Hiroyasu Iso, MD; Chigusa Date, PhD; Kenji Wakai, MD; Mitsuru Fukui, PhD; Akiko Tamakoshi, MD; and the JACC Study Group*
Acknowledgments: The authors thank Dr. Kunio Aoki, Professor Emeritus, Nagoya University School of Medicine and former chairman of the JACC Study Group; Dr. Haruo Sugano, former director of the Cancer Institute of the Japanese Foundation for Cancer Research, who greatly contributed to the initiation of the study; and Professor Aaron R. Folsom, University of Minnesota, for valuable scientific suggestions.
Grant Support: The JACC Study has been supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (61010076, 62010074, 63010074, 1010068, 2151065, 3151064, 4151063, 5151069, 6279102, and 11181101).
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Hiroyasu Iso, MD, Public Health, Department of Social and Environmental Health, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Iso: Public Health, Department of Social and Environmental Health, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan.
Dr. Date: Nara Women's University, Kitauoyanishi-machi, Nara 630-8506, Japan.
Dr. Wakai: Aichi Cancer Center, 1-1 Kanokoden, Chikusan-ku, Nagoya 466-8681, Japan.
Dr. Fukui: Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
Dr. Tamakoshi: Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
Author Contributions: Conception and design: H. Iso.
Analysis and interpretation of the data: H. Iso.
Drafting of the article: H. Iso.
Critical revision of the article for important intellectual content: H. Iso, C. Date, K. Wakai, M. Fukui, A. Tamakoshi.
Final approval of the article: H. Iso, C. Date, K. Wakai, M. Fukui, A. Tamakoshi.
Provision of study materials or patients: The JACC Study Group.
Statistical expertise: H. Iso, K. Wakai, M. Fukui.
Iso H., Date C., Wakai K., Fukui M., Tamakoshi A., ; The Relationship between Green Tea and Total Caffeine Intake and Risk for Self-Reported Type 2 Diabetes among Japanese Adults. Ann Intern Med. 2006;144:554-562. doi: 10.7326/0003-4819-144-8-200604180-00005
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Published: Ann Intern Med. 2006;144(8):554-562.
The prevalence of type 2 diabetes has increased worldwide, particularly in Asian countries where it was previously low (1). In Japan, population-based studies have shown a 2-fold increase in the prevalence of diabetes during the past 2 decades, from 5% to 10% to 10% to 15% (2). Several cohort studies done in Europe and in the United States reported an association between coffee consumption, a major source of caffeine, and reduced risk for diabetes (3-7). Although these studies did not show any association between consumption of black tea and the risk for diabetes, they did not examine the effect of green or oolong teas, major sources of caffeine in Asian countries. Consumption of green tea is common in Japan; 80% of the population drinks green tea, and the average consumption per capita is 2 cups per day (8). We wanted to determine whether there is a relationship between consumption of green tea and the risk for type 2 diabetes and, if so, whether caffeine fully accounts for this relationship. To examine these questions, we analyzed data from a large cohort study of 19 487 middle-aged men and women in 25 communities across Japan. We also examined the effect of age, sex, body mass index (BMI), family history, smoking status, alcohol use, magnesium intake, and physical activity on the association between this mode of caffeine consumption and risk for diabetes.
April 17, 2006
Coffee Consumption in Association with Type 2 DM
I would like to add more information regarding the article, "The Relationship between Green Tea and Total Caffeine Intake and Risk for Self -Reported Type 2 Diabetes among Japanese Adults" by Hiroyasu Iso at el. Few studies were conducted through out different parts of the world regarding this association. Acute administration of caffeine decreases insulin sensitivity and impairs glucose tolerance but Long-term coffee consumption is associated with a statistically significantly lower risk for type 2 diabetes.
Harvard School of Public Health runs study (1) where Salazar- Martinez E et al found that long term coffee consumption has lower the risk for type 2 diabetes. The authors followed 41 934 men from 1986 to 1998 and 84 276 women from 1980 to 1998. These participants did not have diabetes, cancer, or cardiovascular disease at baseline.
In Stockholm, Sweden a study (2) was done by Karolinska Institute (Department of Molecular Medicine, Endocrine and Diabetes Unit). The study comprised 7949 healthy Swedish subjects aged 35-56 years residing within five municipalities of Stockholm. The results of this study indicated that high consumers of coffee have a reduced risk of type 2 diabetes and impaired glucose tolerance.
