Efficacy of Berberine in Patients with Type 2 Diabetes Compared to Metformin.

[Presser]

[h=1]Efficacy of Berberine in Patients with Type 2 Diabetes[/h]

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[h=2]Abstract[/h]Berberine has been shown to regulate glucose and lipid metabolism in vitro and in vivo. This pilot study was to determine the efficacy and safety of berberine in the treatment of type 2 diabetic patients. In study A, 36 adults with newly diagnosed type 2 diabetes were randomly assigned to treatment with berberine or metformin (0.5 g t.i.d.) in a 3-month trial. The hypoglycemic effect of berberine was similar to that of metformin. Significant decreases in hemoglobin A1c (HbA[SUB]1c[/SUB]; from 9.5% ± 0.5% to 7.5% ± 0.4%, P<0.01), fasting blood 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) and plasma triglycerides (from 1.13 ± 0.13 mmol/L to 0.89 ± 0.03 mmol/L, P<0.05) were observed in the berberine group. In study B, 48 adults with poorly controlled type 2 diabetes were treated supplemented with berberine in a 3-month trial. Berberine acted by lowering FBG and PBG from one week to the end of the trial. HbA[SUB]1c[/SUB] decreased from 8.1% ± 0.2% to 7.3% ± 0.3% (P<0.001). Fasting plasma insulin and HOMA-IR were reduced 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. Functional liver or kidney damages were not observed for all patients. In conclusion, this pilot study indicates that berberine is a potent oral hypoglycemic agent with beneficial effects on lipid metabolism.

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[h=2]1. Introduction[/h]Type 2 diabetes is a worldwide health threat and treatment of this disease is limited by availability of effective medications. All of the existing oral hypoglycemic agents have subsequent failure after long term administration. Thus, new oral medications are needed for long-term control of blood glucose in patients with type 2 diabetes. Certain botanical products from generally regarded as safe (GRAS) plants have been widely used in diabetes care because of their anti-oxidation, anti-inflammation, anti-obesity and anti-hyperglycemia properties.[1, 2]. However, the drawback of using GRAS plants is the difficulty in control their quality as most of these botanical products are mixtures of multiple compounds. Compared to other products from GRAS plants, berberine is a single purified compound, and has glucose-lowering effect in vitro and in vivo [3-6].
Berberine (molecular formula C[SUB]20[/SUB]H[SUB]19[/SUB]NO[SUB]5[/SUB] and molecular weight of 353.36) is the main active component of an ancient Chinese herb Coptis chinensis French, which has been used to treat diabetes for thousands of years. Berberine is an Over-the-Counter (OTC) drug, which is used to treat gastrointestinal infections in China. Berberine hydrochloride (B·HCl·nH2O) - the most popular form of berberine, is used in this pilot study. The chemical structure of Berberine and related isoquinoline alkaloids are quite different from the commonly used other hypoglycemic agents, such as sulphonylureas, biguanides, thiazolidinediones, or acarbose. Hence, if the efficacy and safety of berberine are confirmed, it can serve as a new class of anti-diabetic medication.
This pilot study was to assess the efficacy of berberine in human subjects with type 2 diabetes. Berberine was given to both newly diagnosed diabetic patients and poorly controlled diabetic patients alone or combination with other hypoglycemic agents for three months. HbA1c, blood glucose and HOMA index were used to determine the efficacy of berberine.

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[h=2]2. Subjects and methods[/h]The subjects were recruited from diabetes outpatient department of Xinhua Hospital by advertising in the clinic. Ninety-seven Chinese volunteers were screened, and 13 subjects were excluded from the study due to failure to meet the recruitment criteria. Thus, 84 subjects (49 women and 35 men) with type 2 diabetes were included in the study. All participants received written and oral information regarding the natural and potential risks of the study and gave their informed consent. The experimental protocol was approved by the ethics committee of Xinhua Hospital. The monotherapy study was designed to compare berberine with metformin (study A, n = 36). The combination therapy was aimed at evaluating additive or synergistic effects of berberine on the classical anti-diabetic agents (study B, n = 48).
Major inclusion criteria were hemoglobin A[SUB]1c[/SUB] (HbA[SUB]1c[/SUB]) > 7.0% or fasting blood glucose (FBG) > 7.0 mmol/L, BMI > 22 kg/m[SUP]2[/SUP], age 25-75 years, and a negative pregnancy test for female patients. A total of 36 patients who were newly diagnosed for type 2 diabetes were assigned to study A. After a two-month phase during which the patients were treated with diet alone, they were randomly assigned to receive berberine or metformin. A total of 48 type 2 diabetic patients inadequately treated with diet plus sulfonylureas, metformin, acarbose or insulin therapy alone or with a combination were assigned to study B (Table 1). The dose of the medications was stable for at least 2 months before enrollment in the study and remained unchanged throughout the study. All participants were instructed to maintain their lifestyle habits during the course of the study.

