Abstract
Berberine has been shown to regulate glucose and lipid metabolism invitro and in vivo. This pilot study was to determine the efficacy and safety ofberberine in the treatment of type 2 diabetic patients. In study A, 36 adultswith newly diagnosed type 2 diabetes were randomly assigned to treatment withberberine or metformin (0.5 g t.i.d.) in a 3-month trial. The hypoglycemiceffect of berberine was similar to that of metformin. Significant decreases inhemoglobin A1c (HbA1c; from 9.5% ± 0.5% to7.5% ± 0.4%, P<0.01), fastingblood glucose (FBG; from 10.6 ± 0.9 mmol/L to 6.9 ± 0.5 mmol/L,P<0.01), postprandial blood glucose (PBG; from 19.8± 1.7 to 11.1 ± 0.9 mmol/L, P<0.01) andplasma triglycerides (from 1.13 ± 0.13 mmol/L to 0.89 ± 0.03mmol/L, P<0.05) were observed in the berberine group.In study B, 48 adults with poorly controlled type 2 diabetes were treatedsupplemented with berberine in a 3-month trial. Berberine acted by lowering FBGand PBG from one week to the end of the trial. HbA1c decreased from8.1% ± 0.2% to 7.3% ± 0.3%(P<0.001). Fasting plasma insulin and HOMA-IR werereduced by 28.1% and 44.7% (P<0.001),respectively. Total cholesterol and low-density lipoprotein cholesterol (LDL-C)were decreased significantly as well. During the trial, 20 (34.5%)patients suffered from transient gastrointestinal adverse effects. Functionalliver or kidney damages were not observed for all patients. In conclusion, thispilot study indicates that berberine is a potent oral hypoglycemic agent withbeneficial effects on lipid metabolism.
1. Introduction
Type 2 diabetes is a worldwide health threat and treatment of this disease islimited by availability of effective medications. All of the existing oralhypoglycemic agents have subsequent failure after long term administration. Thus,new oral medications are needed for long-term control of blood glucose in patientswith type 2 diabetes. Certain botanical products from generally regarded as safe(GRAS) plants have been widely used in diabetes care because of theiranti-oxidation, anti-inflammation, anti-obesity and anti-hyperglycemiaproperties.[1, 2]. However, the drawback of using GRAS plants isthe difficulty in control their quality as most of these botanical products aremixtures of multiple compounds. Compared to other products from GRAS plants,berberine is a single purified compound, and has glucose-lowering effect in vitroand in vivo [3-6].
Berberine (molecular formula C20H19NO5 andmolecular weight of 353.36) is the main active component of an ancient Chinese herbCoptis chinensis French, which has been used to treat diabetesfor thousands of years. Berberine is an Over-the-Counter (OTC) drug, which is usedto treat gastrointestinal infections in China. Berberine hydrochloride(B·HCl·nH2O) - the most popular form of berberine, is used in thispilot study. The chemical structure of Berberine and related isoquinoline alkaloidsare quite different from the commonly used other hypoglycemic agents, such assulphonylureas, biguanides, thiazolidinediones, or acarbose. Hence, if the efficacyand safety of berberine are confirmed, it can serve as a new class of anti-diabeticmedication.
This pilot study was to assess the efficacy of berberine in human subjectswith type 2 diabetes. Berberine was given to both newly diagnosed diabetic patientsand poorly controlled diabetic patients alone or combination with other hypoglycemicagents for three months. HbA1c, blood glucose and HOMA index were used to determinethe efficacy of berberine.
2. Subjects and methods
The subjects were recruited from diabetes outpatient department of XinhuaHospital by advertising in the clinic. Ninety-seven Chinese volunteers werescreened, and 13 subjects were excluded from the study due to failure to meet therecruitment criteria. Thus, 84 subjects (49 women and 35 men) with type 2 diabeteswere included in the study. All participants received written and oral informationregarding the natural and potential risks of the study and gave their informedconsent. The experimental protocol was approved by the ethics committee of XinhuaHospital. The monotherapy study was designed to compare berberine with metformin(study A, n = 36). The combination therapy was aimed atevaluating additive or synergistic effects of berberine on the classicalanti-diabetic agents (study B, n = 48).
