Debate persists whether coffee is beneficial or problematic for human health. Coffee consumption has been associated with a decrease in risk of developing type 2 diabetes, and numerous epidemiological studies have demonstrated that healthy, habitual coffee drinkers are more protected from the risk of contracting diabetes than individuals who do not drink coffee. Coffee consumption has been associated with a reduced incidence of impaired glucose tolerance, hyperglycaemia and insulin sensitivity. Data suggest that several coffee components, such as chlorogenic acids, are involved in the health benefits of coffee. Various mechanisms for this protective effect have been proposed, including effects on incretin release, liver glucose metabolism and insulin sensitivity. Epidemiological data support numerous other health benefits for coffee, including reduced cardiovascular disease (CVD), a protective effect against some neurodegenerative conditions, a favourable effect on liver function and a protective effect against certain cancers. These associations are based mainly on observational studies and are currently insufficient to recommend coffee consumption as an interventional strategy for risk reduction in type 2 diabetes and other metabolic diseases. While excessive consumption can have adverse effects on some conditions, particularly in terms of sleep quality, these effects vary among individuals and most people do not have any symptoms from coffee drinking. Moderate coffee consumption is associated with no or little risk of severe diseases and may offer substantial health benefits. Thus, coffee is a safe, low-energy beverage and suitable for most adult people.
Editorial assistance was provided by Katrina Mountfort at Touch Medical Media.
Caffeine, chlorogenic acid, coffee, diabetes, Parkinson
Siamak Bidel has no conflicts of interest to declare. Jaakko Tuomilehto has received research funding for investigator-initiated research from the Institute for Scientific Information on Coffee, and has received travel and lecture fees from Programa de Promoción de Consumo Toma Café, Colombia.
April 10, 2012 Accepted
May 20, 2013
Siamak Bidel, Hjelt Institute, Faculty of Medicine, University of Helsinki, PO Box 41 (Mannerheimintie 172, 6 krs.), FIN-00014 University of Helsinki, Finland. E: firstname.lastname@example.org
The publication of this article was funded by Mondelêz International, Inc. The views and opinions expressed are those of the authors and not necessarily those of Mondelêz International, Inc.
Coffee is a complex chemical mixture that contains many bioactive molecules. These include chlorogenic acid, polyphenols, methylxanthines including caffeine, carbohydrates, lipids, nitrogenous compounds, nicotinic acid, potassium and magnesium.1
With the exception of water, coffee is the most consumed beverage in the world and almost 500 billion cups are consumed annually. In 2007, Finland was the top coffee consuming country with 12 kg per capita.2
World coffee production for 2012–13 is forecast at a record high of 148 million bags.3
The impact of coffee on human health and disease has long been recognised: in the late-16th century it was observed that coffee accelerated digestion and increased the heart rate. A growing body of epidemiological research data suggests that coffee consumption may help prevent several chronic diseases, including type 2 diabetes, Parkinson’s disease and liver disease. This article aims to review epidemiological and clinical evidence for the impact of coffee on type 2 diabetes, and other aspects of human health.
Coffee Consumption and the Incidence of Type 2 Diabetes
Type 2 diabetes is one of the most serious global health concerns and its incidence is increasing: the total number of people with diabetes worldwide is projected to rise from 366 million in 2011 to 552 million by 2030.4
In 2012, type 2 diabetes imposed direct and indirect costs of an estimated $245 billion in the US.5
Given the high cost of diabetes in terms of both human lives and healthcare costs, the prevention of diabetes is vital. Developing interventions to prevent and manage type 2 diabetes depends on an understanding of the dietary and lifestyle factors that underlie the development of the disease.
Recent evidence suggests that coffee consumption is associated with a decreased risk of type 2 diabetes. The first epidemiological report indicating an inverse association between coffee consumption and type 2 diabetes dates back to 2002. A Dutch cohort study reported that participants drinking at least 7 cups of coffee per day were half as likely to develop type 2 diabetes compared with those who did not consume coffee.6
This finding has been supported by numerous cohort studies (see Table 1
). The association does not depend on race, gender or geographic distribution of the study population and is consistently observed, despite the fact that many of these studies reported that coffee consumption was associated with lifestyle factors that tend to be associated with an increased risk of cardiovascular and metabolic disease, such as smoking, high body mass index (BMI), low levels of physical activity and poor diet.