Table 1
Baseline characteristics of administration of hypoglycemic agents


Each study involved a 13-week treatment. For study A, 18 subjects took 500 mg berberine three times daily at the beginning of each major meal or 500 mg metformin three times daily after major meals. For study B, 500 mg berberine three times daily was added to their previous treatment for 3 months. If heavy gastrointestinal side-effects occurred, the dose of berberine was reduced to 300 mg three times daily.
Patients were evaluated weekly for the first 5 weeks of treatment and then every 4 weeks until the end of study. The primary efficacy end point was glycemic control as determined by HbA[SUB]1c[/SUB] levels. Secondary efficacy parameters included 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. Adverse events were recorded throughout the study by direct questioning.
[h=3]2.1. Measurements[/h]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). HbA[SUB]1c[/SUB] was analyzed using the high-pressure liquid chromatography (BioRad, Hercules, CA). Plasma triglyceride, total cholesterol, HDL-C, LDL-C, alanine thansaminase (ALT), γ glutamyl transpeptidase (γ-GT) and creatinine concentrations were determined by enzymatic assays (Roche, Basel, Switzerland). The HOMA method was used to compare differences in the profiles for insulin resistance (HOMA-IR) and for β-cell dysfunction (HOMA-β cell) [7]. Ten insulin-treated subjects were excluded from the HOMA analysis.
HOMA-IR = fasting insulin (μU/ml)×fasting glucose (mmol/L)/22.5
HOMA-β cell = [20 − fasting insulin (μU/ml)] / [fasting glucose (mmol/L) - 3.5]

[h=3]2.2. Statistical analysis[/h]Descriptive statistics and analysis were performed in SPSS 12.0 for Windows. In study A, the significance of the differences between means of metformin and berberine groups was analyzed by Wilcoxon Rank Sum Test. The statistical differences between baseline and endpoint were calculated using Wilcoxon signed rank test. In study B, the significance of the differences among different time points was analyzed by repeated measure ANOVA. The α level was set at 0.05.

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[h=2]3. Results[/h]In study A, 36 patients were included and randomly assigned to metformin or berberine treatment. Three patients of the berberine group and two patients of the metformin group withdrew from the study because of treatment failure. In study B, 48 patients 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, one failed in lack of participation time, and one was excluded due to lack of compliance (pill count < 80%). Thus, 74 participants were eligible for the final analysis.
[h=3]3.1. Berberine verse metformin (study A)[/h]In newly-diagnosed diabetic patients, berberine reduced blood glucose and lipids (Table 2). There were significant decreases in HbA[SUB]1c[/SUB] (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. The FBG (or PBG) declined progressively during the berberine treatment, reaching a nadir that was 3.7 mmol/L (or 8.7 mmol/L) below baseline by week 5, and remained at this level until the end of the study (Fig 1A). 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 trend of HDL-C and LDL-C; however, no significant differences between week 1 and week 13 were observed in the berberine group. Compared with metformin, berberine exhibited an identical effect in the regulation of glucose metabolism, such as HbA[SUB]1c[/SUB], FBG, PBG, fasting insulin and postprandial insulin. In the regulation of lipid metabolism, berberine activity is better than metformin. By week 13, triglycerides and total cholesterol in the berberine group had decreased and were significantly lower than in the metformin group (P<0.05).

Fig. 1
Both berberine and metformin decreased FBG and PBG of type 2 diabetic patients significantly from week 1 to week 13. A, means ± SEM of 15 patients treated with berberine alone. B, means ± SEM of 16 patients treated with metformin alone. ...

Table 2
Monotherapeutic effects of metformin and berberine



[h=3]3.2. Combination-therapy of berberine (study B)[/h]In the first 7 days of treatment, berberine led to a reduction in FBG from 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 PBG declined 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, and remained at this level thereafter.
In the combination-therapy for 5 weeks, berberine led to a reduction in HbA[SUB]1c[/SUB] from 8.1% to 7.3% (P < 0.001; Table 3). FBG and PBG declined remarkably, too (P < 0.001). Fasting insulin and HOMA-IR reduced by 29.0% (P < 0.01) and 46.7% (P < 0.001), respectively. Blood lipids including triglyceride, total cholesterol and LDL-C decreased and were significantly lower than baseline. In the absence of weight change, waist and waist/hip of the patients declined significantly. No significant changes in the criteria were observed between week 5 and week 13 except the increment of fasting C-peptide (P < 0.05) and postprandial C-peptide (P < 0.01). During the study, fasting C-peptide of the patients with insulin treatment went down then up and postprandial C-peptide increased by 70.5% (P<0.01) at 13 weeks.

Table 3
Berberine in combination-therapy



[h=3]3.3. Safety results[/h]Incidence of gastrointestinal adverse events was 34.5% during the 13 weeks of berberine treatment including monotherapy and combination-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 were observed 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 a consequence of gastrointestinal adverse events. Of the 14 patients, ten were treated with metformin or acarbose in combination with berberine. The rest were treated with insulin combined with berberine. None of the patients suffered from severe gastrointestinal adverse events when berberine was used alone. In combination-therapy, the adverse events disappeared in one week after reduction in 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 significant changes of plasma ALT, γ-GT and creatinine were observed during the 13 weeks of berberine treatment (Table 3). None of the patients were observed with pronounced (more than 50%) elevation in liver enzymes or creatinine.

