Berberine – A Natural Alternative for Diabetes Treatment?

s-l1000 squareBerberine is a yellow compound found in several different plants including barberry, goldenseal, phellodendron and oregon grape. Berberine has antibacterial, anti-inflammatory and immune enhancing properties, but in recent years, much research has been published around its role in protecting against cardiovascular disease as well as treating diabetes and insulin resistance.


How Does It Work?

blood_cellssquareBerberine activates a specific enzyme called adenosine monophosphate-activated protein kinase, or AMPK. AMPK is also sometimes called the “metabolic master switch” because it plays an important role in regulating metabolism in the body.

Increased AMPK activity benefits the body in so many ways.

For those with Diabetes, AMPK more efficiently stimulates the uptake of glucose into the cells, improves insulin sensitivity and reduces glucose production in the liver.

In Cardiovascular Disease, AMPK prevents harmful fat deposition and boosts fat burning in the mitochondria. It also stimulates the release of nitric oxide (NO), which in turns increases blood flow and lowers blood pressure.


The Research

micro squareIn a clinical trial published in the journal Metabolism in 2008, newly diagnosed Type 2 Diabetics were randomly divided into groups and assigned to take berberine or metformin (500 mg 3 times a day) in a 3-month trial.

Berberine was able to control blood sugar and lipid metabolism as effectively as metformin. Significant decreases in hemoglobin A1c, fasting blood glucose, postprandial blood glucose and plasma triglycerides were observed in the berberine group as well. In addition, total cholesterol and low-density lipoprotein cholesterol (LDL-C) were decreased significantly.

Overall, the results were incredibly promising for a more natural form of diabetes treatment.

A recent meta-analysis combined data from 14 randomized trials involving 1068 participants. Treatment with both berberine and lifestyle modifications showed significant blood sugar and cholesterol lowering effects. These effects did not differ from those obtained by the standard diabetic drugs metformin, glipizide, or rosiglitazone, but avoided the side-effects caused by the more conventional pharmaceuticals.

A December 2004 article described berberine as “a novel cholesterol-lowering drug” that worked through a “unique mechanism distinct from statins.” In this study, berberine was given to 32 patients with high cholesterol for 3 months. The treatment reduced serum cholesterol by 29 percent, triglycerides by 35 percent, and LDL-cholesterol by 25 percent.


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Thorne Research Clinical Research Report: Berberine: A Versatile Botanical Compound with Wide Clinical Application

Metabolic Syndrome

Berberine has been shown to help modulate some of the factors associated with Metabolic Syndrome (MetS). Although there is no agreed upon definition of MetS, a consensus between the International Diabetes Foundation and the American Heart Association/National Heart, Lung, and Blood Institute defines MetS as the presence of any three of the following: increased waist circumference (>102 cm in men and >88 cm in women), elevated blood pressure (>130/85 mmHg), elevated blood sugar (fasting glucose >100 mg/dL), low high-density lipoprotein (HDL) cholesterol (<40 mg/dL in men and <50 mg/dL in women), and high triglycerides (>150 mg/dL). MetS increases the risk for cardiovascular disease, type 2 diabetes, fatty liver, and other sequelae.

In a small pilot study of adults (n=7 in final analysis) with a body mass index (BMI) of >30, subjects were given 500 mg berberine HCl three times daily for 12 weeks. Several aspects of metabolic syndrome improved, including a 23-percent decrease in triglycerides (from 134.9 mg/dL to 103.4 mg/dL), a 12-percent decrease in total cholesterol (from 197.6 mg/dL to 173.4 mg/dL), and an average weight loss of five pounds (not statistically significant).

Thirty-two evaluable hyperlipidemic patients were given 500 mg berberine twice daily for three months, while 11 patients received placebo. Subjects taking berberine experienced a 35-percent reduction in triglycerides, a 29-percent reduction in total cholesterol, and a 25-percent reduction in low-density lipoprotein (LDL) cholesterol (all statistically significant); HDL-cholesterol was unchanged.

In a study of 89 women with Polycystic Ovary Syndrome and associated insulin resistance, berberine significantly decreased waist-to-hip ratio and LDL-cholesterol compared to metformin. Compared to placebo, berberine significantly decreased the area under the curve for insulin, triglycerides, total- and LDL-cholesterol, and increased HDL-cholesterol.

Rats with non-alcoholic fatty liver disease (NAFLD) developed increased glucose, insulin, and body fat, and hepatic steatosis concomitant with a down-regulation of insulin receptor substrate-2 (IRS-2) in liver tissue. Administration of berberine up-regulated IRS-2 mRNA, indicating berberine may benefit insulin resistance associated with NAFLD. Further animal research supports this mechanism and demonstrates that insulin receptor gene expression occurs via a protein kinase C-dependent pathway.

