Canadian Study: Alternative medicine for the treatment of type 2 diabetes

Complementary and alternative medicine for the treatment of type 2 diabetes
Richard Nahas MD CCFP Matthew Moher

OBJECTIVE To review clinical evidence supporting complementary and alternative medicine interventions for improving glycemic control in type 2 diabetes mellitus.

QUALITY OF EVIDENCE MEDLINE and EMBASE were searched from January 1966 to August 2008 using the term type 2 diabetes in combination with each of the following terms for specific therapies selected by the Authors: cinnamon, fenugreek, gymnema, green tea, fibre, momordica, chromium, and vanadium. Only human clinical trials were selected for review.

MAIN MESSAGE Chromium reduced glycosylated hemoglobin (HbA1c) and fasting blood glucose (FBG) levels in a large meta-analysis. Gymnema sylvestre reduced HbA1c levels in 2 small open-label trials. Cinnamon improved FBG but its effects on HbA1c are unknown. Bitter melon had no effect in 2 small trials. Fibre had no consistent effect on HbA1c or FBG in 12 small trials. Green tea reduced FBG levels in 1 of 3 small trials. Fenugreek reduced FBG in 1 of 3 small trials. Vanadium reduced FBG in small, uncontrolled trials. There were no trials evaluating microvascular or macrovascular complications or other clinical end points.

CONCLUSION

Chromium, and possibly gymnema, appears to improve glycemic control. Fibre, green tea, and fenugreek have other benefits but there is little evidence that they substantially improve glycemic control. Further research on bitter melon and cinnamon is warranted. There is no complementary and alternative medicine research addressing microvascular or macrovascular clinical outcomes.

Canadian Study

Type 2 diabetes mellitus (DM) is one of the most prevalent and fastest growing diseases in Canada, responsible for expenditures of 9 billion dollars per year.1 Family physicians play a central role in the management of diabetes. Although many drugs improve glycemic control, they do not necessarily provide real-world benefits. In the recent ACCORD (Action to Control Cardiovascular Risk in Diabetes)2 and ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation)3 trials, intensive glycemic control had minimal effect on clinical cardiovascular outcomes. In fact, in a recent meta-analysis, combination therapy with metformin and glyburide increased the risk of a composite end point of cardiovascular events and mortality (relative risk 1.43, 95% confidence interval [CI] 1.10 to 1.85).4 The use of thiazolidinediones has recently been called into question because they increase cardiovascular risk and fracture risk.5

More than one-third of Canadians are using complementary and alternative medicine (CAM) therapies,6 often without consulting or even informing their FPs. It is important for FPs to ask patients about their CAM use and provide evidence-based information about the safety and efficacy of commonly used CAM therapies.

Here we provide a brief review of the evidence supporting the use of several CAM therapies commonly used to treat type 2 DM.

Quality of evidence

MEDLINE and EMBASE were searched from January 1966 to August 2008. The search key words were type 2 diabetes in combination with each of cinnamon, fenugreek, gymnema, green tea, fibre, momordica, chromium, and vanadium. These interventions were selected by the authors based on literature reviews and clinical experience. Results were screened by one author to include clinical trials, systematic reviews, and meta-analyses. Only human clinical trials were selected for review.

Main findings
Relevant findings for each search term are briefly summarized in Table 1 and are detailed as follows:

Cinnamon. True cinnamon (Cinnamomum verum) is a small evergreen tree, the bark of which is a common culinary spice. Most cinnamon sold in the United States and Canada is actually derived from C aromaticum or C cassia, sometimes called “Chinese cinamon” to distinguish it from C verum. Cinnamon has been used for thousands of years to treat diabetes and other conditions. The aqueous extract appears to activate the insulin receptor by multiple mechanisms, and also increases glycogen synthase activity.7-10

No significant adverse effects were reported in the reviewed trials. The only reported risk of cinnamon use is contact dermatitis from volatile oils. Safety in pregnancy has not been studied.

Overall, there is moderate evidence that cinnamon lowers blood glucose levels. Its effect on HbA1c appears negligible, but long-term studies are required to properly evaluate this outcome.

Chromium. Chromium is an essential trace element with many sites of action, including carbohydrate and lipid metabolism. Trivalent chromium is a constituent of a complex known as the “glucose tolerance factor,”15 and chromium deficiency causes reversible insulin resistance and diabetes.16-18

There is strong evidence that 200 to 1000 μg of chromium picolinate daily improves glycemic control.

