Integrative Therapies for Type 2 Diabetes Mellitus: Botanical Supplements
By William C. Haas III, MD/MBA
Integrative Medicine Fellow, Department of Family and Community Medicine, University of Arizona, Tucson
Dr. Haas reports no financial relationships relevant to this field of study.
- More than 1200 different plants have been reported to have glucose-lowering properties.
- Berberine and fenugreek have the best evidence supporting use in patients with type 2 diabetes mellitus.
The burden of type 2 diabetes mellitus (T2DM) is staggering. Recent figures estimate that nearly 10% of the U.S. population suffers from T2DM, contributing to $176 billion in direct medical costs and $69 billion in lost productivity.1,2 Unfortunately, these costs rose by more than 40% over the previous 5-year period.3 Reversing the epidemic of T2DM will require a patient-centered treatment plan that draws on many different evidence-based therapeutic modalities.
Given that Americans spend approximately $34 billion annually on complementary and alternative medicine,4 it should not surprise medical providers that one-third of diabetic patients take non-prescription dietary supplements as part of their treatment.5 Among the various supplements used, botanical remedies consistently rank at the top of surveys.6,7 Botanicals may serve as effective agents in the treatment of diabetes, as more than 1200 different plants have been reported to have glucose-lowering properties.8 In fact, metformin, the first choice pharmaceutical treatment for T2DM, originated from the plant Galega offcinalis (French lilac).9 Botanicals have long been used in traditional healing systems across the world and may offer additional treatment strategies for the management of T2DM.
The previous issue of Integrative Medicine Alert presents evidence for using micronutrient supplements (chromium, magnesium, zinc, etc.) to manage T2DM.10 Part two of this review will focus exclusively on the role of botanicals for treating T2DM. Only recently have rigorous research methods been applied to the study of botanical remedies. Some of the most commonly encountered botanicals used for T2DM are reviewed below.
Berberine is a plant alkaloid found in several different plants including barberry (Berberis vulgaris), goldenseal (Hydrastis canadensis), and Oregon grape (Berberis aquifolium).11 Long used to treat bacterial diarrhea in traditional Chinese and Ayurvedic practices, berberine was only recently noted to have antidiabetics properties.12 Multiple mechanisms for berberine’s hypoglycemic effect have been evaluated, including its ability to increase insulin sensitivity, inhibit hepatic gluconeogenesis, and promote intestinal glucagon-like protein-1 secretion.13
Although large-scale, randomized, controlled trials are lacking, berberine performs exceptionally well in a number of smaller studies evaluating its use in isolation and in conjunction with traditional diabetic medications. As a primary treatment intervention, 500 mg of berberine twice per day has been shown to significantly outperform placebo in hemoglobin A1c (HbA1c) lowering effect (-0.9% vs -0.3%, respectively).14 In another randomized trial, berberine at 500 mg three times per day equaled metformin in HbA1c lowering effect (-2.0% vs 1.5%, respectively; P < 0.05);15 however, it should be noted that metformin was sub-maximally dosed at 500 mg three times per day. A systematic review of 14 randomized trials also found that treatments combining berberine with oral hypoglycemic agents achieved better glycemic control compared with oral hypoglycemic agents alone.16
The research on berberine has rapidly progressed and the preliminary findings show promise for this botanical in the management of T2DM. Until larger, multicenter studies are performed, berberine might be best considered as an adjunct to traditional oral antidiabtetic medications. Unfortunately, a 1-month supply of berberine is more expensive than most generic antidiabetic medications, ranging from $20-$40. The plant alkaloid is generally well-tolerated, with no reports of hypoglycemic events at the typical dose of 1 g/day. Drug interactions should be considered when using berberine due to decreased activity of several cytochromes (CYP2D6, 2C9, 3A4).17 Finally, berberine is contraindicated in pregnancy as it may cause uterine contractions.
Although nearly 250 species of cinnamon have been identified, primarily two species are used to produce the commonly used spice, Cinnamomum verum (Ceylon cinnamon) and Cinnamomum cassia (Chinese cinnamon). Well-known as a flavoring agent, cinnamon is also sold as a preventive and therapeutic supplement for a variety of chronic medical conditions, including T2DM.18 The potential antidiabetic properties of cinnamon are believed to result from its ability to increase glucose entry into cells via enhanced insulin receptor phosphorylation and translocation of the glucose transporter to the plasma membrane.19
With regard to clinical outcomes, the literature suggests that cinnamon may decrease fasting blood sugar,20 but it fails to consistently reduce HbA1c levels.21,22,23,24 A 2012 Cochrane review concluded that there is insufficient evidence to support the use of cinnamon for T2DM.25 A subsequent meta-analysis reached a similar conclusion, stating that the high degree of heterogeneity among studies limits the application of any findings to direct patient care.26 Despite the conclusions of these meta-analyses, randomized, controlled trials do show a HbA1c lowering effect as high as 0.4% when taking 1 g of Chinese cinnamon per day (~ 1/6 teaspoon/day).27
Overall, cinnamon falls short of its expectations in the treatment of T2DM. At the present time, patients should be advised against supplementing their diet with cinnamon in hopes of improving diabetic outcomes. With that said, the current literature should not dissuade the liberal application of cinnamon to food if so desired.