Major inclusion criteria were hemoglobin A1c (HbA1c)> 7.0% or fasting blood glucose (FBG) > 7.0 mmol/L, BMI> 22 kg/m2, age 25-75 years, and a negative pregnancy test forfemale patients. A total of 36 patients who were newly diagnosed for type 2 diabeteswere assigned to study A. After a two-month phase during which the patients weretreated with diet alone, they were randomly assigned to receive berberine ormetformin. A total of 48 type 2 diabetic patients inadequately treated with dietplus sulfonylureas, metformin, acarbose or insulin therapy alone or with acombination were assigned to study B (Table1). The dose of the medications was stable for at least 2 months beforeenrollment in the study and remained unchanged throughout the study. Allparticipants were instructed to maintain their lifestyle habits during the course ofthe study.
Table 1.
Baseline characteristics of administration of hypoglycemic agents
| Subjects (n) | Diet | Sulfonylureas | Metformin | Acarbose | Insulin |
|---|---|---|---|---|---|
| 36 | + | ||||
| 7 | + | + | |||
| 3 | + | + | |||
| 1 | + | + | |||
| 8 | + | + | |||
| 12 | + | + | + | ||
| 9 | + | + | + | ||
| 4 | + | + | + | ||
| 1 | + | + | + | ||
| 1 | + | + | + |
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Each study involved a 13-week treatment. For study A, 18 subjects took 500 mgberberine three times daily at the beginning of each major meal or 500 mg metforminthree times daily after major meals. For study B, 500 mg berberine three times dailywas added to their previous treatment for 3 months. If heavy gastrointestinalside-effects occurred, the dose of berberine was reduced to 300 mg three timesdaily.
Patients were evaluated weekly for the first 5 weeks of treatment and thenevery 4 weeks until the end of study. The primary efficacy end point was glycemiccontrol as determined by HbA1c levels. Secondary efficacy parametersincluded changes in fasting blood glucose (FBG), postprandial blood glucose (PBG),plasma triglycerides, total cholesterol, high-density lipoprotein cholesterol(HDL-C) and low-density lipoprotein cholesterol (LDL-C) concentrations. Adverseevents were recorded throughout the study by direct questioning.
2.1. Measurements
Blood glucose was determined by a glucose oxidase method (Roche, Basel,Switzerland). Serum insulin and C-peptide were determined by radioimmunoassay(Linco Research, St. Charles, MO). HbA1c was analyzed using thehigh-pressure liquid chromatography (BioRad, Hercules, CA). Plasma triglyceride,total cholesterol, HDL-C, LDL-C, alanine thansaminase (ALT), γ glutamyltranspeptidase (γ-GT) and creatinine concentrations were determined byenzymatic assays (Roche, Basel, Switzerland). The HOMA method was used tocompare differences in the profiles for insulin resistance (HOMA-IR) and forβ-cell dysfunction (HOMA-β cell) [7]. Ten insulin-treated subjects wereexcluded from the HOMA analysis.
HOMA-IR = fasting insulin (μU/ml)×fastingglucose (mmol/L)/22.5
HOMA-β cell = [20 − fasting insulin(μU/ml)] / [fasting glucose (mmol/L) - 3.5]
2.2. Statistical analysis
Descriptive statistics and analysis were performed in SPSS 12.0 forWindows. In study A, the significance of the differences between means ofmetformin and berberine groups was analyzed by Wilcoxon Rank Sum Test. Thestatistical differences between baseline and endpoint were calculated usingWilcoxon signed rank test. In study B, the significance of the differences amongdifferent time points was analyzed by repeated measure ANOVA. The αlevel was set at 0.05.
3. Results
In study A, 36 patients were included and randomly assigned to metformin orberberine treatment. Three patients of the berberine group and two patients of themetformin group withdrew from the study because of treatment failure. In study B, 48patients were included, and 5 subjects were excluded from the study before week 13.Among the five subjects, three failed to complete the study in lack of efficacy, onefailed in lack of participation time, and one was excluded due to lack of compliance(pill count < 80%). Thus, 74 participants were eligible for thefinal analysis.
