Search JIM Advanced Search

Journal of Integrative Medicine ›› 2014, Vol. 12 ›› Issue (1): 1-6.doi: 10.1016/S2095-4964(14)60008-X

Special Issue: Traditional Chinese Medicine

• Review •     Next Articles

The role of central nervous system on hypoglycemia and the feasibility of the brain theory in traditional Chinese medicine on treatment of diabetes mellitus

Hai-li Jianga,b,c, Jing-jing Niua,b,c, Wei-fei Zhangb,c,d, Wen-jin Huanga,c, Ming-yue Zhoub,c,e, Wen-jun Shab,c, Jun-yan Lib,c, Fu-feng Lid, Zhu Tingf, Xin Xiag, Jun Zhangh, Yuan-dong Shenb,c, Li-gang Zhoua,b,c   

  1. Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
    Department of Endocrinology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
    c Diabetes Research Center, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
    d Basic Medical Department, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
    Biology and Biological Science Program, University of California, Santa Barbara, California 93106, USA
    f Department of Gerontology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
    Department of Endocrinology, Shanghai East Hospital, Shanghai 200120, China
    h. Department of Police Training, Shanghai Police College, Shanghai 200137, China
  • Received:2013-10-20 Accepted:2013-12-09 Online:2014-01-10 Published:2014-01-15

The central nervous system (CNS) plays a key regulatory role in glucose homeostasis. In particular, the brain is important in initiating and coordinating protective counterregulatory responses when blood glucose levels fall. This may due to the metabolic dependency of the CNS on glucose, and protection of food supply to the brain. In healthy subjects, blood glucose is normally maintained within a relatively narrow range. Hypoglycemia in diabetic patients can increase the risk of complications, such as heart disease and diabetic peripheral neuropathy. The clinical research finds that the use of traditional Chinese medicine (TCM) has a positive effect on the treatment of hypoglycemia. Here the authors reviewed the current understanding of sensing and counterregulatory responses to hypoglycemia, and discuss combining traditional Chinese and Western medicine and the theory of iatrogenic hypoglycemia in diabetes treatment. Furthermore, the authors clarify the feasibility of treating hypoglycemia on the basis of TCM theory and CNS and have an insight on its clinical practice.

Key words: Diabetes mellitus, Hypoglycemia, Counterrugulation hormone response, Neuroendocrine systems, Hypothalamus, Brain, Review

Figure 1

The proposed mechanism of counterregulatory hormone response to hypoglycemia Decreases in plasma glucose can initiate 1) reduced insulin secretion and increased glucagon secretion, 2) release of epinephrine (E) and norepinephrine (NE) via activation of the hypothalamus-pituitary-adrenal axis, and 3) neuron activation in the hypothalamus, modulating intra-pancreatic hormone responses and hepatic glucose production via sympathetic nervous system in the spinal cord (adapted from Zhou et al 2007[11])."

