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A clinical study of the anti-diabetic effect of a simple Chinese herbal formula, PSP-1
G Model EUJIM 513 No. of Pages 7
European Journal of Integrative Medicine xxx (2015) xxx–xxx
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Research paper
A clinical study of the anti-diabetic effect of a simple Chinese herbal formula, PSP-1 S.H. Chuia,b,* , Y.H. Wongb , M.Y. Fongb , F.C. Chowc , Y.M. Chiub , C.W.K Lama a State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology Foundation, Taipa, Macau, China b Clinical Laboratory, Diagnostix Medical Centre, Central, Hong Kong, China c Modern TCM Ltd., Hong Kong, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 22 June 2015 Received in revised form 23 February 2016 Accepted 23 February 2016 Available online xxx
Introduction: A two armed clinical before and after study was conducted to investigate the efficacy of a proprietary Chinese herbal formula, PSP-1, to improve glycemic control in type 2 diabetic patients and pre-diabetic subjects over a 3 month period. Methods: Sixty-two subjects were recruited and divided into a Diabetic Group (DG) and a Pre-diabetic Group (PG). All subjects were prescribed PSP-1 or placebo and followed-up for 3 months. Blood and spot urine samples were collected at baseline, 1st month and 3rd month for each subject for laboratory tests. Results: For the DG group, PSP-1 subjects showed significant decrease in blood HbA1c level between baseline and 3 months post PSP-1 (p < 0.005), but there was no significant change in fasting plasma glucose concentration. PSP-1 subjects in the PG group showed a significant decrease in both fasting glucose (p < 0.05) and HbA1c (p = 0.001) after 3-months’ treatment. Combining PG and DG groups, a significant decrease in HbA1c was observed for PSP subjects between baseline and 3 months post PSP. Comparison with those on placebo demonstrated no significant changes in either HbA1c level or glucose concentrations. Conclusions: It appeared that 3 months supplementation of PSP-1 formulation was able to reduce blood glucose concentrations in pre-diabetic subjects and lowered blood HbA1c levels for both pre-diabetic and diabetic subjects. ã 2016 Elsevier GmbH. All rights reserved.
Keywords: Diabetes Pre-diabetes Fasting glucose HbA1c Chinese medicine
1. Introduction Diabetes mellitus (DM) is one of the most common noncommunicable diseases in many countries, and type 2 DM (also known as non insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes) accounts for 90–95% of diabetic patients [1]. More than 382 million people in the world suffered from diabetes in 2013 (global prevalence rate of 8.3%) and prevalence has been increasing, particularly of type 2 DM [2]. It is estimated that the number of diabetic patients will rise to 592 million by 2035. In 2011, diabetes was the seventh leading cause of death in the United States with 5.1 million fatalities [3]. Although the severity of type 2 DM can be partially controlled with exercises and diet, medications and monitoring of blood and urine glucose concentrations for improved glycemic control are
* Corresponding author at: 612 Melbourne Plaza, 33 Queen’s Road Central, Hong Kong, China. E-mail address: [email protected] (S.H. Chui).
also important for preventing or slowing down the development of diabetic complications such as chronic renal failure and coronary artery disease [4–8]. Western medicines have been commonly used for controlling blood glucose concentration [9–11]. With fewer side effects and at lower costs, Chinese medicines can be a good alternative to replace or supplement western medications [8,12–14]. According to its clinical manifestation, diabetes mellitus is categorized in traditional Chinese medicine (TCM) as “Xiao Ke”, meaning wasting and thirsting disorder [15]. Depending on the TCM pattern, “Xiao Ke” is classified into three levels that are closely associated with the lungs, stomach and kidneys. The upper level is characterized by the prominence of excessive thirst and a dry mouth. The therapeutic principle is to quench the thirst and relieve dryness as well as nourishing yin and clear away heat. The middle level is characterized by the prominence of excessive hunger, and treatment aims at clearing stomach and purging heat as well as nourishing yin and promoting production of fluid. The lower level is dominated by excessive urination and lumbar pain. The therapeutic rule is to nourish yin and invigorate the kidneys [15–17]. Many Chinese herbal formulas such as the Jin Qi Jiang Tang
http://dx.doi.org/10.1016/j.eujim.2016.02.009 1876-3820/ ã 2016 Elsevier GmbH. All rights reserved.
Please cite this article in press as: S.H. Chui, et al., A clinical study of the anti-diabetic effect of a simple Chinese herbal formula, PSP-1, Eur. J. Integr. Med. (2016), http://dx.doi.org/10.1016/j.eujim.2016.02.009
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Pian and San Huang Jiang Tang decoctions have been developed and are used in the treatment of diabetes in China [15,17,18]. Paederia scandens is the leaves and stems of P. scandens (Lour.) Merrill which is a plant of rubiaceae. It has a sweet and sour flavor and is neutral in property. It has been known to promote blood circulation to relieve pain, clear away heat and toxins, invigorate the spleen and resolve dampness [19]. P. scandens extract has been shown to exert a hypoglycemic effect on diabetic mice [19]. However, no study has been conducted to investigate the antidiabetic effect of P. scandens in humans and its use as an ingredient in anti-diabetic Chinese medicine. This clinical study was conducted to investigate the efficacy of a proprietary simple Chinese herbal formula, PSP-1, with P. scandens as its principal ingredient for treating type 2 DM for improvement of glycemic control and other diabetes-associated parameters, based on clinical and laboratory assessments over a period of 3 months. In this study, blood glycosylated haemoglobin A1c (HbA1c) level was used to monitor recent changes in plasma glucose concentration of the participants. The principle of this test is based on the fact that glucose is attached to haemoglobin of red blood cells which live for about 3 months. In normal subjects, 3–6% of haemoglobin is glycosylated to form HbA1c. With prolonged hyperglycemia, blood HbA1c level may rise beyond 6% to as high as over 10%. Therefore elevated HbA1c levels reflect inadequate diabetic (glycemic) control in the preceding 2–3 months. HbA1c level will normalize after the blood glucose concentration is controlled at lower concentrations [20]. Accordingly, blood HbA1c level is used to monitor glycemic control of DM patients over the past 3 months.
Enrollment
2. Materials and methods 2.1. Study design This was a randomized, double-blind and placebo-controlled study. It was organized by the Macau Institute for Applied Research in Medicine and Health (MIAR), with ethical approval obtained from the Clinical Research Ethics Committee of the Macau University of Science and Technology (MUST). All participants signed an informed consent before the commencement of the study. A flowchart summarizing the trial process is shown in Fig. 1. 2.2. Participants Totally 85 subjects were recruited in Hong Kong through referrals from the Modern TCM Clinic, or from an open lecture and an exhibition on DM (World Diabetes Day Festival 2009), and in Macau through MUST. Twenty-three dropped-out and 62 subjects completed the study. The recruited subjects were divided into two groups: Diabetic Group (DG, N = 37) and Pre-diabetic Group (PG, N = 25) according to the Classifications of the American Diabetes Association (ADA) [21] and following inclusion and exclusion criteria: (1) Inclusion criteria (2) DG subjects (a) confirmed type 2 diabetes mellitus with (b) blood HbA1c level >6.5% or (c) fasting plasma glucose >7.0 mmol/L or (d) 2-hour plasma glucose concentration in the oral glucose tolerance test (OGTT) > 11.0 mmol/L and (e) agreed not to undergo other Chinese medicine treatment during the trial period.
