Botanical Drug products that can reduce insulin resistance

Many TYPE II diabetic patients have normal levels of insulin in the blood. The diabetes is not caused by the destruction of beta cells in the pancreas but by other mechanisms, such as insulin resistance, related to down-regulation of insulin receptors, defects in insulin secretion from the pancreatic beta cells and other changes to the glucose transporter system. Jin-qi was reported to have the pharmacological effect of restoring sensitivity to insulin and therefore, reducing insulin resistance.[1] Jin-qi's composition comprises extracts from honeysuckle flower, milkvetch root and coptis root. Honeysuckle flower is a vine like shrub that grows to a height of 6-9m, with slender, prickly branches and flowers that bloom white then turn yellow, hence the Chinese name meaning ‘gold and silver flower'. The flower, stem and leaves contain inositol, saponin, and tannin. Honeysuckle flower is routinely used for detoxification and thirst. Coptis root is a perennial herb with long trifoliated leaves, small yellowish white flowers and a reddish brown root covered with fine rootlets. This plant is cultivated throughout China and also in parts of northern India . The root is yellowish orange on the inside, the inner pith being deeper in colour, and contains berberine, alkaloids coptisine, palmatine, jatrorrhizine and magnoflorine, etc. among these ingredients, berberine is the most popular and well-characterized compound with demonstrated antidiabetic effects.[2]

Pharmacological studies with Jin-qi were performed using genetically diabetic KK mine (female, 20-22g) and hydrocortisone (HC) induced diabetic mice.[3] Both groups were insulin-resistant and during the experiment, were given Jin-qi daily, and were injected with insulin at 23 and 9 days, respectively. The blood glucose levels in the Jin-qi group were higher than those in the normal control groups, upon i.p. injection of insulin, but significantly lower than those in diabetic groups which were insulin-resistant. The serum insulin concentration in Jin-qi treated KK mice was 12.1±5.5mU/L in the KK mice control.

A single-blinded, randomized, multicentre clinical investigation of Jin-qi was conducted in 1993 at four major hospitals in Beijing , in which a total of 442 patients with TYPE II diabetes participated. The clinical dosage was 7-10 pills (0.42g/pill) of Jin-qi, per dose, and three doses per day.[4] A different antidiabetic herbal drug was used, at eight pills per dose, and three doses per day, as a control. Combined drug treatment using Jin-qi and chemical hypoglycemic agents was also used to evaluate the synergistic effect of chemical – herbal therapeutic drugs.

Discussion

There are several review articles published in various Chinese journals discussing traditional antidiabetic agents and pharmacological studies in China.[5] [6] [7] Due to the different pharmacological roles of those hydro-alcohol extracts, the hypoglycemic mechanism of drug products containing a mixture of those extracts becomes complicated. The authors speculated that polysaccharide-containing agents restored the functions of pancreatic tissues and caused an increase in insulin output by the functional beta cells. Others attributed the hypoglycemic effect of many products to their ability to inhibit the intestinal absorption of glucose, to the increased availability of insulin, or to the facilitation of metabolites in insulin-dependent processes. However, none of the investigators was able to provide conclusive evidence to ascertain the actual hypoglycemic mechanism(s) of a single herbal drug developed in China.

This paper reviews the compositions, pharmacological and clinical effects of seven antidiabetic herbal drugs commercially available in China . Combination formulas, i.e. mixtures of certain herbal extracts, were used in all the drug products, and each product possessed significant dose-dependent blood glucose lowering activity in various animal models as well as in humans. These alterations will further lead to a decrease in atherosclerosis. The difference between a single-herb formula and a multi-herb combination formula is not merely the addition of more herbs, but also the interaction between the components of mixtures of herbs. A system of synergistic interactions among herbal drugs is formed in a combination formula, which is believed to take a multi-targeted therapeutic approach in the treatment.