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[h=2]4. Discussion[/h]The hypoglycemic effect of berberine was reported in 1988 when it was used to treat diarrhea in diabetic patients in China [8]. Since then, berberine has often been used as an anti-hyperglycemic agent by many physicians in China. There are substantial numbers of clinical reports about the hypoglycemic action of berberine in Chinese literature. However, most of the previous studies were not well-controlled and experiments were not well-designed. Additionally, none of them used HbA[SUB]1c[/SUB] as a parameter due to poor research conditions. Thus, the anti-diabetic effect of berberine needs to be carefully evaluated.
In this pilot study, berberine significantly decreased HbA[SUB]1c[/SUB] levels in diabetic patients. The effect of decreasing HbA1c was comparable to that of metformin, a widely-used oral hypoglycemic agent [9, 10]. In monotherapy, berberine and metformin all improved glycemic parameters (HbA[SUB]1c[/SUB], FBG and PBG). But their effects on lipid metabolism were different. Berberine decreased serum triglyceride and total cholesterol significantly. HDL-C and LDL-C levels of patients treated with barbering were also reduced but the decreases did not reach statistic significance. Whether berberine has 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 activities in improvement of glycemic and lipid parameters in diabetic patients. Insulin sensitivity was enhanced by berberine as the HOMA-IR value was reduced by nearly 50%. This effect may be related to fat distribution by berberine because waist and waist/hip of the patients were decreased significantly in the absence of weight change. Interestingly, both fasting and postprandial C-peptides increased significantly in patients when berberine was used together with insulin, which suggests that long-term berberine treatment may improve insulin secretion of the patients with consequent failure of oral hypoglycemic agents. The effects of berberine on islet function need further studies.
The mechanism of berberine on glucose metabolism is still under investigation. We and others have demonstrated that berberine has an insulin sensitizing 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]. In hepatocytes, adipocytes and myotubes, berberine increased glucose consumption and/or glucose uptake in the absence of insulin [3, 6, 14]. Berberine enhancing glucose metabolism may be due to stimulation of glycolysis, which is related to inhibition of oxidation in mitochondria [6]. Berberine may also act as an alpha-glucosidase inhibitor. It inhibited disaccharidases activities and decreased glucose transportation cross the intestinal epithelium [15, 16]. This may contribute to the adverse gastrointestinal effects of berberine in some patients. This side effect was often observed when berberine was used in combination with metformin or acarbose, which also have similar gastrointestinal side effects by themselves. Thus, when combined with these two agents, the dosage of berberine should be reduced to 0.3 g t.i.d. to avoid the severe flatulence or diarrhea.
Berberine is proposed to have potential as a therapeutic agent for lipid lowering. In this pilot study, berberine reduced serum cholesterol, triglycerides and LDL-C. This activity is similar to that reported elsewhere in vivo [17, 18]. However, further studies including outcome studies in humans are needed to confirm this activity and its benefit. The mechanism of berberine regulating lipid metabolism has been investigated by several groups. In hamsters with hyperlipidemia, berberine reduced serum cholesterol and LDL-C, and increased LDL receptor mRNA as well as protein in the liver [19]. These effects were partly due to stabilization of LDL receptor mRNA mediated by the ERK signaling pathway [20]. In addition to up-regulation of the LDL receptor, berberine was reported to inhibit lipid synthesis in human hepatocytes through activation of AMPK [21].
In summary, that berberine is a potent oral hypoglycemic agent with modest effect on lipid metabolism. It is safe and the cost of treatment by berberine is very 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 a much larger population and characterized as a function of the known duration of the diabetes. Further studies are needed to evaluate the action of berberine on type 2 diabetes in other ethnic groups.
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[h=2]Clinical Applications for Berberine[/h][h=3]Potential therapeutic applications in metabolic syndrome, type 2 diabetes, and dyslipidemia[/h]By Jacob Schor, ND, FABNO
[h=3]About The Author[/h]

Jacob Schor ND, FABNO, is a graduate of National College of Naturopathic Medicine, Portland, Oregon, and now practices in Denver, Colorado. He served as president to the Colorado Association of Naturopathic Physicians and is now on the board of directors of both the Oncology Association of Naturopathic Physicians and the American Association of Naturopathic Physicians. He is recognized as a fellow by the American Board of Naturopathic Oncology. He serves on the editorial board for theInternational Journal of Naturopathic Medicine, Naturopathic Doctor News and Review (NDNR),and Integrative Medicine: A Clinician's Journal. In 2008, he was awarded the Vis Award by the American Association of Naturopathic Physicians. His writing appears regularly in NDNR, theTownsend Letter, and Natural Medicine Journal.



[h=3]Abstract[/h]New clinical applications for the alkaloid berberine have come to light in recent years. Applications related to adenosine monophosphate-activated protein kinase (AMPK) activation and berberine’s possible therapeutic use in metabolic syndrome, type 2 diabetes, and dyslipdemia are reviewed in this article. Potential applications related to cancer are not discussed here but are reserved for a second review.
[h=3]Introduction[/h]In recent years, the botanical extract berberine has been pushed from relative obscurity to front and center on our supplement shelves due to newly published research. Over a third of the approximately 2,800 studies on berberine listed on PubMed were published in the last 5 years. These studies reveal that berberine may have clinical applications in a range of conditions.
The chemical berberine is found in a handful of plants widely used in botanical medical practice including Goldenseal (Hydrastis canadensis), Oregon grape (Berberis aquifolium), Barberry (Berberis vulgaris), and Chinese Goldthread (Coptis chinensis). Two other berberine-containing plants that are familiar to practitioners of Chinese medicine are Phellodendron chinense andPhellodendron amurense.
Berberine is yellow in color, and plants containing berberine often have been used as a dye, particularly for coloring wool. Chemically, berberine is classified as an isoquinoline alkaloid.
For the past 15 years, our understanding of berberine has been based on an article written by Tim Birdsall and Greg Kelly that was published in Alternative Medicine Review in 1997.[SUP]1[/SUP] These sagacious colleagues focused on the relatively short list of actions of berberine that were known at the time:

1. Antimicrobial action against bacteria, fungi, protozoa, viruses, helminthes, and Chlamydia
2. Antagonism against the effects of cholera and E coli heat-stable enterotoxin
3. Inhibition of intestinal ion secretion and of smooth muscle contraction
4. Reduction of inflammation
5. Stimulation of bile secretion and bilirubin discharge

At the time the article was written, berberine was assumed to be useful for the treatment of infectious gastritis, and for many years berberine was placed on the pharmacy shelf where supplements for “GI complaints” were found. These days, berberine may deserve a shelf of its own.
There are 3 general conditions for which we should consider berberine: metabolic syndrome, inflammation, and cancer. This review will cover the first of these 3 conditions, metabolic syndrome.
[h=3]AMPK Activation[/h]The fundamental mechanism of action underlying berberine’s impact on human health is probably its action on the adenosine monophosphate-activated protein kinase or AMP-activated protein kinase (AMPK). To understand what berberine does, one must first understand AMPK. This enzyme acts as the central energy regulatory control switch regulating how energy is produced and used in the body. AMPK induces a cascade of events within cells that are all involved in maintaining energy homeostasis. The AMPK system senses and responds to changes in energy metabolism both on the cellular and the whole-body level. It is via AMPK that low energy status switches cellular metabolism from ATP-consuming anabolic pathways to ATP-producing catabolic pathways.
AMPK regulates an array of biological activities that normalize lipid, glucose, and energy imbalances. Metabolic syndrome (MetS) occurs when these AMPK-regulated pathways are turned off, triggering a syndrome that includes hyperglycemia, diabetes, lipid abnormalities, and energy imbalances.[SUP]2[/SUP]
AMPK has been proposed as a target for drug monotherapy treatment of metabolic syndrome. Current MetS treatment typically employs 3 to 5 different medications to manage the different comorbidities such as hyperglycemia, hypertension, hyperlipidemia, and inflammation.3 In theory, a single medication that activates AMPK could replace all of the medications used to treat these various aspects of MetS. Rather than treating symptoms, controlling the AMPK switch may control the entire gamut of metabolic syndrome symptoms.[SUP]4[/SUP]
AMPK helps coordinate the response to these stressors, shifting energy toward cellular repair, maintenance, or a return to homeostasis and improved likelihood of survival. The hormones leptin and adiponectin activate AMPK. In other words, activating AMPK can produce the same benefits as exercise, dieting, and weight loss—the lifestyle modifications considered beneficial for a range of maladies.
While AMPK is activated by energy depletion, it is inhibited by energy excess.
High glucose and glycogen levels inhibit AMPK. This inhibition leads to many of the long-term consequences of diabetes. Exercise and caloric restriction activate AMPK, and this explains their benefit in treating diabetes. High fat intake also inhibits AMPK.
One way to appreciate berberine’s potential is to think of it as having the same effect on a patient as increasing exercise while at the same time restricting calorie intake. Think of the effects of AMPK suppression as similar to those of eating a high-calorie diet while leading a very sedentary lifestyle.
Only a few chemicals are known to activate AMPK. Berberine is one of them. Reports that berberine activates AMPK were first published in 2006.[SUP]5[/SUP] Resveratrol, salicylate, and metformin also activate this chemical pathway.[SUP]6,7[/SUP]
AMPK activation was cited early on as an explanation of berberine’s ability to improve glucose control in diabetic animals. Berberine increases glucose uptake by muscle fibers independent of insulin levels.[SUP]8[/SUP] Berberine triggers AMPK activation and increases glycolysis, leading to decreased insulin resistance and decreased oxygen respiration.[SUP]9[/SUP] The same mechanism leads to a reduction in gluconeogenesis in the liver.[SUP]10[/SUP] AMPK activation also explains why berberine has an antiatherosclerotic effect in mice.[SUP]11[/SUP] The same mechanism is reported to underlie berberine’s antiobesity effects and favorable influence on weight loss.[SUP]12[/SUP]
Caloric restriction and increased exercise also affect the likelihood of one contracting cancer.[SUP]13[/SUP] Thus it is understandable that berberine-induced AMPK activation is cited for some of its anticancer effects—for example, berberine’s ability to inhibit metastasis of melanoma cells.[SUP]14[/SUP] Berberine’s ability to blunt and suppress proinflammatory responses is also mediated through AMPK activation.[SUP]15[/SUP] There is such a significant amount of published and ongoing research into berberine’s anticancer potential that I have chosen not to cover it in this review but instead to review it specifically at a later time.
One way to understand berberine’s action in diabetes is to consider the actions of metformin, a common pharmaceutical drug that is also an AMPK activator.[SUP]16[/SUP] Metformin activates AMPK to a similar degree as berberine, and as a result, they affect metabolism similarly. So it should be no surprise that, like metformin, berberine appears useful for treating type-2 diabetes.
Berberine has been used successfully to treat experimental diabetes in test animals.[SUP]17,18[/SUP] It has also been used to treat type-2 diabetes in human trials.[SUP]19–22[/SUP]