3.1. Berberine verse metformin (study A)
In newly-diagnosed diabetic patients, berberine reduced blood glucoseand lipids (Table 2). There weresignificant decreases in HbA1c (by 2%; P< 0.01), FBG (by 3.8 mmol/L; P < 0.01) and PBG(by 8.8 mmol/L; P < 0.01) in the berberine group. TheFBG (or PBG) declined progressively during the berberine treatment, reaching anadir that was 3.7 mmol/L (or 8.7 mmol/L) below baseline by week 5, and remainedat this level until the end of the study (Fig1A). Triglycerides and total cholesterol decreased by 0.24 mmol/L(P < 0.05) and 0.57 mmol/L (P< 0.05) with berberine treatment. It seemed there was a declining trendof HDL-C and LDL-C; however, no significant differences between week 1 and week13 were observed in the berberine group. Compared with metformin, berberineexhibited an identical effect in the regulation of glucose metabolism, such asHbA1c, FBG, PBG, fasting insulin and postprandial insulin. In theregulation of lipid metabolism, berberine activity is better than metformin. Byweek 13, triglycerides and total cholesterol in the berberine group haddecreased and were significantly lower than in the metformin group(P<0.05).
Table 2.
Monotherapeutic effects of metformin and berberine
| Metformin (n=16) | Berberine (n=15) | |||
|---|---|---|---|---|
| Baseline | End point | Baseline | End point | |
| HbA1c (%) | 9.15 ± 0.57 | 7.72 ± 0.43** | 9.47 ± 0.65 | 7.48 ± 0.40** |
| FBG (mmol/L) | 9.96 ± 0.64 | 7.16 ± 0.71** | 10.63 ± 0.88 | 6.85 ± 0.53** |
| PBG (mmol/L) | 20.53 ± 1.87 | 12.86 ± 0.77** | 19.83 ± 1.66 | 11.05 ± 0.92** |
| Fasting insulin (μU/ml) | 27.3 ± 4.4 | 22.9 ± 5.2 | 29.1 ± 5.3 | 24.0 ± 5.5 |
| Postprandial insulin (μU/ml) | 125.3 ± 29.8 | 110.5 ± 21.4 | 120.4 ± 31.4 | 116.0 ± 26.9 |
| Triglyceride (mmol/L) | 1.19 ± 0.12 | 1.17 ± 0.13 | 1.13 ± 0.13 | 0.89 ± 0.03* |
| Total cholesterol (mmol/L) | 4.31 ± 0.28 | 4.27 ± 0.15 | 4.40 ± 0.21 | 3.83 ± 0.09* |
| HDL-C (mmol/L) | 1.25 ± 0.06 | 1.31 ± 0.08 | 1.33 ± 0.10 | 1.22 ± 0.04 |
| LDL-C (mmol/L) | 2.55 ± 0.38 | 2.43 ± 0.11 | 2.47 ± 0.13 | 2.36 ± 0.06 |
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Data are means ± SEM. Compared with baseline:
*
P<0.05,
**
P<0.01
Fig. 1.
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3.2. Combination-therapy of berberine (study B)
In the first 7 days of treatment, berberine led to a reduction in FBGfrom 9.6 ± 2.7 mmol/L to 7.8 ± 1.8 mmol/L(P<0.001; Fig 1C)and in PBG from 14.8 ± 4.1 mmol/L to 11.7 ± 3.6 mmol/L(P<0.001). During the second week, FBG and PBGdeclined further, reached a nadir that was 2.1 mmol/L (7.5 ± 2.1 mmol/L)and 3.3 mmol/L (10.5 ± 2.5 mmol/L) below the baseline, respectively, andremained at this level thereafter.
In the combination-therapy for 5 weeks, berberine led to a reduction inHbA1c from 8.1% to 7.3% (P< 0.001; Table 3). FBG and PBGdeclined remarkably, too (P < 0.001). Fasting insulinand HOMA-IR reduced by 29.0% (P < 0.01) and46.7% (P < 0.001), respectively. Blood lipidsincluding triglyceride, total cholesterol and LDL-C decreased and weresignificantly lower than baseline. In the absence of weight change, waist andwaist/hip of the patients declined significantly. No significant changes in thecriteria were observed between week 5 and week 13 except the increment offasting C-peptide (P < 0.05) and postprandial C-peptide(P < 0.01). During the study, fasting C-peptide ofthe patients with insulin treatment went down then up and postprandial C-peptideincreased by 70.5% (P<0.01) at 13 weeks.
Table 3.