The treatment of diabetic patients with naturally derived agents has the advantage that it does not cause the significant side effects as do chemical agents such as sulfonylurea. One of the side effects with sulfonylurea is that it causes a decreased amount of insulin production by putting too great a strain on the insulin producing beta cells. Treatment with herbal drugs has an effect of protecting beta cells and smoothing out fluctuations in glucose levels. Some agents, such as Jin-qi, can reduce the insulin resistance and, hence, improve the apparent insulin activity. Improved insulin activity leads to decreased circulating insulin, which leads to lower blood glucose and glycosylated haemoglobin levels as well as total cholesterol, LDL-cholesterol and triglyceride levels, and increased HDL-cholesterol levels. Additionally, the use of these natural agents in conjunction with conventional drug treatments such as a chemical agent or insulin permits the use of lower doses of the drug and/or decreased frequency of administration which decreases the side effects most commonly observed. It was also widely observed during the clinical studies in China that the mixtures of herbal extracts could lower the cholesterol and triglyceride levels, in addition to the blood glucose level. This suggests that the long-term use of herbal drugs may be advantageous over chemical drugs in alleviating some chronic diseases and complications caused by diabetes, which adverse effects of these herbal extracts are minimal.

Flos Lonicerae

Antioxidants are emerging as prophylactic and therapeutic agents for various diseases. Free radicals are highly reactive molecules or chemical species containing unpaired electrons that can cause oxidative stresses that damage lipids, proteins, enzymes, carbohydrates, and DNA in cell and tissues, and have been known to be associated with pathogenesis of various disorders such as cancer, diabetes, cardiovascular diseases, neurodegenerative disorders, and other diseases. The antioxidant properties of various extracts from Flos Lonicerae, a medically useful traditional Chinese medicine herb, have been investigated. Results demonstrated that the water, methanolic and ethanolic extracts of Flos Lonicerae examined here exhibit antioxidant activity and chlorogenic acid is a major contributor to this activity, which implicates that the Flos Lonicerae extract may serve as potential source of natural antioxidants for treatment of diseases such as diabetes.[8] The plant has also been found to suppress the N-nitrosating reaction, hence inhibiting hepatic glucose-6-phosphatase, which is thought to be a major contributor to type II diabetes.[9] Chlorogenic acid is thought to be the major constituent contributing to the antioxidant activity of the plant.[10]

Rhizome Coptidis

Coptidis Rhizoma was found to improve high blood sugar in patients with type II diabetes and has a role in weight loss.[11] It has been demonstrated that berberine is the major active ingredient of the plant, inhibiting the progression of alloxan-induced diabetes in rats. It is thought this may be associated with its hypoglycemic effect, modulating lipids and metabolic effects and its ability to scavenge free radicals.[12]

The effect of Coptidis Rhizoma-Composed Prescription on serum leptin and adiponectin in type 2 diabetic patients

Tong Xiao-Lin, Lian Feng-Mei, Li Ming, Bai Yu, Yao Chen. Zhong Guo Tang Niao Bing Za Zhi. 2009; (3): 171-173.

Objective To observe the effect of Coptidis Rhizoma-Composed Prescription(CRCP) on serum leptin(Lep) and adiponectin(APN) in overweight or obese type 2 diabetic patients. Methods Multicentre, paralleled, prospective clinical trail recruited 250 cases who were randomly divided into 2 groups (n= 125, each). Treatment group were treated with CRCP and control, with metformin. The levels of HbA1c, FPG, 2hPG, BMI, WC, Lep and APN were compared between the two groups after 12 weeks. Results: The levels of HbA1c, FPG, 2hPG, BMI and WC were significantly reduced after treatment versus baseline in both CRCP group and metformin group (all P<0.05), but were not significantly different between CRCP and metformin treatment groups in both baseline and post-treatment (all P<0.05). In CRCP group Lep declined distinctly compared to the baseline (P<0.05) while APN was not. Conclusions Coptidis Rhizoma Composing Prescription can improve high blood sugar status of type 2 diabetic patients and has some role in losing the weight. The effects are identical to metformin.

Fructus Mume Formula in the Treatment of Type 2 Diabetes Mellitus: A Randomized Controlled Pilot Trial

Tu X, Xie CG, Wang F, Chen Q, Zuo ZH, Zhang Q, Wang XS, Zhong S, Jordan JB. Evidence-Based Complementary and Alternative Medicine, Vol 2013, ID 787459, http://dx.doi.org/10.1155/2013/787459

“Fructus Mume or Dark Plum” (pilule form) has been used for many years in Traditional Chinese Medicine (TCM) and may be a valid treatment for type 2 diabetes mellitus (T2DM). Aim. One aspect toward efficacy validation is the evaluation of the blood glucose-lowering effect of Fructus Mume (FM) with T2DM patients in a randomized controlled trial (RCT).

