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Abstract:
Berberine is a plant alkaloid with a long history of medicinal use in both Ayurvedic and Chinese medicine. Berberine HCL has been used and has shown purported benefits in glycemic control, metabolic syndrome, polycystic ovarian syndrome, hyperlipidemia and is being used as an adjunctive therapy in some cancers.
Introduction:
Berberine is present in Hydrastis canadensis (goldenseal), Coptis chinensis (Coptis or goldenthread), Berberis aquifolium (Oregon grape), Berberis vulgaris (barberry), and Berberis aristata (tree turmeric). The berberine alkaloid can be found in the roots, rhizomes, and stem bark of these plants.
Discovery and historical journey:
The earliest record of Rhizoma Coptidis as a medicinal herb was in A.D. 200 in The Herbal Classic of the Divine Plowman (Shen Nong Ben Cao Jing). In about A.D. 500, the anti-diabetes activity of Rhizoma Coptidis was recorded for the first time in a book titled “Note of Elite Physicians.”
Most berberine used in medical practice is not extracted from this herb because of its high cost. Usually, it is prepared from other herbs such as Berberis amurense Rupr. and Phellodendron amurense Rupr. Among many chemical forms of berberine, i.e., berberine hydrochloride, berberine sulfate, berberine citrate or phosphate, berberine hydrochloride is the most common form.
A literature search of Berberine, its uses, mechanism of action, new developments, and delivery systems revealed over 10,000 results. I will narrow down the most relevant and easily digestible fragments to inform you of its uses, side effects and the latest research.
Some proven benefits of berberine:
Recently, basic research has proven that berberine can be used to lower the blood glucose level (Liang et al., 2019), improve insulin resistance (Lou et al., 2011), improve hyperlipidemia (Li et al., 2016), and prevent mild cognitive impairment (Kumar et al., 2016). This feature improves the shortcomings of the combination of statins and metformin and shows potential as a new first-line treatment drug.
Here is a brief list of the purported and proven benefits of berberine. In the following section, I will elaborate on the mechanisms that lead to these benefits.
Mechanism of action:
Several animal and human studies have shown berberine’s unequivocal effects on glucose control. The various mechanistic pathways are:
This study confirmed that administration of berberine (0.5 g three times daily) at the beginning of each meal was able to reduce fasting blood glucose (FBG) and postprandial blood glucose (PBG) in patients with newly-diagnosed type 2 diabetes. Hemoglobin A1c (HbA1c) levels dropped by 2.0%, comparable to the effect of metformin. In poorly-controlled diabetic patients with insulin injection, berberine reduced HbA1c by 0.8%.
In the first in vitro study using hepatocytes (HepG2 cell line), berberine was shown to stimulate glucose consumption in an insulin-independent manner, and the activity was similar to that of metformin. Several studies have confirmed the insulin-independent activity of berberine in other cell models, e.g. muscle cells (L6 and C2C12 cell lines) and adipocytes (3T3-L1 cell line). In the presence of insulin, berberine exhibited a synergetic effect on insulin-induced glucose consumption and glucose uptake.
Berberine was reported to improve lipid metabolism in both animals and human subjects. Two clinical trials showed that berberine decreased triglycerides by 35% and 22%, serum cholesterol by 29% and 16%, and LDL-C by 25% and 20% in patients with dyslipidemia.
Reduction of cholesterol with berberine is related to the induction of LDL receptor (LDLR) expression in liver, which may be due to extended half-life of LDLR mRNA via activation of extracellular signal-regulated kinases (ERK) by berberine.
The antimicrobial activity of berberine is well-established in the treatment of infection caused by bacteria, viruses, fungi, protozoans and helminthes.
This study showed a significant effect of berberine against Staph Aureus. In this study, berberine showed antimicrobial activity against all tested strains of MRSA. Minimum inhibition concentrations (MICs) of berberine against MRSA ranged from 32 to 128 µg/mL. Ninety percent inhibition of MRSA was obtained with 64 µg/mL or less of berberine.
The authors concluded that BBR reduced the antioxidant capacity of S. aureus and the mechanism suggests the inhibition of cell wall synthesis, especially the peptidoglycan synthesis.
Since liver plays a central role in glucose metabolism, numerous studies focused on effects of berberine, especially in fatty liver disease. In newly diagnosed type 2 diabetics with nonalcoholic fatty liver disease as comorbidity, berberine ameliorated liver steatosis in ultrasonic images, decreased AST and ALT, reduced hemorheology indicators, and improved lipid profile. Similar results were obtained in another study. Berberine lowered FBG effectively in chronic hepatitis B and hepatitis C patients with T2DM or impaired fasting glucose. Liver function was improved greatly in these patients as indicated by the reduction of liver enzymes. This data showed that hepatic steatosis was alleviated by berberine through inhibition of fatty acid synthase (FAS) expression. Berberine decreased fasting blood glucose by direct inhibition of gluconeogenic genes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in liver.
The antioxidant activity of berberine may directly result from complex I inhibition which is a major place of superoxide production in the electron transport chain.
Mitochondrial inhibition may play a key role in the activities of berberine such as preventing fatty liver, reducing blood glucose and decreasing blood lipids. The details of the regulation remain to be explored.
The metabolic disorder includes a spectrum of conditions such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes, impaired glucose tolerance (prediabetes), polycystic ovarian syndrome (PCOS), and hyperlipidemia. Previous studies have demonstrated that metabolic disorders are prone to diabetic encephalopathy and atherosclerosis (Barenbrock et al., 1995), which will generate Alzheimer’s disease and coronary heart disease (Razay et al., 2007). NAFLD is closely related to type 2 diabetes and dyslipidemia (Marchesini and Babini, 2006). Characteristic changes in patients with metabolic disorders include a decrease in serum high-density lipoprotein (HDL) or an increase in serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), fasting plasma glucose (FPG), and homeostasis model assessment-insulin resistance (HOMA-IR).
