Berberine compared to Metformin Study

Wednesday, December 05, 2012
by: Beth Baldwin-Lien, ND
Section: Abstracts & Commentary
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About the Author


Beth Baldwin-Lien, ND, is a graduate of Bastyr University and has been a licensed naturopathic physician since 2004. In that time, she has worked in private practice, clinical research, natural product development, and as the medicinary manager for the community clinics program at the National College of Natural Medicine. Baldwin-Lien resides in Portland and is a member of the Oregon Association of Naturopathic Physicians. She currently works in medical affairs and education for Vital Nutrients, a professional nutraceutical manufacturer headquartered in Middletown, Conn.

Reference
Wei W, Zhao H, Wang A, et al. A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur J Endocrinol. 2012;166:99-105.

Design
Randomized, placebo-controlled clinical study of 3 months duration

Participants
One hundred Chinese women of reproductive age who met diagnostic criteria for polycystic ovarian syndrome (PCOS) and insulin resistance were randomized to the study; 89 completed the study.

All subjects received advice from a nutritionist and were instructed to limit dietary fat and carbohydrates without restricting calories. Thirty minutes of moderate to intense exercise per day was recommended but not monitored.

All subjects also received the antiandrogen compound cyproterone acetate (2.0 mg/day) in a combined oral contraceptive pill with 35 mcg ethinyl estradiol, taken in a cyclic fashion.

In addition, subjects were randomly assigned to 1 of 3 treatment groups:
Berberine hydrochloride, 500 mg 3 times/day (n=31)
Metformin, 500 mg 2 times/day for the first week, then 3 times/day for the remainder of the study (n=30)
Placebo tablet 2 times/day (n=28)
Study parameters assessed
Clinical, hormonal and metabolic assessments were made at baseline and repeated after 3 months of treatment.

Clinical assessment included height, weight, body mass index (BMI), waist circumference, and waist-to-hip ratio.

Reproductive hormone parameters assessed were total testosterone, sex hormone–binding globulin, and free androgen index.

Carbohydrate metabolic parameters included fasting plasma glucose, fasting insulin, and 2-hour oral glucose tolerance test. The degree of insulin resistance was then estimated using various methods, including fasting glucose/insulin ratio, homeostasis model assessment for insulin resistance, and area under the curve for insulin.

Lipid profile parameters included triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol.

Key findings
After 3 months of treatment, all 3 treatment groups showed significant reduction in body weight and BMI, with no significant difference between placebo, berberine, and metformin. Waist circumference and waist-to-hip ratio also decreased in all 3 groups; however, the berberine group showed a significantly greater reduction in these measures than the metformin or placebo groups.

All 3 treatment groups showed significant reduction in fasting insulin, homeostasis model assessment for insulin resistance, and area under the curve for insulin. However, in the placebo group, fasting plasma glucose and fasting glucose/insulin ratio remained unchanged. Fasting plasma glucose decreased and fasting glucose/insulin ratio increased in the berberine and metformin groups. Overall, subjects receiving either berberine or metformin had significant improvement in measures of insulin sensitivity compared to placebo. There was no significant difference between the berberine and metformin groups.

In all 3 groups, total testosterone and free androgen index decreased; sex hormone–binding globulin increased. The berberine and metformin groups showed comparable changes in total testosterone and free androgen index, which were significantly greater than placebo. However, sex hormone–binding globulin increased significantly in the berberine group compared with both metformin and placebo.

All 3 groups had reductions in total cholesterol and triglycerides. The berberine group had a significantly greater decrease in triglycerides, total cholesterol, and LDL, and a significantly greater increase in HDL, when compared to metformin.

Practice implications
Insulin resistance plays a critical role in the pathophysiology of PCOS, and the current recommendations for management include lifestyle modification, oral contraceptives, and insulin sensitizers—most commonly the biguanide drug metformin.1

Berberine, an isoquinoline alkaloid derived from medicinal herbs including Coptis chinensis and Hydrastis canadensis (Goldenseal), has been found in previous studies of type 2 diabetic patients to have hypoglycemic effects comparable to those of metformin at the same dosage (500 mg 3 times/day).2 In this current study of PCOS patients, berberine was associated with improvements in fasting plasma glucose and various measures of insulin resistance that were comparable with metformin.

The proposed mechanisms by which berberine increases insulin sensitivity and glucose metabolism are many and varied, and several have been previously discussed in this journal, including AMPK activation and protein kinase C-dependent up-regulation of insulin receptor expression.3 Other hypotheses to explain the antidiabetic mechanisms of berberine include suppression of intestinal disaccharidases4 and modulation of gut microbes.5

Berberine’s insulin-sensitizing action on theca cells of the ovary has been demonstrated in vitro, by inducing insulin resistance with dexamethasone then treating with berberine, which reduced both defective glucose uptake and excessive testosterone production by the theca cells.6 This suggests a potential mechanism for the therapeutic effects on insulin resistance and hyperandrogenism seen in the PCOS study.

