C.Y., Rutin alleviates diabetic cardiomyopathy in a rat model of type 2 diabetes. Exp. Ther. Med. 9 (2015), 451–455.
72. Esmaeili, M.A., Zohari, F., Sadeghi, H., Antioxidant and protective effects of major flavonoids from Teucrium polium on beta-cell destruction in a model of streptozotocin-induced diabetes. Planta Med. 75 (2009), 1418–1420.
73. Cai, E.P., Lin, J.K., Epigallocatechin gallate (EGCG) and rutin suppress the glucotoxicity through activating IRS2 and AMPK signaling in rat pancreatic beta cells. J. Agric. Food Chem. 57 (2009), 9817–9827.
74. Kappel, V.D., Cazarolli, L.H., Pereira, D.F., Postal, B.G., Zamoner, A., Reginatto, F.H., Silva, F.R., Involvement of GLUT-4 in the stimulatory effect of rutin on glucose uptake in rat soleus muscle. J. Pharm. Pharmacol. 65 (2013), 1179–1186.
75. Li, Y.Q., Zhou, F.C., Gao, F., Bian, J.S., Shan, F., Comparative evaluation of quercetin, isoquercetin and rutin as inhibitors of alpha-glucosidase. J. Agric. Food Chem. 57 (2009), 11463–11468.
76. Stanley Mainzen Prince, P., Kamalakkannan, N., Rutin improves glucose homeostasis in streptozotocin diabetic tissues by altering glycolytic and gluconeogenic enzymes. J. Biochem. Mol. Toxicol. 20 (2006), 96–102.
77. Bharti, S., Rani, N., Krishnamurthy, B., Arya, D.S., Preclinical evidence for the pharmacological actions of naringin: a review. Planta Med. 80 (2014), 437–451.
78. Parmar, H.S., Jain, P., Chauhan, D.S., Bhinchar, M.K., Munjal, V., Yusuf, M., Choube, K., et al. DPP-IV inhibitory potential of naringin: an in silico, in vitro and in vivo study. Diab. Res. Clin. Pract. 97 (2012), 105–111.
79. Jung, U.J., Lee, M.K., Jeong, K.S., Choi, M.S., The hypoglycemic effects of hesperidin and naringin are partly mediated by hepatic glucose-regulating enzymes in C57BL/KsJ-db/db mice. J. Nutr. 134 (2004), 2499–2503.
80. Jung, U.J., Lee, M.K., Park, Y.B., Kang, M.A., Choi, M.S., Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mRNA levels in type-2 diabetic mice. Int. J. Biochem. Cell Biol. 38 (2006), 1134–1145.
81. Mahmoud, A.M., Ashour, M.B., Abdel-Moneim, A., Ahmed, O.M., Hesperidin and naringin attenuate hyperglycemia-mediated oxidative stress and proinflamma- tory cytokine production in high fat fed/streptozotocin-induced type 2 diabetic rats. J. Diab. Complications 26 (2012), 483–490.
82. Sharma, A.K., Bharti, S., Ojha, S., Bhatia, J., Kumar, N., Ray, R., Kumari, S., et al. Up-regulation of PPARgamma, heat shock protein-27 and −72 by naringin attenuates insulin resistance, beta-cell dysfunction, hepatic steatosis and kidney damage in a rat model of type 2 diabetes. Br J. Nutr. 106 (2011), 1713–1723.
83. Fu, Y., Luo, J., Jia, Z., Zhen, W., Zhou, K., Gilbert, E., Liu, D., Baicalein protects against type 2 diabetes via promoting islet beta-cell function in obese diabetic mice. Int. J. Endocrinol., 2014, 2014, 846742.
84. Pu, P., Wang, X.A., Salim, M., Zhu, L.H., Wang, L., Chen, K.J., Xiao, J.F., et al. Baicalein, a natural product, selectively activating AMPKalpha(2) and ameliorates metabolic disorder in diet-induced mice. Mol. Cell Endocrinol. 362 (2012), 128–138.
85. Qi, Z., Xu, Y., Liang, Z., Li, S., Wang, J., Wei, Y., Dong, B., Baicalein alters PI3K/Akt/GSK3beta signaling pathway in rats with diabetes-associated cognitive deficits. Int. J. Clin. Exp. Med. 8 (2015), 1993–2000.
86. Stavniichuk, R., Drel, V.R., Shevalye, H., Maksimchyk, Y., Kuchmerovska, T.M., Nadler, J.L., Obrosova, I.G., Baicalein alleviates diabetic peripheral neuropathy through inhibition of oxidative-nitrosative stress and p38 MAPK activation. Exp. Neurol. 230 (2011), 106–113.
87. Yang, L.P., Sun, H.L., Wu, L.M., Guo, X.J., Dou, H.L., Tso, M.O., Zhao, L., et al. Baicalein reduces inflammatory process in a rodent model of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 50 (2009), 2319–2327.
88. Jia, S., Hu, Y., Zhang, W., Zhao, X., Chen, Y., Sun, C., Li, X., et al. Hypoglycemic and hypolipidemic effects of neohesperidin derived from Citrus aurantium L. in diabetic KK-A(y) mice. Food Funct. 6 (2015), 878–886.
89. Ren, B., Qin, W., Wu, F., Wang, S., Pan, C., Wang, L., Zeng, B., et al. Apigenin and naringenin regulate glucose and lipid metabolism, and ameliorate vascular dysfunction in type 2 diabetic rats. Eur. J. Pharmacol. 773 (2016), 13–23.
90. Ahmed, O.M., Hassan, M.A., Abdel-Twab, S.M., Abdel Azeem, M.N., Navel orange peel hydroethanolic extract, naringin and naringenin have anti-diabetic potentials in type 2 diabetic rats. Biomed. Pharmacother. 94 (2017), 197–205.
91. Zang, Y., Igarashi, K., Li, Y., Anti-diabetic effects of luteolin and luteolin-7-O-glucoside on KK-A(y) mice. Biosci. Biotechnol. Biochem. 80 (2016), 1580–1586.
92. Sundaram, R., Shanthi, P., Sachdanandam, P., Effect of tangeretin, a polymethoxylated flavone on glucose metabolism in streptozotocin-induced diabetic rats. Phytomedicine 21 (2014), 793–799.