There are 3 general conditions for which we should consider berberine: metabolic syndrome, inflammation, and cancer.
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Wang reported in 2009 that berberine (100 mg/kg) restored the vascular endothelial function by increasing nitric oxide levels in rats in which diabetes had been induced by a combination of high-fat diets and treatment with streptozotocin.[SUP]23[/SUP]Wang et al reported similar benefits in a similar rat model in 2011. In this case, the diabetic rats were treated with ascending doses of berberine: 0 (control), 50, 100, and 150 mg/kg/d of berberine for 6 weeks. The hypoglycemic effects of berberine were evidenced in the fasting blood glucose levels and insulin-sensitizing effects.[SUP]24[/SUP]
In 2008, Yin reported the results of 2 human trials in the journal Metabolism on patients newly diagnosed with type-2 diabetes who were randomly treated to take either berberine or metformin (500 mg 3 times a day) in a 3-month trial. The hypoglycemic effect of berberine was similar to that of metformin. In the first study (n=36), the hypoglycemic effect of berberine was similar to metformin with a 2% decrease in A1c (P<0.01) and fasting blood glucose (-8.7 mmo/L, P<.01). In the second study (n=48), patients with poorly controlled type-2 diabetes took berberine for 3 months. Hemoglobin A1c decreased from 8.1% to 7.3% (P<.001).[SUP]25[/SUP]
A recent meta-analysis by Dong et al combined data from 14 randomized trials involving 1,068 participants. Treatment with both berberine and lifestyle modification showed significant hypoglycemic and antidyslipidemic benefits. The effects did not differ from those obtained by the standard hypoglycemic drugs metformin, glipizide, or rosiglitazone.[SUP]26[/SUP]
Berberine has been studied and shown to be effective in treating other conditions that respond to metformin.
In January 2012, the European Journal of Endocrinology published results of a clinical trial that found berberine compared favorably with metformin when used to treat women (n=89) with polycystic ovary syndrome (PCOS).[SUP]27[/SUP] A year earlier, an article in Fertility and Sterility reported that berberine reduces insulin resistance in ovarian theca cells and decreased their excessive testosterone production.[SUP]28[/SUP]
Berberine, like metformin, appears to be useful for treating metabolic syndrome. Not only does it reduce insulin resistance but it also normalizes the lipid profiles characteristic of the condition.[SUP]29[/SUP]
Berberine, like metformin, can help reduce the side effect of weight gain triggered by antipsychotic medications.[SUP]30, 31[/SUP]
Researchers have become intrigued by the potential benefit metformin has in treating cancer. It is possible that berberine will have a parallel action.
Berberine increases expression of insulin receptors and so reduces insulin resistance.[SUP]32,33[/SUP] A 2009 study in China suggested that a synergistic action occurs when berberine is combined with metformin or 2,4-thiazolidinedione (THZ) (a peroxisome proliferator-activated receptor [PPAR] activator used to treat diabetes) and might allow a reduction in the amount of these drugs required for treatment and so reduce the risk of toxicity.[SUP]34[/SUP]
If one thinks of AMPK activation as “something that reverses metabolic syndrome,” then several other aspects of metabolic syndrome and potential actions for berberine come to mind. Aside from hyperglycemia, there are 3 other hallmarks of metabolic syndrome: dyslipidemia, fatty liver, and inflammation.
Berberine has a positive impact on all 3.
[h=3]Lipid Profile[/h]A December 2004 article described berberine as “a novel cholesterol-lowering drug” that worked through a “unique mechanism distinct from statins.” The authors had given berberine to 32 hypercholesterolemic patients for 3 months. The treatment reduced serum cholesterol by 29%, triglycerides by 35%, and LDL-cholesterol by 25%.[SUP]35[/SUP]
A 2009 study reported that in rats, AMPK activation triggered by berberine prevented the development of fatty liver.36 This was followed in 2011 by a randomized controlled trial of 60 humans with fatty liver disease. The tracking of numerous biomarkers showed that 3 months of “berberine can obviously improve the conditions.” Liver ultrasounds of the study participants showed a 70% improvement. Total cholesterol and triglycerides also decreased significantly in this trial. These patients took 0.5 g of berberine twice per day.[SUP]37[/SUP]
According to a randomized controlled trial conducted in 2008 with diabetic rats in which dyslipidemia had been induced with a combination of streptozotocin and a high-fat diet, “Berberine reduced diabetic rats’ body weight, liver weight and liver to body weight ratio. Berberine restored the increased blood glucose, hemoglobin A1c, total cholesterol, triglyceride, low density lipoprotein-cholesterol, apolipoprotein B and the decreased high density lipoprotein-cholesterol, apolipoprotein AI levels in diabetic rats to near the control ones. Berberine alleviated the pathological progression of liver and reverted the increased hepatic glycogen and triglyceride to near the control levels.”[SUP]38[/SUP]
A 2010 human clinical trial analyzed changes in serum metabolites, particularly free fatty acid levels, in 60 patients with type-2 diabetes who had taken berberine. The berberine group had significantly lower levels of free fatty acids, chemicals that are toxic to the pancreas and linked with insulin resistance.[SUP]39,40[/SUP]
Berberine’s lipid-lowering mechanism of action is different from that found in the statin drugs.[SUP]41[/SUP] Combining berberine with statin drugs has a synergistic effect and is more effective than using either alone. In 2008, a Chinese researcher reported in the journal Metabolism results of a study that combined berberine with simvastatin. The researchers began by treating hyperlipidemic rats with a combination of both agents together or as monotherapies; the combination of both agents reduced cholesterol by 46% while simvastatin alone reduced cholesterol by 28% and berberine alone by 27%. Combination therapy was then tried on 63 hypercholesterolemic patients. The combined therapy lowered LDL cholesterol 32% more than either monotherapy. Similar benefits were seen with total cholesterol and triglycerides.[SUP]42[/SUP]
Similar synergistic action was seen in an experiment using hyperlipidemic hamsters and treating them with a combination of berberine and plant stanols.[SUP]43[/SUP]
While improving lipids may improve cardiovascular disease (CVD) risk, berberine has other beneficial actions that lower CVD risk. It improves arterial endothelial function and suppresses proinflammatory cytokines, actions that should improve heart health.[SUP]44–48[/SUP]
Adding berberine to cultures of human macrophage–derived foam cells, which had been induced by oxidized LDL, significantly inhibits the effect of oxidized LDL in a dose- and time-dependent manner and inhibits the expression of its lectin-like receptor (LOX-1) actions suggesting that berberine could be useful in treating atherosclerotic diseases.[SUP]49[/SUP]