Summary of Evidence Supporting Alternative Medicine Therapies

INTERVENTION Body of Evidence

Cinnamon FBG level reduction in 2 of 3 trials
Chromium HbA1c and FBG level reduction in meta-analysis
Vanadium FBG level reduction in uncontrolled trials
Fibre HbA1c level reduction (non-significant) in 1 of 3 trials FBG level reduction in 6 of 12 trials
Green tea FBG level reduction in 1 of 3 trials

Other benefits
Bitter melon No benefit to HbA1c or FBG levels in 2 small trials
Fenugreek FBG level reduction in 1 of 3 trials
Other benefits
Gymnema HbA1c level reduction in 2 small trials

HbA1c—glycosylated hemoglobin A1c, FBG—fasting blood glucose.

Vanadium. Vanadium is a poorly understood trace element that is ubiquitous in nature and believed to have many functions in human physiology. In vitro and animal studies have demonstrated its insulinomimetic effects mediated by inhibition of phosphotyrosine phosphatase enzymes that affect the insulin receptor.22-24

A recent meta-analysis identified 5 uncontrolled trials (N = 48) in which 50 to 300 mg of vanadium was administered for 3 to 6 weeks.25 Vanadyl sulfate was used in 4 trials and sodium metavanadate was used in 1 trial. All 5 trials reported reductions in FBG levels, but these were of short duration; none of the trials included controls. Commonly reported side effects included gastrointestinal upset, bloating, and nausea. There is insufficient evidence to support the use of vanadium in the treatment of type 2 DM.

Fibre. Dietary fibre is recognized as an important part of a healthy diet. Soluble and insoluble fibre have positive effects on cardiovascular risk factors,26 intestinal disorders,27 and certain cancers.28-30 Cohort studies suggest
that consumption of cereal fibre and whole grains is inversely related to type 2 DM incidence.31

We identified 12 small RCTs (N = 345) that evaluated the effect of fibre in diabetes patients.32-43 Many different kinds of fibre were used, including wheat, guar, beet, soy, corn, agar, glucomannan, psyllium, and mixtures. Daily doses of 2 to 50 g were administered for 3 to 20 weeks. In 3 trials of 12 to 20 weeks’ duration, only 1 found an improvement in HbA1c levels: in this trial of 76 patients with well-controlled diabetes, a non-significant decrease from 6.6% to 6.1% was seen in those who consumed agar containing 4.5 g fibre daily for 12 weeks. Six of the 12 RCTs reported reductions in FBG; the other 6 RCTs reported no change in this outcome. Most of the studies also reported improvements in other risk factors, particularly those related to cholesterol levels. Some trials reported gastrointestinal side effects, including bloating, diarrhea, and abdominal pain.44

There is little evidence that dietary fibre improves glycemic control. Existing trials are limited by the heterogeneity of fibre formulations and the variation in doses and duration of treatment. Evidence of a short-term hypoglycemic effect in diabetes patients is conflicting. Nonetheless, fibre can be recommended based on its salutary effect on other cardiovascular risk factors.

Green tea. Green and black tea both originate from the leaves of the Camellia sinensis plant. Green tea is heated to inactivate the enzymes that would otherwise oxidize the freshly collected leaves. The numerous health benefits of tea consumption are attributed to polyphenol catechins, particularly epigallocatechin gallate.45,46 These compounds have improved insulin sensitivity and reduced -cell damage in animal and in vitro studies.47-53 Although caffeine initially impairs glucose metabolism, long-term exposure stimulates lipolysis, increases basal energy expenditure, and mobilizes muscle glycogen.54,55 Prospective and retrospective population studies suggest that green tea consumption reduces the risk of type DM by up to 48%.56,57 Surprisingly, only 1 small RCT (N = 49) has evaluated green tea in the context of diabetes. In this study, patients with baseline HbA1c levels of 6.5% to 9.1% were randomized to receive either an extract containing green tea catechins and black tea theaflavins or placebo for 3 months. No improvements in HbA1c levels were seen and FBG values were not measured.58 Side effects included a generalized rash in 1 patient and diaphoresis in 1 patient.