[1] Zhou H, Zhang T, Harmon JS, Bryan J, Robertson RP . Zinc, not insulin, regulates the rat alpha-cell response to hypoglycemia in vivo[J]. Diabetes, 2007,56(4):1107-1112
doi: 10.2337/db06-1454
[2] Xu E, Kumar M, Zhang Y, Ju W, Obata T, Zhang N, Liu S, Wendt A, Deng S, Ebina Y, Wheeler MB, Braun M, Wang Q . Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system[J]. Cell Metab, 2006,3(1):47-58
doi: 10.1016/j.cmet.2005.11.015 pmid: 16399504
[3] Cejvan K, Coy DH, Efendic S . Intra-islet somatostatin regulates glucagon release via type 2 somatostatin receptors in rats[J]. Diabetes, 2003,52(5):1176-1181
doi: 10.2337/diabetes.52.5.1176 pmid: 12716749
[4] Chan O, Chan S, Inouye K, Shum K, Matthews SG, Vranic M . Diabetes impairs hypothalamo-pituitary-adrenal(HPA) responses to hypoglycemia, and insulin treatment normalizes HPA but not epinephrine responses[J]. Diabetes, 2002,51(6):1681-1689
doi: 10.2337/diabetes.51.6.1681
[5] Chan O, Inouye K, Riddell MC, Vranic M, Matthews SG . Diabetes and the hypothalamo-pituitary-adrenal(HPA) axis[J]. Minerva Endocrinol, 2003,28(2):87-102
pmid: 12717340
[6] Taborsky GJ Jr., Mundinger TO . Minireview: The role of the autonomic nervous system in mediating the glucagon response to hypoglycemia[J]. Endocrinology, 2012,153(3):1055-1062
doi: 10.1210/en.2011-2040
[7] Thorens B . Brain glucose sensing and neural regulation of insulin and glucagon secretion[J]. Diabetes Obes Metab, 2011,13(Suppl 1):82-88
doi: 10.1111/j.1463-1326.2011.01453.x pmid: 21824260
[8] Zhou L, Podolsky N, Sang Z, Ding Y, Fan X, Tong Q, Levin BE , McCrimmon RJ.The medial amygdalar nucleus: a novel glucose-sensing region that modulates the counterregulatory response to hypoglycemia[J]. Diabetes, 2010,59(10):2646-2652
doi: 10.2337/db09-0995
[9] Zhou L, Williams T, Lachey JL, Kishi T, Cowley MA, Heisler LK . Serotonergic pathways converge upon central melanocortin systems to regulate energy balance[J]. Peptides, 2005,26(10):1728-1732
doi: 10.1016/j.peptides.2004.12.028 pmid: 15993514
[10] Zhou L, Yueh CY, Lam DD, Shaw J, Osundiji M, Garfield AS, Evans M, Heisler LK . Glucokinase inhibitor glucosamine stimulates feeding and activates hypothalamic neuropeptide Y and orexin neurons[J]. Behav Brain Res, 2011,222(1):274-278
doi: 10.1016/j.bbr.2011.03.043
[11] Zhou L, Sutton GM, Rochford JJ, Semple RK, Lam DD, Oksanen LJ, Thornton-Jones ZD, Clifton PG, Yueh CY, Evans ML , McCrimmon RJ, Elmquist JK, Butler AA, Heisler LK .Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways[J]. Cell Metab, 2007,6(5):398-405
doi: 10.1016/j.cmet.2007.10.008
[12] Cersosimo E, Zaitseva IN, Ajmal M . Effects of beta-adrenergic blockade on hepatic and renal glucose production during hypoglycemia in conscious dogs[J]. Am J Physiol, 1998,275(5 Pt 1):E792-E797
[13] Stumvoll M, Meyer C, Kreider M, Perriello G, Gerich J . Effects of glucagon on renal and hepatic glutamine gluconeogenesis in normal postabsorptive humans[J]. Metabolism, 1998,47(10):1227-1232
doi: 10.1016/S0026-0495(98)90328-6
[14] Stumvoll M . The human kidney as an important producer of glucose[J]. Med Klin (Munich), 1998,93(5):300-306
doi: 10.1007/BF03044865
[15] Aizawa T, Yasuda N, Greer MA . Hypoglycemia stimulates ACTH secretion through a direct effect on the basal hypothalamus[J]. Metabolism, 1981,30(10):996-1000
doi: 10.1016/0026-0495(81)90100-1 pmid: 6268929
[16] Niimi M, Sato M, Tamaki M, Wada Y, Takahara J, Kawanishi K . Induction of Fos protein in the rat hypothalamus elicited by insulin-induced hypoglycemia[J]. Neurosci Res, 1995,23(4):361-364
doi: 10.1016/0168-0102(95)00965-V pmid: 8602275
[17] Suda T, Tozawa F, Yamada M, Ushiyama T, Tomori N, Sumitomo T, Nakagami Y, Demura H, Shizume K . Insulin-induced hypoglycemia increases corticotropin-releasing factor messenger ribonucleic acid levels in rat hypothalamus[J]. Endocrinology, 1988,123(3):1371-1375