A July 2003 study published in the American Journal of Cardiology examined the use of berberine in congestive heart failure (CHF). The authors randomly divided 156 patients with CHF into 2 groups. All patients were treated with conventional therapy but 1 group of 79 patients was also given berberine at a dose of 1.2 to 2.0 grams per day. After 8 weeks of berberine treatment, “there was a significantly greater increase in left ventricular ejection fraction, exercise capacity, improvement of the dyspnea-fatigue index, and a decrease of frequency and complexity of VPCs [ventricular premature complexes] compared with the control group. There was a significant decrease in mortality in the berberine-treated patients during long-term follow-up (7 patients receiving treatment died vs 13 on placebo, P<.02).” Proarrhythmia was not observed, and there were no apparent side effects.”[SUP]50[/SUP]
[h=3]Aldose Reductase[/h]A second chemical pathway of interest when considering therapeutic applications of berberine to diabetes is the aldose reductase pathway. Aldose reductase is the rate-limiting enzyme in the polyol pathway. It reduces glucose to sorbitol using NADPH (nicotinamide adenine dinucleotide phosphate) as a cofactor. Sorbitol is then metabolized to fructose by sorbitol dehydrogenase. In healthy people, only a small amount of glucose (less than 3%) moves through this pathway. However, in the presence of high glucose levels, as much as 30% of total glucose will follow this path. In diabetics, this abnormal flow of glucose down the polyol pathway leads to the accumulation of large amounts of sorbitol, which in turn leads to both osmotic and oxidative stress in the tissues where sorbitol accumulates.[SUP]51[/SUP] Aldose reductase plays a significant role in much of the pathology caused by diabetes, including diabetic neuropathy, retinopathy, and nephropathy.[SUP]52[/SUP]
Lee’s 2002 report in the Journal of Agriculture and Food Chemistry revealed that berberine is an aldose reductase inhibitor.53
In 2 separate articles published in 2008, Liu reported that berberine extracts protected or helped repair the kidneys of diabetic mice partly through aldose reductase inhibition.[SUP]54,55[/SUP] Berberine reduced oxidative stress in the kidneys.[SUP]56[/SUP]
Aldose reductase plays a role in diabetic cataract formation, and inhibition helps prevent cataract formation.[SUP]57[/SUP]
Because of these properties, berberine alkaloids “would clearly have beneficial uses in the development of therapeutic and preventive agents for diabetic complications and diabetes mellitus.”[SUP]58[/SUP]
A number of other chemical pathways have been delineated that underlie berberine’s antidiabetic actions. Berberine inhibits dipeptidyl peptidase-4 (DPP IV) and human protein tyrosine phosphatase 1B (h-PTP 1B).[SUP]59[/SUP] It suppresses production of intestinal disaccharidases, reducing sugar digestion and absorption.[SUP]60[/SUP] It improves glucose metabolism by inducing glycolysis.[SUP]61[/SUP] It also increases glucose transporter-4 (GLUT-4) and glucagon-like peptide-1 (GLP-1) levels.[SUP]62[/SUP] The peptide GLP-a is more commonly known by the name incretin.[SUP]63[/SUP] Historically, incretin is the first hormone to have been identified. It is secreted by the small intestine after eating and triggers release of insulin. Exenatide (Byetta) and liraglutide (Victoza), both incretin mimetics, have been developed and are now prescribed to treat type-2 diabetes.[SUP]64[/SUP]
[h=3]Absorption[/h]Berberine was thought to be poorly absorbed across the gut wall. Pharmacokinetic researchers have certainly found low plasma concentrations—levels so low that “the remarkable variety of pharmacological effects exerted by Ber[berine] at blood concentrations below the effective dose required for activity in vitro has been regarded with considerable skepticism.”[SUP]65[/SUP]
The pharmacokinetics of berberine are “obscure because plasma concentrations after p.o. administration are too low to detect using general analytic approaches such as HPLC.”[SUP]66[/SUP] As a result, it had been assumed that very little if any berberine is absorbed.
It now appears that the situation is more complex; berberine actually appears to be well absorbed. The confusion lies in the fact that it is quickly metabolized. Blood clearance is so fast and biotransformation in the liver so rapid that berberine disappears from the blood faster than it can be measured. Berberine metabolites may be responsible for berberine’s biological action.
Most berberine is metabolized in the liver through phase I demethylation and phase II glucuronidation, after which the metabolites are excreted with the bile.
Considerable interest has been directed toward creating nanoparticle delivery systems for berberine, the assumption being that therapeutic effects will increase with increased absorption. These delivery systems fall into 3 general types: solid lipid nanoparticles, nanoemulsions, and liposomes.[SUP]67[/SUP]
Wang et al compared the blood sugar–lowering effect of a nanoemulsion made of phosphatidyl-choline micelles and berberine against intravenously administered and plain oral berberine in diabetic mice. Intravenous injection of a berberine solution lowered blood sugar by 22% while the oral nanoemulsion of berberine lowered blood sugar levels by 57%. The blood glucose–lowering effect of standard oral berberine did not reach statistical significance in this trial.[SUP]68[/SUP]
Results like these are exciting; they suggest the potential for much stronger impact. Enhanced oral delivery systems that could increase the clinical effectiveness of berberine will likely be introduced in the coming years.
[h=3]What Was Left Out?[/h]This review has by and large ignored several major therapeutic applications for berberine. A second article will review berberine’s potential use in treating inflammatory conditions, cancer, depression, and neurodegenerative illnesses.
[h=3]Conclusion[/h]While the known clinical applications for berberine are diverse and becoming more so over time, there are a few generalizations we might make that will allow us to understand berberine’s potential. Berberine activates AMPK in a manner similar to how exercise stimulates increased strength and weight loss. Thus, any condition that would be favorably impacted by a patient losing weight and/or exercising more may be impacted favorably by oral berberine supplementation. It makes sense to consider using berberine in patients with insulin resistance, pre-diabetes, diabetes, metabolic syndrome, hypertension, heart disease, dyslipidemia, cancer, depression, and other neuropsychiatric diseases. We also can look at conditions improved by other AMPK-activating drugs, in particular metformin, to help make educated guesses of other possible applications that may soon be revealed.