Three open-label trials (N = 141) of 1 to 2 months’ duration reported no changes in HbA1c values.59-61 Investigators in one trial administered 1.5 L of oolong (partly oxidized) tea to 20 patients for 4 weeks and reported a 30% decrease in FBG levels (P < .001).44

There is little evidence to support the use of green tea for glycemic control. Epidemiologic data suggest large potential benefits, but further research is warranted. Green tea consumption should still be recommended for its other potential health benefits.

Bitter melon. Bitter melon (Momordica charantia) is a tropical vine that produces fruit that is used to treat diabetes in many traditional cultures, including Indian Ayurvedic medicine. Several of its active ingredients, including charantin, vicine, and polypeptide-p,62-64 are believed to stimulate insulin secretion and alter hepatic glucose metabolism.65-67
Two RCTs have evaluated the effects of bitter melon in patients with type 2 DM. In one RCT, 40 patients with baseline HbA1c values of 7% to 9% were given either 3 g of fruit and seed extract or placebo. After 3 months, there was no change in HbA1c or FBG values.68 The other trial, in which 51 patients consumed either 6 g of fruit and seed extract or placebo for 1 month, also reported no effect on HbA1c or FBG values.69 No side effects were reported in either trial.
There is no evidence to support the use of bitter melon. It should be noted that stimulating insulin release is probably less desirable than improving insulin sensitivity. Bitter melon’s widespread traditional use merits further study, particularly in patients originating from cultures with a long history of traditional use.

Fenugreek. Fenugreek (Trigonella foenum-graecum) has been cultivated and used medicinally and ceremonially for thousands of years in Asian and Mediterranean cultures. Its leaves and seeds are used to treat diabetes in Ayurvedic and other traditional medical systems. The most studied active ingredient is 4-hydroxyisoleucine, which increases pancreatic insulin secretion and inhibits sucrose -D-glucosidase and -amylase.70-72 Additionally, fenugreek seeds are used to lower cholesterol, as sapogenins in the seeds increase biliary secretion73-80; they are also a good source of fibre. Three small short-term RCTs (N = 50) have evaluated fenugreek in patients with type 2 DM. In one trial, 25 patients consumed 1 g of seed extract or placebo for 2 months with no change in FBG levels.81 In a small crossover study, 10 patients added 25 g of defatted seed powder to 1 meal or ate the meal without the powder for 15 days. Several measures of glucose metabolism were all unchanged.82 A third trial, which used a higher dose (100 g) of defatted seed powder in 15 patients for 10 days, did report improvements in FBG values.83 None of the trials investigated HbA1c levels. No adverse effects were reported.

There is very limited evidence to support the use of fenugreek in diabetes management. High doses of seed powder might be effective but require further study and are likely impractical for most patients. Its widespread traditional use and its reported lipid-lowering benefits warrant further study.

Gymnema. Gymnema sylvestre is also known as gurmar (sugar destroyer) in Hindi. The leaves of this plant are used in Ayurvedic medicine to treat diabetes, cholesterol, and obesity.84 Gymnemic acid, a mixture of many different saponins, is believed to be the active fraction, although a clear mechanism of action is yet to be been determined.85

Two small open-label trials have yielded promising results. In the first trial, 22 patients with type 2 DM were given either 200 mg of an ethanolic extract daily or their usual treatment for 18 to 20 months. Significant improvements in FBG and HbA1c levels (P < .001 for both) were noted in the test group.86 The other trial was uncontrolled, but reported that 3 months of treatment with 800 mg daily of a similar extract reduced FBG levels by 11% and HbA1c levels by 0.6% in a mixed population of 65 patients with type 1 and type 2 diabetes.87 No adverse effects were reported in either trial.

Preliminary evidence of any benefit is probably insufficient to support the widespread use of G sylvestre for diabetes management at this time. The significant improvements in HbA1c levels definitely warrant further study as well as judicious use in selected patients.

Conclusion
Changes in HbA1c values are most often used to evaluate hypoglycemic effects. It is important to consider that the life span of a red blood cell is 120 days. Therefore, studies investigating diabetes management should involve HbA1c measurements and should be of at least 4 months’ duration. Most of these trials were of insufficient duration to evaluate this outcome. None of the research examined has addressed the potential effect of CAM interventions on cardiovascular outcomes. This is important because better glycemic control might not always lead to real-world clinical benefits. It is also important because some interventions can improve other cardiovascular risk factors.