Methods. This pilot study uses a RCT procedure to assess efficacy of FM and Metformin. The trial was for 12 weeks, with 80 T2DM subjects. Both groups were standardized in their diet and exercise routine. Comparisons of several variables were analyzed.

Results. No significant differences were found between groups in the fasting and postprandial glucose levels although both had significant decreases. The values of glycosylated hemoglobin were significantly reduced in both groups. For patients whose body mass index (BMI) was <23, neither FM nor Metformin had an effect on BMI; for those with a BMI between 23 and 25 or the BMI was >25, both FM and Metformin significantly reduce the BMI.

Conclusions. In this pilot study, it was demonstrated that Fructus Mume formula may reduce the levels of blood glucose in patients with type 2 diabetes.

Introduction

It has been said that some traditional chinese medicinal (TCM) formulae could provide clinical benefits for patients with type 2 diabetes mellitus. The reported benefits include optimal glycemic control, amelioration of clinical manifestations, and preventing or improving macrovascular or microvascular complications.[13]

A TCM formula called “Fructus Mume” (Chinese: “Wumei Wan,” Dark Plum fruit pilule) is used to lower blood glucose levels. It was first recorded in the Treatise on Cold Damage Diseases (Chinese: “Shanghanlun”) which was written by the Sage of TCM-Zhang ZhongJing (circa 200–205 CE).

Two animal experimental studies declared that it has blood glucose-lowering effect by facilitating the recovery of islet-cells, increasing the concentration of hepatic glycogen, accelerating the glycogen synthesis, stimulating-cells to excrete insulin, improving the glucose utility of peripheral tissues, and so forth.[14]

Table 1: Traditional chinese medicinal herbs used in the Fructus Mume formula

PinYin name

Latin name

English name

Original dose

Modification

Wumei

Fructus Mume

Dark plum fruit

300 pieces

30 g

Xixin

Herba Asari

Manchurian wildginger

6 tael

Removed

Ganjiang

Rhizoma Zingiberis

Dried ginger

10 tael

15 g

Huanglian

Rhizoma Coptidis

Golden thread

16 tael

30 g

Danggui

Radix Angelicae Sinensis

Chinese angelica

4 tael

10 g

Fuzi

Rhizoma Typhonii Gigantei

Giant typhonium rhizome

6 tael

20 g

Huajiao

Fructus Zanthoxyli

Prickly ash peel

4 tael

5 g

Guizhi

Ramulus Cinnamomi

Cassia twig

6 tael

10 g

Renshen

Radix Ginseng

Ginseng

6 tael

10 g

Huangbai

Cortex Phellodendri

Amur corktree bark

6 tael

20 g

The present researchers assert that the FM formula (composed of ten herbs; Table 1) has potential in the treatment of diabetes. First, it contains some special herbs, which may be directly effective for diabetes. Among these herbs, coptidis is a herb of bitter flavor and cold property and Dark Plum is of sour flavor. Four-qi and Five flavors represent the main effects of Chinese medicinals and are one of the basic concepts in TCM theory. It is therefore necessary in our research to explain the hypoglycemic effect of FM besides Yin-Yang theory. There is no direct correlation of the use of TCM concept vocabulary such as flavors (sour, bitter, and sweet) with Western scientific concepts, so we are limited in our explanation of these concepts. In TCM theory, bitter flavor is in direct opposition to sweet flavor, and sour flavor can neutralize sweet flavor. So the combination of bitter and sour flavors is an excellent approach to counteract sweet flavor.[15] Secondly, it incorporates many basic TCM principles into a formula by using herbs of various flavor and properties.[16]Both hot and cold properties are also in the FM formula. This reflects the basic concept of Yin-Yang in TCM theory, and we interpret this formula as a typical prescription where herbs of cold or hot property are used together to adjust the balance of Yin-Yang. Generally speaking, it is a formula highly revered by ancient and modern TCM practitioners.

Berberine. Coptidis is one of the most popular herbs for diabetes, as it contains berberine. Numerous studies have demonstrated that berberine could exert beneficial effects on the treatment of diabetes.[17]The potential mechanisms include improving insulin sensitivity, inhibiting gluconeogenesis, stimulating glucose uptake through the AMP-AMPK-p38 MAPK pathway, or correcting lipid disorders.[18][19] [20] Some articles have examined the effects and safety of berberine among patients with type 2 diabetes and suggested that it is effective and safe.