93. Kim, M.S., Hur, H.J., Kwon, D.Y., Hwang, J.T., Tangeretin stimulates glucose uptake via regulation of AMPK signaling pathways in C2C12 myotubes and improves glucose tolerance in high-fat diet-induced obese mice. Mol. Cell Endocrinol. 358 (2012), 127–134.
94. Da Silva, D., Casanova, L.M., Marcondes, M.C., Espindola-Netto, J.M., Paixao, L.P., De Melo, G.O., Zancan, P., et al. Antidiabetic activity of Sedum dendroideum: metabolic enzymes as putative targets for the bioactive flavonoid kaempferitrin. IUBMB Life 66 (2014), 361–370.
95. Luo, C., Yang, H., Tang, C., Yao, G., Kong, L., He, H., Zhou, Y., Kaempferol alleviates insulin resistance via hepatic IKK/NF-kappaB signal in type 2 diabetic rats. Int. Immunopharmacol. 28 (2015), 744–750.
96. Kandasamy, N., Ashokkumar, N., Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin-cadmium induced diabetic nephrotoxic rats. Toxicol. Appl. Pharmacol. 279 (2014), 173–185.
97. Behloul, N., Wu, G., Genistein: a promising therapeutic agent for obesity and diabetes treatment. Eur. J. Pharmacol. 698 (2013), 31–38.
98. Lee, H., Li, H., Noh, M., Ryu, J.H., Bavachin from Psoralea corylifolia improves insulin-dependent glucose uptake through insulin signaling and AMPK activation in 3T3-L1 adipocytes. Int. J. Mol. Sci., 17, 2016, 527.
99. Han, Y., Jung, H.W., Park, Y.K., Effects of Icariin on insulin resistance via the activation of AMPK pathway in C2C12 mouse muscle cells. Eur. J. Pharmacol. 758 (2015), 60–63.
100. Ly, C., Yockell-Lelievre, J., Ferraro, Z.M., Arnason, J.T., Ferrier, J., Gruslin, A., The effects of dietary polyphenols on reproductive health and early development. Hum. Reprod. Update 21 (2015), 228–248.
101. Le Sage, F., Meilhac, O., Gonthier, M.P., Anti-inflammatory and antioxidant effects of polyphenols extracted from Antirhea borbonica medicinal plant on adipocytes exposed to Porphyromonas gingivalis and Escherichia coli lipopolysaccharides. Pharmacol. Res. 119 (2017), 303–312.
102. Munir, K.M., Chandrasekaran, S., Gao, F., Quon, M.J., Mechanisms for food polyphenols to ameliorate insulin resistance and endothelial dysfunction: therapeutic implications for diabetes and its cardiovascular complications. Am. J. Physiol. Endocrinol. Metab. 305 (2013), E679–686.
103. Jung, K.H., Choi, H.S., Kim, D.H., Han, M.Y., Chang, U.J., Yim, S.V., Song, B.C., et al. Epigallocatechin gallate stimulates glucose uptake through the phosphatidyli- nositol 3-kinase-mediated pathway in L6 rat skeletal muscle cells. J. Med. Food 11 (2008), 429–434.
104. Collins, Q.F., Liu, H.Y., Pi, J., Liu, Z., Quon, M.J., Cao, W., Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, suppresses hepatic gluconeogenesis through 5’-AMP-activated protein kinase. J. Biol. Chem. 282 (2007), 30143–30149.
105. Lin, C.L., Lin, J.K., Epigallocatechin gallate (EGCG) attenuates high glucose-induced insulin signaling blockade in human hepG2 hepatoma cells. Mol. Nutr. Food Res. 52 (2008), 930–939.
106. Yoon, S.P., Maeng, Y.H., Hong, R., Lee, B.R., Kim, C.G., Kim, H.L., Chung, J.H., et al. Protective effects of epigallocatechin gallate (EGCG) on streptozotocin-induced diabetic nephropathy in mice. Acta Histochem. 116 (2014), 1210–1215.
107. Tsuneki, H., Ishizuka, M., Terasawa, M., Wu, J.B., Sasaoka, T., Kimura, I., Effect of green tea on blood glucose levels and serum proteomic patterns in diabetic (db/db) mice and on glucose metabolism in healthy humans. BMC Pharmacol., 4, 2004, 18.
108. Orsolic, N., Sirovina, D., Gajski, G., Garaj-Vrhovac, V., Jazvinscak Jembrek, M., Kosalec, I., Assessment of DNA damage and lipid peroxidation in diabetic mice: effects of propolis and epigallocatechin gallate (EGCG). Mutat. Res. 757 (2013), 36–44.
109. Ortsater, H., Grankvist, N., Wolfram, S., Kuehn, N., Sjoholm, A., Diet supplemen- tation with green tea extract epigallocatechin gallate prevents progression to glucose intolerance in db/db mice. Nutr. Metab., 9, 2012, 11.
110. Yan, J., Zhao, Y., Suo, S., Liu, Y., Zhao, B., Green tea catechins ameliorate adipose insulin resistance by improving oxidative stress. Free Radic. Biol. Med. 52 (2012), 1648–1657.
111. Chen, N., Bezzina, R., Hinch, E., Lewandowski, P.A., Cameron-Smith, D., Mathai, M.L., Jois, M., et al. Green tea, black tea, and epigallocatechin modify body composition, improve glucose tolerance, and differentially alter metabolic gene expression in rats fed a high-fat diet. Nutr. Res. 29 (2009), 784–793.
112. Li, Y., Zhao, S., Zhang, W., Zhao, P., He, B., Wu, N., Han, P., Epigallocatechin-3-O-gallate (EGCG) attenuates FFAs-induced peripheral insulin resistance through AMPK pathway and insulin signaling pathway in vivo. Diab. Res. Clin. Pract. 93 (2011), 205–214.
113. Kim, S., Jin, Y., Choi, Y., Park, T., Resveratrol exerts anti-obesity effects via mechanisms involving down-regulation of adipogenic and inflammatory processes in mice. Biochem. Pharmacol. 81 (2011), 1343–1351.