Two reviews have examined the body of data relating to type 2 diabetes risk and coffee consumption. A meta-analysis covering 457,922 individuals and 18 studies concluded that an inverse log-linear relationship exists between coffee consumption and subsequent risk of diabetes: each additional cup of coffee consumed per day is associated with a 7 % reduction in the excess risk of diabetes (relative risk [RR] 0.93 95 % confidence interval [CI] 0.91–0.95) after adjustment for potential confounders. Individuals consuming 3 to 4 cups of tea daily have a 28 % lower risk of type 2 diabetes.7
A systematic review of cohort studies (from January 2001 to August 2011) confirmed the association between coffee consumption and reduced risk of type 2 diabetes, and also found an advantage of filtered coffee over pot boiled, decaffeinated coffee over caffeinated coffee and a stronger inverse correlation in those aged less than 60 years.8
The inverse relationship between coffee consumption and type 2 diabetes remains when lifestyle factors are taken into account: analysis of a Finnish cohort study found that the risk of type 2 diabetes was reduced by half in obese and inactive individuals who consumed ≥7 cups of coffee daily compared with those who consumed <2 cups/day (see Figure 1
While cohort studies have provided a large body of evidence for the association of coffee consumption and diabetes risk, such studies have inherent limitations. Most studies employed selfreport questionnaires, which may be imprecise and prone to bias, such as different interpretations of the size of a cup of coffee, and use of milk and sugar. It is not possible to ascertain a cause–effect relationship entirely from observational data. Studies employing urinary or plasma biomarkers of coffee intake may provide a more accurate assessment of coffee intake.10
1. Higdon JV, Frei B, Coffee and health: a review of recent human research, Crit Rev Food Sci Nutr, 2006;46:101–23.
2. International Coffee Organization, Historical coffee statistics, London, United Kingdom: International Coffee Organization, 2008 (available at: http://earthtrends.wri.org/ searchable_db/results.php?years=-1&).
3. UDSA, Coffee: World Markets and Trade (available at: http:// www.fas.usda.gov/psdonline/circulars/coffee.pdf) 2012.
4. International Diabetes Federation (IDF) Diabetes Atlas, 5th edition, Brussels, Belgium, 2011.
5. American Diabetes Association, Economic costs of diabetes in the U.S. in 2012, Diabetes Care, 2013;36:1033–46.
6. van Dam RM, Feskens EJ, Coffee consumption and risk of type 2 diabetes mellitus, Lancet, 2002;360:1477–8.
7. Huxley R, Lee CM, Barzi F, et al., Coffee, decaffeinated coffee, and tea consumption in relation to incident type 2 diabetes mellitus: a systematic review with meta-analysis, Arch Intern Med, 2009;169:2053–63.
8. Muley A, Muley P, Shah M, Coffee to reduce risk of type 2 diabetes?: a systematic review, Curr Diabetes Rev, 2012;8:162–8.
9. Hu G, Jousilahti, P, Peltonen M, et al., Joint association of coffee consumption and other factors to the risk of type 2 diabetes: a prospective study in Finland, Int J Obes, 2006;30:1742–49.
10. Matusheski N, Bidel S, Tuomilehto J, Coffee and Type 2 Diabetes Risk. In: Coffee, Emerging Health Effects and Disease Prevention,first ed., Ames, Iowa: Wiley-Blackwell, 2012;141–80.
11. Loopstra-Masters RC, Liese AD, Haffner SM, et al., Associations between the intake of caffeinated and decaffeinated coffee and measures of insulin sensitivity and beta cell function, Diabetologia, 2011;54:320–28.
12. Arnlov J, Vessby B, Riserus U, Coffee consumption and insulin sensitivity, JAMA, 2004;291:1199–201.
13. Agardh EE, Carlsson S, Ahlbom A, et al., Coffee consumption, type 2 diabetes and impaired glucose tolerance in Swedish men and women, J Intern Med, 2004;255:645–52.
14. van Dam RM, Dekker JM, Nijpels G, et al., Coffee consumption and incidence of impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes: the Hoorn Study, Diabetologia, 2004;47:2152–9.
15. Yamaji T, Mizoue T, Tabata S, et al., Coffee consumption and glucose tolerance status in middle-aged Japanese men, Diabetologia, 2004;47:2145–51.