doi: 10.1210/endo-123-3-1371
[18] De Feo P, Perriello G, Ventura MM, Brunetti P, Santeusanio F, Gerich JE, Bolli GB . The pancreatic-adrenocortical-pituitary clamp technique for study of counterregulation in humans[J]. Am J Physiol, 1987,252(4 Pt 1):E565-E570
[19] Vance ML, Kaiser DL, Rivier J, Vale W, Thorner MO . Dual effects of growth hormone(GH)-releasing hormone infusion in normal men: somatotroph desensitization and increase in releasable GH[J]. J Clin Endocrinol Metab, 1986,62(3):591-594
doi: 10.1210/jcem-62-3-591
[20] Brobeck JR . Hypothalamus, appetite, and obesity[J]. Physiol Pharmacol Physicians, 1963,18:1-6
[21] Muhlhausler BS , McMillen IC, Rouzaud G, Findlay PA, Marrocco EM, Rhind SM, Adam CL .Appetite regulatory neuropeptides are expressed in the sheep hypothalamus before birth[J]. J Neuroendocrinol, 2004,16(6):502-507
doi: 10.1111/j.1365-2826.2004.01197.x
[22] Stagner JI, Samols E . Retrograde perfusion as a model for testing the relative effects of glucose versus insulin on the A cell[J]. J Clin Invest, 1986,77(3):1034-1037
doi: 10.1172/JCI112356
[23] Jackson PA, Cardin S, Coffey CS, Neal DW, Allen EJ, Penaloza AR, Snead WL, Cherrington AD . Effect of hepatic denervation on the counterregulatory response to insulin-induced hypoglycemia in the dog[J]. Am J Physiol Endocrinol Metab, 2000,279(6):E1249-E1257
doi: 10.1152/ajpendo.2000.279.6.E1249
[24] Stumpel F, Jungermann K . Sensing by intrahepatic muscarinic nerves of a portal-arterial glucose concentration gradient as a signal for insulin-dependent glucose uptake in the perfused rat liver[J]. FEBS Lett, 1997,406(1-2):119-122
doi: 10.1016/S0014-5793(97)00254-8
[25] Hertelendy ZI, Patel DG, Skau KA . Progressive and concurrent deterioration of vagus-stimulated and hypoglycemia-induced glucagon secretion in streptozotocin-diabetic rats[J]. Acta Endocrinol (Copenh), 1992,126(1):80-84
doi: 10.1530/acta.0.1260080
[26] Perseghin G, Regalia E, Battezzati A, Vergani S, Pulvirenti A, Terruzzi I, Baratti D, Bozzetti F, Mazzaferro V, Luzi L . Regulation of glucose homeostasis in humans with denervated livers[J]. J Clin Invest, 1997,100(4):931-941
doi: 10.1172/JCI119609 pmid: 9259593
[27] Heptulla RA, Tamborlane WV, Ma TY, Rife F, Sherwin RS . Oral glucose augments the counterregulatory hormone response during insulin-induced hypoglycemia in humans[J]. J Clin Endocrinol Metab, 2001,86(2):645-648
[28] Borg MA, Sherwin RS, Borg WP, Tamborlane WV, Shulman GI . Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats[J]. J Clin Invest, 1997,99(2):361-365
doi: 10.1172/JCI119165
[29] Borg WP, During MJ, Sherwin RS, Borg MA, Brines ML, Shulman GI . Ventromedial hypothalamic lesions in rats suppress counterregulatory responses to hypoglycemia[J]. J Clin Invest, 1994,93(4):1677-1682
doi: 10.1172/JCI117150 pmid: 294214
[30] Levin BE, Becker TC, Eiki J, Zhang BB, Dunn-Meynell AA . Ventromedial hypothalamic glucokinase is an important mediator of the counterregulatory response to insulin-induced hypoglycemia[J]. Diabetes, 2008,57(5):1371-1379
doi: 10.2337/db07-1755
[31] Kang L, Sanders NM, Dunn-Meynell AA, Gaspers LD, Routh VH, Thomas AP, Levin BE . Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons[J]. Am J Physiol Regul Integr Comp Physiol, 2008,294(3):R784-R792
doi: 10.1152/ajpregu.00645.2007
[32] McCrimmon RJ, Evans ML, Fan X, McNay EC, Chan O, Ding Y, Zhu W, Gram DX, Sherwin RS . Activation of ATP-sensitive K+ channels in the ventromedial hypothalamus amplifies counterregulatory hormone responses to hypoglycemia in normal and recurrently hypoglycemic rats[J]. Diabetes, 2005,54(11):3169-3174
doi: 10.2337/diabetes.54.11.3169