146 subjects were assessed for eligibility 61 were not eligible 30 not meeting inclusion criteria 30 declined to participate 1 other reasons
85 eligible subjects were divided into Diabetic Group (DG) and Pre-diabetic Group (PG) according to the Classifications of the American Diabetes Association (ADA) and the inclusion and exclusion criteria of this study
50 subjects of Diabetic Group (DG) were randomised
35 subjects of Pre-diabetic Group (PG) were randomised
46 received allocated intervention 4 did not receive allocated intervention due to the possibility of receiving placebo treatment
30 received allocated intervention 5 did not receive allocated intervention due to the possibility of receiving placebo treatment
37 completed 3 months treatments 9 discontinued intervention due to the following reasons: the bitter taste of the medicine, patient had another sickness and get to the hospital and other personal reasons
25 completed 3 months treatments 5 discontinued intervention due to the following reasons: the bitter taste of the medicine and other personal reasons
Allocation
Follow-Up
Analysis
37 were analysed by repeated measure ANOVA followed by LSD post hoc test using Statistical Product and Service Solutions (SPSS) V12.0 software
25 were analysed by repeated measure ANOVA followed by LSD post hoc test using Statistical Product and Service Solutions (SPSS) V12.0 software
Fig. 1. Trial process flow chart.
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(3) PG subjects (a) blood HbA1c level from 5.6 to 6.5% or (b) fasting plasma glucose concentration from 5.6 to 6.9 mmol/L or (c) 2 h glucose concentration in oral glucose tolerance test (OGTT) from 7.8 to 11 mmol/L and (d) agreed not to undergo other Chinese medicine treatment during the trial period. (2) Exclusion criteria 1. Patients with major health problems affecting with cardiac, respiratory, renal and hepatic functions. 2. HIV subjects (by history only; laboratory confirmation not required). 3. Users of prohibited substances. 4. Use of any traditional Chinese medicine therapy for diabetes mellitus within one month prior to entering the study. 5. Use of any other investigational drug(s) one month prior to entering the study. 6. Major illnesses which in the opinion of the investigators would make the subject unsuitable for the study or unable to comply with the treatment or laboratory schedule. All subjects were then randomly assigned into either test or placebo subjects. 2.3. Methods (1) PSP-1 PSP-1 is a proprietary Chinese herbal formula that is composed of P. scandens (48%), coicis semen (24%), citri reticulatae pericarpium (4%) and pork (24%). The medicine used in this study was manufactured by Hong Yee Pharmaceutical Factory, Taipa, Macau, China. The preparation method is outlined as follows. Firstly, all raw herbs in the formula were extracted together twice with 7 times (v/v) of 100 C water. The liquids filtered from the two extractions were combined and evaporated at 60–80 C to a specific gravity between 1.03 and 1.10. The condensed extract was
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filtered and spray-dried at 115–125 C. The dried powder was collected and pressed into strips, which were crushed and filtered through a size 12 mesh. The filtered powder was compressed into granules which were composed of 40–60% fine powder. The granules were sieved further through a size 1 and a size 5 mesh respectively. The granules passing through the size 1 mesh but retained on the size 5 mesh were of the appropriate granular size. The rest was returned to the dry press to repeat the dry granulation process. The final product in granule form was packaged at 15 g per packet. A flowchart summarizing the PSP-1 production process is shown in Fig. 2. PSP-1 was tested for heavy metals, pesticide residues and microbial contamination for safety assessments prior to its use in the clinical study. The placebo granules were made of water soluble starch, food coloring substances, flavor agent and water containing no medicine. It was prepared through a process involving similar extraction, condensation, filtration, spray drying, and dry granulation. The final product in granule form was packaged at 15 g per packet. (2) Study arrangements This was a randomized, double-blind and placebo-controlled study in which neither the participant nor the research team members were aware of the treatment assignment and the randomization schedule until completion of the study. Randomization was achieved using randomization tables managed by a registered Chinese medicine practitioner unrelated to the study. A copy of the randomization schedule was provided to the personnel responsible for distributing the investigational products. All subjects were tested for their glycemic status (fasting plasma glucose concentration and blood HbA1c level), and other hematological and biochemical parameters including complete blood picture (CBP), serum alanine transaminase (ALT) activity and creatinine concentration for screening purpose. Urine albumin to creatinine ratio was also tested for possible diabetic nephropathy. All selected subjects were interviewed by a Chinese medicine practitioner at the beginning of the study (baseline), end of the 1st
Raw herbs
Extraction
Condensation
Filtration
Condensation
Spray Drying
Dry Granulation Fig. 2. PSP-1 production flowchart.
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month and 3rd month from commencement of participating in the study. Laboratory analyses were performed 3 times: at baseline, end of the 1st month and the 3rd month from the beginning of the study. The subjects, who were taking anti-diabetic medicine, kept their medications without any change while taking PSP throughout the study. (3) Administration of Intervention Test subjects belonging to either the DG or the PG groups were prescribed PSP-1, two packets daily (2 times per day) for 3 months. Each packet contained 15 g of PSP-1. Those subjects receiving the placebo were provided with similar packets and provided with the same instructions for use. (4) Laboratory investigations After fasting for >10 h, 10 mL blood samples were collected from participants at baseline, end of the 1st month and 3rd month, and analysed for the following parameters: 1. Biochemistry and haematology tests for safety monitoring of PSP-1 i. plasma alanine transaminase (ALT) activity ii. plasma creatinine concentration iii. estimated glomerular filtration rate (eGFR) iv. plasma lipid profile (total, HDL and LDL-cholesterol, and triglyceride) v. complete blood picture (CBP) 2. Indicator tests for assessing efficacy of treatment i. plasma glucose concentration ii. blood HbA1c level iii. either standard OGTT or 2 h postprandial glucose measurement performed at baseline and end of the 3rd month iv. spot urine samples were also taken at baseline, end of the 1st month and 3rd month and analysed for albumin to creatinine ratio (UACR) All biochemistry tests were performed by a NATA-accredited clinical laboratory (NATA = National Association of Testing Authorities of Australia), Diagnostix Medical Centre, Hong Kong using the Dimension RXL analyzer (Siemens Healthcare Diagnostics Inc.,
Newark, DE 19714, U.S.A.). CBP was performed in the same laboratory using the Beckman Coulter LH750Hematology Analyzer (Beckman Coulter Inc., Brea, CA 92821, U.S.A.) For data analysis, repeated measure ANOVA followed by LSD post hoc test were performed using Statistical Product and Service Solutions (SPSS) V12.0 software (IBM Corporation, Armonk, New York 10504–1722, USA). A probability value (P) < 0.05 was considered significant. 3. Results As indicated by the blood test results in Table 1, no significant changes were observed for all biochemical drug-safety monitoring parameters of both the combined cohort (DG + PG) and the placebo group throughout the treatment period. These showed that oral administration of PSP-1 for 3 months produced no adverse effects on liver function, renal function and lipid metabolism of the participants. No significant changes were observed for haematological parameters of all subjects (data not shown). Blood test results for glycemic control (Table 2) showed that a statistically significant decrease in fasting plasma glucose concentration was observed for the PG subjects treated with PSP-1 between baseline and 3 months (mean +/ SD of 6.1+/ 0.7 vs. 5.9+/ 0.8 mmol/L, P < 0.05). No such change was observed for either the DG or placebo subjects. Table 2 also shows that there was a significant decrease in blood HbA1c level of DG subjects treated with PSP-1 between baseline and 3 months (7.2+/ 0.7 vs.6.9+/ 0.7%, P < 0.005). No such change was observed at one month post PSP-1 of these DG subjects, or for the placebo group. For the PG subjects, a significant decrease in HbA1c was also observed between baseline and 3 months post PSP-1 (Table 2, 6.2+/ 0.3 vs. 6.0+/ 0.3, P < 0.001). No such change was observed at one month post PSP-1, or among the placebo subjects. For the combined cohort, there was no significant change in plasma glucose concentration throughout the treatment period (Table 3). However, a significant decrease in HbA1c was observed between baseline and 3 months of PSP-1 treatment (6.8+/ 0.8 vs. 6.6+/ 0.8%, P < 0.001). No significant change was observed at one month post PSP-1. Placebo subjects showed no significant change in HbA1c level.