16. Bidel S, Hu G, Sundvall J, et al., Effects of coffee consumption on glucose tolerance, serum glucose and insulin levels–a cross-sectional analysis, Horm Metab Res, 2006;38:38–43.
17. Lane JD, Barkauskas CE, Surwit RS, et al., Caffeine impairs glucose metabolism in type 2 diabetes, Diabetes Care, 2004;27:2047–8.
18. Moisey LL, Kacker S, Bickerton AC, et al., Caffeinated coffee consumption impairs blood glucose homeostasis in response to high and low glycemic index meals in healthy men, Am J Clin Nutr, 2008;87:1254–61.
19. Graham TE, Hibbert E, Sathasivam P, Metabolic and exercise endurance effects of coffee and caffeine ingestion, J Appl Physiol, 1998;85:883–9.
20. Ohnaka K, Ikeda M, Maki T, et al., Effects of 16-week consumption of caffeinated and decaffeinated instant coffee on glucose metabolism in a randomized controlled trial, J Nutr Metab, 2012;2012:207426.
21. Natella F, Scaccini C, Role of coffee in modulation of diabetes risk, Nutr Rev, 2012;70:207–17.
22. Yoshida Y, Hayakawa M, Niki E, Evaluation of the antioxidant effects of coffee and its components using the biomarkers hydroxyoctadecadienoic acid and isoprostane, J Oleo Sci, 2008;57:691–7.
23. Thom E, The effect of chlorogenic acid enriched coffee on glucose absorption in healthy volunteers and its effect on body mass when used long-term in overweight and obese people, J Int Med Res, 2007;35:900–908.
24. van Dijk AE, Olthof MR, Meeuse JC, et al., Acute effects of decaffeinated coffee and the major coffee components chlorogenic acid and trigonelline on glucose tolerance, Diabetes Care, 2009;32:1023–5.
25. Cardenas C, Quesada AR, Medina MA, Anti-angiogenic and anti-inflammatory properties of kahweol, a coffee diterpene, PLoS One, 2011;6:e23407.
26. Ong KW, Hsu A, Tan BK, Chlorogenic acid stimulates glucose transport in skeletal muscle via AMPK activation: a contributor to the beneficial effects of coffee on diabetes, PLoS One, 2012;7:e32718.
27. Oka K, [Pharmacological bases of coffee nutrients for diabetes prevention], Yakugaku Zasshi, 2007;127:1825–36.
28. Perrone D, Farah A, Donangelo CM, Influence of coffee roasting on the incorporation of phenolic compounds into melanoidins and their relationship with antioxidant activity of the brew, J Agric Food Chem, 2012;60:4265–75.
29. Mullen W, Nemzer B, Ou B, et al., The antioxidant and chlorogenic acid profiles of whole coffee fruits are influenced by the extraction procedures, J Agric Food Chem, 2011;59:3754–62.
30. Matei MF, Jaiswal R, Kuhnert N, Investigating the chemical changes of chlorogenic acids during coffee brewing: conjugate addition of water to the olefinic moiety of chlorogenic acids and their quinides, J Agric Food Chem, 2012;60:12105–15.
31. McCarty MF, A chlorogenic acid-induced increase in GLP-1 production may mediate the impact of heavy coffee consumption on diabetes risk, Med Hypotheses, 2005;64:848–53.
32. Rohn S, Rawel HM, Kroll J, Inhibitory effects of plant phenols on the activity of selected enzymes, J Agric Food Chem, 2002;50:3566–71.
33. Narita Y, Inouye K, Kinetic analysis and mechanism on the inhibition of chlorogenic acid and its components against porcine pancreas alpha-amylase isozymes I and II, J Agric Food Chem, 2009;57:9218–25.
34. Hemmerle H, Burger HJ, Below P, et al., Chlorogenic acid and synthetic chlorogenic acid derivatives: novel inhibitors of hepatic glucose-6-phosphate translocase, J Med Chem, 1997;40:137–45.
35. Arion WJ, Canfield WK, Ramos FC, et al., Chlorogenic acid and hydroxynitrobenzaldehyde: new inhibitors of hepatic glucose 6-phosphatase, Arch Biochem Biophys, 1997;339:315–22.
