Planta Medica, Table of Contents

Planta Med 2022; 88(01): 33-42
DOI: 10.1055/a-1385-8015

Biological and Pharmacological Activity

Original Papers

Berberine Ameliorates Glucose Metabolism in Diabetic Rats through the alpha7 Nicotinic Acetylcholine Receptor-Related Cholinergic Anti-Inflammatory Pathway

Dingkun Wang

¹Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

,

Yanlin Ren

²Department of Traditional Chinese Medicine, ZhongShan hospital of Hubei province, Wuhan, Hubei, China

,

Wei Sun

³Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

,

Jing Gong

¹Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

,

Xin Zou

⁴Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

,

Hui Dong

⁴Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

,

Lijun Xu

⁴Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

,

Kaifu Wang

⁴Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

,

Fuer Lu

⁴Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

› Author Affiliations

Abstract

Berberine is an isoquinoline derivative alkaloid extracted from Chinese herbs. Recent studies have demonstrated the therapeutic effect of berberine on glucose metabolic disorders. However, its specific mechanism is still unclear. Our study aimed to research the glucose-lowering effect of berberine in diabetic rats and to reveal the possible role of the cholinergic anti-inflammatory pathway. Diabetic rats induced by administration of a high-calorie diet and streptozocin tail vein injection were assessed by the oral glucose tolerance test. Then, the diabetic rats were divided into two groups, those with or without the alpha7 nicotinic acetylcholine receptor gene downregulated, respectively, followed by treatment including berberine for 6 weeks. Results of this study show that the administration of berberine downregulated levels of fasting blood glucose and fasting insulin, and ameliorated insulin resistance in diabetic rats. Treatment with berberine inhibited acetylcholinesterase activity, and upregulated acetylcholine levels in the serum and alpha7 nicotinic acetylcholine receptor gene expression in the liver tissue. Meanwhile, berberine reversed elevated expression of cytokines interleukin-1β and TNF-α in the serum and downregulated nuclear factor κB expression. However, berberine administration showed no glucose-lowering or anti-inflammatory effect in diabetic rats in which alpha7 nicotinic acetylcholine receptor gene expression was downregulated, and acetylcholinesterase activity was also significantly inhibited. In conclusion, berberine may ameliorate glucose metabolism by activating the alpha7 nicotinic acetylcholine receptor-mediated cholinergic anti-inflammatory pathway.

Key words

Key words

berberine - glucose metabolism - α7nAchR - cholinergic anti-inflammatory pathway - Ranunculaceae - Berberidaceae - Rutaceae