In this study, the authors showed that berberine significantly reduced waist circumference and waist/hip ratio significantly in the absence of weight change. Similar results were also reported by other groups. It was indicated that berberine may inhibit visceral fat accumulation. In diabetic rats, adipocyte size and the ratio of white adipose tissue to body weight were decreased, and adipocyte number was increased with berberine treatment.
Although berberine was shown to suppress fat accumulation, the current evidence on mechanisms is controversial.
Berberine may also reduce the risk of developing metabolic syndrome through its beneficial effects on the gut microbiota. In the last decade, many studies have indicated that the composition of gut microbiota is associated with the regulation of the host’s health and metabolism. Dysbiosis, defined as an alteration in the quality and/or quantity of the intestinal microbiota, can affect the host’s physiology and may be a factor that leads to the onset of various diseases, including obesity and T2DM, as well as cardiovascular diseases, Crohn’s disease, and cancer.
The results in this study showed that berberine (BBR) supplementation can significantly lower TC, TG, LDL, Fasting blood glucose (FBG), insulin, HbA1c, HOMA-IR, SBP, weight, BMI, and waist circumference (WC) and can elevate HDL. The significant effects of Berberine on HDL and WC were only seen in doses of more than 1 g/day, on FBG and HOMA-IR in the durations of more than 8 weeks, and on HbA1c and weight in both mentioned higher subgroups of dose (>1 g/d) and duration (>8 weeks). Moreover, BBR was significantly effective in alleviating cardiovascular risk factors, mainly in subgroups with impaired metabolic health such as NAFLD, type 2 diabetes, and metabolic syndrome. In addition, BBR was effective for the improvement of LDL, HDL, and FBG only in subgroups with abnormal ranges (HDL ≤ 40, LDL > 100 mg/dl, and FBG > 100 mg/dl). The optimum dose for BBR was 1 g/day for TG, TC, and weight, 1.8 g/day for insulin and HOMA-IR, and 5 g/day for HDL. The most effective duration was 40 weeks for FBG and 50 weeks from the beginning of BBR supplementation for DBP and WC.
BBR is suggested to upregulate the expression of LDL receptors in the human hepatoma cell line (HepG2) and to inhibit both cholesterol and TG synthesis in the liver, dose-dependently. AMPK agonist activity of berberine leads to the inhibition of cholesterol and TG synthesis by inactivating two enzymes, β-Hydroxy β-methylglutaryl-CoA (HMG-CoA) and ACC (acetyl-coenzyme A carboxylase). AMPK activation also increases energy production hence normalizing the imbalance between glucose, lipid, and energy. This activation can also impose anti-inflammatory effects and can speed up the transport of glucose in the serum by promoting glucose transporter type 4 (GLUT4) translocation, although GLUT4 involvement is still unclear.
Berberine has exhibited ability to suppress tumor metastasis (Lin et al., 2006; Serafim et al., 2008; Cai et al., 2014). Matrix metalloproteinases (MMPs) degrade the tissue matrix, allowing tumor cells to break through the normal tissue barrier and invade the surrounding normal tissue and distant organs. Berberine inhibits the release of MMP-2 from tumor cells and thus inhibits tumor cell destruction of the tissue matrix.
In vitro studies have demonstrated that the inhibition of FAK, IKK, NF-kB, u-PA, MMP-2, and MMP-9 significantly reduced metastasis.
How is berberine absorbed in the human body?
Berberine exhibits poor absorption, efflux, and extensive metabolism in the human gut. The absolute bioavailability of berberine is far less than 1%. Accordingly, one of the approaches for improving berberine’s efficacy is through studying a variety of formulations to improve its bioavailability from the gut.
Which formulations of berberine are the best?
Berberine HCL is the most commonly available preparation. There is explosive research in progress to figure out the best way to increase the bioavailability of berberine.
One groundbreaking area is that of nanoparticles. Nanoparticles are fat-loving particles that help in protecting a drug from the breakdown of gastric enzymes and transport the drug to the bloodstream. Various nanoparticle formulations are being used in cancer treatments.
Nanoparticle formulations that encapsulate berberine for sustained release and improved bioavailability include the use of polymeric natural (e.g., chitosan) and synthetic (PLGA, PLGA-PEG, etc.) agents. Others include a self-micro emulsifying berberine-phospholipid complex of polyethylene glycol 1000 succinate (TPGS 1000) and SiO₂, phytosomes loaded with berberine-phospholipid complex, solid lipid nanoparticles, micelles, liposomes of various nature, etc.
Berberine NPs produced by both APSP and EPN methods have shown promising activities against gram positive and gram negative bacteria, and yeasts, with NPs prepared through the EPN method showing superior results compared to those made with the APSP method and the unprocessed drug.
Side effects and adverse effects of berberine:
Berberine is clinically safe and well-tolerated by the human body. Few adverse reactions are reported, and no negative effect is observed on participants’ diet.
In this study, none of the patients suffered from severe gastrointestinal adverse events when berberine was used alone. In combination-therapy (metformin + berberine) the adverse events disappeared in one week after reduction in berberine dosage. The data suggest that berberine at dosage of 30mmg three times daily is well tolerated in combination therapy. Liver and kidney functions were monitored in this study. No significant changes in plasma ALT, γ-GT and creatinine were observed during the 13 weeks of berberine treatment.
It is recommended that berberine be taken with food and if possible, as a gastroprotective coated formulation.
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