Context Only a few studies of coffee consumption and diabetes mellitus (DM)
have been reported, even though coffee is the most consumed beverage in the
world.
Objective To determine the relationship between coffee consumption and the incidence
of type 2 DM among Finnish individuals, who have the highest coffee consumption
in the world.
Design, Setting, and Participants 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. Coffee consumption and other study parameters were determined
at baseline using standardized measurements.
Main Outcome Measures Hazard ratios (HRs) for the incidence of type 2 DM were estimated for
different levels of daily coffee consumption.
Results During a mean follow-up of 12 years, there were 381 incident cases of
type 2 DM. After adjustment for confounding factors (age, study year, body
mass index, systolic blood pressure, education, occupational, commuting and
leisure-time physical activity, alcohol and tea consumption, and smoking),
the HRs of DM associated with the amount of coffee consumed daily (0-2, 3-4,
5-6, 7-9, ≥10 cups) were 1.00, 0.71 (95% confidence interval [CI], 0.48-1.05),
0.39 (95% CI, 0.25-0.60), 0.39 (95% CI, 0.20-0.74), and 0.21 (95% CI, 0.06-0.69)
(P for trend<.001) in women, and 1.00, 0.73 (95%
CI, 0.47-1.13), 0.70 (95% CI, 0.45-1.05), 0.67 (95% CI, 0.40-1.12), and 0.45
(95% CI, 0.25-0.81) (P for trend = .12) in men, respectively.
In both sexes combined, the multivariate-adjusted inverse association was
significant (P for trend <.001) and persisted
when stratified by younger and older than 50 years; smokers and never smokers;
healthy weight, overweight, and obese participants; alcohol drinker and nondrinker;
and participants drinking filtered and nonfiltered coffee.
Conclusion 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.
Centuries of coffee drinking has made it the most consumed beverage
in the world. During the last decade, research has attempted to make clear
health benefits or detriments received from coffee drinking. Effects of coffee
and caffeine on cardiovascular disease,1 hypertension,2 neurological diseases,3 different
types of cancer,4 hormonal changes,5-7 gallstones,8 renal stones,9 as well
as diabetes mellitus (DM)10-12 have
been studied through epidemiological, clinical, or experimental research.
Type 2 DM is one of the diseases that is largely determined by lifestyle factors.13,14
The role of coffee in relation to DM has not been investigated thoroughly.
A large Dutch cohort study12 recently showed
an inverse association between coffee consumption and the risk of DM. It is
well known that caffeine stimulates insulin secretion of the pancreatic beta
cells in vivo. However, coffee with its complex compounds may influence many
other processes that may take part in the development of DM.
According to international statistics, the Finnish population has the
highest per capita coffee consumption in the world with 11.3 kg in 2000.15 Therefore, research into potential health effects
of coffee in this population is of particular interest. Our large prospective
study aimed at determining whether the suggested inverse relationship between
coffee and type 2 DM exists among the Finnish population. In addition, we
evaluated a possible effect modification of the major determinants of type
2 DM and assessed the effects of different types of prepared coffee on the
risk of DM.
We performed baseline surveys in 2 eastern Finnish provinces, North
Karelia and Kuopio, and in the Turku-Loimaa region in southwestern Finland
in 1982, 1987, and 1992. The survey was expanded to the Helsinki capital area
in 1992. In the 3 surveys, the sample included participants aged 25 to 64
years. The 1982, 1987, and 1992 cohorts were combined in this analysis. The
original random sample was stratified by sex and 4 equally large 10-year age
groups according to the World Health Organization MONItoring trends and determinants
of CArdiovascular disease (MONICA) protocol16,17 and
consisted of 21 630 participants. The participation rate varied by year
from 74% to 88%.18 Our analysis included 16 670
participants aged 35 to 64 years due to the few cases of type 2 DM in participants
aged 25 to 34 years during the follow-up. The final sample comprised 6974
men and 7655 women after excluding participants diagnosed with coronary heart
disease or stroke (n = 590), participants with known DM at baseline (n = 435),
and participants with incomplete data on any variables required for this analysis
(n = 1016). We excluded participants with coronary heart disease and stroke
because there may be bias regarding their exposure (coffee drinking due to
their disease) or confounding factors (diet and physical activity, their survival
probability is lower, and they may be using drugs that trigger DM). These
surveys were conducted according to the ethical rules of the National Public
Health Institute and the investigations were performed in accordance with
the Declaration of Helsinki. At the time the baseline surveys were performed,
oral informed consent was obtained from the participants and if not received,
the survey data were not collected from these participants (they were considered
nonresponders).