[33] He B, White BD, Edwards GL, Martin RJ . Longer-term fourth ventricular 5-thioglucose infusion increases body fat in the rat[J]. Proc Soc Exp Biol Med, 1998,217(2):168-172
doi: 10.3181/00379727-217-44219 pmid: 9452140
[34] Jacob RJ, Dziura J, Blumberg M, Morgen JP, Sherwin RS . Effects of recurrent hypoglycemia on brainstem function in diabetic BB rats: protective adaptation during acute hypoglycemia[J]. Diabetes, 1999,48(1):141-145
doi: 10.2337/diabetes.48.1.141
[35] Kern W, Born J, Kerner W, Fehm HL . Different effects of human and porcine insulin on hypoglycemia-induced abnormalities of brainstem sensory function[J]. Clin Physiol Biochem, 1990,8(3):122-127
[36] Rekate HL, Nadkarni TD, Teaford PA, Wallace D . Brainstem dysfunction in chiari malformation presenting as profound hypoglycemia: presentation of four cases, review of the literature, and conjecture as to mechanism[J]. Neurosurgery, 1999,45(2):386-391
doi: 10.1097/00006123-199908000-00040
[37] Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J . Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans[J]. Diabetes, 1994,43(11):1311-1317
doi: 10.2337/diab.43.11.1311
[38] Silver IA, Erecinska M . Glucose-induced intracellular ion changes in sugar-sensitive hypothalamic neurons[J]. J Neurophysiol, 1998,79(4):1733-1745
doi: 10.1007/s002329900363 pmid: 9535943
[39] Popp DA, Shah SD, Cryer PE . Role of epinephrine-mediated beta-adrenergic mechanisms in hypoglycemic glucose counterregulation and posthypoglycemic hyperglycemia in insulin-dependent diabetes mellitus[J]. J Clin Invest, 1982,69(2):315-326
doi: 10.1172/JCI110455
[40] Powell AM, Sherwin RS, Shulman GI . Impaired hormonal responses to hypoglycemia in spontaneously diabetic and recurrently hypoglycemic rats. Reversibility and stimulus specificity of the deficits[J]. J Clin Invest, 1993,92(6):2667-2674
doi: 10.1172/JCI116883
[41] Gupta V, Wahoff DC, Rooney DP, Poitout V, Sutherland DE, Kendall DM, Robertson RP . The defective glucagon response from transplanted intrahepatic pancreatic islets during hypoglycemia is transplantation site-determined[J]. Diabetes, 1997,46(1):28-33
doi: 10.2337/diab.46.1.28
[42] Hamaguchi T, Fukushima H, Uehara M, Wada S, Shirotani T, Kishikawa H, Ichinose K, Yamaguchi K, Shichiri M . Abnormal glucagon response to arginine and its normalization in obese hyperinsulinaemic patients with glucose intolerance: importance of insulin action on pancreatic alpha cells[J]. Diabetologia, 1991,34(11):801-806
doi: 10.1007/BF00408354
[43] Hsieh SD, Iwamoto Y, Matsuda A, Kuzuya T . Pancreatic B-cell function in non-insulin-dependent diabetes mellitus during successive periods of sulfonylurea and insulin treatment: serum C-peptide response to glucagon and urine C-peptide excretion[J]. Endocrinol Jpn, 1987,34(4):561-567
doi: 10.1507/endocrj1954.34.561
[44] Otonkoski T, Hayek A . Constitution of a biphasic insulin response to glucose in human fetal pancreatic beta-cells with glucagon-like peptide 1[J]. J Clin Endocrinol Metab, 1995,80(12):3779-3783
doi: 10.1210/jcem.80.12.8530635
[45] Cryer PE . Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus[J]. Adv Pharmacol, 1998,42:620-622
[46] Cryer PE . Hypoglycemia-associated autonomic failure in diabetes[J]. Am J Physiol Endocrinol Metab, 2001,281(6):E1115-E1121
doi: 10.1152/ajpendo.2001.281.6.E1115
[47] Cryer PE . Hypoglycemia-associated autonomic failure in diabetes[J]. Handb Clin Neurol, 2013,117:295-307
doi: 10.1016/B978-0-444-53491-0.00023-7
[48] Cryer PE . Mechanisms of hypoglycemia-associated autonomic failure in diabetes[J]. N Engl J Med, 2013,369(4):362-372
doi: 10.1056/NEJMra1215228
[49] Sang Z, Zhou L, Fan X , McCrimmon RJ.Radix astragali(huangqi) as a treatment for defective hypoglycemia counterregulation in diabetes[J]. Am J Chin Med, 2010,38(6):1027-1038