114. Chen, L.L., Zhang, H.H., Zheng, J., Hu, X., Kong, W., Hu, D., Wang, S.X., et al. Resveratrol attenuates high-fat diet-induced insulin resistance by influencing skeletal muscle lipid transport and subsarcolemmal mitochondrial beta-oxidation. Metabolism 60 (2011), 1598–1609.
115. Kang, W., Hong, H.J., Guan, J., Kim, D.G., Yang, E.J., Koh, G., Park, D., et al. Resveratrol improves insulin signaling in a tissue-specific manner under insulin-resistant conditions only: in vitro and in vivo experiments in rodents. Metabolism 61 (2012), 424–433.
116. Zheng, X., Zhu, S., Chang, S., Cao, Y., Dong, J., Li, J., Long, R., et al. Protective effects of chronic resveratrol treatment on vascular inflammatory injury in streptozotocin-induced type 2 diabetic rats: role of NF-kappa B signaling. Eur. J. Pharmacol. 720 (2013), 147–157.
117. Chen, S., Li, J., Zhang, Z., Li, W., Sun, Y., Zhang, Q., Feng, X., et al. Effects of resveratrol on the amelioration of insulin resistance in KKAy mice. Can. J. Physiol. Pharmacol. 90 (2012), 237–242.
118. Guo, R., Liu, B., Wang, K., Zhou, S., Li, W., Xu, Y., Resveratrol ameliorates diabetic vascular inflammation and macrophage infiltration in db/db mice by inhibiting the NF-kappaB pathway. Diab. Vasc. Dis. Res. 11 (2014), 92–102.
119. Bagul, P.K., Middela, H., Matapally, S., Padiya, R., Bastia, T., Madhusudana, K., Reddy, B.R., et al. Attenuation of insulin resistance, metabolic syndrome and hepatic oxidative stress by resveratrol in fructose-fed rats. Pharmacol. Res. 66 (2012), 260–268.
120. Rivera, L., Moron, R., Zarzuelo, A., Galisteo, M., Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats. Biochem. Pharmacol. 77 (2009), 1053–1063.
121. Beaudoin, M.S., Snook, L.A., Arkell, A.M., Simpson, J.A., Holloway, G.P., Wright, D.C., Resveratrol supplementation improves white adipose tissue function in a depot-specific manner in Zucker diabetic fatty rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305 (2013), R542–551.
122. Burgess, T.A., Robich, M.P., Chu, L.M., Bianchi, C., Sellke, F.W., Improving glucose metabolism with resveratrol in a swine model of metabolic syndrome through alteration of signaling pathways in the liver and skeletal muscle. Arch. Surg. 146 (2011), 556–564.
123. Jimenez-Gomez, Y., Mattison, J.A., Pearson, K.J., Martin-Montalvo, A., Palacios, H.H., Sossong, A.M., Ward, T.M., et al. Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. Cell Metab. 18 (2013), 533–545.
124. Szkudelski, T., Szkudelska, K., Resveratrol and diabetes: from animal to human studies. Biochim. Biophys. Acta 1852 (2015), 1145–1154.
125. Um, J.H., Park, S.J., Kang, H., Yang, S., Foretz, M., McBurney, M.W., Kim, M.K., et al. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 59 (2010), 554–563.
126. Baur, J.A., Biochemical effects of SIRT1 activators. Biochim. Biophys. Acta 1804 (2010), 1626–1634.
127. Alberdi, G., Rodriguez, V.M., Macarulla, M.T., Miranda, J., Churruca, I., Portillo, M.P., Hepatic lipid metabolic pathways modified by resveratrol in rats fed an obesogenic diet. Nutrition 29 (2013), 562–567.
128. Deng, J.Y., Hsieh, P.S., Huang, J.P., Lu, L.S., Hung, L.M., Activation of estrogen receptor is crucial for resveratrol-stimulating muscular glucose uptake via both insulin-dependent and −independent pathways. Diabetes 57 (2008), 1814–1823.
129. Hong, H.J., Kang, W., Kim, D.G., Lee, D.H., Lee, Y., Han, C.H., Effects of resveratrol on the insulin signaling pathway of obese mice. J. Vet. Sci. 15 (2014), 179–185.
130. Movahed, A., Nabipour, I., Lieben Louis, X., Thandapilly, S.J., Yu, L., Kalantarhor-mozi, M., Rekabpour, S.J., et al. Antihyperglycemic effects of short term resveratrol supplementation in type 2 diabetic patients. Evid. Based Complement. Alternat. Med., 2013, 2013, 851267.
131. Brasnyo, P., Molnar, G.A., Mohas, M., Marko, L., Laczy, B., Cseh, J., Mikolas, E., et al. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br. J Nutr. 106 (2011), 383–389.
132. Bhatt, J.K., Thomas, S., Nanjan, M.J., Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr. Res. 32 (2012), 537–541.
133. Dash, S., Xiao, C., Morgantini, C., Szeto, L., Lewis, G.F., High-dose resveratrol treatment for 2 weeks inhibits intestinal and hepatic lipoprotein production in overweight/obese men. Arterioscler Thromb. Vasc. Biol. 33 (2013), 2895–2901.
134. Bashmakov, Y.K., Assaad-Khalil, S.H., Abou Seif, M., Udumyan, R., Megallaa, M., Rohoma, K.H., Zeitoun, M., et al. Resveratrol promotes foot ulcer size reduction in type 2 diabetes patients. ISRN Endocrinol., 2014, 2014, 816307.
135. Nabavi, S.F., Thiagarajan, R., Rastrelli, L., Daglia, M., Sobarzo-Sanchez, E., Alinezhad, H., Nabavi, S.M., Curcumin: a natural product for diabetes and its complications. Curr. Top. Med. Chem. 15 (2015), 2445–2455.
136. El-Azab, M.F., Attia, F.M., El-Mowafy, A.M., Novel role of curcumin combined with bone marrow transplantation in reversing experimental diabetes: effects on pancreatic islet regeneration, oxidative stress, and inflammatory cytokines. Eur. J. Pharmacol. 658 (2011), 41–48.
137. He, H.J., Wang, G.Y., Gao, Y., Ling, W.H., Yu, Z.W., Jin, T.R., Curcumin attenuates Nrf2 signaling defect, oxidative stress in muscle and glucose intolerance in high fat diet-fed mice. World J. Diab. 3 (2012), 94–104.