A Second study (4) conducted in Sweden on A random population sample of 1361 women, aged 39-65 years, without prior diabetes or cardiovascular disease took part in a screening study in 1979-1981 with questionnaires, physical examination and blood sampling under Department of Medicine, Sahlgrenska University Hospital/Ostra, Goteborg, Sweden. This study also support the hypothesis that coffee consumption protects from the development of diabetes in women.
In Finland a study (3) carried out by Department of Epidemiology and Health Promotion, National Public Health Institute; Department of Public Health, University of Helsinki; and Institute of Biomedicine, Helsinki. Since Finnish individuals, who have the highest coffee consumption in the world, A prospective study from combined surveys conducted in 1982, 1987, and 1992 of 6974 Finnish men and 7655 women aged 35 to 64 years without history of stroke, coronary heart disease, or DM at baseline, with 175 682 person-years of follow-up. The conclusion was, Coffee drinking has a graded inverse association with the risk of type 2 DM; however, the reasons for this risk reduction associated with coffee remain unclear.
In UK study (4), was conducted under Centre for Nutrition and Food Safety, School of Biomedical and Molecular Sciences, University of Surrey, Guildford. This small study was upon 9 healthy fasted volunteers. Conclusion was "chlorogenic acid might have an antagonistic effect on glucose transport".
We hope, more useful research approach in this area will show more appropriate outcome measures of glucose metabolism under the influence of coffee consumption. Reference:
1. Coffee consumption and risk for type 2 diabetes mellitus. Salazar- Martinez E, Willett WC, Ascherio A, Manson JE, Leitzmann MF, Stampfer MJ, Hu FB. Ann Intern Med. 2004 Jan 6;140(1):I17
2. Coffee consumption, type 2 diabetes and impaired glucose tolerance in Swedish men and women. Agardh EE, Carlsson S, Ahlbom A, Efendic S, et al. J Intern Med. 2004 Jun;255(6):645-52.
3. Coffee Consumption and Risk of Type 2 Diabetes Mellitus Among Middle-aged Finnish Men and Women. Tuomilehto J, Hu G, Bidel S, LindstrÃ¶m J, Jousilahti P. JAMA. 2004;291:1213-1219.
4. Coffee acutely modifies gastrointestinal hormone secretion and glucose tolerance in humans: glycemic effects of chlorogenic acid and caffeine. Johnston KL, Clifford MN, Morgan LM. Am J Clin Nutr. 2003 Oct; 78(4):728-33.
Tsung O Cheng
George Washington University
April 18, 2006
Green Tea Can Reduce Risk for Diabetes
Iso et al  reported an inverse relation between green tea (not black tea) consumption and risk for diabetes and attributed it to caffeine. However, the importance of other constituents in the green tea should not be underestimated .
For ages, plants containing flavonoids have been used to treat diabetes in Indian medicine . The green tea flavonoid has been shown to have insulin-like activities  as well as insulin-enhancing activity . However, epigallocatechin gallate, which is the principal catechin in green tea, differs from insulin in that it affects several insulin- activated kinases with slower kinetics . Furthermore, epigallocatechin regulates genes that encode gluconeogenic enzymes and protein-tyrosine- phosphorylation by modulating the redox state of the cell . Thus epigallocatechin gallate may be an antidiabetic agent.
Mouse experiment by Japanese investigators , in fact, documented that a certain serum protein may be involved in the antihyperglycemic effect of green tea. Taiwanese investigators  demonstrated recently that green tea increases insulin sensitivity in Sprague-Dawley rats and that the green tea polyphenol is one of the active components. In a fructose-fed rat model, the same Taiwanese investigators  found that green tea ameliorates insulin resistance and increases glucose transporter IV content of adipocytes isolated from the epididymal fat pads. In Japan  and Taiwan , oolong tea was shown to be an effective adjunct to oral hypoglycemic agents in the treatment of patients with type 2 diabetes.
Obviously, more research is needed to see if tea drinking should be a standard recommendation for those who have diabetes or are at risk for developing diabetes . However, if one is a diabetic and likes tea, this is another good reason to keep drinking it . However, one should refrain from using added milk, soy milk, or nondairy creamer, because they may reduce the positive effect of tea on insulin activity .
1. Iso H, Date C, Wakai K, Fukui M, Tamakoshi A, the 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;144:554-562
2. Cheng TO: All teas are not created equal. The Chinese green tea and cardiovascular health. Int J Cardiol 2006;108:301-308.
3. Waltner-Law ME, Wang XL, Law BK, Hall RK, Nawano M, Granner DK: Epigallocatechin gallate, a consituent of green tea, represses hepatic glucose production. J Biol Chem 2002;277:34933-34940.