EDITOR’S Key points
• Chromium (200 to 1000 μg per day) is the only complementary and alternative medicine intervention with level 1 evidence to support its use in diabetes management, but a large-scale clinical trial is needed to confirm these findings.
• Small studies indicate that Gymnema sylvestre improves HbA1c levels. Larger studies are required to confirm these promising findings.
• Cinnamon probably lowers blood glucose levels, but its effects on HbA1c levels are unknown.
• Bitter melon has a long history of traditional use, but preliminary evidence suggests its benefits might be limited.
• Vanadium is poorly understood, has potential adverse side effects, and should probably be avoided.
• Green tea, fenugreek, and fibre can be recommended on account of their other health benefits, but evidence that they improve glycemic control is limited and conflicting.
Points de repère du rédacteur
Overall, there is a paucity of research evaluating CAM therapies that are commonly used to treat type 2 DM. This should be a high priority for CAM researchers and funding agencies.

Dr Nahas is a Lecturer in the Department of Family Medicine at the University of Ottawa and Medical Director of the Seekers Centre for Integrative Medicine in Ottawa, Ont. Mr Moher is a fourth-year medical student at the University of Ottawa.

Contributors
Dr Nahas and Mr Moher contributed to the literature review, selection and review of studies, and preparation of the manuscript for publication.

Competing interests
None declared

Correspondence
Dr R. Nahas, Medical Director, Seekers Centre for Integrative Medicine, 6 Deakin St, Ottawa, ON K2E 1B3; e-mail richard@seekerscentre.com