A self-administered questionnaire was sent to the participants to be
completed at home. The questionnaire included questions on medical history,
socioeconomic factors, physical activity, smoking habits, and alcohol, coffee,
and tea consumption. Education level, measured as the total number of school
years, was divided into birth cohort specific tertiles. Physical activity
included occupational, commuting, and leisure-time physical activity. A detailed
description of the questions is presented elsewhere,19 and
these questions were the same as those used in the studies in the Nordic countries19,20 and similar to those used and validated
in the Seven Countries study.21
The participants reported their occupational physical activity as light,
moderate, or active. The daily commuting journey to or from work was grouped
into 3 categories: using motorized transportation or not working outside the
home (0 minutes of walking or cycling); walking or bicycling 1 to 29 minutes;
and walking or bicycling 30 or more minutes. Self-reported leisure-time physical
activity was classified as low, moderate, or high. Based on the responses,
the participants were classified as never, ex-smokers, or current smokers.
Current smokers were categorized into those participants who smoked less than
20 or 20 or more cigarettes per day.
The participants were asked, "How many cups of coffee or tea do you
drink per day?" Coffee consumption was categorized into 5 categories: 0 to
2 cups, 3 to 4 cups, 5 to 6 cups, 7 to 9 cups, and 10 or more cups. Tea consumption
was categorized as none, 1 to 2 cups, and 3 or more cups because only a few
people drank tea. Alcohol consumption was categorized as none, 1 to 100, 101
to 300, or more than 300 g of alcohol per week. Because only a few women drank
more than 300 g of alcohol per week, we combined the 2 higher categories in
women.
At the study site, specially trained nurses measured height, weight,
and blood pressure using the standardized protocol according to the World
Health Organization MONICA project.17 Blood
pressure was measured from the right arm of the participant who was seated
for 5 minutes before the measurement was taken using a standard sphygmomanometer.
Body mass index (BMI) was calculated as weight in kilograms divided by the
square of height in meters. In stratified analyses, the participants were
classified in 3 categories: normal weight (BMI <25.0), overweight (25 to
<30), and obese (≥30).
We ascertained incident cases of DM from the National Hospital Discharge
Register and the Drug Register of the National Social Insurance Institution.
These register data were linked to the risk factor survey data with the unique
personal identification numbers assigned to every resident of Finland. Antidiabetic
drugs prescribed by a physician are free of charge in Finland subject to approval
of the application to the National Social Insurance Institution with a case
history prepared by the treating physician attached. The physician confirms
the diagnosis of DM on the basis of the World Health Organization criteria
after 198022; before 1980, Finnish national
guidelines were applied. All patients receiving free-of-charge medication
(either oral antidiabetic agents or insulin) are entered into a register maintained
by the National Social Insurance Institution. The National Hospital Discharge
Register includes hospitalizations for patients admitted to hospitals with
a primary or secondary diagnosis of DM in Finland nationwide. Follow-up of
each participant in our present analysis continued until December 31, 1998,
or until death.
Sex-specific differences in risk factors based on different levels of
coffee consumption were tested using univariate analysis of variance or logistic
regression after adjustment for age and study year. The association between
coffee consumption at baseline and the risk of type 2 DM was analyzed by using
Cox proportional hazards regression models. Different levels of coffee consumption
were included in the models as dummy variables. All analyses were adjusted
for age, study year, BMI, systolic blood pressure, education, occupational,
commuting, and leisure-time physical activity, alcohol and tea drinking, and
smoking. The significance of the trend over different categories of coffee
consumption was tested in the same models by giving an ordinal numeric value
for each dummy variable. To assess whether the effect differed between the
sexes, first-level interactions between coffee consumption and sex were analyzed.
Because no statistically significant interactions were found, men and women
were combined in subgroup analyses adjusted for sex. Statistical significance
was considered to be P<.05. All statistical analyses
were performed with SPSS version 11.0 (SPSS Inc, Chicago, Ill).