Ginsenosides. A recent article has declared that malonyl ginsenosides (one of the natural ginsenosides of ginseng, another herb used in FM) could alleviate hyperglycemia, hyperlipemia, and insulin resistance of type 2 diabetes.[21] Cho and coworkers reported that ginsenoside Re could lower blood glucose and lipid levels and exerts protective actions against the occurrence of oxidative stress in the eye and kidney of diabetic rats.[22]

Radix Astragali

Radix Astragali has been found to improve impaired endothelial dependent vasodilation in food-induced obese rats, reducing serum triglycerides, total cholesterol and free fatty acid levels. These effects may also induce a positive effect in the treatment of type II diabetes.[23] This was supported by another study, which showed polysaccharides derived from Radix Astragali could improve insulin sensitivity of obesity rats and increase the glucose infusion rate of insulin resistant rats.[24] In conjunction with two other traditional Chinese medicines (Radix Codonopsis and Cortex Lycii) it was shown to have protective effectives on apoptosis in pancreatic β-cells and decrease NO production indicating anti-oxidative and anti-diabetic effects in vitro.[25]

Effects of astragalus polysaccharides on insulin sensitivity in obesity rats fed with high-fat diet

Liang Hui, Wang Tao, Chen Lu-lu. Xi An Jiao Tong Da Xue Xue Bao: Yi Xue Ban. 2009; 30(5): 631-634. 

Objective: To establish obesity model of rats and study the effect of astragalus polysaccharides (APS) on insulin resistance in vivo. Methods: Fifty male Sprague-Dawley rats were randomly divided into two groups: the normal control group (n= 10) and the obesity group (n = 40). Rats in the normal control group were fed with ordinary diet while those in the obesity group were fed with high-fat diet for five weeks. Then the rats in the obesity group were randomly divided into four groups: the model control group, the low-APS group, the medium-APS group and the high-APS group, with 10 rats in each. APS of different dosages [200, 400, or 800 mg/ (kg · d)] or normal saline was intragastrically administered for two weeks. Glucose infusion rate (GIR) of the rats in each group was detected by hyperinsulinemic-englucemic clamp technique (GCT). The levels of plasma glucose, insulin and lipidemia were also measured. Results: The weight of rats increased more obviously in the obesity group than in the normal control group (P<0.05). (2) The levels of plasma total triglyceride (TG), total cholesterol (TC), glucose and insulin of rats were significantly higher in the model control group than in the normal control group (P<0.05). Compared with those in the model control group, the above-mentioned indexes in low-and medium-APS groups were improved significantly (P<0.05). (2) GCT showed that GIR in all the obesity groups decreased compared with that in the normal control group (P<0.05). Compared with that in the model control group, GIR in the medium-APS group increased significantly (P (0.05), but GIR in the low-and high-APS group did not significantly increase (P<0.05). Conclusion: (1) The obesity IR rat model was established after five weeks’ high-fat diet feeding. GCT demonstrates that the IR rat model is successfully established. (2) APS can improve insulin sensitivity of obesity rats and increase GIR of IR rats.

Radix Astragali Improves Impaired Endothelial Dependent Vasodilation in Obese Rat

Deng Gang, Yu Ye-rongza. Si Chuan Da Xue Xue Bao: Yi Xue Ban. 2009; 40(4): 608-611. 

Objective To investigate the effects of Radix Astragali, a traditional Chinese medicine, on endothelium-dependent and non-dependent vasodilation in food-induced obese SD rats. Methods Fifteen male Sprague-Dawley rats were divided into 3 groups: The control group (n-= 5) was fed with normal chow; The obese group (n=5) was fed with high fat chow; The Astragali group (n=5) was fed with high fat chow and Astragali in drinking water. At the end of six weeks, all rats were killed and heart blood samples were taken to assess serum triglyceride, total cholesterol, and free fat acid. The thoracic aortas rings were harvested and equilibrated in Krebs-Henseleit solution. To measure the endothelium-dependent relaxation, the aortas rings were constricted in response to norepinephrine. After a stable contraction plateau was reached, cumulative dose-response for relaxation to Acetylcholine (10^-8-10^-4 mol/L) were obtained in each rings. Identical experiments were conducted with 10^-8-10^-4 mol/L sodium nitroprusside as the endothelium independent vasorelaxting agent. Responses to vasodilators were expressed as percentage relaxation in all preconstricted state. Results: The ratio of celiac fat and body weight in the obese rats was higher than in the controls. The levels of serum triglyceride, total cholesterol, and free fat acid were elevated in the Obese Group compared with the Control Group. The Astragali Group had lower triglyceride and free fat acid levels than the Obese Group. Compared with the rats with high-fat diet, the rats fed with Astragali lost about 32% of celiac fat. Acetylcholine (10^-8-10^-4 mol/L) caused a concentration-dependent relaxation in all preconstricted aortic rings. Compared to the control group, maximal endothelium dependent relaxation in the obese group was impaired (P<0.05). In the Astragali group, the relaxation to acetylcholine was intermediate between control and obese group (P<0.05). Sodium nitroprusside (10^-8-10^-4 mol/L) induced potent relaxation (endothelium independent relaxation) in all rat aortic rings that did not differ statistically between groups. Conclusion Astragalus has salutary effects on impaired endothelial dysfunction in the context of obesity.