Perhaps most importantly in terms of the long-term health risks associated with PCOS, this study demonstrated the superiority of berberine vs metformin in reducing waist circumference, waist-to-hip ratio, triglycerides, total and LDL cholesterol, and increasing HDL cholesterol, in PCOS patients. These findings were consistent with earlier studies in which berberine was successfully used to treat dyslipidemia in type-2 diabetics.7 Given that increased waist circumference, waist-to-hip ratio, triglycerides, total and LDL cholesterol, and decreased HDL, are all known risk factors for cardiovascular disease, these data suggest that berberine may have greater potential for reducing cardiovascular disease risk than metformin for women with PCOS.

In terms of the long-term health risks associated with PCOS, this study demonstrated the superiority of berberine versus metformin.


In addition to improving anthropomorphic measures and lipid profiles, berberine may have an additional protective effect against cardiovascular disease, though reports are conflicting. One 2009 study in mice suggests that berberine may actually promote atherosclerosis by inducing foam cell formation.8 Other studies reach the opposite conclusion: that berberine protects against foam cell formation.9,10 Another suggests that berberine protects against hyperglycemia-induced endothelial cell injury and endothelial dysfunction.11

Though previous studies have reported transient GI side effects in up to 34.5% of berberine users,12 in this study adverse effects were minimal and fewer than with metformin. Nine subjects who received metformin complained of transient abdominal discomfort including nausea, vomiting, mild diarrhea, and flatulence, while 3 who received berberine complained of a bitter taste in the mouth.

With fewer side effects, comparable insulin-sensitizing effects, and greater potential for reduction of cardiovascular risk factors including waist circumference, waist-to-hip ratio, and dyslipidemia, berberine may prove a viable alternative to metformin in optimizing the health outcomes of women with PCOS.

It is important to note that berberine is contraindicated in pregnancy, as it has been reported to inhibit bilirubin metabolism in newborns, hypothetically increasing the risk for bilirubin encephalopathy.13

References
1. U.S. Department of Health and Human Services, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. Beyond Infertility: Polycystic Ovary Syndrome (PCOS). www.nichd.nih.gov/publications/pubs/upload/PCOS_booklet.pdf. Accessed Oct. 31, 2012.
2. Yin J, Xing H, Ye J. Efficacy of berberine in patients with type 2 diabetes. Metabolism. 2008 May;57(5):712-717.
3. Steriti R. Berberine for Diabetes Mellitus Type 2. Nat Med J. Oct 1, 2010. www.naturalmedicinejournal.com/article_content.asp?article=61. Accessed Oct 31, 2012.
4. Liu L, Yu YL, Yang JS, et al. Berberine suppresses intestinal disaccharidases with beneficial metabolic effects in diabetic states, evidences from in vivo and in vitro study. Naunyn Schmiedebergs Arch Pharmacol. 2010 Apr;381(4):371-381.
5. Han J, Lin H, Huang W. Modulating gut microbiota as an anti-diabetic mechanism of berberine. Med Sci Monit. 2011 Jul;17(7): 164-167.
6. Zhao L, Li W, Han F, et al. Berberine reduces insulin resistance induced by dexamethasone in theca cells in vitro. Fertil Steril. 2011 Jan;95(1):461-463
7. Zhang Y, Li X, Zou D, et al. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab. 2008;93:2559-2565.
8. Li K, Yao W, Zheng X, Liao K. Berberine promotes the development of atherosclerosis and foam cell formation by inducing scavenger receptor A expression in macrophage. Cell Res. 2009; 19(:1006-1017.
9. Lee TS, Pan CC, Peng CC, Kou YR, Chen CY, Ching LC, Tsai TH, Chen SF, Lyu PC, Shyue SK. Anti-atherogenic effect of berberine on LXRalpha-ABCA1-dependent cholesterol efflux in macrophages.J Cell Biochem. 2010 Sep 1;111(1):104-110.
10. Guan S, Wang B, Li W, Guan J, Fang X. Effects of berberine on expression of LOX-1 and SR-BI in human macrophage-derived foam cells induced by ox-LDL. Am J Chin Med. 2010;38(6):1161-1169.
11. Wang Y, Huang Y, Lam KS, et al. Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase. Cardiovasc Res. 2009 Jun 1;82(3):484-492.
12. Yin J, Xing H, Ye J. Efficacy of berberine in patients with Type 2 diabetes. Metabolism. 2008 May;57(5):712-717.
13. Chan E. Displacement of bilirubin from albumin by berberine. Biol Neonate. 1993;63(4):201-208.