4. Anderson RA, Polansky MM: Tea enhances insulin activity. J Agric Food Chem 2002;50:7182-7186.
5. Tsuneki H, Ishizuka M, Terasawa M, Wu JB, Sasaoka T, Kimura I: Effect of green tea on blood glucose levels and serum proteomic patterns in diabetic (db/db) mice and on glucose metabolism in healthy humans. BMC Pharmacol 2004;4:18.
6. Wu LY, Juan CC, Ho LT, Hsu YP, Hwang LS: Effect of green tea supplementation on insulin sensitivity in Sprague-Dawley rats. J Agric Food Chem 2004;52:643-648.
7. 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;43:116-124.
8. Shimada K, Kawarabayashi T, Tanaka A, Fukuda D, Nakamura Y, Yoshiyama M, Takeuchi K, Sawaki T, Hosoda K, Yoshikawa J: Oolong tea increases plasma adiponectin levels and low-density lipoprotein particle size in patients with coronary artery disease. Diabetes Res Clin Pract 2004;65:227-234.
9. Hosoda K, Wang MF, Liao ML, Chuang CK, Iha M, Clevidence B, Yamamoto S: Antihyperglycemic effect of oolong tea in type 2 diabetes. Diabetes Care 2003;26:1714-1718.
10.Campbell AP: Time for tea? Diabetes Self Manag 2004;21(2):8-10,12.
Rob M. van Dam
Department of Nutrition, Harvard School of Public Health
April 20, 2006
Coffee versus caffeine intake in relation to risk for type 2 diabetes
Dr. Iso and colleagues present interesting results on the association between green tea and coffee consumption and a lower risk for type 2 diabetes in Japanese adults. They also examined caffeine intake and state that they think that the observed inverse associations for coffee and green tea were mostly due to the inverse association between caffeine intake and risk for type 2 diabetes. I do not think this emphasis on caffeine intake is appropriate. First, calculated caffeine intake was the weighted sum of coffee and tea intakes and would therefore be highly correlated with intake of any other food component for which both coffee and tea are important sources. Coffee and tea both supply many substances for which beneficial effects on glucose metabolism are plausible including phenolic compounds, phytoestrogens, and minerals.(1) Second, a higher consumption of decaffeinated coffee has been associated with a lower risk for type 2 diabetes in four U.S. cohort studies.(2,3,4) In a recently published study, the inverse association between caffeine intake and risk for type 2 diabetes could be completely explained by coffee consumption.(4) Third, a short-term randomized trial showed that decaffeinated coffee intake acutely improved glucose tolerance, whereas caffeine capsules acutely reduced glucose tolerance.(5) Although beneficial effects of long-term caffeine intake on glucose metabolism cannot be excluded, the currently available evidence does not indicate that caffeine can explain most of the inverse association between coffee consumption and risk for type 2 diabetes.
1. van Dam RM. Coffee and type 2 diabetes: from beans to beta-cells. Nutr Metab Cardiovasc Dis 2006; 2006;16:69-77.
2. Salazar-Martinez E, Willett WC, Ascherio A, Manson JE, Leitzmann MF, Stampfer MJ, et al. Coffee consumption and risk for type 2 diabetes mellitus. Ann Intern Med 2004;140:1-8.
3. Greenberg JA, Axen KV, Schnoll R, Boozer CN. Coffee, tea and diabetes: the role of weight loss and caffeine. Int J Obes Relat Metab Disord 2005.
4. van Dam RM, Willett WC, Manson JE, Hu FB. Coffee, caffeine, and risk of type 2 diabetes: a prospective cohort study in younger and middle-aged U.S. women. Diabetes Care 2006;29:398-403.
5. Battram DS, Arthur R, Weekes A, Graham TE. The glucose intolerance induced by caffeinated coffee ingestion is les pronounced than that due to alkaloid caffeine in men. J Nutr 2006;136:1276-80.
Comando Brigata alpina
April 27, 2006
Lowering body iron stores by tea and coffe consumption and the risk of type 2 diabetes.
TO THE EDITOR "“ Iso and colleagues found significant and inverse associations of green tea and coffee consumption with the risk of type 2 diabetes. We suggest that some of the mechanisms involved in this beneficial association might be related to the reduced iron absorption induced by tea and coffee. These beverages have been shown to strongly inhibit the absorption of nonheme iron (1-3). On the other hand, serum ferritin, a good indicator of iron stored in the body, has been shown to be associated with an increased risk for diabetes (4). Furthermore, a small intervention study in type 2 diabetic patients with elevated ferritin levels provided evidence that blood letting, which resulted in 50% reduction of serum ferritin concentrations, improved glycemia and insulin sensitivity (5). Thus, increased intake of tea and coffee may maintain a relatively low iron status and may therefore reduce the risk of diabetes.