 

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I'm actually going to pick some of this stuff up today

 

[Area 1255]

Berberine is also a potent nitric oxide releaser and natural PDE-5 inhibitor.


http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3466.2001.tb00068.x/abstract
Keywords:

• Antiarrhythmic drugs;
• Arrhythmia;
• Berberine;
• Cardiovascular drugs;
• Chinese medicine;
• Heart failure;
• Vasodilation

ABSTRACT


Berberine, is an alkaloid from Hydrastis canadensis L., Chinese herb Huanglian, and many other plants. It is widely used in traditional Chinese medicine as an antimicrobial in the treatment of dysentery and infectious diarrhea. This manuscript describes cardiovascular effects of berberine and its derivatives, tetrahydroberberine and 8-oxoberberine. Berberine has positive inotropic, negative chronotropic, antiarrhythmic, and vasodilator properties. Both derivatives of berberine have antiarrhythmic activity. Some of cardiovascular effects of berberine and its derivatives are attributed to the blockade of K[SUP]+[/SUP] channels (delayed rectifier and K[SUB]ATP[/SUB]) and stimulation of Na[SUP]+[/SUP]-Ca[SUP]2+[/SUP]exchanger. Berberine has been shown to prolong the duration of ventricular action potential. Its vasodilator activity has been attributed to multiple cellular mechanisms. The cardiovascular effects of berberine suggest its possible clinical usefulness in the treatment of arrhythmias and/or heart failure.

Zhonghua Nan Ke Xue. 2004 Dec;10(12):890-3.

[Effect of berberine on the mRNA expression of phosphodiesterase type 5 (PDE5) in rat corpus cavernosum].

[Article in Chinese]
Tan Y1, Tang Q, Hu B, Xiang J.
Author information



Abstract

OBJECTIVE:

<abstracttext label="OBJECTIVE" nlmcategory="OBJECTIVE">To further investigate the action mechanisms of berberine (Ber) and to assess the effects of Ber on the mRNA expression of phosphodiesterase type 5 (PDE5) in rat corpus cavernosum.</abstracttext>
METHODS:

<abstracttext label="METHODS" nlmcategory="METHODS">After incubating with Ber for 1 or 3 h respectively, we examined the levels of PDE5 mRNA by reverse transcription polymerase chain reaction (RT-PCR).</abstracttext>
RESULTS:

<abstracttext label="RESULTS" nlmcategory="RESULTS">There were PDE5A1 and PDE5A2 mRNA expressions in the rat corpus cavernosum with PDE5A2 as the dominant isoform. Ber could obviously inhibit the mRNA expression of the two isoforms in the rat penis and bring on a pronounced decrease in PDE5A2 (P < 0.01).</abstracttext>
CONCLUSION:

<abstracttext label="CONCLUSION" nlmcategory="CONCLUSIONS">The present study indicates that the inhibitory effect of Ber on PDE5 mRNA expression, especially on PDE5A2, might account for its molecular mechanism for treating ED.</abstracttext>


<dt style="font-size: 0.8465em; line-height: 1.4em; color: rgb(87, 87, 87); display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; white-space: nowrap; margin-left: 0px !important;">PMID:</dt><dd style="font-size: 0.8465em; line-height: 1.4em; color: rgb(87, 87, 87); margin: 0px; display: inline; padding: 0px; white-space: nowrap;">15638014</dd><dd style="font-size: 0.8465em; line-height: 1.4em; color: rgb(87, 87, 87); margin: 0px; display: inline; padding: 0px; white-space: nowrap;">[PubMed - indexed for MEDLINE]</dd>

Acta Pharmacol Sin. 2005 Nov;26(11):1334-8.
Roles of nitric oxide in protective effect of berberine in ethanol-induced gastric ulcer mice.