36. Goldfine AB, Fonseca V, Shoelson SE, Therapeutic approaches to target inflammation in type 2 diabetes, Clin Chem, 2011;57:162–7.
37. Zampelas A, Panagiotakos DB, Pitsavos C, et al., Associations between coffee consumption and inflammatory markers in healthy persons: the ATTICA study, Am J Clin Nutr, 2004;80:862–7.
38. Kotani K, Tsuzaki K, Sano Y, et al., The relationship between usual coffee consumption and serum C-reactive protein level in a Japanese female population, Clin Chem Lab Med, 2008;46:1434–7.
39. Lopez-Garcia E, van Dam RM, Qi L, et al., Coffee consumption and markers of inflammation and endothelial dysfunction in healthy and diabetic women, Am J Clin Nutr, 2006;84:888–93.
40. Maki T, Pham NM, Yoshida D, et al., The relationship of coffee and green tea consumption with high-sensitivity C-reactive protein in Japanese men and women, Clin Chem Lab Med, 2010;48:849–54.
41. Imatoh T, Tanihara S, Miyazaki M, et al., Coffee consumption but not green tea consumption is associated with adiponectin levels in Japanese males, Eur J Nutr, 2011;50:279–84.
42. Williams CJ, Fargnoli JL, Hwang JJ, et al., Coffee consumption is associated with higher plasma adiponectin concentrations in women with or without type 2 diabetes: a prospective cohort study, Diabetes Care, 2008;31:504–7.
43. Yamashita K, Yatsuya H, Muramatsu T, et al., Association of coffee consumption with serum adiponectin, leptin, inflammation and metabolic markers in Japanese workers: a cross-sectional study, Nutr Diabetes, 2012;2:e33.
44. Li S, Shin, HJ, Ding, EL, et al., Adipenectin levels and risk of type 2 diabetes: a systematic review and meta-analysis, JAMA, 2009;302:179–88.
45. Kempf K, Herder C, Erlund I, et al., Effects of coffee consumption on subclinical inflammation and other risk factors for type 2 diabetes: a clinical trial, Am J Clin Nutr, 2010;91:950–57.
46. Carstensen M, Herder C, Kempf K, et al., Sfrp5 correlates with insulin resistance and oxidative stress, Eur J Clin Invest, 2013;43(4):350–57.
47. Shan J, Fu J, Zhao Z, et al., Chlorogenic acid inhibits lipopolysaccharide-induced cyclooxygenase-2 expression in RAW264.7 cells through suppressing NF-kappaB and JNK/AP-1 activation, Int Immunopharmacol, 2009;9:1042–8.
48. Muscat S, Pelka J, Hegele J, et al., Coffee and Maillard products activate NF-kappaB in macrophages via H2O2 production, Mol Nutr Food Res, 2007;51:525–35.
49. Fujioka K, Shibamoto T, Quantitation of volatiles and nonvolatile acids in an extract from coffee beverages: correlation with antioxidant activity, J Agric Food Chem, 2006;54:6054–8.
50. Olthof MR, Hollman PC, Buijsman MN, et al., Chlorogenic acid, quercetin-3-rutinoside and black tea phenols are extensively metabolized in humans, J Nutr, 2003;133:1806–14.
51. Paur I, Balstad TR, Blomhoff R, Degree of roasting is the main determinant of the effects of coffee on NF-kappaB and EpRE, Free Radic Biol Med, 2010;48:1218–27.
52. Allred KF, Yackley KM, Vanamala J, et al., Trigonelline is a novel phytoestrogen in coffee beans, J Nutr, 2009;139:1833–8.
53. Yoshinari O, Igarashi K, Anti-diabetic effect of trigonelline and nicotinic acid, on KK-A(y) mice, Curr Med Chem, 2010;17:2196–202.
54. Atanasov AG, Dzyakanchuk AA, Schweizer RA, et al., Coffee inhibits the reactivation of glucocorticoids by 11betahydroxysteroid dehydrogenase type 1: a glucocorticoid connection in the anti-diabetic action of coffee?, FEBS Lett, 2006;580:4081–5.
55. Mascitelli L, Pezzetta F, Sullivan JL, Inhibition of iron absorption by coffee and the reduced risk of type 2 diabetes mellitus, Arch Intern Med, 2007;167:204–5; author reply 5.