doi: 10.1142/S0192415X10008445
[1] Louisa Sylvia, Emerson West, Allyson M. Blackburn, Carina Gupta, Eric Bui, Tara Mahoney, Geraldine Duncan, Edward C. Wright, Simon Lejeune, Thomas J. Spencer. Acceptability of an adjunct equine-assisted activities and therapies program for veterans with posttraumatic stress disorder and/or traumatic brain injury. Journal of Integrative Medicine, 2020, 18(2): 169-173.
[2] Dona Nirmani Ann Wijewickrama Samarakoon, Deepthi Inoka Uluwaduge, Malith Aravinda Siriwardhene. Mechanisms of action of Sri Lankan herbal medicines used in the treatment of diabetes: A review. Journal of Integrative Medicine, 2020, 18(1): 13-20.
[3] Mohadeseh Ostovar, Abolfazl Akbari, Mohammad Hossein Anbardar, Aida Iraji, Mohsen Salmanpour, Salar Hafez Ghoran, Mojtaba Heydari, Mesbah Shams. Effects of Citrullus colocynthis L. in a rat model of diabetic neuropathy. Journal of Integrative Medicine, 2020, 18(1): 59-67.
[4] Lena Grönblom Lundström, Ulrika Aasa, Yan Zhang, Tobias Sundberg. Health care in light of different theories of health—A proposed framework for integrating a social humanistic perspective into health care. Journal of Integrative Medicine, 2019, 17(5): 321-327.
[5] Jia Xu, Fu-qing Zhang, Jian Pei, Jun Ji . Acupuncture for migraine without aura: A systematic review and meta-analysis. Journal of Integrative Medicine, 2018, 16(5): 312-321.
[6] Olakunle Bamikole Afolabi, Omotade Ibidun Oloyede, Shadrack Oludare Agunbiade. Inhibitory potentials of phenolic-rich extracts from Bridelia ferruginea on two key carbohydrate-metabolizing enzymes and Fe2+-induced pancreatic oxidative stress. Journal of Integrative Medicine, 2018, 16(3): 192-198.
[7] Wen-jie Xu, Ling-tai Wang, Zhi-ping Zhao, Li-ming Zhu, Liang-hua Zu, Qi Zhang, Dan-bo Dou. Prospects of a comprehensive evaluation system for traditional Chinese medicine services. Journal of Integrative Medicine, 2017, 15(6): 426-432.
[8] Chun-song Hu, Tengiz Tkebuchava. SEEDi1.0-3.0 strategies for major noncommunicable diseases in China. Journal of Integrative Medicine, 2017, 15(4): 265-269.
[9] Uduak Akpan Okon, Idorenyin Udo Umoren. Comparison of antioxidant activity of insulin, Ocimum gratissimum L., and Vernonia amygdalina L. in type 1 diabetic rat model. Journal of Integrative Medicine, 2017, 15(4): 302-309.
[10] Naseem Akhtar Qureshi, Gazzaffi Ibrahim Ali, Tamer Shaban Abushanab, Ahmed Tawfik El-Olemy, Meshari Saleh Alqaed, Ibrahim S. El-Subai, Abdullah M.N. Al-Bedah. History of cupping (Hijama): A narrative review of literature. Journal of Integrative Medicine, 2017, 15(3): 172-181.
[11] Nazli Samadi, Hassan Mozaffari-Khosravi, Masoud Rahmanian, Mohsen Askarishahi. Effects of bee propolis supplementation on glycemic control, lipid profile and insulin resistance indices in patients with type 2 diabetes: A randomized, double-blind clinical trial. Journal of Integrative Medicine, 2017, 15(2): 124-134.
[12] Tom Fleischer, Tung-Ti Chang, Hung-Rong Yen. Post-hematopoietic stem cell transplantation in patients with hematologic disorders: Chinese herbal medicine for an unmet need. Journal of Integrative Medicine, 2016, 14(5): 322-335.
[13] Yee Chi Peggy Wong. Need of integrated dietary therapy for persons with diabetes mellitus and “unhealthy” body constitution presentations. Journal of Integrative Medicine, 2016, 14(4): 255-268.
[14] Eric Wei Chiang Chan, Siu Kuin Wong, Hung Tuck Chan. Apocynaceae species with antiproliferative and/or antiplasmodial properties: A review of ten genera. Journal of Integrative Medicine, 2016, 14(4): 269-284.
[15] Ausanee Wanchai, Duangjai Phrompayak. Use of complementary and alternative medicine among Thai patients with type 2 diabetes mellitus. Journal of Integrative Medicine, 2016, 14(4): 297-305.
Full text