Luca Mascitelli, MD Sanitary Service Comando Brigata alpina "Julia" Udine, Italy 33100
Francesca Pezzetta, MD Cardiology Service Ospedale di San Vito al Tagliamento San Vito al Tagliamento, Italy 33078
1. Mork TA, Lynch SR, Cook JD. Inhibition of food iron absorption by coffee. Am J Clin Nutr 1983; 37: 416-20.
2. Hallberg L, Hulthen L. Prediction of dietary iron absorption: an alghorithm for calculating absorption and bioavilability of dietary iron. Am J Clin Nutr 2000; 71: 1147-60.
3. Samman S, Sandstrom B, Toft MB. Green tea or rosemary extract added to foods reduces nonheme-iron absorption. Am J Clin Nutr 2001; 73: 607-12.
4. Jiang R, Manson JE, Meigs JB, Ma J, Rifai N, Hu FB. Body iron stores in relation to risk of type 2 diabetes in apparently healthy women. JAMA 2004; 291: 711-7.
5. Fernandez-Real JM, PeÃ±arroja G, Castro A, Garcia-Bragado F, Hernandez-Aguado I, Ricart W. Blood letting in high-ferritin type 2 diabetes: effects on insulin sensitivity and beta-cell function. Diabetes 2002; 51: 1000-4.
University College London
May 4, 2006
Green Tea and Diabetes Risk
To the Editor:
Dr Iso and colleagues (1) reported that consumption of green tea and coffee could significantly reduce the risk of type 2 diabetes. Their findings were not consistent between men and women. Diabetes was not associated with green tea and total caffeine intake in men, which seemed not due to its sample size. The combined results of men and women generated an overall significant association of diabetes with beverage consumption for the total population, but probably making its conclusion inaccurate. Furthermore, a highly significant difference in the response rate to the 5-year follow-up questionnaire between men (44.3%) and women (52.1%) would not suggest such gender combination. It may be worthy of investigating differences in BMI and other important factors between respondents and non-respondents in each category of consumption for men and women.
Socio-economic status (SES) - an important predictor of illness outcomes "“ was not adjusted for the analysis. Low SES is related to depression and other factors (2), increasing the risk of type 2 diabetes (3). In the same JACC data Fujino et al (4) reported a positive association of educational level with consumption of green tea and consumption of fruits and vegetables. A recent study in Japan (5) showed that DFSA dietary pattern, including a high intake of fruits and vegetables, was associated with a reduced risk of impaired fasting glucose, impaired glucoses tolerance or type 2 diabetes. It would be of interest to see whether or not SES adjustment would change the study results, particularly in overweight men.
While the authors suggested clinical trials to confirm the protective effect of green tea and coffee on type 2 diabetes, further analysis, including long-term mortality from diabetes in the JACC men and women, may clarify the issues.
1. 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;144:554-62.
2. Chen R, Wei R, Hu Z, Qin Z, Copeland JRM, Hemingway H. Depression in older people in rural China. Arch Intern Med. 2005;165:2019- 25.
3. Knol MJ, Twisk JW, Beekman AT, Heine RJ, Snoek FJ, Pouwer F. Depression as a risk factor for the onset of type 2 diabetes mellitus. A meta-analysis. Diabetologia. 2006;49:837-45.
4. Fujino Y, Tamakoshi A, Ohno Y, Mizoue T, Tokui N, Yoshimura T; JACC Study Group. Japan Collaborative Cohort Study for Evaluation of Cancer Risk. Prospective study of educational background and stomach cancer in Japan. Prev Med. 2002;35:121-7.
5. Mizoue T, Yamaji T, Tabata S, Yamaguchi K, Ogawa S, Mineshita M, Kono S. Dietary patterns and glucose tolerance abnormalities in Japanese men. J Nutr. 2006;136:1352-8.
Tsurumi University, School of Dental Medicine
May 9, 2006
Could green tea prevent developing diabetes?