Berberine in combination-therapy
| Week 0 | Week 5 | Week 13 | |
|---|---|---|---|
| BMI | 26.0 ± 0.6 | 26.1 ± 0.8 | 26.0 ± 0.8 |
| Waist (cm) | 89.0 ± 1.5 | 86.9 ± 1.8** | 87.0 ± 1.7** |
| Waist/hip | 0.89 ± 0.01 | 0.86 ± 0.01* | 0.86 ± 0.01 |
| HbA1c (%) | 8.1 ± 0.2 | 7.3 ± 0.2*** | 7.3 ± 0.3*** |
| FBG (mmol/L) | 9.6 ± 0.4 | 7.6 ± 0.3*** | 7.6 ± 0.3*** |
| PBG (mmol/L) | 14.8 ± 0.7 | 10.8 ± 0.6*** | 9.7 ± 0.9*** |
| Fasting insulin (μU/ml) | 35.2 ± 3.3 | 25.0 ± 2.6** | 25.3 ± 5.3** |
| Postprandial insulin (μU/ml) | 104.1 ± 9.5 | 88.0± 11.4 | 76.5 ± 15.6 |
| HOMA-IR | 15.2 ± 1.6 | 8.1 ± 1.0*** | 8.4 ± 1.8*** |
| HOMA-β cell | 128.6 ± 12.2 | 164.2 ± 27.3 | 151.7 ± 28.6 |
| Fasting C-peptide (ng/ml) | 0.96 ± 0.28 | 0.85 ± 0.24 | 1.12 ± 0.12*ˆ |
| Postprandial C-peptide (ng/ml) | 2.27 ± 0.72 | 2.28 ± 0.80 | 3.87 ± 0.14**ˆˆ |
| Triglyceride (mmol/L) | 1.73 ± 0.17 | 1.39 ± 0.18* | 1.49 ± 0.49 |
| Total cholesterol (mmol/L) | 4.97 ± 0.13 | 4.20 ± 0.13*** | 4.38 ± 0.40* |
| HDL-C (mmol/L) | 1.37 ± 0.04 | 1.31 ± 0.05 | 1.32 ± 0.05 |
| LDL-C (mmol/L) | 3.00 ± 0.10 | 2.50 ± 0.10*** | 2.59 ± 0.27** |
| ALT (U/L) | 31.5 ± 4.1 | 26.5 ± 2.6 | 25.2 ± 7.0 |
| γ-GT (U/L) | 41.8 ± 7.8 | 41.5 ± 8.4 | 41.4 ± 1.2 |
| Creatinine (mmol/L) | 88.5 ± 3.1 | 90.8 ± 3.7 | 90.8 ± 8.1 |
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Data are means ± SEM of the patients with combination-therapyincluding berberine. Values of fasting insulin, postprandial insulin,HOMA-IR and HOMA-β cell were obtained from 33 patients treatedonly with oral hypoglycemic agents. Values of fasting c-peptide andpostprandial c-peptide were obtained from the other 10 patients treatedincluding insulin. The rest parameters were obtained from all the 43patients with combination-therapy. Compared with Week 0:
*
P<0.05.
**
P<0.01.
***
P<0.001.
Compared with Week 5:
ˆ
P<0.05,
ˆˆ
P<0.01
3.3. Safety results
Incidence of gastrointestinal adverse events was 34.5% duringthe 13 weeks of berberine treatment including monotherapy andcombination-therapy. These events included diarrhea (n: 6;percentage: 10.3%), constipation (4; 6.9%), flatulence (11;19.0%) and abdominal pain (2; 3.4%). The side effects wereobserved only in the first four weeks in most patients. In 14 (24.1%)patients, berberine dosage decreased from 0.5 g t.i.d. to 0.3 g t.i.d. as aconsequence of gastrointestinal adverse events. Of the 14 patients, ten weretreated with metformin or acarbose in combination with berberine. The rest weretreated with insulin combined with berberine. None of the patients suffered fromsevere gastrointestinal adverse events when berberine was used alone. Incombination-therapy, the adverse events disappeared in one week after reductionin berberine dosage. The data suggest that berberine at dosage of 0.3 g t.i.d.is well tolerated in combination-therapy.
Liver and kidney functions were monitored in this study. No significantchanges of plasma ALT, γ-GT and creatinine were observed during the 13weeks of berberine treatment (Table 3).None of the patients were observed with pronounced (more than 50%)elevation in liver enzymes or creatinine.