Table 1 Changes in biochemical parameters of the combined cohort on PSP-1 and the placebo subjects. Group DG + PG (n = 53)
Placebo (n = 12)
Test
Baseline
1 month post PSP-1
3 months post PSP-1
Baseline
1 month post PSP-1
3 months post PSP-1
ALT a (Female: 14–59, Male:16–63 IU/L) Creatinine a (Female: 53–88, Male: 71–115 umol/L) Total cholesterol a (<5.2 mmol/L) HDLCholesterol a (>1.03 mmol/L) LDL- cholesterol a (<3.4 mmol/L) Triglyceride a (<1.7 mmol/L) UACR a (<0.03)
44.3 16.1
44.6 17.2
43.1 19.3
51.0 43.9
55.3 37.4
57.1 46.3
75.8 17.3
69.9 17.3
73.2 16.9
83.8 15.5
72.2 17.2
74.5 13.8
5.1 0.9
5.4 1.2
5.4 1.1
4.9 0.8
4.8 0.8
4.7 0.8
1.4 0.3
1.3 0.4
1.3 0.3
1.3 0.3
1.3 0.3
1.3 0.3
3.1 0.8
3.3 1.0
3.3 0.9
3.1 0.7
3.0 0.7
2.8 0.6
1.5 0.9
1.7 1.4
1.6 0.9
1.1 0.5
1.4 0.5
1.2 0.8
0.02 0.04
0.02 0.02
0.02 0.01
0.01 0.00
0.02 0.02
0.02 0.04
a
Reference ranges for normal subjects.
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Table 2 Changes in fasting plasma glucose concentration and HbA1c level of the DG, PG and placebo groups at one month and 3 months post PSP-1/placebo (“a” indicates P < 0.05; “b” indicates P < 0.005; “c” indicates P = 0.001). Result Fasting plasma glucose concentration (mmol/L)
HbA1c (%)
Baseline
1 month post PSP-1
3 months post PSP-1
Baseline
1 month post PSP-1
3 months post PSP-1
Diabetic (n = 34) Placebo (n = 3)
8.3 1.7
8.6 1.6
8.1 1.8
7.2 0.7b
7.1 0.7
6.9 0.7b
7.0 0.9
7.9 0.4
7.6 1.9
6.7 0.4
6.6 0.3
6.8 0.5
Pre-diabetic (n = 19) Placebo (n = 6)
6.1 0.7a
6.3 0.8
5.9 0.8a
6.2 0.3c
6.1 0.3
6.0 0.3c
6.2 0.5
6.4 0.6
6.1 0.6
6.2 0.4
6.2 0.4
6.0 0.5
Groups DG
PG
Table 3 Changes in fasting plasma glucose concentration and HbA1c level of the combined cohort treated with PSP-1 (DG + PG, n = 53) and the placebo subjects (n = 9). (“d” indicates P < 0.001). Result Fasting plasma glucose (mmol/L)
HbA1c (%)
Group
Baseline
1 month post PSP-1
3 months post PSP-1
Baseline
1 month post PSP-1
3 months post PSP-1
DG + PG (n = 53) Placebo (n = 9)
7.5 1.7
7.7 1.8
7.4 1.8
6.8 0.8d
6.8 0.8
6.6 0.8d
6.5 0.7
6.9 0.9
6.6 1.3
6.4 0.5
6.3 0.4
6.3 0.6
Table 4 Changes in glucose concentrations in the OGTT for DG (n = 19) and PG (n = 22) subjects. Results
Groups DG
PG
Fasting plasma glucose (mmol/L)
1 h glucose concentration (mmol/L)
2 h glucose concentration (mmol/L)
Baseline
3 months post PSP-1
Baseline
3 months post PSP-1
Baseline
3 months post PSP-1
PSP-1 (n = 16) Placebo (n = 3)
7.3 1.2
7.1 1.3
16.2 3.3
15.0 3.0
15.2 4.9
15.0 4.1
7.0 1.5
7.6 1.9
17.3 3.1
17.7 4.3
16.9 8.3
17.0 7.0
PSP-1 (n = 16) Placebo (n = 6)
6.1 0.6
5.8 0.7
11.6 3.4
11.0 3.0
8.8 2.7
8.8 2.8
6.2 0.8
6.1 0.6
11.3 3.6
11.5 2.4
8.3 2.8
8.8 2.2
There were 19 DG subjects (16 treated with PSP-1 and 3 with placebo) and 22 PG subjects (16 treated with PSP-1 and 6 with placebo) who undertook the OGTT. Table 4 shows changes in plasma glucose concentration in the OGTT test for DG and PG subjects. Apparently, there were no significant changes in blood glucose concentration of the fasting, 1-h post glucose intake and 2h post glucose intake time-points for all subjects at 3 months after PSP-1 treatment. However, it was observed that there was a decreasing trend in blood glucose concentration between baseline and 3 months for all subjects treated with PSP-1 despite the fact that such changes did not reach statistical significance. No such trend was observed for the placebo subjects. 4. Discussion No reports of adverse symptoms were received from any of the 62 participants completing the study. In addition, over the 3month treatment period, no significant adverse effects were
observed on all participants’ well being with regard to all biochemical and hematological tests, such as plasma ALT activity, creatinine concentration and lipid profile (Table 1), and complete blood picture (data not shown). Therefore, PSP-1 appeared to cause no harmful effects on the health of the human body clinically and biochemically as well as hematologically. Tests on plasma creatinine and urine albumin: creatinine ratio was to monitor deterioration of renal function in diabetic patients. There were no significant changes in these parameters throughout the treatment period (Table 1). This suggests that PSP-1 did not cause any nephrotoxicity. It is concluded that PSP-1 should be safe to use on diabetic patients. As shown from Table 2, PSP-1 treatment resulted in better control of fasting blood glucose concentration in the pre-diabetic group than the diabetic group. There was a significant change in fasting blood glucose concentration in pre-diabetic subjects treated with PSP-1 (P < 0.05) but no such change was observed for the diabetic subjects and placebo subjects of both groups. This
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might be due to the fact that 3-month treatment of PSP-1 was not sufficient to significantly bring down the glucose concentration of the diabetic subjects who were at a more severe state of plasma glucose dysregulation. Also, due to the physiological fluctuation or disturbance from a recent hyperglycemic episode, snapshots of fasting plasma glucose concentration over the 1 and 3-month time points might not be sensitive enough for detecting the change of glucose homeostasis especially when the difference was small. It can be anticipated that the combined cohort of the DG and PG showed no significant change in the fasting plasma glucose concentration since the subjects in the DG outnumbered the PG group (n = 37 vs. n = 25). The combined placebo group also showed no significant change in fasting blood glucose concentration. Blood HbA1c level reflects the average plasma glucose concentration over the immediate past 2–3 months. It is not greatly influenced by episodic fluctuations in plasma glucose concentration. For diabetic patients, the desirable HbA1c level should be below 6.5% [22]. As shown in Table 2, PSP-1 had a lowering effect on HbA1c level in both DG and PG groups. For the DG group, the mean HbA1c level was reduced significantly from 7.2% at baseline to 6.9% after 3 months treatment with PSP-1 (P < 0.005). For the PG group, the mean HbA1c was reduced significantly from 6.2 to 6.0% (P < 0.001) which is at the upper limit of normal values. For the combined cohort, a significant decrease in HbA1c (mean values of 6.8–6.6%) was also observed after treatment with PSP-1 for 3 months. These results suggest that PSP-1 is effective in lowering HbA1c level. Therefore it may have a beneficial effect on controlling hyperglycemia of the diabetic and pre-diabetic patients. As shown in Table 3, a decreasing trend in plasma glucose concentration was observed between baseline and 3 months