References
1. Health Canada. It’s your health. Type 2 diabetes. Ottawa, ON: Health Canada; 2004. Available from: www.hc-sc.gc.ca/hl-vs/iyh-vsv/diseases-maladies/diabete-eng.php. Accessed 2009 Apr 17.
2. Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC,Miller ME, Byington RP, Goff DC Jr, Bigger JT, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358(24):2545-59. Epub
2008 Jun 6.
3. ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal B, Billot L, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358(24):2560-72. Epub 2008 Jun 6.
4. Rao AD, Kuhadiya N, Reynolds K, Fonseca VA. Is the combination of sulfonylureas and metformin associated with an increased cardiovascular disease or all-cause mortality? A meta-analysis of observational studies. Diabetes Care 2008;31(8):1672-8. Epub 2008 May 5.
5. Lipscombe LL. Thiazolidinediones: do harms outweigh benefits? CMAJ 2009;180(1):16-7. Epub 2008 Dec 10.
6. McFarland B, Bigelow D, Zani B, Newsom J, Kaplan M. Complementary and alternative medicine use in Canada and the United States. Am J Public Health 2002;92(10):1616-8.
7. Imparl-Radosevich J, Deas S, Polansky MM, Baedke DA, Ingebritsen TS, Anderson RA, et al. Regulation of PTP-1 and insulin receptor kinase by fractions from cinnamon: implications for cinnamon regulation of insulin signaling.
Horm Res 1998;50(3):177-82.
8. Jarvill-Taylor KJ, Anderson RA, Graves DJ. A hydroxychalcone derived from cinnamon functions as a mimetic for insulin in 3T3-L1 adipocytes. J Am Coll Nutr 2001;20(4):327-36.
9. Qin B, Nagasaki M, Ren M, Bajotto G, Oshida Y, Sato Y. Cinnamon extract (traditional herb) potentiates in vivo insulin-regulated glucose utilization via enhancing insulin signaling in rats. Diabetes Res Clin Pract 2003;62(3):139-48.
10. Cao H, Polansky MM, Anderson RA. Cinnamon extract and polyphenols affect the expression of tristetraprolin, insulin receptor, and glucose transporter 4 in mouse 3T3-L1 adipocytes. Arch Biochem Biophys 2007;459(2):214-22. Epub 2007 Jan 25.
11. Baker WL, Gutierrez-Williams G, White CM, Kluger J, Coleman CI. Effect of cinnamon on glucose control and lipid parameters. Diabetes Care 2008;31(1):41-3. Epub 2007 Oct 1.
12. Khan A, Safdar M, Ali Khan MM, Khattak KN, Anderson RA. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care 2003;26(12):3215-8.
13. Mang B, Wolters M, Schmitt B, Kelb K, Lichtinghagen R, Stichtenoth DO, 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(5):340-4.
14. Blevins SM, Leyva MJ, Brown J, Wright J, Scofield RH, Aston CE. Effect of cinnamon on glucose and lipid levels in non insulin-dependent type 2 diabetes. Diabetes Care 2007;30(9):2236-7. Epub 2007 Jun 11.
15. Schwarz K, Mertz W. Chromium (III) and the glucose tolerance factor. Arch Biochem Biophys 1959;85:292-5.
16. Jeejeebhoy KN, Chu RC, Marliss EB, Greenberg GR, Bruce-Robertson A. Chromium deficiency, glucose intolerance, and neuropathy reversed by chromium supplementation, in a patient receiving long-term total parenteral
nutrition. Am J Clin Nutr 1977;30(4):531-8.
17. Brown RO, Forloines-Lynn S, Cross RE, Heizer WD. Chromium deficiency after long-term total parenteral nutrition. Dig Dis Sci 1986;31(6):661-4.
18. Freund H, Atamian S, Fischer JE. Chromium deficiency during total parenteral nutrition. JAMA 1979;241(5):496-8.
19. Balk EM, Tatsioni A, Lichtenstein AH, Lau J, Pittas AG. Effect of chromium supplementation on glucose metabolism and lipids: a systematic review of randomized controlled trials. Diabetes Care 2007;30(8):2154-63. Epub 2007 May 22.
20. Albarracin CA, Fuqua BC, Evans JL, Goldfine ID. Chromium picolinate and biotin combination improves glucose metabolism in treated, uncontrolledoverweight to obese patients with type 2 diabetes. Diabetes Metab Res Rev
2008;24(1):41-51.
21. Geohas J, Daly A, Juturu V, Finch M, Komorowski JR. Chromium picolinate and biotin combination reduces atherogenic index of plasma in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized
clinical trial. Am J Med Sci 2007;333(3):145-53.
22. O’Connell BS. Selected vitamins and minerals in the management of diabetes. Diabetes Spectrum 2001;14(3):133-48. Available from: http://spectrum.diabetesjournals.org/cgi/reprint/14/3/133.pdf. Accessed 2009 Apr 17.