56. Tuomainen TP, Lagundoye A, Voutilainen S, Coffee intake and glucose homeostasis: is there a role for body iron?, Arch Intern Med, 2010;170:1400–1401.
57. Mooren FC, Kruger K, Volker K, et al., Oral magnesium supplementation reduces insulin resistance in non-diabetic subjects – a double-blind, placebo-controlled, randomized trial, Diabetes Obes Metab, 2011;13:281–4.
58. Tunnicliffe JM, Shearer J, Coffee, glucose homeostasis, and insulin resistance: physiological mechanisms and mediators, Appl Physiol Nutr Metab, 2008;33:1290–300.
59. Lopez-Garcia E, van Dam RM, Li TY, et al., The relationship of coffee consumption with mortality, Ann Intern Med, 2008;148:904–14.
60. Freedman ND, Park Y, Abnet CC, et al., Association of coffee drinking with total and cause-specific mortality, N Engl J Med, 2012;366:1891–904.
61. Grobbee DE, Rimm EB, Giovannucci E, et al., Coffee, caffeine, and cardiovascular disease in men, N Engl J Med, 1990;323:1026–32.
62. Stensvold I, Tverdal A, The relationship of coffee consumption to various self-reported cardiovascular events in middle-aged Norwegian men and women, Scand J Soc Med, 1995;23:103–9.
63. LaCroix AZ, Mead LA, Liang KY, et al., Coffee consumption and the incidence of coronary heart disease, N Engl J Med, 1986;315:977–82.
64. Wilson PW, Garrison RJ, Kannel WB, et al., Is coffee consumption a contributor to cardiovascular disease? Insights from the Framingham Study, Arch Intern Med, 1989;149:1169–72.
65. Bidel ST, Tuomilehto J, Coffee and Cardiovascular Diseases. In: Coffee, Emerging Health Effects and Disease Prevention (first ed.), Ames, Iowa: Wiley-Blackwell, 2012;181–96.
66. Robertson D, Wade D, Workman R, et al., Tolerance to the humoral and hemodynamic effects of caffeine in man, J Clin Invest, 1981;67:1111–7.
67. Jee SH, He J, Appel LJ, et al., Coffee consumption and serum lipids: a meta-analysis of randomized controlled clinical trials, Am J Epidemiol, 2001;153:353–62.
68. Nardini M, D’Aquino M, Tomassi G, et al., Inhibition of human low-density lipoprotein oxidation by caffeic acid and other hydroxycinnamic acid derivatives, Free Radic Biol Med, 1995;19:541–52.
69. Wu JN, Ho SC, Zhou C, et al., Coffee consumption and risk of coronary heart diseases: a meta-analysis of 21 prospective cohort studies, Int J Cardiol, 2009;137:216–25.
70. Floegel A, Pischon T, Bergmann MM, et al., Coffee consumption and risk of chronic disease in the European Prospective Investigation into Cancer and Nutrition (EPIC)- Germany study, Am J Clin Nutr, 2012;95:901–8.
71. Mineharu Y, Koizumi A, Wada Y, et al., Coffee, green tea, black tea and oolong tea consumption and risk of mortality from cardiovascular disease in Japanese men and women, J Epidemiol Community Health, 2011;65:230–40.
72. Lopez-Garcia E, Rodriguez-Artalejo F, Rexrode KM, et al., Coffee consumption and risk of stroke in women, Circulation, 2009;119:1116–23.
73. Cornelis MC, El-Sohemy A, Kabagambe EK, et al., Coffee, CYP1A2 genotype, and risk of myocardial infarction, JAMA, 2006;295:1135–41.
74. Winkelmayer WC, Stampfer MJ, Willett WC, et al., Habitual caffeine intake and the risk of hypertension in women, JAMA, 2005;294:2330–35.
75. Steffen M, Kuhle C, Hensrud D, et al., The effect of coffee consumption on blood pressure and the development of hypertension: a systematic review and meta-analysis, J Hypertens, 2012;30:2245–54.
76. Mesas A, Leon-Muñoz, LM, Rodriguez-Artalejo, F, et al., The effect of coffee on blood pressure and cardiovascular disease in hypertensive individuals: a systematic review and meta-analysis, Am J Clin Nutr, 2011;94:1113–26.