Nelumbo nucifera (Ou Jie)

Nelumbo nucifera was found to reduce the effect of nutritional obesity in rats in addition to reducing abdominal fat, and significantly improve insulin resistance.[26] The mechanism of this anti-obesity effect has been demonstrated as being through a concentration-dependent inhibition of digestive enzymes such as α-amylase and lipase and up regulation of lipid metabolism and energy expenditure. It also prevented an increase in body weight, parametrial adipose tissue weight and liver triacylglycerol levels in mice with obesity induced by a high-fat diet.[27] Oral administration of the ethanolic extract of rhizomes of Nelumbo nucifera have been found to markedly reduce the blood sugar levels of normal, glucose-fed hyperglycemic and streptozotocin-induced diabetic rats. The extract also improved glucose tolerance and potentiated the action of exogenously injected insulin in normal rats.[28]

Effect of Nelumbo nucifera rhizome extract on blood sugar level in rats

Pulok K. Mukherjee, Kakali Saha, M. Pal, B.P. Saha. Journal of Ethnopharmacology 58 (1997)207 213

Oral administration of the ethanolic extract of rhizomes of Nelumbo nucifera markedly reduced the blood sugar level of normal, glucose-fed hyperglycemic and streptozotocin-induced diabetic rats, when compared with control animals. The extract improved glucose tolerance and potentiated the action of exogenously injected insulin in normal rats. When compared with tolbutamide, the extract exhibited activity of 73 and 67% of that of tolbutamide in normal and diabetic rats, respectively.

Influence of Ou Zha, Ou Jie and Ou Ya on rat models with nutritional obesity.

Pan Ling, Li Deliang. Zhong Yao Yao Li Yu Lin Chuang. 2004; 20(2): 24-26.

Objective: To evaluate the reducing effect of Ou Zha, Ou Jie and Ou Ya over body weight and fat in adult rats with obesity. Methods: Rat models with nutritional obesity were established and fed with Ou Zha, Ou Jie and Ou Ya, their influences over body weight, amount of abdominal fat, blood insulin and blood fat were observed. Results: compared with the model group, the body weight in the Ou Jie group and Ou Ya group were both decreased obviously, and the amount of abdominal fat tended to decrease. Ou Jie could still prevent the increase of blood insulin in rat models with nutritional obesity, increase its insulin sensitive index. Conclusion: Both Ou Jie and Ou Ya had the effect of preventing nutritional obesity in rats, Ou Jie could still significantly improve insulin resistance.

Momordica charantia

The oral administration of the plant is known to induce hypoglycemic effects in animal models and in human clinical trials. The aqueous extract of the plant has been found to reduce plasma glucose, thiobarbituric acid-reactive substances, lipid-hydroperoxides, alpha-tocopherol and significantly improve ascorbic acid, reduce glutathione and insulin. The treatment also resulted in a significant reduction in thiobarbituric acid reactive substances, lipid-hydroperoxides, superoxide dismutase, catalase, glutathione peroxidase and significant improvement in reduced glutathione in pancreas of drug treated diabetic rats when compared to the untreated diabetic rats. From these results, the plant was found to effectively normalize impaired oxidative stress and hence treat streptozotocin induced-diabetes.[29] In animal models, the alcoholic extract of the pulp of Momordica charantia was found to improve the oral glucose tolerance causing significant (P<0.002) reduction in plasma glucose in streptozotocin diabetes rats. Data from this experiment suggested that the mechanism of action of M. charantia could be partly attributed to increased glucose utilization in the liver rather than an insulin secretion effect.[30]  In humans, the oral administration of the fruit juice of Momordica charantia was found to improve glucose intolerance in 73% of patients treated.[31]