23. Verma S, Cam MC, McNeill JH. Nutritional factors that can favorably influence the glucose/insulin system: Vanadium. J Am Coll Nutr 1998;17(1):11-8.
24. Pandey SK, Anand-Srivastava MB, Srivastava AK. Vanadyl sulfate-stimulated glycogen synthesis is associated with activation of phosphatidylinositol 3-kinase and is independent of insulin receptor tyrosine phosphorylation. Biochemistry 1998;37(19):7006-14.
25. Smith DM, Pickering RM, Lewith GT. A systematic review of vanadium oral supplements for glycaemic control in type 2 diabetes mellitus. QJM 2008;101(5):351-8. Epub 2008 Mar 4.
26. Galisteo M, Duarte J, Zarzuelo A. Effects of dietary fibers on disturbances clustered in the metabolic syndrome. J Nutr Biochem 2008;19(2):71-84. Epub 2007 Jul 6.
27. Marlett JA, McBurney MI, Slavin JL; American Dietetic Association. Position of the American Dietetic Association: health implications of dietary fiber. J Am Diet Assoc 2002;102(7):993-1000.
28. Cummings JH, Bingham SA, Heaton KW, Eastwood MA. Fecal weight, colon cancer risk and dietary intake of nonstarch polysaccharides (dietary fiber). Gastroenterology 1992;103(6):1783-9.
29. Howe GR, Benito E, Castelleto R, Cornée J, Estève J, Gallagher RP, et al. Dietary intake of fiber and decreased risk of cancers of the colon and rectum: evidence from the combined analysis of 13 case–control studies. J Natl Cancer Inst 1992;84(24):1887-96.
30. Prentice RL. Future possibilities in the prevention of breast cancer: fat and fiber and breast cancer research. Breast Cancer Res 2000;2(4):268-76. Epub 2000 May 19.
31. Murakami K, Okubo H, Sasaki S. Effect of dietary factors on incidence of type 2 diabetes: a systematic review of cohort studies. J Nutri Sci Vitaminol (Tokyo) 2005;51(4):292-310.
32. Beattie VA, Edwards CA, Hosker JP, Cullen DR, Ward JD, Read NW. Does adding fibre to a low energy, high carbohydrate, low fat diet confer any benefit to the management of newly diagnosed overweight type II diabetics? Br
Med J (Clin Res Ed) 1988;296(6630):1147-9.
33. Vuksan V, Jenkins DJ, Spadafora P, Sievenpiper JL, Owen R, Vidgen E, et al. Konjac-mannan (glucomannan) improves glycemia and other associated risk factors for coronary heart disease in type 2 diabetes. A randomized controlled metabolic trial. Diabetes Care 1999;22(6):913-9.
34. Rodríguez-Morán M, Guerrero-Romero F, Lazcano-Burciaga G. Lipid- and glucose-lowering efficacy of Plantago Psyllium in type II diabetes. J Diabetes Complications 1998;12(5):273-8.
35. Mahalko JR, Sandstead HH, Johnson LK, Inman LF, Milne DB, Warner RC, et al. Effect of consuming fiber from corn bran, soy hulls, or apple powder on glucose tolerance and plasma lipids in type 2 diabetes. Am J Clin Nutr
1984;39(1):25-34.
36. Maeda H, Yamamoto R, Hirao K, Tochikubo O. Effects of agar (kanten) diet on obese patients with impaired glucose tolerance and type 2 diabetes. Diabetes Obes Metab 2005;7(1):40-6.
37. Karlander S, Armyr I, Efendic S. Metabolic effects and clinical value of beet fibre treatment in NIDDM patients. Diabetes Res Clin Pract 1991;11(2):65-71.
38. Cho SH, Kim TH, Lee NH, Son HS, Cho IJ, Ha TY. Effects of Cassia tora fibre supplement on serum lipids in Korean diabetic patients. J Med Food 2005;8(3):311-8.
39. Jenkins DJ, Kendall CW, Augustin LS, Martini MC, Axelsen M, Faulkner D, et al. Effect of wheat bran on glycemic control and risk factors for cardiovascular disease in type 2 diabetes. Diabetes Care 2002;25(9):1522-8.
40. Karlström B, Vessby B, Asp NG, Boberg M, Gustafsson IB, Lithell H, et al. Effects of an increased content of cereal fibre in the diet of type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1984;26(4):272-7.
41. Hollenbeck CB, Coulston AM, Reaven GM. To what extent does increased dietary fiber improve glucose and lipid metabolism in patients with noninsulin-dependent diabetes mellitus (NIDDM)? Am J Clin Nutr 1986;43(1):16-24.
42. Lu ZX, Walker KZ, Muir JG, O’Dea K. Arabinoxylan fibre improves metabolic control in people with type II diabetes. Eur J Clin Nutr 2004;58(4):621-8.
43. Chandalia M, Garg A, Lutjohann D, von Bergmann K, Grundy S, Brinkley LJ. Beneficial effects of high dietary fiber intake in patients with type 2 diabetes mellitus. N Engl J Med 2000;342(19):1392-8.