The seeds of the legume Fenugreek (Trigonella foenum-graecum) have been used as both a culinary and a medicinal agent in various cultures around the world. In the Ayurvedic tradition, defatted fenugreek seeds have been used to treat diabetes for centuries. Along with its high fiber content, fenugreek contains 4-hydroxyisoleucine, which increases pancreatic insulin secretion.28 Additionally, fenugreek is hypothesized to inhibit sucrose α-d-glucosidase and α-amylase,29 further contributing to its possible antidiabetic effect through slowed carbohydrate absorption.
From a clinical standpoint, the evidence for fenugreek trends toward an overall benefit, although the methodological quality of the various studies is suboptimal. Early studies of small sample size and short duration were mixed in their outcomes;30,31,32 however, a more sizable and extended trial later found a robust HbA1c lowering effect of 1.4% among fenugreek users compared to 0.4% among placebo users (P < 0.05).33 A recent meta-analysis also noted improvements in HbA1c (-0.85%; 95% confidence interval, -1.49% to -0.22%), but ultimately concluded that higher quality studies are needed to provide more conclusive evidence.34
If supported by stronger studies, fenugreek may ultimately serve as an important antidiabetic agent. In the meantime, the botanical still may be recommended for diabetics given its high fiber content, a nutrient known to be beneficial across a variety of disease states. A commonly recommended dose is 2.5 g twice daily of the powdered seed capsulated. Fenugreek may produce a harmless maple syrup smell to urine and has rarely been reported to cause hypokalemia.35
Gymnema (Gymnema sylvestre) is a large, woody plant found in the tropical forests of India, Africa, and Australia.36 Both the dried leaf and dried root have been used therapeutically in the Ayurvedic system as it causes a loss of sweet taste when chewed. The active constituent of gymnema is believed to be gymnemic acid, a mixture of different saponins; however, a clear mechanism for its glucose-lowering effect has not been determined.37
In comparison to the other botanical supplements discussed, gymnema lacks a large body of research to draw definitive conclusions. The two strongest studies found improvements in glucose metabolism as well as a reduction in the use of antidiabetic medications.38,39 Unfortunately, both studies possessed small sample sizes and lacked randomization. Other commonly referenced studies included type 1 diabetics,40,41 thereby limiting conclusions for patients with T2DM.
Although the existing evidence for gymnema appears positive, the overall verdict is inconclusive given the scarcity of high-quality data. If consumed, gymnema typically is taken in a capsule or tea form, standardized to 24% gymnemic acids. One case report has implicated high-dose gymnema tea as a cause for acute hepatitis.42
Ivy gourd (Coccinia grandis), also know as baby watermelon, is a perennial herb originally found in India, but has spread rapidly across the world. The antidiabetic mechanism of ivy gourd is not well understood, but the fruit and leaves of the plant appear to have insulin-mimetic properties.43
Several studies, including a few randomized, controlled trials, have demonstrated a positive effect of ivy gourd in the management of T2DM. The British Medical Journal initially published a small study in 1980 reporting a glucose-lowering effect of ivy gourd when compared to placebo.44 Subsequently, two open-label prospective trials have also noted a hypoglycemic effect among diabetics consuming ivy gourd.43,45 More recently, two randomized, double-blind, placebo-controlled trials have been performed and found significant improvements in both fasting and postprandial blood sugars as well as a modest reduction in HbA1c (-0.6%, P < 0.05).46,47
Although they are mostly single-center studies with small sample sizes, preliminary investigations of ivy gourd are promising, and the herb may be recommended to diabetics with confidence pending more rigorous studies. Unfortunately, dosing recommendations are somewhat difficult given the different formulations used in each study. No adverse events were reported in the studies reviewed, although they were not specifically designed to identify harm.
Several other botanical supplements, including bitter melon (Momordica charantia) and nopal (Opuntia), are commonly referenced as having antidiabetic effects. Unfortunately, evidence for these supplements is limited. Two Cochrane reviews have concluded that there is insufficient evidence to recommend bitter melon,48,49 and the majority of research on nopal is limited to animal models aside from a preliminary study of small sample size (< 20 patients).50 Although other botanicals may be encountered as well, the supplements with the best available research have been presented above.