post PSP-1 for all subjects treated with PSP-1. This suggests that PSP-1 is effective in reducing the plasma glucose concentration although the change was not statistically significant. It is expected a significant result might be achieved if the treatment period is extended. Unlike Western medicine which usually contains a single active ingredient aiming for a specific mechanism, a Chinese medicinal formula may contain various active ingredients targeting multiple mechanisms [8]. The mechanisms of Chinese medicines for treating type 2 diabetes include enhancement of insulin sensitivity, stimulation of insulin secretion, reduction of carbohydrate absorption, enhancement of glucose utilization in the peripheral tissue, exerting antioxidant effects and decreasing cell apoptosis, promotion of glycogenesis or inhibition of hepatic glycogenolysis. [8,12,13,15,17]. The integration of TCM and allopathic drugs can lead to a better control of the disease, resulting in a decrease in drug dosage(s) and the number of medications, therby minimizing the effects of adverse reactions. It may also reduce or slow down the development of diabetic complications [15]. In the PSP-1 formula, P. scandens is the Principal Drug which has the effects of dispelling pathogenic wind, eliminating dampness, clearing heat, detoxication and removing food stagnation. Coicis semen is the second importing herb, the Assistant Drug which helps promote urination and eliminate dampness, invigorate the spleen and clear away heat. It is also known to have an effect of reducing plasma glucose concentration [12]. Citri reticulatae pericarpium is added as an Adjuvant whose main actions are regulating the qi, normalizing the function of the spleen and stomach and resolving phlegm. “Pork” refers to the lean meat from the thigh of a pig. From the Chinese medicine point of view, pork has the function of nourishing “yin” which represents the structural or material aspect (especially those substances in liquid form, e.g. secretions) of the human body. Diabetes mellitus is considered as a disease with yin deficiency so pork also plays an important role in the formula. In traditional Chinese Medicine, putting food (meat or vegetables etc)
in a mixture of Chinese herbs to make a decoction, or strictly speaking, a herbal soup, is a common treatment method or prevention measure for some diseases including diabetes mellitus, so called the “dietary therapy of Chinese medicine”. The overall effect of the formula (or more accurately, the herbal soup with pork) is to improve the function of the spleen and stomach, and to eliminate dampness and phlegm. However, the actual mechanism of PSP-1 in lowering HbA1c in this study remains unclear, nor the actions of P. scandens and/or coicis semen and other ingredients from the western medical point of view. It is also worth mentioning that according to the feedback of the participants who experienced a general improvement of quality of life, it appears that PSP-1 has no obvious different effects on the three levels of “Xiao Ke”, i.e, upper diabetes (dryness-heat in the lung), middle diabetes ( blazing stomach fire) and lower diabetes (kidney impairment) as far as clinical symptoms concerned. In conclusion, 3 months supplementation of the PSP1 formulation was able to reduce fasting plasma glucose concentration in pre-diabetic subjects and lower blood HbA1c level for both pre-diabetic and diabetic subjects. PSP-1 may further benefit diabetic control in patients already receiving western medications, and contribute to an integrative therapeutic management of diabetes. Authors contribution All research was done by the authors. Funding The authors have declared that this research was supported by Ms Rose Cheung from United States. Conflict of interest The authors have declared that there is no conflict of interest. References [1] American Diabetes Association, American Diabetes Association Diagnosis and classification of diabetes mellitus, Diabetes Care 34 (Suppl. (1)) (2011) S62– S69. [2] International Diabetes Federation, IDF Diabetes Atlas, 6th edition, International Diabetes Federation, 2013, 2016. [3] Centers for Disease Control and Prevention, National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA, 2011. [4] U.K. Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet 352 (1998) 837–853. [5] The Advance Collaborative Group, Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes, N. Eng. J. Med. 358 (2008) 2560–2572. [6] Diabetes Control and Complications Trial (DCCT) Research Group, The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial, Diabetes 44 (1995) 968–983. [7] Yasuo Ohkubo, Hideki Kishikawa, Eiichi Araki, Takao Miyata, Satoshi Isami, Sadatoshi Motoyoshi, Yujiro Kojima, et al., Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6year study, Diabetes Res. Clin. Pract. 28 (1995) 103–117. [8] Zhijun Wang, Jeffrey Wang, Patrick Chan, Treating type 2 diabetes mellitus with traditional chinese and indian medicinal herbs, Evid. Based Complement. Altern. Med. (2013) (17 Pages, Article ID 343594). [9] NHS Choices. Type 2 diabetes treatment. Retrieved from the NHS Choices, (2014) . http://www.nhs.uk/Conditions/Diabetes-type2/Pages/Treatment. aspx. [10] David M. Nathan, John B. Buse, Mayer B. Davidson, Ele Ferrannini, Rury R. Holman, Robert Sherwin, Bernard Zinman, Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the american diabetes
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[17] Zou Chen-hui, Shen Zhu-fang, Anti-diabetic traditional Chinese medicine formulae and the progress in pharmacological research of their active ingredients, in: Yong-Xiang Zhang (Ed.), Pharmacology of Traditional Chinese Medicine: The New Theories, People’s Medical Publishing House Co. Ltd., China, 2004, pp. 256–271. [18] Jia Wei, Gao Wenyuan, Tang Lida, Antidiabetic herbal drugs officially approved in China, Phytother. Res. 17 (2003) 1127–1134. [19] Zhang Xiao-feng, Ji Bao-ping, Zhang Hong-juan, Effects of Paederia scandens extracts on blood glucose and blood lipid in streptozotocin-induced diabetic ICR mice, Food Sci. 29 (1) (2008) 292–295. [20] R.A. Sacher, R.A. McPherson, Widmann’s Clinical Interpretation of Laboratory Tests, 11th ed., F.A Davis, Philadelphia, 2000, pp. 815. [21] American Diabetes Association, Standards of medical care in diabetes—2012, Diabetes Care 35 (Suppl. (1)) (2012) s1. [22] W.J. Valentine, A.J. Palmer, L. Nicklasson, D. Cobden, S. Roze, Improving life expectancy and decreasing the incidence of complications associated with type 2 diabetes: a modelling study of HbA1c targets, Int. J. Clin. Pract. 60 (September (9)) (2006) 1138–1145.