77. Wirdefeldt K, Adami HO, Cole P, et al., Epidemiology and etiology of Parkinson’s disease: a review of the evidence, Eur J Epidemiol, 2011;26(Suppl. 1):S1–58.
78. Noyce AJ, Bestwick JP, Silveira-Moriyama L, et al., Metaanalysis of early nonmotor features and risk factors for Parkinson disease, Ann Neurol, 2012;72:893–901.
79. Liu R, Guo X, Park Y, et al., Caffeine intake, smoking, and risk of Parkinson disease in men and women, Am J Epidemiol, 2012;175:1200–1207.
80. Santos C, Costa J, Santos J, et al., Caffeine intake and dementia: systematic review and meta-analysis, J Alzheimers Dis, 2010;20 Suppl. 1:S187–204.
81. Eskelinen M, Ngandu T, Tuomilehto J, et al., Midlife coffee and tea drinking and the risk of late-life dementia: a population-based CAIDE study, J Alzheimers Dis, 2009;16:85–91.
82. Arendash GW, Cao C, Caffeine and coffee as therapeutics against Alzheimer’s disease, J Alzheimers Dis, 2010;20(Suppl. 1):S117–26.
83. Eskelinen MH, Kivipelto M, Caffeine as a protective factor in dementia and Alzheimer’s disease, J Alzheimers Dis, 2010;20(Suppl. 1):S167–74.
84. Maughan RJ, Griffin J, Caffeine ingestion and fluid balance: a review, J Hum Nutr Diet, 2003;16:411–20.
85. Ganio MS, Casa DJ, Armstrong LE, et al., Evidence-based approach to lingering hydration questions, Clin Sports Med, 2007;26:1–16.
86. Bravi F, Bosetti C, Tavani A, et al., Coffee drinking and hepatocellular carcinoma risk: a meta-analysis, Hepatology, 2007;46:430–35.
87. Sang LX, Chang B, Li XH, et al., Consumption of coffee associated with reduced risk of liver cancer: a metaanalysis, BMC Gastroenterol, 2013;13:34.
88. Hu G, Tuomilehto, J, Pukkala E, et al., Joint Effects of Coffee Consumption and Serum Gamma-Glutamyltransferase on the Risk of Liver Cancer, Hepatology, 2008;48:129–36.
89. Klatsky AL, Morton C, Udaltsova N, et al., Coffee, cirrhosis, and transaminase enzymes, Arch Intern Med, 2006;166:1190–95.
90. Molloy JW, Calcagno CJ, Williams CD, et al., Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis, Hepatology, 2012;55:429–36.
91. Ikeda M, Maki T, Yin G, et al., Relation of coffee consumption and serum liver enzymes in Japanese men and women with reference to effect modification of alcohol use and body mass index, Scand J Clin Lab Invest, 2010;70:171–9.
92. Arab L, Epidemiologic evidence on coffee and cancer, Nutr Cancer, 2010;62:271–83.
93. Lucas M, Mirzaei F, Pan A, et al., Coffee, caffeine, and risk of depression among women, Arch Intern Med, 2011;171:1571–8.
94. Kawachi I, Willett WC, Colditz GA, et al., A prospective study of coffee drinking and suicide in women, Arch Intern Med, 1996;156:521–5.
95. Mets M, Baas D, van Boven I, et al., Effects of coffee on driving performance diring prolonged simulated highway driving, Psychopharmacology (Berl), 2012;222:337–42.
96. Klatsky AL, Hasan AS, Armstrong MA, et al., Coffee, caffeine, and risk of hospitalization for arrhythmias, Perm J, 2011;15:19–25.
97. Glatter KA, Myers R, Chiamvimonvat N, Recommendations regarding dietary intake and caffeine and alcohol consumption in patients with cardiac arrhythmias: what do you tell your patients to do or not to do?, Curr Treat Options Cardiovasc Med, 2012;14:529–35.
98. Kleemola P, Jousilahti, P, Pietinen, P et al, Coffee consumption and the Risk of Coronary Heart Disease and Death, Arch Intern Med, 2000;160:3393–400.
99. Hindmarch I, Rigney U, Stanley N, et al., A naturalistic investigation of the effects of day-long consumption of tea, coffee and water on alertness, sleep onset and sleep quality, Psychopharmacology (Berl), 2000;149:203–16.