138. Soetikno, V., Sari, F.R., Veeraveedu, P.T., Thandavarayan, R.A., Harima, M., Sukumaran, V., Lakshmanan, A.P., et al. Curcumin ameliorates macrophage infiltration by inhibiting NF-kappaB activation and proinflammatory cytokines in streptozotocin induced-diabetic nephropathy. Nutr. Metab., 8, 2011, 35.
139. Suryanarayana, P., Satyanarayana, A., Balakrishna, N., Kumar, P.U., Reddy, G.B., Effect of turmeric and curcumin on oxidative stress and antioxidant enzymes in streptozotocin-induced diabetic rat. Med. Sci. Monit. 13 (2007), 286–292.
140. Chougala, M.B., Bhaskar, J.J., Rajan, M.G., Salimath, P.V., Effect of curcumin and quercetin on lysosomal enzyme activities in streptozotocin-induced diabetic rats. Clin. Nutr. 31 (2012), 749–755.
141. Nishiyama, T., Mae, T., Kishida, H., Tsukagawa, M., Mimaki, Y., Kuroda, M., Sashida, Y., et al. Curcuminoids and sesquiterpenoids in turmeric (Curcuma longa L.) suppress an increase in blood glucose level in type 2 diabetic KK-Ay mice. J. Agric. Food Chem. 53 (2005), 959–963.
142. Ponnusamy, S., Zinjarde, S., Bhargava, S., Rajamohanan, P.R., Ravikumar, A., Discovering Bisdemethoxycurcumin from Curcuma longa rhizome as a potent small molecule inhibitor of human pancreatic alpha-amylase, a target for type-2 diabetes. Food Chem. 135 (2012), 2638–2642.
143. Nizamutdinova, I.T., Jin, Y.C., Chung, J.I., Shin, S.C., Lee, S.J., Seo, H.G., Lee, J.H., et al. The anti-diabetic effect of anthocyanins in streptozotocin-induced diabetic rats through glucose transporter 4 regulation and prevention of insulin resistance and pancreatic apoptosis. Mol. Nutr. Food Res. 53 (2009), 1419–1429.
144. Takikawa, M., Inoue, S., Horio, F., Tsuda, T., Dietary anthocyanin-rich bilberry extract ameliorates hyperglycemia and insulin sensitivity via activation of AMP-activated protein kinase in diabetic mice. J. Nutr. 140 (2010), 527–533.
145. Huang, M., Wang, P., Xu, S., Xu, W., Xu, W., Chu, K., Lu, J., Biological activities of salvianolic acid B from Salvia miltiorrhiza on type 2 diabetes induced by high-fat diet and streptozotocin. Pharm. Biol. 53 (2015), 1058–1065.
146. Tsuda, T., Ueno, Y., Aoki, H., Koda, T., Horio, F., Takahashi, N., Kawada, T., et al. Anthocyanin enhances adipocytokine secretion and adipocyte-specific gene expression in isolated rat adipocytes. Biochem. Biophys. Res. Commun. 316 (2004), 149–157.
147. Sasaki, R., Nishimura, N., Hoshino, H., Isa, Y., Kadowaki, M., Ichi, T., Tanaka, A., et al. Cyanidin 3-glucoside ameliorates hyperglycemia and insulin sensitivity due to downregulation of retinol binding protein 4 expression in diabetic mice. Biochem. Pharmacol. 74 (2007), 1619–1627.
148. Chang, W., Chen, L., Hatch, G.M., Berberine as a therapy for type 2 diabetes and its complications: from mechanism of action to clinical studies. Biochem. Cell Biol. 93 (2015), 479–486.
149. Krenisky, J.M., Luo, J., Reed, M.J., Carney, J.R., Isolation and antihyperglycemic activity of bakuchiol from Otholobium pubescens (Fabaceae), a Peruvian medicinal plant used for the treatment of diabetes. Biol. Pharm. Bull. 22 (1999), 1137–1140.
150. Singh, P., Jayaramaiah, R.H., Agawane, S.B., Vannuruswamy, G., Korwar, A.M., Anand, A., Dhaygude, V.S., et al. Potential dual role of eugenol in inhibiting advanced glycation end products in diabetes: proteomic and mechanistic insights. Sci. Rep., 6, 2016, 18798.
151. Jeong, K.J., Kim, D.Y., Quan, H.Y., Jo, H.K., Kim, G.W., Chung, S.H., Effects of eugenol on hepatic glucose production and AMPK signaling pathway in hepatocytes and C57BL/6J mice. Fitoterapia 93 (2014), 150–162.
152. Liu, J., Wang, S., Feng, L., Ma, D., Fu, Q., Song, Y., Jia, X., et al. Hypoglycemic and antioxidant activities of paeonol and its beneficial effect on diabetic encephalopathy in streptozotocin-induced diabetic rats. J. Med. Food 16 (2013), 577–586.
153. Poudyal, H., Lemonakis, N., Efentakis, P., Gikas, E., Halabalaki, M., Andreadou, I., Skaltsounis, L., et al. Hydroxytyrosol ameliorates metabolic, cardiovascular and liver changes in a rat model of diet-induced metabolic syndrome: pharmacolo- gical and metabolism-based investigation. Pharmacol. Res. 117 (2017), 32–45.
154. Tutino, V., Orlando, A., Russo, F., Notarnicola, M., Hydroxytyrosol inhibits cannabinoid CB1 receptor gene expression in 3T3-L1 preadipocyte cell line. J. Cell Physiol. 231 (2016), 483–489.
155. Chen, C., Huang, K., Hao, J., Huang, J., Yang, Z., Xiong, F., Liu, P., et al. Polydatin attenuates AGEs-induced upregulation of fibronectin and ICAM-1 in rat glomerular mesangial cells and db/db diabetic mice kidneys by inhibiting the activation of the SphK1-S1P signaling pathway. Mol. Cell Endocrinol. 427 (2016), 45–56.