Chromium

Chromium is an essential nutrient involved in normal carbohydrate, lipid metabolism and play a role in glucose intolerance. The chromium requirement is postulated to increase with increased glucose intolerance and diabetes. It was found that supplemental chromium had significant beneficial effects on HbA1c, glucose, insulin, and cholesterol variables in subjects with type 2 diabetes.[32] In another study conducted in China that has been supported by studies in the United States, supplemental chromium as chromium picolinate improved the blood glucose, insulin, cholesterol, and hemoglobin A1C in people with Type 2 diabetes mellitus in a dose dependent manner. The mechanism of action of chromium involves increased insulin binding, increased insulin receptor number, and increased insulin receptor phosphorylation leading to increased insulin sensitivity. Supplemental chromium has been shown to have beneficial effects without any documented side effects on people with varying degrees of glucose intolerance ranging from mild glucose intolerance to overt Type 2 diabetes mellitus.[33]

Diabetes & Chromium

Evidence shows that taking chromium picolinate orally can decrease fasting blood glucose, insulin levels, and glycosylated hemoglobin (HbA1c) and increase insulin sensitivity in people with type 2 diabetes. Some evidence also suggests that chromium picolinate might decrease weight gain and fat accumulation in type 2 diabetes patients who are taking a sulfonylurea.

Higher chromium doses might be more effective and work more quickly. Higher doses might also reduce triglyceride and total serum cholesterol levels in some patients.

Preliminary evidence also suggest that chromium picolinate might have the same benefits in patients with type 1 diabetes and in patients who have diabetes secondary to corticosteroid use.

Some evidence also shows that a specific combination of biotin and chromium might lower blood glucose levels and HbA1C levels in type 2 diabetes patients who are poorly controlled despite treatment with oral hypoglycemic agents. However, there is no reliable evidence that this combination is more effective than taking chromium alone.

Epidemiological research also links lower toenail chromium levels to increased risk of diabetes and cardiovascular disease, but there is no clinical evidence to suggest that chromium supplements can lower disease risk.

But not all evidence is positive. An analysis of pooled results from previous studies found inconclusive results due to the small number of trials, small study size and inconsistent patient population studied. One of the largest studies that found benefit enrolled patients in China where poor nutritional status is more likely, and therefore, benefit from supplementation is also more likely, compared to Western populations. There is speculation that chromium supplements might primarily benefit patients with poor nutritional status or low chromium levels. Chromium levels can be below normal in patients with diabetes.[34]

References

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[3] Shen ZF, Xie MZ, Liu HF. 1997. The influence of Jinqi on blood lipid level, insulin resistance, and immunity in experimental animals. Trad Chin Drug Res Clin Pharm 8: 23–26

[4] Cui WQ. 2000. Clinical observation on the treatment of type II diabetes with Jinqi. Chin Trad Herbal Drugs 31: 18–19

[5] Liu TH, Lu RH. 2000. The mechanisms of TCM for the prevention of diabetes and its complications. J Beijing Univ TCM 23: 69–71.

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[9] Xiang, Z.-n., Zhan, Y., & Ning, Z.-x. (2007). Purification of chlorogenic acid in Flos Lonicerae with system of polar ordered resins. Journal of Central South University of Technology, 14(3), 357-362.

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[11] Tong Xiao-lin, Lian Feng-mei, Li Ming, Bai Yu, Yao Chen. (2009) The effect of Coptidis Rhizoma-Composed Prescription on serum leptin and adiponectin in type 2 diabetic patients. Zhong Guo Tang Niao Bing Za Zhi. (3): 171-173.

[12] Tang, L.-Q., Wei, W., Chen, L.-M., & Liu, S. (2006). Effects of berberine on diabetes induced by alloxan and a high-fat/high-cholesterol diet in rats. Journal of Ethnopharmacology, 108(1), 109-115.

[13] X. L. Tong, L. Dong, L. Chen et al., “Treatment of diabetes using traditional Chinese medicine: past, present and future,” The American Journal of Chinese Medicine, vol. 40, no. 5, pp. 877–886, 2012. 

[14] J. Lu, Y. Li, and L. Z. Wang, “Explorations on the mechanisms behind the blood glucose-lowering effect of Wumei Pill,” Chinese Archives of Traditional Chinese Medicine, vol. 23, no. 5, pp. 292–293, 2005.