44. Chuang LM, Jou TS, Yang WS, Wu HP, Huang SH, Tai TY, et al. Therapeutic effect of guar gum in patients with non-insulin-dependent diabetes mellitus. J Formos Med Assoc 1992;91(1):15-9.
45. Higdon JV, Frei B. Tea catechins and polyphenols: health effects, metabolism, and antioxidant functions. Crit Rev Food Sci Nutr 2003;43(1):89-143.
46. Nagle DG, Ferreira D, Zhou YD. Epigallocatechin-3-gallate (EGCG): chemical and biomedical perspectives. Phytochemistry 2006;67(17):1849-55. Epub 2006 Jul 31.
47. Anderson RA, Polansky MM. Tea enhances insulin activity. J Agric Food Chem 2002;50(24):7182-6.
48. Gomes A, Vedasiromoni JR, Das M, Sharma RM, Ganguly DK. Antihyperglycemic
effect of black tea (Camellia sinensis) in rat. J Ethnopharmacol 1995;45(3):223-6.
49. Broadhurst CL, Polansky MM, Anderson RA. Insulin-like biological activity of culinary and medicinal plant aqueous extracts in vitro. J Agric Food Chem 2000;48(3):849-52.
50. Wu LY, Juan CC, Hwang LS, Hsu YP, Ho PH, Ho LT. Green tea supplementation ameliorates insulin resistance and increases glucose transporter IV content in a fructose-fed rat model. Eur J Nutr 2004;43(2):116-24. Epub 2004 Jan 6.
51. Waltner-Law ME, Wang XL, Law BK, Hall RK, Nawano M, Granner DK. Epigallocatechin gallate, a constituent of green tea, represses hepatic glucose production. J Biol Chem 2002;277(38):34933-40. Epub 2002 Jul 12.
52. Sabu MC, Smitha K, Kuttan R. Anti-diabetic activity of green tea polyphenols and their role in reducing oxidative stress in experimental diabetes. J Ethnopharmacol 2002;83(1-2):109-16.
53. Wolfram S, Raederstorff D, Preller M, Wang Y, Teixeira SR, Riegger C, et al. Epigallocatechin gallate supplementation alleviates diabetes in rodents. J Nutr 2006;136(10):2512-8.
54. Lane JD, Barkauskas CE, Surwit RS, Feinglos MN. Caffeine impairs glucose metabolism in type 2 diabetes. Diabetes Care 2004;27(8):2047-8.
55. Robinson LE, Savani S, Battram DS, McLaren DH, Sathasivam P, Graham TE. Caffeine ingestion before an oral glucose tolerance test impairs blood glucose management in men with type 2 diabetes. J Nutr 2004;134(10):2528-33.
56. Iso H, Date C, Wakai K, Fukui M, Tamakoshi A; JACC Study Group. The relationship between green tea and total caffeine intake and risk for self-reported type 2 diabetes among Japanese adults. Ann Intern Med 2006;144(8):554-62.
57. Polychronopoulos E, Zeimbekis A, Kastorini CM, Papairakleous N, Vlachou I, Bountziouka V, et al. Effects of black and green tea consumption on blood glucose levels in non-obese elderly men and women from Mediterranean Islands
(MEDIS epidemiological study). Eur J Nutr 2008;47(1):10-6. Epub 2008 Jan 18.
58. Mackenzie T, Leary L, Brooks WB. The effect of an extract of green and black tea on glucose control in adults with type 2 diabetes mellitus: doubleblind randomized study. Metabolism 2007;56(10):1340-4.
59. Ryu OH, Lee J, Lee KW, Kim HY, Seo JA, Kim SG, et al. Effects of green tea consumption on inflammation, insulin resistance and pulse wave velocity in type 2 diabetes patients. Diabetes Res Clin Pract 2006;71(3):356-8. Epub 2005 Sep 19.
60. Fukino Y, Shimbo M, Aoki N, Okubo T, Iso H. Randomized controlled trial for an effect of green tea consumption on insulin resistance and inflammation markers. J Nutr Sci Vitaminol (Tokyo) 2005;51(5):335-42.
61. Hosoda K, Wang MF, Liao ML, Chuang CK, Iha M, Clevidence B, et al. Antihyperglycemic effect of oolong tea in type 2 diabetes. Diabetes Care 2003;26(6):1714-8.
62. Torres WD. Momordica charantia Linn. (Family: Cucurbitaceae)—chemistry and pharmacology [review]. Las Vegas, NV: American Academy of Anti- Aging Medicine; 2004. Available from: www1.charanteausa.com/ bittermelonstudies/2006/07/17/momordica-charantia-linn-familycucurbitaceae. Accessed 2009 Apr 17.
63. Basch E, Gabardi S, Ulbricht C. Bitter melon (Momordica charantia): a review of efficacy and safety. Am J Health Syst Pharm 2003;60(4):356-9.
64. Baldwa VS, Bhandari CM, Pangaria A, Goyal RK. Clinical trial in patients with diabetes mellitus of an insulin-like compound obtained from plant source. Ups J Med Sci 1977;82:39-41.