156. Wang, Y., Ye, J., Li, J., Chen, C., Huang, J., Liu, P., Huang, H., Polydatin ameliorates lipid and glucose metabolism in type 2 diabetes mellitus by downregulating proprotein convertase subtilisin/kexin type 9 (PCSK9). Cardiovasc. Diabetol., 15, 2016, 19.
157. Hao, J., Chen, C., Huang, K., Huang, J., Li, J., Liu, P., Huang, H., Polydatin improves glucose and lipid metabolism in experimental diabetes through activating the Akt signaling pathway. Eur. J. Pharmacol. 745 (2014), 152–165.
158. Abdel-Moneim, A., Yousef, A.I., Abd El-Twab, S.M., Abdel Reheim, E.S., Ashour, M.B., Gallic acid and p-coumaric acid attenuate type 2 diabetes-induced neurodegeneration in rats. Metab. Brain Dis. 32 (2017), 1279–1286.
159. Amalan, V., Vijayakumar, N., Indumathi, D., Ramakrishnan, A., Antidiabetic and antihyperlipidemic activity of p-coumaric acid in diabetic rats, role of pancreatic GLUT 2: In vivo approach. Biomed. Pharmacother. 84 (2016), 230–236.
160. Jung, U.J., Lee, M.K., Park, Y.B., Jeon, S.M., Choi, M.S., Antihyperglycemic and antioxidant properties of caffeic acid in db/db mice. J. Pharmacol. Exp. Ther. 318 (2006), 476–483.
161. Choi, R., Kim, B.H., Naowaboot, J., Lee, M.Y., Hyun, M.R., Cho, E.J., Lee, E.S., et al. Effects of ferulic acid on diabetic nephropathy in a rat model of type 2 diabetes. Exp. Mol. Med. 43 (2011), 676–683.
162. Narasimhan, A., Chinnaiyan, M., Karundevi, B., Ferulic acid exerts its antidiabetic effect by modulating insulin-signalling molecules in the liver of high-fat diet and fructose-induced type-2 diabetic adult male rat. Appl. Physiol. Nutr. Metab. 40 (2015), 769–781.
163. Gandhi, G.R., Jothi, G., Antony, P.J., Balakrishna, K., Paulraj, M.G., Ignacimuthu, S., Stalin, A., et al. Gallic acid attenuates high-fat diet fed-streptozotocin-induced insulin resistance via partial agonism of PPARgamma in experimental type 2 diabetic rats and enhances glucose uptake through translocation and activation of GLUT4 in PI3K/p-Akt signaling pathway. Eur. J. Pharmacol. 745 (2014), 201–216.
164. Hafizur, R.M., Hameed, A., Shukrana, M., Raza, S.A., Chishti, S., Kabir, N., Siddiqui, R.A., Cinnamic acid exerts anti-diabetic activity by improving glucose tolerance in vivo and by stimulating insulin secretion in vitro. Phytomedicine 22 (2015), 297–300.
165. Chang, W.C., Wu, J.S., Chen, C.W., Kuo, P.L., Chien, H.M., Wang, Y.T., Shen, S.C., Protective effect of vanillic acid against hyperinsulinemia, hyperglycemia and hyperlipidemia via alleviating hepatic insulin resistance and inflammation in high-fat diet (HFD)-fed rats. Nutrients 7 (2015), 9946–9959.
166. Harini, R., Pugalendi, K.V., Antihyperglycemic effect of protocatechuic acid on streptozotocin-diabetic rats. J. Basic Clin. Physiol. Pharmacol. 21 (2010), 79–91.
167. Jin, S., Chang, C., Zhang, L., Liu, Y., Huang, X., Chen, Z., Chlorogenic acid improves late diabetes through adiponectin receptor signaling pathways in db/db mice. PLoS One, 10, 2015, e0120842.
168. Mubarak, A., Hodgson, J.M., Considine, M.J., Croft, K.D., Matthews, V.B., Supplementation of a high-fat diet with chlorogenic acid is associated with insulin resistance and hepatic lipid accumulation in mice. J. Agric. Food Chem. 61 (2013), 4371–4378.
169. Yoshimura, Y., Nishii, S., Zaima, N., Moriyama, T., Kawamura, Y., Ellagic acid improves hepatic steatosis and serum lipid composition through reduction of serum resistin levels and transcriptional activation of hepatic ppara in obese, diabetic KK-A(y) mice. Biochem. Biophys. Res. Commun. 434 (2013), 486–491.
170. Beukes, N., Levendal, R.A., Frost, C.L., Selected terpenoids from medicinal plants modulate endoplasmic reticulum stress in metabolic disorders. J. Pharm. Pharmacol. 66 (2014), 1505–1525.
171. Magnone, M., Ameri, P., Salis, A., Andraghetti, G., Emionite, L., Murialdo, G., De Flora, A., et al. Microgram amounts of abscisic acid in fruit extracts improve glucose tolerance and reduce insulinemia in rats and in humans. Faseb J. 29 (2015), 4783–4793.
172. Ding, L.L., Li, J.M., Song, B.L., Xiao, X., Huang, W.D., Zhang, B.F., Tang, X.W., et al. Andrographolide prevents high-fat diet-induced obesity in C57BL/6 mice by suppressing the sterol regulatory element-binding protein pathway. J. Pharmacol. Exp. Ther. 351 (2014), 474–483.
173. Wang, X., Liu, R., Zhang, W., Zhang, X.D., Liao, N., Wang, Z., Li, W.L., et al. Oleanolic acid improves hepatic insulin resistance via antioxidant, hypolipidemic and anti-inflammatory effects. Mol. Cell Endocrin. 376 (2013), 70–80.
174. Guan, L.L., Feng, H.Y., Gong, D.Z., Zhao, X., Cai, L., Wu, Q., Yuan, B., et al. Genipin ameliorates age-related insulin resistance through inhibiting hepatic oxidative stress and mitochondrial dysfunction. Exp. Gerontol. 48 (2013), 1387–1394.
175. Gao, Y.F., Zhang, M.N., Wu, T.C., Xu, M.Y., Cai, H.N., Zhang, Z.S., Effects of D-pinitol on insulin resistance through the PI3K/Akt signaling pathway in type 2 diabetes mellitus rats. J. Agric. Food Chem. 63 (2015), 6019–6026.