Berberine was shown to improve lipid dysregulation – decreasing fat mass and improving fatty liver in obese rodent models. Berberine appears to inhibit adipogenesis in obese mice fed a high-fat diet – reducing weight gain, food intake, glucose, triglycerides, and total cholesterol levels. This occurs in part by inhibiting peroxisome proliferator-activated receptor-gamma (PPAR-y) target genes associated with adipocyte differentiation.


In a three-month clinical study, 116 subjects with Type 2 Diabetes and dyslipidemia received either 1g berberine daily or placebo. Statistically significant decreases were seen in the berberine group in fasting and post-prandial glucose levels, hemoglobin A1c (HbA1c), triglycerides, and total- and LDL-cholesterol. In a two-month study, 50 Type 2 Diabetic patients were assigned to 1g berberine HCl (500 mg twice daily) and compared to 26 patients on metformin and 21 patients on rosiglitazone. Similar significant reductions in fasting glucose and HbA1c were seen in both groups, while only the berberine group experienced significant decreases in triglycerides. In another three-month study, 36 individuals with newly diagnosed Type 2 Diabetes were given 500mg three times daily of berberine or metformin. Significant improvements in glucose metabolism (fasting and post-prandial glucose and HbA1c) were seen in both groups (e.g., berberine resulted in a decrease of HbA1c from 9.47 ± 0.65 to 7.48 ± 0.40), while berberine was more effective than metformin at decreasing total cholesterol. These same researchers performed a similar study in 48 poorly controlled Type 2 Diabetics. Berberine (500 mg three times daily), added to their current regimen for three months, resulted in significant decreases from baseline in fasting glucose, post-prandial glucose, and HbA1c.

In addition to mechanisms discussed above in terms of its effect on insulin sensitivity, berberine was shown in an animal model to inhibit gluconeogenesis. It also appears to enhance anaerobic glycolysis, producing ATP from glucose, and may even protect pancreatic beta cells from destruction.

Some complications of Diabetes are associated with cellular sorbitol accumulation, which is potentiated when glucose is converted to sorbitol with the help of the enzyme aldose reductase. Berberine has been shown to inhibit aldose reductase, so it may help prevent complications associated with hyperglycemia. Other studies have found berberine can prevent the development of advanced glycation end-products and increase production of nitric oxide, improving endothelial function and microcirculatory complications associated with Diabetes.


Congestive Heart Failure
In a clinical study of 156 patients with Congestive Heart Failure, 79 patients received 1.2-2 g berberine daily plus conventional medications, while 77 patients received placebo plus conventional medications, for eight weeks. Subjects in the berberine group had statistically significant improvements in cardiac function (NYHA classification), six-minute walking test, left ventricular ejection fraction, dyspnea-fatigue indexes, resting blood pressure, and mortality (seven in the berberine group and 13 in the placebo group).


Antimicrobial Effects
Berberine is probably best known for its antimicrobial effects against bacteria, fungi, viruses, yeast, protozoa, helminthes, and chlamydia. An in vitro study found berberine inhibited the growth of several microorganisms, including both sensitive and resistant strains of bacteria. The inhibition was as follows: Staphylococcus aureus (gram-positive bacteria) > Pseudomonas aeruginosa (gram-negative bacteria; sensitive) > Escherichia coli (gram-negative bacteria; sensitive) > P. aeruginosa (resistant) > E. coli (resistant) > Bacillus subtilis (gram-positive bacteria) > Zoogloea ramigera (gram-negative bacteria) > Candida albicans (yeast) > Saccharomyces cerevisiae (yeast) > Aureobasidium pullulans (filamentous fungi; black) > A. pullulans (white) > Trichoderma viride (filamentous fungi; brown) > Microsporum gypseum (filamentous fungi) > Aspergillus niger (filamentous fungi) > Fusarium nivale (filamentous fungi) > Penicillium chrysogenum (filamentous fungi) > T. viride (green).21 It has also shown in vitro antimicrobial activity against other organisms, including Bacillus pumilus, B. cereus, Corynebacterium diphtheriae, Shigella boydii, Klebsiella pneumonia, Cryptococcus neoformans, Vibrio cholera, Clostridium perfringens, and methicillin-resistant S. aureus. Berberine appears to inhibit FtsZ protein involved in bacterial cell division.


Urinary Tract Infections
The anti-infective action of berberine in Urinary Tract Infections is thought to be due in part to its ability to prevent adhesion to the epithelial cells of the urinary tract. A uropathogenic strain of E. coli, cultured with berberine for 18 hours, showed complete inhibition of fimbrial filaments, removing their ability to adhere to the bladder wall. Another study found berberine inhibits the capacity of Streptococcus pyogenes to adhere to host cells.


