Theory exploration of ginseng-jujube-licorice group in the prevention and treatment of type 2 diabetes mellitus

Lian-Xue Zhao ,Ren-Song Yue* ,Yang Bo ,Chang-Sheng Li

1Department of Endocrine,Hospital of Chengdu University of Traditional Chinese Medicine,Chengdu 610075,China.2School of Sports Medicine and Health,Chengdu Sport University,Chengdu 610041,China.

Abstract Diabetes is a chronic disease characterized by hyperglycemia,of which type 2 diabetes mellitus (T2DM) accounts for about 95% [1].In addition,the prevalence of T2DM is still rising,seriously threatening human health.As the mechanism of T2DM is not fully understood,most of the current drugs for the treatment of T2DM focus on lowering blood glucose without solving its underlying problem.This review discusses the application of ginseng-jujube-licorice group in T2DM based on theory of traditional Chinese medicine and research of modern pharmacology,in order to provide a reference for the development of new drugs and future research.

Keywords: ginseng-jujube-licorice group;diabetes;theory exploration

Background

Diabetes mellitus belongs to the category of "Xiaoke" (consumptive thirst) and "Pidan" (spleen disease) in traditional Chinese medicine.The traditional view is that the basic pathogenesis of thirst is Yin deficiency and dryness and heat as the symptoms,and that thirst is divided into "Shangxiao" (upper consumption),"Zhongxiao" (middle consumption) and "Xiaxiao" (lower consumption),with the lung,spleen and kidney as the sites of disease respectively.The key to treatment is to support the spleen,calm the stomach and help the spleen to disperse essence.As one of the classical combinations of ginseng (Panax ginseng),jujube (Ziziphus jujuba) and licorice(Glycyrrhiza uralensis),it plays an important role in the treatment of type 2 diabetes mellitus (T2DM),and its theoretical basis is discussed below.

Exploration of traditional Chinese medical theory

Weakness of the spleen is the initiating factor of thirst

The treatment of thirst from the spleen can be traced in many medical texts.TheLing Shu -Ben Zang(Miraculous Pivot) [1] states that "a brittle spleen is prone to disease and injury," pointing out that a deficient spleen is prone to thirst,and theSu Wen-The Treatise on the Meridians(Plain Questions) [2] describes the physiological functions of the spleen: "Drinking enters the stomach and overflows the essence,which is transferred upwards to the spleen,the spleen disperses the essence and returns upwards to the lungs,the water channels are regulated and transferred downwards to the bladder.Water essence is distributed in all directions,and the five meridians run in parallel."The food digested by the stomach needs to be transformed into water and grain essence by the spleen and transferred to the whole body by its function of dispersing essence.If the spleen is deficient in dispersing essence,the essence of water and grain will be lost in transport and transformed,and will be retained in the blood,resulting in high blood sugar and thirst."If the spleen is not moistened,the gastric qi is thick ...and is the source of abscess thirst." TheLaw of the Medical Doctrine -Continuation of the Treatise on Thirst Elimination[3]mentioned: "It begins in the stomach and ends in the lungs and kidneys." Mr.Zhang Xichen even emphasized in theIntergrating Chinese And Western Medicine[4] that "the evidence of thirst ...is said to all start in the middle jiao and extreme up and down." It is pointed out that the dysfunction of the spleen and stomach in the Zhongjiao is the root cause of the onset of abdominal thirst.

Modern lifestyle habits often predispose to spleen deficiency and the onset of thirst.On the one hand,poor diet is a major risk factor for type 2 diabetes [5].With the improvement in living standards,people often eat more fatty,sweet and greasy things that injure the spleen.In theSu Wen -Treatise on Strange Diseases[2],it is said that "the five tastes are imported and hidden in the stomach,and the spleen carries out its essence for it.TheLing Shu -Five Changes[2] said,"Where the treatment of consumption and disease,fat and noble people are also the disease of anointed sorghum." On the other hand,modern people are often under a lot of pressure and tend to overthink and injure their spleen.The Seventh Volume of the Medical Treatise [6] says,"Thinking leads to qi knotting,knotting in the heart and injuring the spleen as well."

Ginseng-jujube-licorice group (GWZ) in T2DM

As mentioned earlier,in the prevention and treatment of T2DM,strengthening the spleen should be the key.According to Yuan-Yu Huang,"Ginseng is mellow in quality and goes straight to Huangting to nourish the middle Qi" [7]."It enters the foot Yangming stomach and the foot Taiyin spleen meridian.It enters the earth to benefit the stomach Qi and goes to the Hex earth to help the spleen Yang.It is the first to regulate the middle and quench thirst..." [7].Hong-Jing Tao said inMing Yi Bie Lu(The Record of Famous Doctors)[8] that it"regulates the middle and quenches thirst," which shows that ancient literature has already suggested that ginseng can not only strengthen the spleen but also be applied to the treatment of thirst.It has been suggested in ancient literature that ginseng not only strengthens the spleen but also can be used to treat thirst.InBen Cao Qiu Zhen[9],it is said that"jujube is used for the spleen and stomach.It is sweet in taste and warm in temperature,red in colour and moist in the flesh,and is an important remedy for the spleen and stomach";andMing Yi Bie Lu(The Record of Famous Doctors)[8] says,"Jujube nourishes the middle of the body and benefits the Qi,strengthens the will and does not cause hunger when taken for a long time",pointing out that jujube can also suppress the appetite to a certain extent while nourishing the spleen and stomach.In his clinical practice,his mentor,Professor Ren-Song Yue,often used large doses of jujube to treat patients with T2DM and hyperphagia.Ben Cao Yue Yan[10]states that licorice"is a suitable tonic for those with spleen deficiency",andBen Cao Meng Quan[11]states that licorice can"strengthen the spleen and stomach".From the above,it can be seen that ginseng,jujube and licorice all have the effect of tonifying the middle Qi,and the group of the three herbs is found in 11 formulas in theTreatise on Typhoid Miscellaneous Diseases[12,13],which have a good effect of strengthening the spleen and benefiting the Qi;the combination of the three herbs can tonify the spleen-yin of the spleen,generate fluid and stop thirst,and suppress gastric fire,which can target the core pathogenesis of T2DM in Chinese medicine,that is,the weakness of the spleen and the strength of the stomach,and achieve better clinical efficacy.