176. Kim, H.J., Park, K.S., Lee, S.K., Min, K.W., Han, K.A., Kim, Y.K., Ku, B.J., Effects of pinitol on glycemic control, insulin resistance and adipocytokine levels in patients with type 2 diabetes mellitus. Ann. Nutr. Metab. 60 (2012), 1–5.
177. Mnonopi, N., Levendal, R.A., Mzilikazi, N., Frost, C.L., Marrubiin, a constituent of Leonotis leonurus, alleviates diabetic symptoms. Phytomedicine 19 (2012), 488–493.
178. Deepa, B., Venkatraman Anuradha, C., Effects of linalool on inflammation, matrix accumulation and podocyte loss in kidney of streptozotocin-induced diabetic rats. Toxicol. Mech. Methods 23 (2013), 223–234.
179. Babukumar, S., Vinothkumar, V., Sankaranarayanan, C., Srinivasan, S., Geraniol, a natural monoterpene, ameliorates hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in streptozotocin-induced diabetic rats. Pharm. Biol. 55 (2017), 1442–1449.
180. Lee, J., Lee, H.I., Seo, K.I., Cho, H.W., Kim, M.J., Park, E.M., Lee, M.K., Effects of ursolic acid on glucose metabolism, the polyol pathway and dyslipidemia in non-obese type 2 diabetic mice. Indian J. Exp. Biol. 52 (2014), 683–691.
181. Kim, S.J., Quan, H.Y., Jeong, K.J., Kim, D.Y., Kim, G., Jo, H.K., Chung, S.H., Beneficial effect of betulinic acid on hyperglycemia via suppression of hepatic glucose production. J. Agric. Food Chem. 62 (2014), 434–442.
182. Wang, X., Lu, Q., Yu, D.S., Chen, Y.P., Shang, J., Zhang, L.Y., Sun, H.B., et al. Asiatic acid mitigates hyperglycemia and reduces islet fibrosis in Goto-Kakizaki rat, a spontaneous type 2 diabetic animal model. Chin. J. Nat. Med. 13 (2015), 529–534.
183. Ramachandran, V., Saravanan, R., Glucose uptake through translocation and activation of GLUT4 in PI3K/Akt signaling pathway by asiatic acid in diabetic rats. Hum. Exp. Toxicol. 34 (2015), 884–893.
184. Liu, J., Sun, H., Duan, W., Mu, D., Zhang, L., Maslinic acid reduces blood glucose in KK-Ay mice. Biol. Pharm. Bull. 30 (2007), 2075–2078.
185. Liu, J., Wang, X., Chen, Y.P., Mao, L.F., Shang, J., Sun, H.B., Zhang, L.Y., Maslinic acid modulates glycogen metabolism by enhancing the insulin signaling pathway and inhibiting glycogen phosphorylase. Chin. J. Nat. Med. 12 (2014), 259–265.
186. Takagi, S., Miura, T., Ishihara, E., Ishida, T., Chinzei, Y., Effect of corosolic acid on dietary hypercholesterolemia and hepatic steatosis in KK-Ay diabetic mice. Biomed. Res. 31 (2010), 213–218.
187. Kalaiarasi, P., Pugalendi, K.V., Antihyperglycemic effect of 18 beta-glycyrrhetinic acid aglycone of glycyrrhizin, on streptozotocin-diabetic rats. Eur. J. Pharmacol. 606 (2009), 269–273.
188. Wu, J.B., Kuo, Y.H., Lin, C.H., Ho, H.Y., Shih, C.C., Tormentic acid, a major component of suspension cells of Eriobotrya japonica, suppresses high-fat diet-induced diabetes and hyperlipidemia by glucose transporter 4 and AMP-activated protein kinase phosphorylation. J. Agric. Food Chem. 62 (2014), 10717–10726.
189. Imperatore, C., Aiello, A., D'Aniello, F., Senese, M., Menna, M., Alkaloids from marine invertebrates as important leads for anticancer drugs discovery and development. Molecules 19 (2014), 20391–20423.
190. Derosa, G., Maffioli, P., Alkaloids in the nature: pharmacological applications in clinical practice of berberine and mate tea. Curr. Top. Med. Chem. 14 (2014), 200–206.
191. Ni, W.J., Ding, H.H., Tang, L.Q., Berberine as a promising anti-diabetic nephropathy drug: an analysis of its effects and mechanisms. Eur. J. Pharmacol. 760 (2015), 103–112.
192. Lee, Y.S., Kim, W.S., Kim, K.H., Yoon, M.J., Cho, H.J., Shen, Y., Ye, J.M., et al. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes 55 (2006), 2256–2264.
193. Kim, W.S., Lee, Y.S., Cha, S.H., Jeong, H.W., Choe, S.S., Lee, M.R., Oh, G.T., et al. Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity. Am. J. Physiol. Endocrinol. Metab. 296 (2009), E812–819.
194. Leng, S.H., Lu, F.E., Xu, L.J., Therapeutic effects of berberine in impaired glucose tolerance rats and its influence on insulin secretion. Acta Pharmacol. Sin. 25 (2004), 496–502.
195. Kong, W.J., Zhang, H., Song, D.Q., Xue, R., Zhao, W., Wei, J., Wang, Y.M., et al. Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression. Metabolism 58 (2009), 109–119.
196. Gu, J.J., Gao, F.Y., Zhao, T.Y., A preliminary investigation of the mechanisms underlying the effect of berberine in preventing high-fat diet-induced insulin resistance in rats. J. Physiol. Pharmacol. 63 (2012), 505–513.
197. Jiang, Q., Liu, P., Wu, X., Liu, W., Shen, X., Lan, T., Xu, S., et al. Berberine attenuates lipopolysaccharide-induced extracelluar matrix accumulation and inflammation in rat mesangial cells: involvement of NF-kappaB signaling pathway. Mol. Cell Endocrinol. 331 (2011), 34–40.
198. Yang, W., She, L., Yu, K., Yan, S., Zhang, X., Tian, X., Ma, S., et al. Jatrorrhizine hydrochloride attenuates hyperlipidemia in a high-fat diet-induced obesity mouse model. Mol. Med. Rep. 14 (2016), 3277–3284.