Historically, botanical preparations have been used to treat hyperglycemia in many traditional healing systems. Driven partly by increased patient use, botanical preparations have been studied more rigorously over the past few decades. Mounting evidence suggests that some of botanicals may be suitable for managing T2DM. The current evidence most strongly supports the use of berberine and fenugreek, with an even stronger recommendation for these botanicals pending larger, multicenter trials. Both ivy gourd and gymnema have demonstrated positive effects in several small studies; however, additional research will be required to recommend these botanicals with confidence. Finally, generally high-quality evidence favors against supplementing with cinnamon for improving T2DM; however, diabetic patients should not be dissuaded from using it liberally as a flavoring agent. Despite these general conclusions, clinicians should bear in mind that the research surrounding botanicals is evolving and should be closely monitored as patients increasingly seek additional treatment options.
- National Diabetes Information Clearinghouse. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. Atlanta, GA: U.S. Department of Health and Human Services; 2014. Available at: http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report- web.pdf. Accessed Sept. 1, 2015.
- American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. Diabetes Care 2013;36:1033-1046.
- American Diabetes Association. Economic costs of diabetes in the U.S. in 2007. Diabetes Care 2008;31:596-615.
- Nahin RL, et al. Costs of Complementary and Alternative Medicine (CAM) and Frequency of Visits to CAM Practitioners: United States, 2007. National Health Statistics Reports; no 18. Hyattsville, MD: National Center for Health Statistics. 2009.
- Ryan EA, et al. Use of alternative medicine in diabetes mellitus. Diabet Med 2001;18:242-245.
- Egede LE, et al. The prevalence and pattern of complementary and alternative medicine use in individuals with diabetes. Diabetes Care 2002;25:324-329.
- Yeh GY, et al. Complementary and alternative medicine use among patients with diabetes mellitus: Results of a national survey. Am J Pub Health 2002;92:1648-1652.
- Marles RJ, Farnsworth NR. Antidiabetic plants and their active constituents. Phytomedicine 1995;2:137-189.
- Oubre AY, et al. From plant to patient: An ethnomedical approach to the identification of new drugs for the treatment of NIDDM. Diabetologia 1997;40:614-617.
- Haas W. Integrative therapies for type 2 diabetes mellitus: Micronutrient supplements. Altern Med Alert 2015;18:97-101.
- Singh IP, Mahajan S. Berberine and its derivatives: A patent review (2009-2012). Expert Opin Ther Pat 2013;23:215-231.
- Chen QM, Xie MZ. Studies on the hypoglycemic effect of Coptis chinensis and berberine. Acta Pharmaceutica Sinica 1986;21:401-406.
- Zhang Q, et al. Berberine moderates glucose and lipid metabolism through multipathway mechanism. Evid Based Complement Alternat Med 2011;2011:10.
- Zhang Y, et al. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab 2008;93:2559-2565.
- Yin J, et al. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism 2008;57:712-717.
- Dong H, et al. Berberine in the treatment of type 2 diabetes mellitus: A systemic review and meta-analysis. Evid Based Complement Altern Med 2012;2012:12.
- Guo Y, et al. Repeated administration of berberine inhibits cytochromes P450 in humans. Eur J Clin Pharmacol 2012;68:213-217.
- Rafehi H, et al. Controversies surrounding the clinical potential of cinnamon for the management of diabetes. Diabetes Obes Metab 2012;14:493-499.
- Choi K, Kim YB. Molecular mechanism of insulin resistance in obesity and type 2 diabetes. Korean J Intern Med 2010;25:119-129.
- Davis PA, Yokoyama W. Cinnamon intake lowers fasting blood glucose: Meta-analysis. J Med Food 2011;14:884-889.
- Mang B, et al. Effects of a cinnamon extract on plasma glucose, HbA, and serum lipids in diabetes mellitus type 2. Eur J Clin Invest 2006;36:340-344.
- Suppapitiporn SKN, Suppapitiporn S. The effect of cinnamon cassia powder in type 2 diabetes mellitus. J Med Assoc Thai 2006;89(Suppl 3):S200-S205.
- Vanschoonbeek KTB, et al. Cinnamon supplementation does not improve glycemic control in postmenopausal type 2 diabetes patients. J Nutr 2006;136:977-980.
- Blevins SM, et al. Effect of cinnamon on glucose and lipid levels in non insulin-dependent type 2 diabetes. Diabetes Care 2007;30:2236-2237.