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European Journal of Integrative Medicine xxx (2015) xxx–xxx
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Research paper
A clinical study of the anti-diabetic effect of a simple Chinese herbal formula, PSP-1 S.H. Chuia,b,* , Y.H. Wongb , M.Y. Fongb , F.C. Chowc , Y.M. Chiub , C.W.K Lama a State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology Foundation, Taipa, Macau, China b Clinical Laboratory, Diagnostix Medical Centre, Central, Hong Kong, China c Modern TCM Ltd., Hong Kong, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 22 June 2015 Received in revised form 23 February 2016 Accepted 23 February 2016 Available online xxx
Introduction: A two armed clinical before and after study was conducted to investigate the efficacy of a proprietary Chinese herbal formula, PSP-1, to improve glycemic control in type 2 diabetic patients and pre-diabetic subjects over a 3 month period. Methods: Sixty-two subjects were recruited and divided into a Diabetic Group (DG) and a Pre-diabetic Group (PG). All subjects were prescribed PSP-1 or placebo and followed-up for 3 months. Blood and spot urine samples were collected at baseline, 1st month and 3rd month for each subject for laboratory tests. Results: For the DG group, PSP-1 subjects showed significant decrease in blood HbA1c level between baseline and 3 months post PSP-1 (p < 0.005), but there was no significant change in fasting plasma glucose concentration. PSP-1 subjects in the PG group showed a significant decrease in both fasting glucose (p < 0.05) and HbA1c (p = 0.001) after 3-months’ treatment. Combining PG and DG groups, a significant decrease in HbA1c was observed for PSP subjects between baseline and 3 months post PSP. Comparison with those on placebo demonstrated no significant changes in either HbA1c level or glucose concentrations. Conclusions: It appeared that 3 months supplementation of PSP-1 formulation was able to reduce blood glucose concentrations in pre-diabetic subjects and lowered blood HbA1c levels for both pre-diabetic and diabetic subjects. ã 2016 Elsevier GmbH. All rights reserved.
Keywords: Diabetes Pre-diabetes Fasting glucose HbA1c Chinese medicine
1. Introduction Diabetes mellitus (DM) is one of the most common noncommunicable diseases in many countries, and type 2 DM (also known as non insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes) accounts for 90–95% of diabetic patients [1]. More than 382 million people in the world suffered from diabetes in 2013 (global prevalence rate of 8.3%) and prevalence has been increasing, particularly of type 2 DM [2]. It is estimated that the number of diabetic patients will rise to 592 million by 2035. In 2011, diabetes was the seventh leading cause of death in the United States with 5.1 million fatalities [3]. Although the severity of type 2 DM can be partially controlled with exercises and diet, medications and monitoring of blood and urine glucose concentrations for improved glycemic control are
* Corresponding author at: 612 Melbourne Plaza, 33 Queen’s Road Central, Hong Kong, China. E-mail address: [email protected] (S.H. Chui).
also important for preventing or slowing down the development of diabetic complications such as chronic renal failure and coronary artery disease [4–8]. Western medicines have been commonly used for controlling blood glucose concentration [9–11]. With fewer side effects and at lower costs, Chinese medicines can be a good alternative to replace or supplement western medications [8,12–14]. According to its clinical manifestation, diabetes mellitus is categorized in traditional Chinese medicine (TCM) as “Xiao Ke”, meaning wasting and thirsting disorder [15]. Depending on the TCM pattern, “Xiao Ke” is classified into three levels that are closely associated with the lungs, stomach and kidneys. The upper level is characterized by the prominence of excessive thirst and a dry mouth. The therapeutic principle is to quench the thirst and relieve dryness as well as nourishing yin and clear away heat. The middle level is characterized by the prominence of excessive hunger, and treatment aims at clearing stomach and purging heat as well as nourishing yin and promoting production of fluid. The lower level is dominated by excessive urination and lumbar pain. The therapeutic rule is to nourish yin and invigorate the kidneys [15–17]. Many Chinese herbal formulas such as the Jin Qi Jiang Tang
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Pian and San Huang Jiang Tang decoctions have been developed and are used in the treatment of diabetes in China [15,17,18]. Paederia scandens is the leaves and stems of P. scandens (Lour.) Merrill which is a plant of rubiaceae. It has a sweet and sour flavor and is neutral in property. It has been known to promote blood circulation to relieve pain, clear away heat and toxins, invigorate the spleen and resolve dampness [19]. P. scandens extract has been shown to exert a hypoglycemic effect on diabetic mice [19]. However, no study has been conducted to investigate the antidiabetic effect of P. scandens in humans and its use as an ingredient in anti-diabetic Chinese medicine. This clinical study was conducted to investigate the efficacy of a proprietary simple Chinese herbal formula, PSP-1, with P. scandens as its principal ingredient for treating type 2 DM for improvement of glycemic control and other diabetes-associated parameters, based on clinical and laboratory assessments over a period of 3 months. In this study, blood glycosylated haemoglobin A1c (HbA1c) level was used to monitor recent changes in plasma glucose concentration of the participants. The principle of this test is based on the fact that glucose is attached to haemoglobin of red blood cells which live for about 3 months. In normal subjects, 3–6% of haemoglobin is glycosylated to form HbA1c. With prolonged hyperglycemia, blood HbA1c level may rise beyond 6% to as high as over 10%. Therefore elevated HbA1c levels reflect inadequate diabetic (glycemic) control in the preceding 2–3 months. HbA1c level will normalize after the blood glucose concentration is controlled at lower concentrations [20]. Accordingly, blood HbA1c level is used to monitor glycemic control of DM patients over the past 3 months.