199. Song, C., Ji, Y., Zou, G., Wan, C., Tetrandrine down-regulates expression of miRNA-155 to inhibit signal-induced NF-kappaB activation in a rat model of diabetes mellitus. Int. J. Clin. Exp. Med. 8 (2015), 4024–4030.
200. Jiang, X., Zhang, D., Jiang, W., Coffee and caffeine intake and incidence of type 2 diabetes mellitus: a meta-analysis of prospective studies. Eur. J. Nutr. 53 (2014), 25–38.
201. Dewar, L., Heuberger, R., The effect of acute caffeine intake on insulin sensitivity and glycemic control in people with diabetes. Diab. Metab. Syndr. 115 (2017), 5631–5635.
202. Okumura, T., Tsukui, T., Hosokawa, M., Miyashita, K., Effect of caffeine and capsaicin on the blood glucose levels of obese/diabetic KK-A(y) mice. J. Oleo. Sci. 61 (2012), 515–523.
203. Consolim-Colombo, C.T., Sangaleti, F.O., Costa, T.L., Morais, H.F., Lopes, J.M., Motta, M.C., et al. Galantamine alleviates inflammation and insulin resistance in patients with metabolic syndrome in a randomized trial. JCI Insight, 2, 2017, 93340.
204. Mao, X.Y., Cao, D.F., Li, X., Yin, J.Y., Wang, Z.B., Zhang, Y., Mao, C.X., et al. Huperzine A ameliorates cognitive deficits in streptozotocin-induced diabetic rats. Int. J. Mol. Sci. 15 (2014), 7667–7683.
205. Atal, S., Agrawal, R.P., Vyas, S., Phadnis, P., Rai, N., Evaluation of the effect of piperine per se on blood glucose level in alloxan-induced diabetic mice. Acta Pol. Pharm. 69 (2012), 965–969.
206. Papadimitriou, A., Silva, K.C., Peixoto, E.B., Borges, C.M., Lopes de Faria, J.M., Lopes de Faria, J.B., Theobromine increases NAD(+)/Sirt-1 activity and protects the kidney under diabetic conditions. Am. J. Physiol. Renal. Physiol. 308 (2015), F209–225.
207. Demidowich, A.P., Davis, A.I., Dedhia, N., Yanovski, J.A., Colchicine to decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation. Med. Hypotheses 92 (2016), 67–73.
208. Zeng, X.Y., Wang, H., Bai, F., Zhou, X., Li, S.P., Ren, L.P., Sun, R.Q., et al. Identification of matrine as a promising novel drug for hepatic steatosis and glucose intolerance with HSP72 as an upstream target. Br. J. Pharmacol. 172 (2015), 4303–4318.
209. Guo, C., Han, F., Zhang, C., Xiao, W., Yang, Z., Protective effects of oxymatrine on experimental diabetic nephropathy. Planta Med. 80 (2014), 269–276.
210. Wang, T., Kusudo, T., Takeuchi, T., Yamashita, Y., Kontani, Y., Okamatsu, Y., Saito, M., et al. Evodiamine inhibits insulin-stimulated mTOR-S6K activation and IRS1 serine phosphorylation in adipocytes and improves glucose tolerance in obese/diabetic mice. PLoS One, 8, 2013, e83264.
211. Tsutsumi, T., Kobayashi, S., Liu, Y.Y., Kontani, H., Anti-hyperglycemic effect of fangchinoline isolated from Stephania tetrandra Radix in streptozotocin-diabetic mice. Biol. Pharm. Bull. 26 (2003), 313–317.
212. Hsieh, T.J., Hsieh, P.C., Wu, M.T., Chang, W.C., Hsiao, P.J., Lin, K.D., Chou, P.C., et al. Betel nut extract and arecoline block insulin signaling and lipid storage in 3T3-L1 adipocytes. Cell Biol. Toxicol. 27 (2011), 397–411.
213. Moses, T., Papadopoulou, K.K., Osbourn, A., Metabolic and functional diversity of saponins, biosynthetic intermediates and semi-synthetic derivatives. Crit. Rev. Biochem. Mol. Biol. 49 (2014), 439–462.
214. Sun, Y., Liu, Y., Chen, K., Roles and mechanisms of ginsenoside in cardiovascular diseases: progress and perspectives. Sci. China Life Sci. 59 (2016), 292–298.
215. Nah, S.Y., Ginseng ginsenoside pharmacology in the nervous system: involvement in the regulation of ion channels and receptors. Front. Physiol., 5, 2014, 98.
216. Ni, H.X., Yu, N.J., Yang, X.H., The study of ginsenoside on PPARgamma expression of mononuclear macrophage in type 2 diabetes. Mol. Biol. Rep. 37 (2010), 2975–2979.
217. Li, W., Zhang, M., Gu, J., Meng, Z.J., Zhao, L.C., Zheng, Y.N., Chen, L., et al. Hypoglycemic effect of protopanaxadiol-type ginsenosides and compound K on Type 2 diabetes mice induced by high-fat diet combining with streptozotocin via suppression of hepatic gluconeogenesis. Fitoterapia 83 (2012), 192–198.
218. Kim, K.S., Jung Yang, H., Lee, I.S., Kim, K.H., Park, J., Jeong, H.S., Kim, Y., et al. The aglycone of ginsenoside Rg3 enables glucagon-like peptide-1 secretion in enteroendocrine cells and alleviates hyperglycemia in type 2 diabetic mice. Sci. Rep., 5, 2015, 18325.
219. Lee, H.M., Lee, O.H., Kim, K.J., Lee, B.Y., Ginsenoside Rg1 promotes glucose uptake through activated AMPK pathway in insulin-resistant muscle cells. Phytother. Res. 26 (2012), 1017–1022.
220. Shi, Y., Wan, X., Shao, N., Ye, R., Zhang, N., Zhang, Y., Protective and antiangio- pathy effects of ginsenoside Re against diabetes mellitus via the activation of p38 MAPK, ERK1/2 and JNK signaling. Mol. Med. Rep. 14 (2016), 4849–4856.
221. Jiang, B., Yang, Y., Jin, H., Shang, W., Zhou, L., Qian, L., Chen, M., Astragaloside IV attenuates lipolysis and improves insulin resistance induced by TNFalpha in 3T3-L1 adipocytes. Phytother. Res. 22 (2008), 1434–1439.