65. Welihinda J, Karunanayake EH, Sheriff MH, Jayasinghe KS. Effect of Momordica charantia on the glucose tolerance in maturity onset diabetes. J Ethnopharmacol 1986;17(3):277-82.
66. Shibib BA, Khan LA, Rahman R. Hypoglycaemic activity of Coccinia indica and Momordica charantia in diabetic rats: depression of the hepatic gluconeogenic enzymes glucose-6-phosphatase and fructose-1,6-bisphosphatase and elevation of both liver and red-cell shunt enzyme glucose-6-phosphate dehydrogenase. Biochem J 1993;292(Pt 1):267-70.
67. Yeh GY, Eisenberg DM, Kaptchuk TJ, Phillips RS. Systematic review of herbs and dietary supplements for glycemic control in diabetes. Diabetes Care 2003;26(4):1277-94.
68. Dans AM, Villarruz MV, Jimeno CA, Javelosa MA, Chua J, Bautista R, et al. The effect of Momordica charantia capsule preparation on glycemic control in type 2 diabetes mellitus needs further studies. J Clin Epidemiol 2007;60(6):554-9. Epub 2006 Nov 13.
69. John AJ, Cherian R, Subhash HS, Cherian AM. Evaluation of the efficacy of bitter gourd (momordica charantia) as an oral hypoglycemic agent—a randomized controlled clinical trial. Indian J Physiol Pharmacol 2003;47(3):363-5.
70. Sauvaire Y, Petit P, Broca C, Manteghetti M, Baissac Y, Fernandez-Alvarez J, et al. 4-Hydroxyisoleucine: a novel amino acid potentiator of insulin secretion. Diabetes 1998;47(2):206-10.
71. Ajabnoor MA, Tilmisany AK. Effect of Trigonella foenum graceum on blood glucose levels in normal and alloxan-diabetic mice. J Ethnopharmacol 1988;22(1):45-9.
72. Amin R, Abdul-Ghani AS, Suleiman MS. Effect of Trigonella feonum graecum on intestinal absorption. Proc. Of the 47th Annual Meeting of the American Diabetes Assocation (Indianapolis U.S.A.). Diabetes 1987;36(Suppl 1):211a.
73. Stark A, Madar Z. The effect of an ethanol extract derived from fenugreek (Trigonella foenum-graecum) on bile acid absorption and cholesterol levels in rats. Br J Nutr 1993;69(1):277-87.
74. Petit P, Sauvaire Y, Ponsin G, Manteghetti M, Fave A, Ribes G. Effects of a fenugreek seed extract on feeding behaviour in the rat: metabolic-endocrine correlates. Pharmacol Biochem Behav 1993;45(2):369-74.
75. Al-Habori M, Al-Aghbari AM, Al-Mamary M. Effects of fenugreek seeds and its extracts on plasma lipid profile: a study on rabbits. Phytother Res 1998;12(8):572-5.
76. Al-Habori M, Raman A. Antidiabetic and hypocholesterolaemic effects of fenugreek. Phytother Res 1998;12(4):233-42.
77. Valette G, Sauvaire Y, Baccou JC, Ribes G. Hypocholesterolaemic effect of fenugreek seeds in dogs. Atherosclerosis 1984;50(1):105-11.
78. Sauvaire Y, Ribes G, Baccou JC, Loubatieères-Mariani MM. Implication of steroid saponins and sapogenins in the hypocholesterolemic effect of fenugreek. Lipids 1991;26(3):191-7.
79. Varshney IP, Sharma SC. Saponins and sapogenins: part XXXII. Studies on Trigonella foenum-graecum Linn. seeds. J Indian Chem Soc 1966;43:564-7.
80. Sidhu GS, Oakenfull DG. A mechanism for the hypocholesterolaemic activity of saponins. Br J Nutr 1986;55(3):643-9.
81. Gupta A, Gupta R, Lal B. 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;49:1057-61.
82. Raghuram TC, Sharma RD, Sivakumar B, Sahay BK. Effect of fenugreek seeds on intravenous glucose disposition in non-insulin dependent diabetic patients. Phytother Res 1994;8(2):83-6.
83. Sharma RD, Raghuram TC. Hypoglycaemic effect of fenugreek seeds in noninsulin dependent diabetics subjects. Nutr Res 1990;10(7):731-9.
84. Bone K. Gymnema: a key herb in the management of diabetes. Port Townsend, WA: Townsend Letter for Doctors and Patients; 2002. Available from: www.townsendletter.com/Dec2002/phytotherapy1202.htm. Accessed 2009 Apr 17.
85. Porchezhian E, Dobriyal RM. An overview on the advances of Gymnema sylvestre: chemistry, pharmacology and patents. Pharmazie 2003;58(1):5-12.
86. Baskaran K, Kizar Ahamath B, Radha Shanmugasundaram K, Shanmugasundaram ER. Antidiabetic effect of a leaf extract from Gymnema sylvestre in non-insulin-dependent diabetes mellitus patients. J Ethnopharmacol 1990;30(3):295-305.
87. Joffe D. Gymnema sylvestre lowers HbA1c. Diabetes Control Newsl 2001;76:1. Available from: www.diabetesincontrol.com/studies/ gymnema1_2.shtml. Accessed 2009 Apr 17.