According to Iso and coworkers' article (1), the multivariable odds ratio for diabetes among participants who frequently drank green tea (>6 cups/day) was 0.67 compared with those who drank less than 1 cup per week (1). However, the inverse relationship between risk for type 2 diabetes and consumption of green tea was not significant in men, but significant only in women. The authors speculated the possibilities that men did not report their consumption of green tea or consumption of cola is more popular among men than women (1). Only from their speculations, it would be unlikely that green tea brought favorable effect for prevention of developing type 2 diabetes only in women. Would it be true that consumption of green tea actually prevent the development of type 2 diabetes? There is now evidence from large-scale observational studies, and from intervention studies, of powerful synergistic interactions between diet, obesity, exercise, smoking, and alcohol in the development of glucose intolerance (2). Iso and colleagues showed that much larger percentage of men took both alcohol and tobacco than women in their present study (1). The same group reported that preference of fatty food was reported by 10 to 35% of individuals with a higher frequency among men than women (3). Taken together those results, the favorable results for prevention of diabetes by green tea in women, would be explained by the difference of lifestyle between men and women. In addition, consumption of coffee could not significantly prevent the development of type 2 diabetes both in men and women (1). In contrast, Salazar-Martienz et al. reported that long-term coffee consumption is associated with a statistically significantly lower risk for type 2 diabetes both in men and women (4). It would be needed to do the analysis with larger-size and longer-follow up in order to evaluate the preventative role of coffee-consumption for type 2 diabetes in Asian populations. References:
(1) Ann Int Med 2006;144:554-62.
(2) Proc Nutr Soc 2002;61:543-51.
(3) J Epidemiol 2005;15:S24-42.
(4) Ann Int Med 2004;140:1-8.
Osaka University School of Medicine
June 26, 2006
To Dr. Ruoling Chen RE: Green tea and diabetes IN RESPONSE: There was no difference in mean BMI between respondents and non- respondents in each category of green tea and coffee consumption, except for the category of green tea >= 6 cups/d in men (22.6 vs 22.9 kg/m2, respectively, P for difference = 0.02), and the category of coffee 1-6 cups/wk in men (22.6 vs 23.0 kg/m2, respectively, P for difference = 0.008) and women (22.8 vs 23.2 kg/m2, respectively, P for difference = 0.005) where no protective effect was found in Table 3. Thus, the difference of BMI in these categories of green tea and coffee did not explain follow-up bias.
Even after we adjusted for educational levels(education years =< 15, 16-18 and >=19), the multivariable odds ratios of diabetes for frequent drinkers of green tea and coffee consumption (>= 6 cups per day and >=3 cups per day, respectively) and the highest quintile of caffeine intake did not change materially: 0.68 (95%CI, 0.48-0.96), p for trend=0.247, 0.59 (95%CI, 0.38-0.92), p for trend=0.037 and 0.69 (0.48- 0.97), p for trend=0.027, respectively. For the overweight men, the multivariable odds ratio of the highest quintile of caffeine intake was 0.36 (95%CI, 0.13-0.99), p for trend=0.026.
We could not confirm the protective effect of green tea and coffee on mortality from diabetes since the number of deaths due to diabetes (ICD10:E100-149) was only 33.
To Dr. Tsung O Cheng RE: Green tea can reduce risk for diabetes IN RESPONSE: As for mechanisms, we focused on an effect of caffeinem, but addressed briefly another mechanism of an antidaibetic effect of epigallocatechin. It was nice of you to comment more detailed evidence on an antidiabetic effect of epigallocatechin or other constituents.
A potential adverse effect of added milk, soy milk or non-dairy creamer on the reduction of the positive effect of tea on insulin activity, addressed by Dr. Cheng is uncertain since the adding milk or cream to tea was not associated with insulin sensitivity.1
1.Arnlov J, Vessbby B, Riserus U. Coffee consumption and insulin sensitivity. JAMA 2004:291:1199-1201.
To Dr. Francesca Pezzetta: RE: Lowering iron stores by tea and coffee consumption and the risk of diabetes. IN RESPONSE: Thank you for your comments on another mechanism for green tea and coffee consumption and the risk of Type 2 diabetes. The mechanism you addressed is plausible although there is the limited evidence that chronic consumption of tea and coffee actually lowers the non-hem iron store in the body.
To Dr. Rob M. van Dam: RE: Coffee vs caffeine intake in relation to risk for Type 2 diabetes. IN RESPONSE: Thank you for your comments on mechanisms for the inverse associations of green tea and coffee consumption with the risk of Type 2 diabetes. We stressed an effect of caffeine as a major mechanism, and briefly commented effects of chlorogenic acid and magnesium. There is growing evidence than various constituents in coffee and tea affects glucose metabolism. As Dr. Dam pointed out, the improvement of glucose tolerance by decaffeinated coffee supports that constituents other than caffeine lower the risk of Type 2 diabetes. Decaffeinated coffee has been uncommon in Japan, and we did not discriminate regular and decaffeinated coffee in our cohort study.
Hiroyasu Iso, MD Osaka University School of Medicine Osaka Japan 565-0871
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