In a study of 165 adults, 63 with E. coli-associated Diarrhea were given 400 mg berberine sulfate (n=33) or placebo (n=30). During the eight hours following the single dose, stool volume significantly decreased in the berberine group (48-percent decrease by the end of the 24-hour observational period). Diarrhea stopped after 24 hours in 42 percent of the berberine group and 20 percent of the placebo group. The remainder of the 165 subjects had Diarrhea associated with Vibrio cholera. Berberine was not effective in this population, either alone or as an additive effect with tetracycline.26 Berberine provided an anti-secretory effect on enterotoxins of E. coli and V. cholera, inhibiting the response by approximately 70 percent in rabbit and mouse models.27


Inflammatory Bowel Disease
Animal and in vitro research supports the use of berberine for Inflammatory Bowel Disease (IBD) because of its anti-secretory and anti-inflammatory effects. Stress on the endoplasmic reticulum (ER) in colonic epithelium plays a significant role in the pathogenesis of IBD. In vitro studies demonstrate berberine’s capacity to inhibit pro-inflammatory cytokine-induced ER stress. Another study on human colonic mucosa from colectomy specimens demonstrated berberine inhibits intestinal fluid secretion induced by proinflammatory cytokines. Berberine also inhibited inducible cyclooxygenase-2 expression in an animal model of intestinal inflammation. An animal study found oral doses of berberine (15 mg/kg/day) for one week to rats with colitis reduced morphological damage and histological lesions; interleukin (IL)-8 was also decreased. IL-8 is a potent neutrophil chemoattractant found in high concentrations in the mucosa of patients with active inflammatory bowel disease.


Oncology Support
Berberine has potential application for support of Oncology patients; it might help attenuate the side effects of radiotherapy. In a study of cancer patients, 36 patients with Lymphoma or Seminoma were given 300 mg berberine three times daily (n=18) or nothing (n=18), and 42 patients with Cervical Cancer were randomized to berberine (same dose; n=21) or control (n=21), both groups prior to therapy. Another eight patients already experiencing Radiation-Induced Acute Intestinal Symptoms (RIAIS) were given 300mg berberine three times daily from the third to fifth week of treatment. Pretreatment in the first two groups resulted in a significant decrease in RIAIS incidence and severity compared to the control group. Following berberine treatment, RIAIS was reduced in patients already experiencing side effects. Berberine also demonstrated intestinal protection from side effects of abdominal radiation in a murine model.

Hemorrhagic cystitis is one of the potential side effects of the cyclophosphamide class of chemotherapy drugs. In an animal model, berberine was shown to reduce or completely prevent the occurrence of cyclophosphamide-induced cystitis.

In vitro studies show cell cycle arrest and apoptosis of human MC-7 breast cancer cell lines, colon cancer cells, and prostate cancer cells when exposed to berberine.


Allergies/Autoimmune Disease
The effect of berberine on inflammatory cytokine profiles has been studied extensively. One study examining the effect of berberine on dendritic cells and macrophages found an increase in IL-12 production in conjunction with enhanced interferon-gamma and decreased IL-4. This profile reflects a down-regulation of T-helper 2 (Th2) cells and enhancement of T-helper 1 cells and suggests a possible role for berberine in Th2-mediated conditions such as allergies and some autoimmune conditions.


Potential Neuropsychiatric Applications
Animal studies have shown berberine has effects on the central nervous system, including increasing norepinephrine, serotonin, and dopamine – in part by inhibiting monoamine oxidase A (thus inhibiting the breakdown of these neurotransmitters). These effects suggest berberine’s potential as an antidepressant botanical extract.

Preliminary research suggests berberine may provide an important tool for support of patients with Alzheimer’s Disease and other Cognitive Dysfunction. In a mouse model, berberine helped regulate amyloid precursor protein, which in turn prevented accumulation of beta-amyloid peptide. Inhibition of acetylcholinesterase (the enzyme involved in breakdown of acetylcholine) is believed to be another mechanism by which berberine protects cognition. In a study of streptozotocin-diabetic rats subjected to chronic hyperglycemia and memory impairment, berberine enhanced memory and learning, decreased acetylcholinesterase activity, and decreased blood sugar.


In a randomized, crossover study of healthy males, two weeks of berberine (300 mg three times daily) decreased the activity of the cytochrome p450 (CYP) enzymes CYP2D6, CYP2C9, and CYP3A4. Decreasing the activity of cytochrome p450 enzymes can slow the clearance of drugs metabolized by these enzymes, resulting in higher than expected blood levels. Berberine is contraindicated during pregnancy because it is thought to stimulate uterine contractions.