[1] Wei-xiong Liang. Problems-solving strategies in clinical treatment guideline for traditional Chinese medicine and integrative medicine. Journal of Chinese Integrative Medicine, 2008, 6(1): 1-4
[2] Jun Hu, Jian-ping Liu. Non-invasive physical treatments for chronic/recurrent headache. Journal of Chinese Integrative Medicine, 2008, 6(1): 31
[3] Jun Cai, Hua Wang, Sheng Zhou, Bin Wu, Hua-rong Song, Zheng-rong Xuan. Effect of Sijunzi Decoction and enteral nutrition on T-cell subsets and nutritional status in patients with gastric cancer after operation: A randomized controlled trial. Journal of Chinese Integrative Medicine, 2008, 6(1): 37-40
[4] Wei Zhang, Xiang-feng Lu, Xiao-mei Zhang, Jian-jun Wu, Liang-duo Jiang. A rat model of pulmonary fibrosis induced by infusing bleomycin quickly through tracheal intubation. Journal of Chinese Integrative Medicine, 2008, 6(1): 60-67
[5] Li Zhou, Hong-xing Zhang, Ling-guang Liu, Wen-jun Wan. Effect of electro-acupuncture at Fenglong (GV 16) on nitric oxide and endothelin in rats with hyperlipidemia. Journal of Chinese Integrative Medicine, 2008, 6(1): 89-92
[6] Ning-qun Wang, Liang-duo Jiang, Zong-xing Li. Research progress in asthma-related quality of life. Journal of Chinese Integrative Medicine, 2008, 6(1): 93-97
[7] Daniel Weber, Janelle M Wheat, Geoffrey M Currie. Inflammation and cancer: Tumor initiation, progression and metastasis,and Chinese botanical medicines. Journal of Chinese Integrative Medicine, 2010, 8(11): 1006-1013
[8] Bo Wang , Wei Yan , Li-hui Hou, Xiao-ke Wu. Disorder of Tiangui (kidney essence) and reproductive dysfunction in patients with polycystic ovary syndrome. Journal of Chinese Integrative Medicine, 2010, 8(11): 1018-1022
[9] Ya-bing Zhou, Jian-er Yu, Jie Wu, Li Bai, Li-li Huo, Xin-guang Zhang, Li-qing Li . Effects of Chinese herbal medicine Bushen Gubiao Recipe on toll-like receptor 4 and CD4 +CD25 +foxp3 +regulatory T cells in mice with recurrent respiratory tract infections. Journal of Chinese Integrative Medicine, 2010, 8(11): 1053-1059
[10] Jing-yuan Mao, Chang-xiao Liu, Heng-he Wang, Guang-li Wei , Zhen-peng Zhang, Jie Xing, Wang Xian liang , Ying-fei Bi . Effects of Shenmai Injection on serum concentration and pharmacokinetics of digoxin in dogs with heart failure. Journal of Chinese Integrative Medicine, 2010, 8(11): 1070-1074