100. Shilo L, Sabbah H, Hadari R, et al., The effects of coffee consumption on sleep and melatonin secretion, Sleep Med, 2002;3:271–3.
101. Horne J, Anderson C, Platten C, Sleep extension versus nap or coffee, within the context of ‘sleep debt’, J Sleep Res, 2008;17:432–6.
102. Shapiro RE, Caffeine and headaches, Curr Pain Headache Rep, 2008;12:311–15.
103. Ogawa N, Ueki H, Clinical importance of caffeine dependence and abuse, Psychiatry Clin Neurosci, 2007;61:263–8.
104. Nehlig A, Armspach, JP, Namer, IJ et al, SPECT assessment of brain activation induced by caffeine: no effect on areas involved in dependence, Dialogues Clin Neurosci, 2010;12:255–63.
105. Juliano LM, Griffiths RR, A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features, Psychopharmacology (Berl), 2004;176:1–29.
106. Smith A, Effects of caffeine on human behavior, Food Chem Toxicol, 2002;40:1243–55.
107. Dewey KG, Romero-Abal ME, Quan de Serrano J, et al., Effects of discontinuing coffee intake on iron status of irondeficient Guatemalan toddlers: a randomized intervention study, Am J Clin Nutr, 1997;66:168–76.
108. Munoz LM, Lonnerdal B, Keen CL, et al., Coffee consumption as a factor in iron deficiency anemia among pregnant women and their infants in Costa Rica, Am J Clin Nutr, 1988;48:645–51.
109. Wisborg K, Kesmodel U, Bech BH, et al., Maternal consumption of coffee during pregnancy and stillbirth and infant death in first year of life: prospective study, BMJ, 2003;326:420.
110. Jacobs A, Consumption of coffee during pregnancy: data do not support claim, BMJ, 2003;326:1268–9; author reply 9.
111. Tsoi L, Consumption of coffee during pregnancy: article raises more questions than it answers, BMJ, 2003;326:1268; author reply 9.
112. Weng X, Odouli R, Li DK, Maternal caffeine consumption during pregnancy and the risk of miscarriage: a prospective cohort study, Am J Obstet Gynecol, 2008;198:279 e1–8.
113. Savitz D, Chan, RL, Herring, AH et al, Caffeine and miscarriage risk, Epidemiology, 2008;19:55–62.
114. American College of Obstetricians, Gynecologists, ACOG Committee Opinion No. 462: Moderate caffeine consumption during pregnancy, Obstet Gynecol, 2010;116:467–8.
115. World Health Organization, The World Health Report 2002. Reducing Risks, Promoting Healthy Life, Geneva, Switzerland, 2002.
116. Saremi A, Tulloch-Reid M, Knowler WC, Coffee consumption and the incidence of type 2 diabetes, Diabetes Care, 2003;26:2211–12.
117. Reunanen A, Heliovaara M, Aho K, Coffee consumption and risk of type 2 diabetes mellitus, Lancet, 2003;361:702–3; author reply 3.
118. Rosengren A, Dotevall A, Wilhelmsen L, et al., Coffee and incidence of diabetes in Swedish women: a prospective 18-year follow-up study, J Intern Med, 2004;255:89–95.
119. Salazar-Martinez E, Willett WC, Ascherio A, et al., Coffee consumption and risk for type 2 diabetes mellitus, Ann Intern Med, 2004;140:1–8.
120. Tuomilehto J, Hu G, Bidel S, et al., Coffee consumption and risk of type 2 diabetes mellitus among middle-aged Finnish men and women, JAMA, 2004;291:1213–19.
121. Carlsson S, Hammar N, Grill V, et al., Coffee consumption and risk of type 2 diabetes in Finnish twins, Int J Epidemiol, 2004;33:616–17.
122. van Dam RM, Willett WC, Manson JE, et al., 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.
123. Iso H, Date C, Wakai K, et al., The relationship between green tea and total caffeine intake and risk for selfreported type 2 diabetes among Japanese adults, Ann Intern Med, 2006;144:554–62.
124. Pereira MA, Parker ED, Folsom AR, Coffee consumption and risk of type 2 diabetes mellitus: an 11-year prospective study of 28 812 postmenopausal women, Arch Intern Med, 2006;166:1311–16.