A total of 381 cases of type 2 DM were identified during a mean follow-up
of 12 years. In general, older persons were less likely to drink coffee (Table 1). After adjustment for age and
study year, higher coffee consumption was associated with higher BMI and cigarette
smoking, and lower blood pressure, education level, light occupational physical
activity, leisure-time physical activity, tea consumption, and alcohol use.
Coffee Consumption and Risk of Type 2 DM
Age-adjusted and study year–adjusted hazard ratios (HRs) of DM
in participants who drank 0 to 2, 3 to 4, 5 to 6, 7 to 9, and 10 or more cups
of coffee were 1.00, 0.72 (95% confidence interval [CI], 0.49-1.04), 0.49
(95% CI, 0.32-0.73), 0.47 (95% CI, 0.25-0.87), and 0.26 (95% CI, 0.08-0.85; P for trend = .002) in women, and 1.00, 0.83 (95% CI, 0.54-1.25),
0.88 (95% CI, 0.60-1.30), 0.86 (95% CI, 0.53-1.39), and 0.69 (95% CI, 0.40-1.19; P for trend = .74) in men, respectively (Table 2). After further adjustment for BMI, systolic blood pressure,
education, occupational, commuting, and leisure-time physical activity, alcohol
and tea consumption, and smoking, this inverse association remained highly
significant among women (P for trend<.001). In
men, a similar trend was observed and the risk of DM was significantly reduced
in those participants who drank at least 10 cups of coffee (HR, 0.45; 95%
CI, 0.25-0.81). When data for men and women were combined, sex-adjusted and
multivariate-adjusted HRs were 1.00, 0.76 (95% CI, 0.57-1.01), 0.54 (95% CI,
0.40-0.73), 0.55 (95% CI, 0.37-0.81), and 0.39 (95% CI, 0.24-0.64; P for trend<.001), respectively.
The risk of DM did not differ between total coffee abstainers and light
coffee drinkers (HR, 1.20; 95% CI, 0.74-1.97). Sex-adjusted and multivariate-adjusted
(including coffee consumption) HRs of DM by tea consumption of 0, 1 to 2,
3 or more cups were 1.00, 0.81 (95% CI, 0.63-1.05), and 0.98 (95% CI, 0.67-1.42; P for trend = .27), respectively. To avoid the potential
bias from subclinical disease, additional analyses were also performed excluding
cases of type 2 DM, which occurred during the first 4 years of follow-up (n
= 27). The sex-adjusted and multivariate-adjusted HRs by coffee consumption
of 0 to 2, 3 to 4, 5 to 6, 7 to 9, and 10 or more cups did not vary and were
1.00, 0.74 (95% CI, 0.55-1.00), 0.54 (95% CI, 0.39-0.74), 0.54 (95% CI, 0.36-0.81),
and 0.41 (95% CI, 0.25-0.68; P for trend<.001).
Coffee Consumption and Risk of Type 2 DM in Subgroup Analyses
Multivariate-adjusted inverse association between coffee consumption
and DM risk was present in participants aged 35 to 49 years (P for trend = .23) and 50 to 64 years (P for
trend = .001; Table 3). Similarly,
the inverse association was observed in nonsmokers (P for
trend = .001), in overweight participants (P for
trend = .01), and in nondrinkers (P for trend <.001).
A nonsignificant association was observed in smokers (P for trend = .07), in healthy weight participants (P for trend = .35), in participants who were obese (P for trend = .05), in alcohol drinkers (P for
trend = .25), in filtered coffee drinkers (P for
trend = .07), and in pot-boiled coffee drinkers (P for
trend = .06). There were 22 incident cases of DM among participants aged 25
to 34 years at baseline who were not included in the analyses. An additional
analysis including the youngest age group also did not change the results.
The type of coffee consumption was assessed in the surveys from 1987
and 1992. More than 80% of Finnish coffee consumers used filtered coffee at
baseline. There was no interaction between the type of coffee and the amount
of coffee for the risk of type 2 DM (χ21 = 2.63,
0.85, and 2.13 for men, women, and for men and women combined, respectively;
all P>.10). Men and women who drank pot-boiled coffee
without filtering showed a similar inverse trend in risk of type 2 DM vs participants
who drank filtered coffee (Table 3).
However, men who drank pot-boiled coffee showed a 2.9 times higher risk for
development of DM (HR, 2.86; 95% CI, 1.76-4.63) compared with men who drank
filtered coffee after multivariate adjustment for risk factors of DM, including
the amount of coffee consumed (Table 4).