4. Discussion
The hypoglycemic effect of berberine was reported in 1988 when it was usedto treat diarrhea in diabetic patients in China [8]. Since then, berberine has often been used asan anti-hyperglycemic agent by many physicians in China. There are substantialnumbers of clinical reports about the hypoglycemic action of berberine in Chineseliterature. However, most of the previous studies were not well-controlled andexperiments were not well-designed. Additionally, none of them used HbA1cas a parameter due to poor research conditions. Thus, the anti-diabetic effect ofberberine needs to be carefully evaluated.
In this pilot study, berberine significantly decreased HbA1clevels in diabetic patients. The effect of decreasing HbA1c was comparable to thatof metformin, a widely-used oral hypoglycemic agent [9, 10]. Inmonotherapy, berberine and metformin all improved glycemic parameters(HbA1c, FBG and PBG). But their effects on lipid metabolism weredifferent. Berberine decreased serum triglyceride and total cholesterolsignificantly. HDL-C and LDL-C levels of patients treated with berberine were alsoreduced but the decreases did not reach statistic significance. Whether berberinehas a lowering effect on HDL-C needs further investigation. Compared with berberine,metformin had little effects on these lipid parameters.
In combination with other agents, berberine exhibited consistent activitiesin improvement of glycemic and lipid parameters in diabetic patients. Insulinsensitivity was enhanced by berberine as the HOMA-IR value was reduced by nearly50%. This effect may be related to fat distribution by berberine becausewaist and waist/hip of the patients were decreased significantly in the absence ofweight change. Interestingly, both fasting and postprandial C-peptides increasedsignificantly in patients when berberine was used together with insulin, whichsuggests that long-term berberine treatment may improve insulin secretion of thepatients with consequent failure of oral hypoglycemic agents. The effects ofberberine on islet function need further studies.
The mechanism of berberine on glucose metabolism is still underinvestigation. We and others have demonstrated that berberine has an insulinsensitizing effect in vivo and in vitro [3, 4, 5, 11, 12]. In diet-induced obese rats,berberine reduced insulin resistance, similar to metformin [13, 6]. Inhepatocytes, adipocytes and myotubes, berberine increased glucose consumption and/orglucose uptake in the absence of insulin [3, 6, 14]. Berberine enhancing glucose metabolism maybe due to stimulation of glycolysis, which is related to inhibition of oxidation inmitochondria [6]. Berberinemay also act as an alpha-glucosidase inhibitor. It inhibited disaccharidasesactivities and decreased glucose transportation cross the intestinal epithelium[15, 16]. This may contribute to the adversegastrointestinal effects of berberine in some patients. This side effect was oftenobserved when berberine was used in combination with metformin or acarbose, whichalso have similar gastrointestinal side effects by themselves. Thus, when combinedwith these two agents, the dosage of berberine should be reduced to 0.3 g t.i.d. toavoid the severe flatulence or diarrhea.
Berberine is proposed to have potential as a therapeutic agent for lipidlowering. In this pilot study, berberine reduced serum cholesterol, triglyceridesand LDL-C. This activity is similar to that reported elsewhere in vivo[17, 18]. However, further studies including outcomestudies in humans are needed to confirm this activity and its benefit. The mechanismof berberine regulating lipid metabolism has been investigated by several groups. Inhamsters with hyperlipidemia, berberine reduced serum cholesterol and LDL-C, andincreased LDL receptor mRNA as well as protein in the liver [19]. These effects were partly due tostabilization of LDL receptor mRNA mediated by the ERK signaling pathway[20]. In addition toup-regulation of the LDL receptor, berberine was reported to inhibit lipid synthesisin human hepatocytes through activation of AMPK [21].
In summary, that berberine is a potent oral hypoglycemic agent with modesteffect on lipid metabolism. It is safe and the cost of treatment by berberine isvery low. It may serve as a new drug candidate in the treatment of type 2 diabetes.However, this is a pilot study. The efficacy of berberine needs to be tested in amuch larger population and characterized as a function of the known duration of thediabetes. Further studies are needed to evaluate the action of berberine on type 2diabetes in other ethnic groups.
Acknowledgments
Financial support for this study was provided by Xinhua Hospital. This study ispartially supported by NIH grant (P50 AT02776-020002) to J Ye.
Footnotes
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