However,as all three of these medicines are sweet in taste,there are concerns that they may raise blood glucose.In this regard,the tutor,Professor Ren-Song Yue,believes that the rational use of sweet tasting herbs will not raise blood sugar,but can regulate the function of the internal organs of the patient and improve metabolic disorders,based on the theory of "following the appropriate" [14].TheShang Shu -Hong Fan[15] says,"The earth is the source of the harvest ...and the harvest is the source of sweetness...The earth is sweet in nature.The spleen is a part of the earth,so the sweetness enters the spleen,and the sweetness is the first medicine to nourish the spleen.In the experience of medical practitioners in treating thirst since the Qin and Han dynasties,the taste of the medicines they used was all sweet in the first place [16].For example,Wuling San used a large number of sweet-tasting herbs such as Fuling (Poria cocos),Zexie (Alisma orientale),Zhuling (Polyporus umbellatus) and Baizhu (Atractylodes macrocephala) to treat type 2 diabetes combined with obesity [17];Liuwei Dihuang Wan with sweet-tasting herbs such as Shudihuang(Rehmannia glutinosa),Shanyao (Dioscorea opposita),Fuling (Poria cocos)and Zexie(Alisma orientale)was widely used in the treatment of type 2 diabetes[18];Buzhong Yiqi decoction used sweet-tasting herbs such as Huangqi (Astragalus membranaceus),Baizhu (Atractylodes macrocephala) and Renshen (Panax ginseng) to treat diabetes mellitus and diabetic diarrhoea due to weakness of the spleen and stomach[19].In addition,patients with T2DM often have an excessive appetite,and as stated inSu Wen -Treatise on Strange Diseases[2],"sweetness makes the spleen full in the middle," the rational use of sweet-tasting herbs not only strengthens the spleen and helps it,but also regulates appetite,which is of great significance to patients with T2DM.

Modern pharmacological research

Modern pharmacological studies have shown that the components contained in sweet herbs are mainly sugars,saponins,sterols,proteins,amino acids,vitamins and fats,which have the effects of enhancing body immunity,sterilization,lowering blood sugar,lowering blood lipids and lowering blood pressure [20].The ginseng-jujube-licorice group is the basic structure of Banxia Xiexin decoction.Several studies have proved that Banxia Xiexin decoction can lower blood sugar,regulate glucose and lipid metabolism,improve insulin resistance,protect pancreatic islet cells and treat T2DM [21-23].

The main active ingredient in ginseng is saponin,and Wen-Bin Shang et al.[24] showed that ginsenosides can promote the use of glucose by skeletal muscle cells and adipocytes;Lee et al.[25] and Kim et al.[26] demonstrated that ginsenosides can increase the uptake of glucose by skeletal muscle cells and thus lower blood glucose;in addition,it was also shown that ginsenosides can improve the complications of diabetes to some extent.Cho et al.[27] showed that ginsenosides protect the eyes and kidneys during diabetes and speculated that they may reduce diabetic microangiopathy.

The main component of jujube is jujube polysaccharide,which was shown to improve glucose tolerance in normal mice by Roiza Wahav et al.[28];Zhong-Gao Jiao [29] reported that jujube polysaccharide could inhibit α-amylase and α-glucosidase activities and reduce postprandial blood glucose;oxidative stress is an important pathogenic factor in diabetic vasculopathy [30] and Hua-Pei Zhou[31] suggested that jujube peel red pigment could treat diabetic complications due to its antioxidant activity.

Glycyrrhetinic acid and flavonoids in licorice are its main active ingredients in the treatment of diabetes.Studies have shown that glycyrrhetinic acid not only lowers cholesterol and triacylglycerol,but also lowers fasting blood glucose and insulin levels and reduces insulin resistance [32,33].Jin-Jing Zhao et al.[34] reported that licorice flavonoids could reduce blood glucose,urine glucose and glycated haemoglobin levels,and also improve the body's sensitivity to insulin.

Our team found that the connotation of GWZ"supporting the spleen and suppressing the stomach" may be mainly related to the bidirectional regulation of cyclic adenosine monophosphate (cAMP)content in the secretory cells of gastrointestinal tissues,thus increasing the intestinal appetite suppressants glucagon-like peptide-1(GLP-1) and peptide YY (supporting the spleen) and decreasing the gastric appetite stimulants such as Ghrelin (suppressing the stomach).

Problems and prospects

In recent years,GLP-1 agonists,sodium-dependent glucose transporters 2 inhibitors and other new drugs that can suppress appetite and reduce glucose reabsorption have become hot spots in the clinical treatment of T2DM.Appetite suppression is of great importance in the prevention and treatment of modern diabetes and is also a trend in the future treatment of T2DM,so the development of a safe appetite suppressant is of great significance for the prevention and treatment of T2DM.Chinese medicine has the characteristics of multi-targeting,low side effects and high efficacy,and the ginseng-jujube-licorice group is feasible for the treatment of diabetes from both Chinese medical theory and modern pharmacological studies.However,there are few studies on this drug pair,its mechanism of action is still unclear,and further experimental validation is lacking to provide new ideas and methods for the prevention and treatment of diabetes and the development of new drugs.