- Leach MJ, Kumar S. Cinnamon for diabetes mellitus. Cochrane Database Syst Rev 2012;9:CD007170.
- Allen R, et al. Cinnamon use in type 2 diabetes: An updated systematic review and meta-analysis. Ann Fam Med 2013;11:452-459.
- Crawford P. Effectiveness of cinnamon for lowering hemoglobin A1c in patient with type 2 diabetes: A randomized, controlled trial. J Am Board Fam Med 2009;22:507-512.
- Sauvaire Y, et al. Steroid saponins from fenugreek and some of their biological properties. Adv Exp Med Biol 1996;405:37-46.
- Amin R, et al. Effect of Trigonella feonum graecum on intestinal absorption. Proceedings of the 47th annual meeting of the American Diabetes Association. Diabetes 1987;36(Suppl 1):211a.
- Gupta A, et al. Effect of Trigonella foenum-graecum (fenugreek) seeds on glycaemic control and insulin resistance in type 2 diabetes mellitus: A double blind placebo controlled study. J Assoc Physicians India 2001;49:1057-1061.
- Raghuram TC, et al. Effect of fenugreek seeds on intravenous glucose disposition in non-insulin dependent diabetic patients. Phytother Res 1994;8:83-86.
- Sharma RD, Raghuram TC. Hypoglycaemic effect of fenugreek seeds in non-insulin dependent diabetics subjects. Nutr Res 1990;10:731-739.
- Lu FR, et al. Clinical observation on Trigonella foenum-graecum L. total saponins in combination with sulfonylureas in the treatment of type 2 diabetes mellitus. Chin J Integr Med 2008;14:56-60.
- Neelakantan N, et al. Effect of fenugreek (Trigonella foenum-graecum L.) intake on glycemia: A meta-analysis of clinical trials. Nutr J 2014;13:7. doi:10.1186/1475-2891-13-7.
- Haber SL, Keonavong J. Fenugreek use in patients with diabetes mellitus. Am J Health Syst Pharm 2013;70:1198-1203.
- Bone K. Clinical Applications of Ayurvedic and Chinese Herbs. Warwick, Queensland, Australia: Phytotherapy Press, 1997.
- Porchezhian E, Dobriyal RM. An overview on the advances of Gymnema sylvestre: chemistry, pharmacology and patents. Pharmazie 2003;58:5-12.
- Baskaran K, et al. Antidiabetic effect of a leaf extract from Gymnema sylvester in non-insulin diabetes mellitus patients. J Ethnopharmacol 1990;30:295-300.
- Kumar S, et al. An open-label study on the supplementation of Gymnema sylvestre in type 2 diabetics. J Diet Suppl 2010;7:273-282.
- Shanmugasundaram E, et al. Use of Gymnema sylvestre leaf extract in the control of blood glucose in insulin-dependent diabetes mellitus. J Ethnopharmacol 1990;30:281-294.
- Joffe D. Gymnema sylvestre lowers HbA1c. Diabetes Control Newsl 2001;76.
- Shiyovich A, et al. Toxic hepatitis induced by Gymnema sylvestre, a natural remedy for type 2 diabetes mellitus. Am J Med Sci 2010;340:514-517.
- Kamble SM, et al. Influence of Coccinia indica on certain enzymes in glycolytic and lipolytic pathway in human diabetes. Indian J Med Sci 1998;52:143-146.
- Khan AK, et al. Treatment of diabetes mellitus with Coccinia indica. Br Med J 1980;280:1044.
- Kuppurajan K, et al. Hypoglycaemic effect of Coccinia indica in diabetes mellitus. Nagarjun 1986;29:1-4
- Kuriyan R, et al. Effect of supplementation of Coccinia cordifolia extract on newly detected diabetic patients. Diabetes Care 2008;31:216-220.
- Munasinghe MA, et al. Blood sugar lowering effect of Coccinia grandis (L.) J. Voigt: Path for a new drug for diabetes mellitus. Exp Diabetes Res 2011;2011:978762.
- Ooi CP, et al. Momordica charantia for type 2 diabetes mellitus. Cochrane Database Syst Rev 2010;2:CD007845.
- Ooi CP, et al. Momordica charantia for type 2 diabetes mellitus. Cochrane Database Syst Rev 2012;8:CD007845.
- Frati-Munari AC, et al. Hypoglyemic effect of Opuntia streptacantha Lemaire in NIDDM. Diabetes Care 1998;11:63-66.
This review will focus exclusively on the role of botanicals for treating type 2 diabetes mellitus. Only recently have rigorous research methods been applied to the study of botanical remedies.
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