222. Lv, L., Wu, S.Y., Wang, G.F., Zhang, J.J., Pang, J.X., Liu, Z.Q., Xu, W., et al. Effect of astragaloside IV on hepatic glucose-regulating enzymes in diabetic mice induced by a high-fat diet and streptozotocin. Phytother. Res. 24 (2010), 219–224.
223. Han, L.K., Zheng, Y.N., Yoshikawa, M., Okuda, H., Kimura, Y., Anti-obesity effects of chikusetsusaponins isolated from Panax japonicus rhizomes. BMC Complement. Altern. Med., 5, 2005, 9.
224. Naidu, P.B., Ponmurugan, P., Begum, M.S., Mohan, K., Meriga, B., RavindarNaik, R., Saravanan, G., Diosgenin reorganises hyperglycaemia and distorted tissue lipid profile in high-fat diet-streptozotocin-induced diabetic rats. J. Sci. Food Agric. 95 (2015), 3177–3182.
225. Tharaheswari, M., Jayachandra Reddy, N., Kumar, R., Varshney, K.C., Kannan, M., Sudha Rani, S., Trigonelline and diosgenin attenuate ER stress, oxidative stress-mediated damage in pancreas and enhance adipose tissue PPARgamma activity in type 2 diabetic rats. Mol. Cell Biochem. 396 (2014), 161–174.
226. Chen, T., Gao, J., Xiang, P., Chen, Y., Ji, J., Xie, P., Wu, H., et al. Protective effect of platycodin D on liver injury in alloxan-induced diabetic mice via regulation of Treg/Th17 balance. Int. Immunopharmacol. 26 (2015), 338–348.
227. O'Brien, P.J., Molecular mechanisms of quinone cytotoxicity. Chem. Biol. Interact. 80 (1991), 1–41.
228. Zhang, X., Zhang, R., Lv, P., Yang, J., Deng, Y., Xu, J., Zhu, R., et al. Emodin up-regulates glucose metabolism, decreases lipolysis, and attenuates inflammation in vitro. J. Diab. 7 (2015), 360–368.
229. Wang, Y.J., Huang, S.L., Feng, Y., Ning, M.M., Leng, Y., Emodin, an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor, regulates adipocyte function in vitro and exerts anti-diabetic effect in ob/ob mice. Acta Pharmacol. Sin. 33 (2012), 1195–1203.
230. Song, P., Kim, J.H., Ghim, J., Yoon, J.H., Lee, A., Kwon, Y., Hyun, H., et al. Emodin regulates glucose utilization by activating AMP-activated protein kinase. J. Biol. Chem. 288 (2013), 5732–5742.
231. Du, H., Shao, J., Gu, P., Lu, B., Ye, X., Liu, Z., Improvement of glucose tolerance by rhein with restored early-phase insulin secretion in db/db mice. J. Endocrinol. Invest. 35 (2012), 607–612.
232. Lin, Y.J., Hu, G., Li, K.J., Zhao, Y.F., Wei, J., Zhen, Y.Z., The protection of Rhein lysinate to liver in diabetic mice induced by high-fat diet and streptozotocin. Arch. Pharm. Res. 38 (2015), 885–892.
233. Lee, M.S., Sohn, C.B., Anti-diabetic properties of chrysophanol and its glucoside from rhubarb rhizome. Biol. Pharm. Bull. 31 (2008), 2154–2157.
234. Bettaieb, A., Hosein, E., Chahed, S., Abdulaziz, A., Kucera, H.R., Gaikwad, N.W., Haj, F.G., Decreased adiposity and enhanced glucose tolerance in shikonin treated mice. Obesity 23 (2015), 2269–2277.
235. Wei, Y., Gao, J., Qin, L., Xu, Y., Wang, D., Shi, H., Xu, T., et al. Tanshinone I alleviates insulin resistance in type 2 diabetes mellitus rats through IRS-1 pathway. Biomed. Pharmacother. 93 (2017), 352–358.
236. Kim, E.J., Jung, S.N., Son, K.H., Kim, S.R., Ha, T.Y., Park, M.G., Jo, I.G., et al. Antidiabetes and antiobesity effect of cryptotanshinone via activation of AMP-activated protein kinase. Mol. Pharmacol. 72 (2007), 62–72.
237. Sunil, C., Duraipandiyan, V., Agastian, P., Ignacimuthu, S., Antidiabetic effect of plumbagin isolated from Plumbago zeylanica L. root and its effect on GLUT4 translocation in streptozotocin-induced diabetic rats. Food Chem. Toxicol. 50 (2012), 4356–4363.
238. Sayed, A.A., Thymoquinone and proanthocyanidin attenuation of diabetic nephropathy in rats. Eur. Rev. Med. Pharmacol. Sci. 16 (2012), 808–815.
239. Zhu, R., Liu, H., Liu, C., Wang, L., Ma, R., Chen, B., Li, L., et al. Cinnamaldehyde in diabetes: a review of pharmacology, pharmacokinetics and safety. Pharmacol. Res. 122 (2017), 78–89.
240. Pucci, G., Alcidi, R., Tap, L., Battista, F., Mattace-Raso, F., Schillaci, G., Sex- and gender-related prevalence, cardiovascular risk and therapeutic approach in metabolic syndrome: a review of the literature. Pharmacol. Res. 120 (2017), 34–42.
241. Mameli, C., Zuccotti, G.V., Carnovale, C., Galli, E., Nannini, P., Cervia, D., Perrotta, C., An update on the assessment and management of metabolic syndrome, a growing medical emergency in paediatric populations. Pharmacol. Res. 119 (2017), 99–117.
242. Campesi, I., Franconi, F., Seghieri, G., Meloni, M., Sex-gender-related therapeutic approaches for cardiovascular complications associated with diabetes. Pharmacol. Res. 119 (2017), 195–207.
243. Yang, H., Zhang, J., Ji, Y., He, Y., Lee, Y., Experimental demonstration of multi-dimensional resources integration for service provisioning in cloud radio over fiber network. Sci. Rep., 6, 2016, 30678.