125. Smith B, Wingard DL, Smith TC, et al., Does coffee consumption reduce the risk of type 2 diabetes in individuals with impaired glucose?, Diabetes Care, 2006;29:2385–90.
126. Paynter NP, Yeh HC, Voutilainen S, et al., Coffee and sweetened beverage consumption and the risk of type 2 diabetes mellitus: the atherosclerosis risk in communities study, Am J Epidemiol, 2006;164:1075–84.
127. Hamer M, Witte DR, Mosdol A, et al., Prospective study of coffee and tea consumption in relation to risk of type 2 diabetes mellitus among men and women: the Whitehall II study, Br J Nutr, 2008;100:1046–53.
128. Odegaard AO, Pereira MA, Koh WP, et al., Coffee, tea, and incident type 2 diabetes: the Singapore Chinese Health Study, Am J Clin Nutr, 2008;88:979–85.
129. Lin WY, Xaiver Pi-Sunyer F, Chen CC, et al., Coffee consumption is inversely associated with type 2 diabetes in Chinese, Eur J Clin Invest, 2011;41:659–66.
130. Zhang Y, Lee ET, Cowan LD, et al., Coffee consumption and the incidence of type 2 diabetes in men and women with normal glucose tolerance: the Strong Heart Study, Nutr Metab Cardiovasc Dis, 2011;21:418–23.
131. Eskelinen MH, Ngandu T, Tuomilehto J, Midlife coffee and tea drinking and the risk of late-life dementia: a populationbased CAIDE study, J Alzheimers Dis, 2009;16:85–91.
132. Li XJ, Ren ZJ, Qin JW, et al., Coffee consumption and risk of breast cancer: an up-to-date meta-analysis, PLoS One, 2013;8:e52681.
133. Sinha R, Cross AJ, Daniel CR, et al., Caffeinated and decaffeinated coffee and tea intakes and risk of colorectal cancer in a large prospective study, Am J Clin Nutr, 2012;96:374–81.
134. Gunter MJ, Schaub JA, Xue X, et al., A prospective investigation of coffee drinking and endometrial cancer incidence, Int J Cancer, 2012;131:E530–36.
135. Leitzmann MF, Willett WC, Rimm EB, et al., A prospective study of coffee consumption and the risk of symptomatic gallstone disease in men, JAMA, 1999;281:2106–12.
136. Leitzmann MF, Stampfer MJ, Willett WC, et al., Coffee intake is associated with lower risk of symptomatic gallstone disease in women, Gastroenterology, 2002;123:1823–30.
137. Bidel S, Hu G, Jousilahti P, et al., Coffee consumption and risk of gastric and pancreatic cancer–a prospective cohort study, Int J Cancer, 2013;132:1651–9.
138. Eurohepygast Study G, Risk factors for atrophic chronic gastritis in a European population: results of the Eurohepygast study, Gut, 2002;50:779–85.
139. Pasquale LR, Wiggs JL, Willett WC, et al., The Relationship between caffeine and coffee consumption and exfoliation glaucoma or glaucoma suspect: a prospective study in two cohorts, Invest Ophthalmol Vis Sci, 2012;53:6427–33.
140. Choi HK, Curhan G, Coffee consumption and risk of incident gout in women: the Nurses’ Health Study, Am J Clin Nutr, 2010;92:922–7.
141. Choi HK, Willett W, Curhan G, Coffee consumption and risk of incident gout in men: a prospective study, Arthritis Rheum, 2007;56:2049–55.
142. Braem MG, Onland-Moret NC, Schouten LJ, et al., Coffee and tea consumption and the risk of ovarian cancer: a prospective cohort study and updated meta-analysis, Am J Clin Nutr, 2012;95:1172–81.
143. Hu G, Bidel S, Jousilahti P, et al., Coffee and tea consumption and the risk of Parkinson’s disease, Mov Disord, 2007;22:2242-8.
144. Geybels MS, Neuhouser ML, Stanford JL, Associations of tea and coffee consumption with prostate cancer risk, Cancer Causes Control, 2013;24:941–8.
145. Montella M, Tramacere I, Tavani A, et al., Coffee, decaffeinated coffee, tea intake, and risk of renal cell cancer, Nutr Cancer, 2009;61:76–80.
Caffeine, chlorogenic acid, coffee, diabetes, Parkinson