Pan LR1, Tang Q, Fu Q, Hu BR, Xiang JZ, Qian JQ.
Author information



Abstract

AIM:

<abstracttext label="AIM" nlmcategory="OBJECTIVE">To investigate the protective effects of berberine on ethanol-induced gastric ulcer in mice.</abstracttext>
METHODS:

<abstracttext label="METHODS" nlmcategory="METHODS">Gastric ulcers were induced by oral ingestion of ethanol. Nitric oxide (NO) content was measured, and mRNA expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) were analyzed by reverse transcription-polymerase chain reaction (RT-PCR).</abstracttext>
RESULTS:

<abstracttext label="RESULTS" nlmcategory="RESULTS">The ulcer index (UI) at 1 h, 2 h, 3 h and 6 h after oral administration of ethanol was 23.8+/-1.4, 23.3+/-2.2, 22.3+/-1.2 and 20.8+/-1.1, respectively. The UI in the berberine-treated groups (5 mg/kg and 50 mg/kg) was less than the control group. The content of NO in the control group was 73.3+/-7.3 microL/L, 94.0+/-9.2 microL/L, 109.6+/-6.4 microL/L and 138.2+/-10.2 microL/L in gastric juice and 5.8+/-1.1 micromol/g protein, 8.3+/-1.1 micromol/g protein, 9.8+/-1.1 micromol/g protein and 11.9+/-1.2 micromol/g protein in gastric tissue at 1 h, 2 h, 3 h and 6 h, respectively, after the oral administration of ethanol. The content of NO in the berberine-treated groups (5 mg/kg and 50 mg/kg) was higher than the control group at 1 h after the oral administration of ethanol (P<0.05), and was lower at 6 h (P<0.05). Analysis by RT-PCR showed that expression of eNOS was inhibited but iNOS expression was enhanced by ethanol. However, the expression of eNOS could be enhanced and iNOS expression could be inhibited by berberine (P<0.01).</abstracttext>
CONCLUSION:

<abstracttext label="CONCLUSION" nlmcategory="CONCLUSIONS">Berberine could significantly protect gastric mucosa from damage by ethanol. This effect may be related to the increased expression of eNOS mRNA and inhibited expression of iNOS mRNA.</abstracttext>


<dl class="rprtid" style="margin-right: 15px; margin-left: 0px; font-size: 0.8465em; line-height: 1.4em; display: inline;"><dt style="display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px !important; white-space: nowrap;">PMID:</dt> <dd style="margin: 0px; display: inline; padding: 0px; white-space: nowrap;">16225755</dd> <dd style="margin: 0px; display: inline; padding: 0px; white-space: nowrap;">[PubMed - indexed for MEDLINE] </dd><dd style="margin: 0px; display: inline; padding: 0px; white-space: nowrap;"></dd></dl>Free full text

Acta Pharmacol Sin. 2007 Dec;28(12):1914-8.Antioxidant properties of berberine on cultured rabbit corpus cavernosum smooth muscle cells injured by hydrogen peroxide.

Tan Y1, Tang Q, Hu BR, Xiang JZ.
Author information



Abstract

AIM:

<abstracttext label="AIM" nlmcategory="OBJECTIVE">To investigate the antioxidant properties of berberine (Ber) on corpus cavenosum smooth muscle cells (CCSMC) in penile erectile dysfunction.</abstracttext>
METHODS:

<abstracttext label="METHODS" nlmcategory="METHODS">We examined the effects of Ber on cultured rabbit CCSMC damaged by hydrogen peroxide (H2O2) through examining cell viability by methyl thiazolyl tetrazolium assay and assessing the level of malondialdehyde (MDA), superoxide dismutase (SOD) activity, nitric oxide (NO) products, and lactate dehydrogenase (LDH) release in cells after stimulation with H2O2.</abstracttext>
RESULTS:

<abstracttext label="RESULTS" nlmcategory="RESULTS">Treatment with 1 mmol/L H2O2 significantly decreased the cell viability, NO products, and SOD activity of CCSMC from 100% to 48.57%+/-4.1% (P<0.01), 66.8+/-16.3 to 6.7+/-2.1 micromol/L (P<0.01), and 49.5+/-1.8 to 30.1+/-2.6 U/mL (P<0.01), respectively, and increased LDH release and MDA content from 497.6+/-69.5 to 1100.5+/-56.3 U/L (P<0.01) and 3.7+/-1.3 to 78.4+/-2.9 nmol/mg protein (P<0.01), respectively. However, treatment with different concentrations of Ber (10-1000 micromol/L) inhibited the damaging effects of H2O2, with increased cell viability (P<0.05 or P<0.01), NO production (P<0.01), and SOD activity (P<0.01) and decreased LDH release and MDA content (both P<0.01).</abstracttext>
CONCLUSION:

<abstracttext label="CONCLUSION" nlmcategory="CONCLUSIONS">Ber could produce its antioxidant action on oxidative stress-induced cultured CCSMC. These effects may be of benefit in the prevention of penile erectile dysfunction.</abstracttext>


<dl class="rprtid" style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; margin-right: 15px; margin-left: 0px; font-size: 0.8465em; line-height: 1.4em; display: inline;"><dt style="display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px !important; white-space: nowrap;">PMID:</dt> <dd style="margin: 0px; display: inline; padding: 0px; white-space: nowrap;">18031604</dd> <dd style="margin: 0px; display: inline; padding: 0px; white-space: nowrap;">[PubMed - indexed for MEDLINE] </dd><dd style="margin: 0px; display: inline; padding: 0px; white-space: nowrap;"></dd></dl>Free full text

 

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