Enrollment
2. Materials and methods 2.1. Study design This was a randomized, double-blind and placebo-controlled study. It was organized by the Macau Institute for Applied Research in Medicine and Health (MIAR), with ethical approval obtained from the Clinical Research Ethics Committee of the Macau University of Science and Technology (MUST). All participants signed an informed consent before the commencement of the study. A flowchart summarizing the trial process is shown in Fig. 1. 2.2. Participants Totally 85 subjects were recruited in Hong Kong through referrals from the Modern TCM Clinic, or from an open lecture and an exhibition on DM (World Diabetes Day Festival 2009), and in Macau through MUST. Twenty-three dropped-out and 62 subjects completed the study. The recruited subjects were divided into two groups: Diabetic Group (DG, N = 37) and Pre-diabetic Group (PG, N = 25) according to the Classifications of the American Diabetes Association (ADA) [21] and following inclusion and exclusion criteria: (1) Inclusion criteria (2) DG subjects (a) confirmed type 2 diabetes mellitus with (b) blood HbA1c level >6.5% or (c) fasting plasma glucose >7.0 mmol/L or (d) 2-hour plasma glucose concentration in the oral glucose tolerance test (OGTT) > 11.0 mmol/L and (e) agreed not to undergo other Chinese medicine treatment during the trial period.
146 subjects were assessed for eligibility 61 were not eligible 30 not meeting inclusion criteria 30 declined to participate 1 other reasons
85 eligible subjects were divided into Diabetic Group (DG) and Pre-diabetic Group (PG) according to the Classifications of the American Diabetes Association (ADA) and the inclusion and exclusion criteria of this study
50 subjects of Diabetic Group (DG) were randomised
35 subjects of Pre-diabetic Group (PG) were randomised
46 received allocated intervention 4 did not receive allocated intervention due to the possibility of receiving placebo treatment
30 received allocated intervention 5 did not receive allocated intervention due to the possibility of receiving placebo treatment
37 completed 3 months treatments 9 discontinued intervention due to the following reasons: the bitter taste of the medicine, patient had another sickness and get to the hospital and other personal reasons
25 completed 3 months treatments 5 discontinued intervention due to the following reasons: the bitter taste of the medicine and other personal reasons
Allocation
Follow-Up
Analysis
37 were analysed by repeated measure ANOVA followed by LSD post hoc test using Statistical Product and Service Solutions (SPSS) V12.0 software
25 were analysed by repeated measure ANOVA followed by LSD post hoc test using Statistical Product and Service Solutions (SPSS) V12.0 software
Fig. 1. Trial process flow chart.
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(3) PG subjects (a) blood HbA1c level from 5.6 to 6.5% or (b) fasting plasma glucose concentration from 5.6 to 6.9 mmol/L or (c) 2 h glucose concentration in oral glucose tolerance test (OGTT) from 7.8 to 11 mmol/L and (d) agreed not to undergo other Chinese medicine treatment during the trial period. (2) Exclusion criteria 1. Patients with major health problems affecting with cardiac, respiratory, renal and hepatic functions. 2. HIV subjects (by history only; laboratory confirmation not required). 3. Users of prohibited substances. 4. Use of any traditional Chinese medicine therapy for diabetes mellitus within one month prior to entering the study. 5. Use of any other investigational drug(s) one month prior to entering the study. 6. Major illnesses which in the opinion of the investigators would make the subject unsuitable for the study or unable to comply with the treatment or laboratory schedule. All subjects were then randomly assigned into either test or placebo subjects. 2.3. Methods (1) PSP-1 PSP-1 is a proprietary Chinese herbal formula that is composed of P. scandens (48%), coicis semen (24%), citri reticulatae pericarpium (4%) and pork (24%). The medicine used in this study was manufactured by Hong Yee Pharmaceutical Factory, Taipa, Macau, China. The preparation method is outlined as follows. Firstly, all raw herbs in the formula were extracted together twice with 7 times (v/v) of 100 C water. The liquids filtered from the two extractions were combined and evaporated at 60–80 C to a specific gravity between 1.03 and 1.10. The condensed extract was
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filtered and spray-dried at 115–125 C. The dried powder was collected and pressed into strips, which were crushed and filtered through a size 12 mesh. The filtered powder was compressed into granules which were composed of 40–60% fine powder. The granules were sieved further through a size 1 and a size 5 mesh respectively. The granules passing through the size 1 mesh but retained on the size 5 mesh were of the appropriate granular size. The rest was returned to the dry press to repeat the dry granulation process. The final product in granule form was packaged at 15 g per packet. A flowchart summarizing the PSP-1 production process is shown in Fig. 2. PSP-1 was tested for heavy metals, pesticide residues and microbial contamination for safety assessments prior to its use in the clinical study. The placebo granules were made of water soluble starch, food coloring substances, flavor agent and water containing no medicine. It was prepared through a process involving similar extraction, condensation, filtration, spray drying, and dry granulation. The final product in granule form was packaged at 15 g per packet. (2) Study arrangements This was a randomized, double-blind and placebo-controlled study in which neither the participant nor the research team members were aware of the treatment assignment and the randomization schedule until completion of the study. Randomization was achieved using randomization tables managed by a registered Chinese medicine practitioner unrelated to the study. A copy of the randomization schedule was provided to the personnel responsible for distributing the investigational products. All subjects were tested for their glycemic status (fasting plasma glucose concentration and blood HbA1c level), and other hematological and biochemical parameters including complete blood picture (CBP), serum alanine transaminase (ALT) activity and creatinine concentration for screening purpose. Urine albumin to creatinine ratio was also tested for possible diabetic nephropathy. All selected subjects were interviewed by a Chinese medicine practitioner at the beginning of the study (baseline), end of the 1st
Raw herbs
Extraction
Condensation
Filtration
Condensation
Spray Drying
Dry Granulation Fig. 2. PSP-1 production flowchart.
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month and 3rd month from commencement of participating in the study. Laboratory analyses were performed 3 times: at baseline, end of the 1st month and the 3rd month from the beginning of the study. The subjects, who were taking anti-diabetic medicine, kept their medications without any change while taking PSP throughout the study. (3) Administration of Intervention Test subjects belonging to either the DG or the PG groups were prescribed PSP-1, two packets daily (2 times per day) for 3 months. Each packet contained 15 g of PSP-1. Those subjects receiving the placebo were provided with similar packets and provided with the same instructions for use. (4) Laboratory investigations After fasting for >10 h, 10 mL blood samples were collected from participants at baseline, end of the 1st month and 3rd month, and analysed for the following parameters: 1. Biochemistry and haematology tests for safety monitoring of PSP-1 i. plasma alanine transaminase (ALT) activity ii. plasma creatinine concentration iii. estimated glomerular filtration rate (eGFR) iv. plasma lipid profile (total, HDL and LDL-cholesterol, and triglyceride) v. complete blood picture (CBP) 2. Indicator tests for assessing efficacy of treatment i. plasma glucose concentration ii. blood HbA1c level iii. either standard OGTT or 2 h postprandial glucose measurement performed at baseline and end of the 3rd month iv. spot urine samples were also taken at baseline, end of the 1st month and 3rd month and analysed for albumin to creatinine ratio (UACR) All biochemistry tests were performed by a NATA-accredited clinical laboratory (NATA = National Association of Testing Authorities of Australia), Diagnostix Medical Centre, Hong Kong using the Dimension RXL analyzer (Siemens Healthcare Diagnostics Inc.,
Newark, DE 19714, U.S.A.). CBP was performed in the same laboratory using the Beckman Coulter LH750Hematology Analyzer (Beckman Coulter Inc., Brea, CA 92821, U.S.A.) For data analysis, repeated measure ANOVA followed by LSD post hoc test were performed using Statistical Product and Service Solutions (SPSS) V12.0 software (IBM Corporation, Armonk, New York 10504–1722, USA). A probability value (P) < 0.05 was considered significant. 3. Results As indicated by the blood test results in Table 1, no significant changes were observed for all biochemical drug-safety monitoring parameters of both the combined cohort (DG + PG) and the placebo group throughout the treatment period. These showed that oral administration of PSP-1 for 3 months produced no adverse effects on liver function, renal function and lipid metabolism of the participants. No significant changes were observed for haematological parameters of all subjects (data not shown). Blood test results for glycemic control (Table 2) showed that a statistically significant decrease in fasting plasma glucose concentration was observed for the PG subjects treated with PSP-1 between baseline and 3 months (mean +/ SD of 6.1+/ 0.7 vs. 5.9+/ 0.8 mmol/L, P < 0.05). No such change was observed for either the DG or placebo subjects. Table 2 also shows that there was a significant decrease in blood HbA1c level of DG subjects treated with PSP-1 between baseline and 3 months (7.2+/ 0.7 vs.6.9+/ 0.7%, P < 0.005). No such change was observed at one month post PSP-1 of these DG subjects, or for the placebo group. For the PG subjects, a significant decrease in HbA1c was also observed between baseline and 3 months post PSP-1 (Table 2, 6.2+/ 0.3 vs. 6.0+/ 0.3, P < 0.001). No such change was observed at one month post PSP-1, or among the placebo subjects. For the combined cohort, there was no significant change in plasma glucose concentration throughout the treatment period (Table 3). However, a significant decrease in HbA1c was observed between baseline and 3 months of PSP-1 treatment (6.8+/ 0.8 vs. 6.6+/ 0.8%, P < 0.001). No significant change was observed at one month post PSP-1. Placebo subjects showed no significant change in HbA1c level.