References
1 DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 2004; 88: 787-835
2 Arner P, Rydén M. Fatty acids, obesity and insulin resistance. Obes Facts 2015; 8: 147-155
3 Rieusset J. Contribution of mitochondria and endoplasmic reticulum dysfunction in insulin resistance: Distinct or interrelated roles?. Diabetes Metab 2015; 41: 358-368
4 Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006; 116: 1793-1801
5 Zhang Y, Zhou B, Zhang F, Wu J, Hu Y, Liu Y, Zhai Q. Amyloid-beta induces hepatic insulin resistance by activating JAK2/STAT3/SOCS-1 signaling pathway. Diabetes 2012; 61: 1434-1443
6 Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112: 1821-1830
7 Sykiotis GP, Papavassiliou AG. Serine phosphorylation of insulin receptor substrate-1: a novel target for the reversal of insulin resistance. Mol Endocrinol 2001; 15: 1864-1869
8 McNelis JC, Olefsky JM. Macrophages, immunity, and metabolic disease. Immunity 2014; 41: 36-48
9 Bullo M, Garcia-Lorda P, Megias I, Salas-Salvado J. Systemic inflammation, adipose tissue tumor necrosis factor, and leptin expression. Obes Res 2003; 11: 525-531
10 Bencherif M, Lippiello PM, Lucas R, Marrero MB. Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases. Cell Mol Life Sci 2011; 68: 931-949
11 Borovikova LV, Ivanova S, Nardi D, Zhang M, Yang H, Ombrellino M, Tracey KJ. Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation. Auton Neurosci 2000; 85: 141-147
12 Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003; 421: 384-388
13 Ahren B. Autonomic regulation of islet hormone secretion – implications for health and disease. Diabetologia 2000; 43: 393-410
14 Gilon P, Henquin JC. Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell function. Endocr Rev 2001; 22: 565-604
15 Wang X, Yang Z, Xue B, Shi H. Activation of the cholinergic antiinflammatory pathway ameliorates obesity-induced inflammation and insulin resistance. Endocrinology 2011; 152: 836-846
16 Marrero MB, Lucas R, Salet C, Hauser TA, Mazurov A, Lippiello PM, Bencherif M. An alpha7 nicotinic acetylcholine receptor-selective agonist reduces weight gain and metabolic changes in a mouse model of diabetes. J Pharmacol Exp Ther 2010; 332: 173-180
17 Yao J, Kong W, Jiang J. Learning from berberine: Treating chronic diseases through multiple targets. Sci China Life Sci 2015; 58: 854-859
18 Lan J, Zhao Y, Dong F, Yan Z, Zheng W, Fan J, Sun G. Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. J Ethnopharmacol 2015; 161: 69-81
19 Xia X, Yan J, Shen Y, Tang K, Yin J, Zhang Y, Yang D, Liang H, Ye J, Weng J. Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis. PLoS One 2011; 6: e16556
20 Leng SH, Lu FE, Xu LJ. Therapeutic effects of berberine in impaired glucose tolerance rats and its influence on insulin secretion. Acta Pharmacol Sin 2004; 25: 496-502
21 Li Z, Geng YN, Jiang JD, Kong WJ. Antioxidant and anti-inflammatory activities of berberine in the treatment of diabetes mellitus. Evid Based Complement Alternat Med 2014; 2014: 289264
22 Ma X, Chen Z, Wang L, Wang G, Wang Z, Dong X, Wen B, Zhang Z. The pathogenesis of diabetes mellitus by oxidative stress and inflammation: its inhibition by berberine. Front Pharmacol 2018; 9: 782
23 Pei C, Zhang Y, Wang P, Zhang B, Fang L, Liu B, Meng S. Berberine alleviates oxidized low-density lipoprotein-induced macrophage activation by downregulating galectin-3 via the NF-kappaB and AMPK signaling pathways. Phytother Res 2019; 33: 294-308
24 Zhao C, Wang Y, Yuan X, Sun G, Shen B, Xu F, Fan G, Jin M, Li X, Liu G. Berberine inhibits lipopolysaccharide-induced expression of inflammatory cytokines by suppressing TLR4-mediated NF-kB and MAPK signaling pathways in rumen epithelial cells of Holstein calves. J Dairy Res 2019; 86: 171-176
25 Yao M, Fan X, Yuan B, Takagi N, Liu S, Han X, Ren J, Liu J. Berberine inhibits NLRP3 Inflammasome pathway in human triple-negative breast cancer MDA-MB-231 cell. BMC Complement Altern Med 2019; 19: 216
26 Li F, Zhao YB, Wang DK, Zou X, Fang K, Wang KF. Berberine relieves insulin resistance via the cholinergic anti-inflammatory pathway in HepG2 cells. J Huazhong Univ Sci Technolog Med Sci 2016; 36: 64-69
27 Chandirasegaran G, Elanchezhiyan C, Ghosh K. Effects of Berberine chloride on the liver of streptozotocin-induced diabetes in albino Wistar rats. Biomed Pharmacother 2018; 99: 227-236
28 Fernandez-Cabezudo MJ, George JA, Bashir G, Mohamed YA, Al-Mansori A, Qureshi MM, Lorke DE, Petroianu G, Al-Ramadi BK. Involvement of acetylcholine receptors in cholinergic pathway-mediated protection against autoimmune diabetes. Front Immunol 2019; 10: 1038
29 Gomes JP, Watad A, Shoenfeld Y. Nicotine and autoimmunity: The lotusʼ flower in tobacco. Pharmacol Res 2018; 128: 101-109
30 Saisho Y. Metformin and inflammation: Its potential beyond glucose-lowering effect. Endocr Metab Immune Disord Drug Targets 2015; 15: 196-205
31 Kawashima K, Fujii T. Basic and clinical aspects of non-neuronal acetylcholine: overview of non-neuronal cholinergic systems and their biological significance. J Pharmacol Sci 2008; 106: 167-173
32 George JA, Bashir G, Qureshi MM, Mohamed YA, Azzi J, Al-Ramadi BK, Fernandez-Cabezudo MJ. Cholinergic stimulation prevents the development of autoimmune diabetes: evidence for the modulation of Th17 effector cells via an IFNgamma-Dependent mechanism. Front Immunol 2016; 7: 419
33 Hanes WM, Olofsson PS, Kwan K, Hudson LK, Chavan SS, Pavlov VA, Tracey KJ. Galantamine attenuates type 1 diabetes and inhibits anti-insulin antibodies in nonobese diabetic mice. Mol Med 2015; 21: 702-708
34 Zou X, Huang W, Lu F, Fang K, Wang D, Zhao S, Jia J, Xu L, Wang K, Wang N, Dong H. 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: 165
35 Zheng XX, Chen YW, Yue YS, Li YC, Xia SZ, Li Y, Deng HH, He J, Cao YJ. Icariin ameliorates learning and memory impairments through ERK/CaMKIIα/CREB signaling and HPA axis in prenatally stressed female offspring. Biomed Pharmacother 2019; 117: 109077