[15] B. Chang, Z. Zhen, L. Chen et al., “The application of Chinese herbs of bitter flavor and cold property in obese type 2 diabetes mellitus,” Tianjin Journal of Traditional Chinese Medicine, vol. 26, no. 1, pp. 35–36, 2009.

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[18] Q. Zhang, X. H. Xiao, T. Wang et al., “Mechanism of berberine regulating glucose and lipid metabolism studied with RT PCR array,” Acta Laboratorium Animalis Scientia Sinica, vol. 9, no. 1, pp. 29–33, 2011.

[19] L. Zhou, Y. Yang, X. Wang et al., “Berberine stimulates glucose transport through a mechanism distinct from insulin,” Metabolism, vol. 56, no. 3, pp. 405–412, 2007. 

[20] Z. Cheng, T. Pang, M. Gu et al., “Berberine-stimulated glucose uptake in L6 myotubes involves both AMPK and p38 MAPK,” Biochimica et Biophysica Acta, vol. 1760, no. 11, pp. 1682–1689, 2006.

[21] Z. Liu, W. Li, X. Li et al., “Antidiabetic effects of malonyl ginsenosides from Panax ginseng on type 2 diabetic rats induced by high-fat diet and streptozotocin,” Journal of Ethnopharmacology, vol. 145, no. 1, pp. 233–240, 2013. 

[22] W. C. S. Cho, W. S. Chung, S. K. W. Lee, A. W. N. Leung, C. H. K. Cheng, and K. K. M. Yue, “Ginsenoside Re of Panax ginseng possesses significant antioxidant and antihyperlipidemic efficacies in streptozotocin-induced diabetic rats,” European Journal of Pharmacology, vol. 550, no. 1–3, pp. 173–179, 2006. 

[23] Deng Gang, Yu Ye-rongza. (2009) Radix Astragali Improves Impaired Endothelial Dependent Vasodilation in Obese Rat .Si Chuan Da Xue Xue Bao: Yi Xue Ban. 40(4): 608-611.

[24] Xiao-gang, LIANG Hui, WANG Tao, CHEN Lu-lu. (2009) Effects of astragalus polysaccharides on insulin sensitivity in obesity rats fed with high-fat diet. Xi An Jiao Tong Da Xue Xue Bao: Yi Xue Ban. 30(5): 631-634.

[25] Chan, J. Y.-W., Leung, P.-C., Che, C.-T., & Fung, K.-P. (2008). Protective effects of an herbal formulation of Radix Astragali, Radix Codonopsis and Cortex Lycii on streptozotocin-induced apoptosis in pancreatic β-cells: an implication for its treatment of diabetes mellitus. Phytotherapy Research, 22(2), 190-196.

[26] Pan Ling, Li Deliang. Zhong Yao Yao Li Yu Lin Chuang. (2004) Influence of Ou Zha, Ou Jie and Ou Ya on rat models with nutritional obesity. 20(2): 24-26.

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[28] Mukherjee, P. K., Saha, K., Pal, M., & Saha, B. P. (1997). Effect of Nelumbo nucifera rhizome extract on blood sugar level in rats. Journal of Ethnopharmacology, 58(3), 207-213.

[29] Sathishsekar, D., & Subramanian, S. (2005). Beneficial Effects of Momordica charantia Seeds in the Treatment of STZ-Induced Diabetes in Experimental Rats. Biological & Pharmaceutical Bulletin, 28(6), 978-983.

[30] Sarkar, S., Pranava, M., & Rosalind Marita, A. (1996). DEMONSTRATION OF THE HYPOGLYCEMIC ACTION OF MOMORDICA CHARANTIA IN A VALIDATED ANIMAL MODEL OF DIABETES. Pharmacological Research, 33(1), 1-4.

[31] Welihinda, J., Karunanayake, E. H., Sheriff, M. H. H., & Jayasinghe, K. S. A. (1986). Effect of Momordica charantia on the glucose tolerance in maturity onset diabetes. Journal of Ethnopharmacology, 17(3), 277-282.

[32] Anderson, R. A., Cheng, N., Bryden, N. A., Polansky, M. M., Chi, J., & Feng, J. (1997). Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes, 46(11), 1786-1791.

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[34] NMCD, 2016. http://naturaldatabase.therapeuticresearch.com/nd/PrintVersion.aspx?id=932