Table 1 Changes in biochemical parameters of the combined cohort on PSP-1 and the placebo subjects. Group DG + PG (n = 53)
Placebo (n = 12)
Test
Baseline
1 month post PSP-1
3 months post PSP-1
Baseline
1 month post PSP-1
3 months post PSP-1
ALT a (Female: 14–59, Male:16–63 IU/L) Creatinine a (Female: 53–88, Male: 71–115 umol/L) Total cholesterol a (<5.2 mmol/L) HDLCholesterol a (>1.03 mmol/L) LDL- cholesterol a (<3.4 mmol/L) Triglyceride a (<1.7 mmol/L) UACR a (<0.03)
44.3 16.1
44.6 17.2
43.1 19.3
51.0 43.9
55.3 37.4
57.1 46.3
75.8 17.3
69.9 17.3
73.2 16.9
83.8 15.5
72.2 17.2
74.5 13.8
5.1 0.9
5.4 1.2
5.4 1.1
4.9 0.8
4.8 0.8
4.7 0.8
1.4 0.3
1.3 0.4
1.3 0.3
1.3 0.3
1.3 0.3
1.3 0.3
3.1 0.8
3.3 1.0
3.3 0.9
3.1 0.7
3.0 0.7
2.8 0.6
1.5 0.9
1.7 1.4
1.6 0.9
1.1 0.5
1.4 0.5
1.2 0.8
0.02 0.04
0.02 0.02
0.02 0.01
0.01 0.00
0.02 0.02
0.02 0.04
a
Reference ranges for normal subjects.
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Table 2 Changes in fasting plasma glucose concentration and HbA1c level of the DG, PG and placebo groups at one month and 3 months post PSP-1/placebo (“a” indicates P < 0.05; “b” indicates P < 0.005; “c” indicates P = 0.001). Result Fasting plasma glucose concentration (mmol/L)
HbA1c (%)
Baseline
1 month post PSP-1
3 months post PSP-1
Baseline
1 month post PSP-1
3 months post PSP-1
Diabetic (n = 34) Placebo (n = 3)
8.3 1.7
8.6 1.6
8.1 1.8
7.2 0.7b
7.1 0.7
6.9 0.7b
7.0 0.9
7.9 0.4
7.6 1.9
6.7 0.4
6.6 0.3
6.8 0.5
Pre-diabetic (n = 19) Placebo (n = 6)
6.1 0.7a
6.3 0.8
5.9 0.8a
6.2 0.3c
6.1 0.3
6.0 0.3c
6.2 0.5
6.4 0.6
6.1 0.6
6.2 0.4
6.2 0.4
6.0 0.5
Groups DG
PG
Table 3 Changes in fasting plasma glucose concentration and HbA1c level of the combined cohort treated with PSP-1 (DG + PG, n = 53) and the placebo subjects (n = 9). (“d” indicates P < 0.001). Result Fasting plasma glucose (mmol/L)
HbA1c (%)
Group
Baseline
1 month post PSP-1
3 months post PSP-1
Baseline
1 month post PSP-1
3 months post PSP-1
DG + PG (n = 53) Placebo (n = 9)
7.5 1.7
7.7 1.8
7.4 1.8
6.8 0.8d
6.8 0.8
6.6 0.8d
6.5 0.7
6.9 0.9
6.6 1.3
6.4 0.5
6.3 0.4
6.3 0.6
Table 4 Changes in glucose concentrations in the OGTT for DG (n = 19) and PG (n = 22) subjects. Results
Groups DG
PG
Fasting plasma glucose (mmol/L)
1 h glucose concentration (mmol/L)
2 h glucose concentration (mmol/L)
Baseline
3 months post PSP-1
Baseline
3 months post PSP-1
Baseline
3 months post PSP-1
PSP-1 (n = 16) Placebo (n = 3)
7.3 1.2
7.1 1.3
16.2 3.3
15.0 3.0
15.2 4.9
15.0 4.1
7.0 1.5
7.6 1.9
17.3 3.1
17.7 4.3
16.9 8.3
17.0 7.0
PSP-1 (n = 16) Placebo (n = 6)
6.1 0.6
5.8 0.7
11.6 3.4
11.0 3.0
8.8 2.7
8.8 2.8
6.2 0.8
6.1 0.6
11.3 3.6
11.5 2.4
8.3 2.8
8.8 2.2
There were 19 DG subjects (16 treated with PSP-1 and 3 with placebo) and 22 PG subjects (16 treated with PSP-1 and 6 with placebo) who undertook the OGTT. Table 4 shows changes in plasma glucose concentration in the OGTT test for DG and PG subjects. Apparently, there were no significant changes in blood glucose concentration of the fasting, 1-h post glucose intake and 2h post glucose intake time-points for all subjects at 3 months after PSP-1 treatment. However, it was observed that there was a decreasing trend in blood glucose concentration between baseline and 3 months for all subjects treated with PSP-1 despite the fact that such changes did not reach statistical significance. No such trend was observed for the placebo subjects. 4. Discussion No reports of adverse symptoms were received from any of the 62 participants completing the study. In addition, over the 3month treatment period, no significant adverse effects were
observed on all participants’ well being with regard to all biochemical and hematological tests, such as plasma ALT activity, creatinine concentration and lipid profile (Table 1), and complete blood picture (data not shown). Therefore, PSP-1 appeared to cause no harmful effects on the health of the human body clinically and biochemically as well as hematologically. Tests on plasma creatinine and urine albumin: creatinine ratio was to monitor deterioration of renal function in diabetic patients. There were no significant changes in these parameters throughout the treatment period (Table 1). This suggests that PSP-1 did not cause any nephrotoxicity. It is concluded that PSP-1 should be safe to use on diabetic patients. As shown from Table 2, PSP-1 treatment resulted in better control of fasting blood glucose concentration in the pre-diabetic group than the diabetic group. There was a significant change in fasting blood glucose concentration in pre-diabetic subjects treated with PSP-1 (P < 0.05) but no such change was observed for the diabetic subjects and placebo subjects of both groups. This
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might be due to the fact that 3-month treatment of PSP-1 was not sufficient to significantly bring down the glucose concentration of the diabetic subjects who were at a more severe state of plasma glucose dysregulation. Also, due to the physiological fluctuation or disturbance from a recent hyperglycemic episode, snapshots of fasting plasma glucose concentration over the 1 and 3-month time points might not be sensitive enough for detecting the change of glucose homeostasis especially when the difference was small. It can be anticipated that the combined cohort of the DG and PG showed no significant change in the fasting plasma glucose concentration since the subjects in the DG outnumbered the PG group (n = 37 vs. n = 25). The combined placebo group also showed no significant change in fasting blood glucose concentration. Blood HbA1c level reflects the average plasma glucose concentration over the immediate past 2–3 months. It is not greatly influenced by episodic fluctuations in plasma glucose concentration. For diabetic patients, the desirable HbA1c level should be below 6.5% [22]. As shown in Table 2, PSP-1 had a lowering effect on HbA1c level in both DG and PG groups. For the DG group, the mean HbA1c level was reduced significantly from 7.2% at baseline to 6.9% after 3 months treatment with PSP-1 (P < 0.005). For the PG group, the mean HbA1c was reduced significantly from 6.2 to 6.0% (P < 0.001) which is at the upper limit of normal values. For the combined cohort, a significant decrease in HbA1c (mean values of 6.8–6.6%) was also observed after treatment with PSP-1 for 3 months. These results suggest that PSP-1 is effective in lowering HbA1c level. Therefore it may have a beneficial effect on controlling hyperglycemia of the diabetic and pre-diabetic patients. As shown in Table 3, a decreasing trend in plasma glucose concentration was observed between baseline and 3 months post PSP-1 for all subjects treated with PSP-1. This suggests that PSP-1 is effective in reducing the plasma glucose concentration although the change was not statistically significant. It is expected a significant result might be achieved if the treatment period is extended. Unlike Western medicine which usually contains a single active ingredient aiming for a specific mechanism, a Chinese medicinal formula may contain various active ingredients targeting multiple mechanisms [8]. The mechanisms of Chinese medicines for treating type 2 diabetes include enhancement of insulin sensitivity, stimulation of insulin secretion, reduction of carbohydrate absorption, enhancement of glucose utilization in the peripheral tissue, exerting antioxidant effects and decreasing cell apoptosis, promotion of glycogenesis or inhibition of hepatic glycogenolysis. [8,12,13,15,17]. The integration of TCM and allopathic drugs can lead to a better control of the disease, resulting in a decrease in drug dosage(s) and the number of medications, therby minimizing the effects of adverse reactions. It may also reduce or slow down the development of diabetic complications [15]. In the PSP-1 formula, P. scandens is the Principal Drug which has the effects of dispelling pathogenic wind, eliminating dampness, clearing heat, detoxication and removing food stagnation. Coicis semen is the second importing herb, the Assistant Drug which helps promote urination and eliminate dampness, invigorate the spleen and clear away heat. It is also known to have an effect of reducing plasma glucose concentration [12]. Citri reticulatae pericarpium is added as an Adjuvant whose main actions are regulating the qi, normalizing the function of the spleen and stomach and resolving phlegm. “Pork” refers to the lean meat from the thigh of a pig. From the Chinese medicine point of view, pork has the function of nourishing “yin” which represents the structural or material aspect (especially those substances in liquid form, e.g. secretions) of the human body. Diabetes mellitus is considered as a disease with yin deficiency so pork also plays an important role in the formula. In traditional Chinese Medicine, putting food (meat or vegetables etc)
in a mixture of Chinese herbs to make a decoction, or strictly speaking, a herbal soup, is a common treatment method or prevention measure for some diseases including diabetes mellitus, so called the “dietary therapy of Chinese medicine”. The overall effect of the formula (or more accurately, the herbal soup with pork) is to improve the function of the spleen and stomach, and to eliminate dampness and phlegm. However, the actual mechanism of PSP-1 in lowering HbA1c in this study remains unclear, nor the actions of P. scandens and/or coicis semen and other ingredients from the western medical point of view. It is also worth mentioning that according to the feedback of the participants who experienced a general improvement of quality of life, it appears that PSP-1 has no obvious different effects on the three levels of “Xiao Ke”, i.e, upper diabetes (dryness-heat in the lung), middle diabetes ( blazing stomach fire) and lower diabetes (kidney impairment) as far as clinical symptoms concerned. In conclusion, 3 months supplementation of the PSP1 formulation was able to reduce fasting plasma glucose concentration in pre-diabetic subjects and lower blood HbA1c level for both pre-diabetic and diabetic subjects. PSP-1 may further benefit diabetic control in patients already receiving western medications, and contribute to an integrative therapeutic management of diabetes. Authors contribution All research was done by the authors. Funding The authors have declared that this research was supported by Ms Rose Cheung from United States. Conflict of interest The authors have declared that there is no conflict of interest. References [1] American Diabetes Association, American Diabetes Association Diagnosis and classification of diabetes mellitus, Diabetes Care 34 (Suppl. (1)) (2011) S62– S69. [2] International Diabetes Federation, IDF Diabetes Atlas, 6th edition, International Diabetes Federation, 2013, 2016. [3] Centers for Disease Control and Prevention, National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA, 2011. [4] U.K. Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet 352 (1998) 837–853. [5] The Advance Collaborative Group, Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes, N. Eng. J. Med. 358 (2008) 2560–2572. [6] Diabetes Control and Complications Trial (DCCT) Research Group, The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial, Diabetes 44 (1995) 968–983. [7] Yasuo Ohkubo, Hideki Kishikawa, Eiichi Araki, Takao Miyata, Satoshi Isami, Sadatoshi Motoyoshi, Yujiro Kojima, et al., Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6year study, Diabetes Res. Clin. Pract. 28 (1995) 103–117. [8] Zhijun Wang, Jeffrey Wang, Patrick Chan, Treating type 2 diabetes mellitus with traditional chinese and indian medicinal herbs, Evid. Based Complement. Altern. Med. (2013) (17 Pages, Article ID 343594). [9] NHS Choices. Type 2 diabetes treatment. Retrieved from the NHS Choices, (2014) . http://www.nhs.uk/Conditions/Diabetes-type2/Pages/Treatment. aspx. [10] David M. Nathan, John B. Buse, Mayer B. Davidson, Ele Ferrannini, Rury R. Holman, Robert Sherwin, Bernard Zinman, Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the american diabetes
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