This association was also observed among men and women combined.
This study revealed unequivocal evidence for an inverse and graded association
between coffee consumption and type 2 DM independent of other risk factors
for type 2 DM. Because the Finnish population drinks more coffee than other
populations,15 we had power to determine the
risk of DM at high levels of coffee consumption. The significant inverse association
between coffee consumption and the risk of type 2 DM was found in both sexes.
In a previous study among the Finnish population,23 no
association between the coffee consumption and incidence of type 2 DM was
observed. One possible explanation for the different results is that at the
time of their baseline survey, in 1973 and 1977, most Finnish individuals
drank pot-boiled coffee. At the end of the 1960s, 75% of the Finnish population
drank boiled coffee24 but by 1987 this proportion
had decreased to 24%, although 69% drank filtered coffee.25 However,
although we were able to determine the type of the coffee consumed in our
surveys in 1987 and 1992, there was no interaction effect between type of
coffee and amount of coffee on the risk of type 2 DM in either men or women.
Nevertheless, there was a significant, almost 3-fold, increase in the risk
of diabetes among men who drank pot-boiled coffee compared with men who drank
filtered coffee.
Van Dam and Feskens12 investigated the
association between coffee consumption and risk of type 2 DM in a prospective
study. They also obtained similar inverse associations between coffee consumption
and the risk of type 2 DM, similar to our results. Recently, data from large
US cohorts of men and women also showed that long-term coffee consumption
and total caffeine intake were significantly associated with a reduced risk
of type 2 DM.26 A Japanese cross-sectional
study comprising 1916 men and 2704 women aged 40 to 50 years found that coffee
intake or caffeine intake from coffee was inversely associated with the prevalence
of fasting hyperglycemia (fasting plasma glucose, ≥110 mg/dL [≥6.1 mmol/L]).27
Although the biological mechanism behind the inverse association between
coffee consumption and the risk of DM is unknown, several putative mechanisms
can be proposed. The protective effect of coffee may be due to the inhibition
of glucose-6-phosphatase activity by chlorogenic acid.28 Hepatic
glucose-6-phosphatase may be a key control site in the homeostatic regulation
of blood glucose concentration,29,30 and
glucose-6-phosphatase is widely held to be a significant factor in the abnormally
high rates of hepatic glucose production observed in the diabetic state. Reduced
glucose-6-phosphatase hydrolysis or its inhibition may reduce plasma glucose
output leading to reduced plasma glucose concentration.28 Hypoglycemic
effect of chlorogenic acid has been presented in streptozotocin-induced diabetic
rats as well.31 Johnston et al32 also
suggest that chlorogenic acid might have an antagonistic effect on glucose
transport. It is possible that habitual differences between the coffee consumers
and different manufacturing process of coffee from green seeds may also result
in different effects. For instance, roasting and some other manipulation of
processing coffee will partly destroy chlorogenic acid and may oxidize some
other compounds to form new compounds,33 leading
subsequently to differential metabolic effects.
In addition to the inhibitory effects of chlorogenic acid on glucose-6-phosphatase
affecting glucose regulation at hepatic stage, it has also been reported to
inhibit glucose transporters (sodium-dependent glucose transporter) at the
intestinal stage.34 Coffee may also influence
the secretion of gastrointestinal peptides such as glucagon-like peptide 1
and gastric inhibitory polypeptide, both of which are known for their glucose
lowering effects.35,36
Coffee also contains magnesium, approximately 11 mg per 100 g of dry
coffee. This component is another possible factor, which may result in positive
effects on glucose tolerance and prevention of type 2 DM. There is a significant
inverse correlation between serum magnesium and the incidence of type 2 DM;
both serum and ionized magnesium were consistently found to be decreased in
patients with DM.37-40
It is well known that caffeine and theophylline are strong stimulants
of pancreatic beta cells.41 Stimulation of
insulin secretion may be beneficial in people at risk of type 2 DM who usually
have impaired insulin secretion.11 In addition,
caffeine may increase insulin sensitivity.42 It
has also been suggested that the thermogenic effect of caffeine may overcome
the energy imbalance accompanied by unfavorable lifestyle and improve glucose
homoeostasis.
The inverse association between coffee consumption and the risk of DM
tended to be stronger in women than in men, although the sex-interaction was
not statistically significant. Previous studies have revealed that caffeine
may be positively associated with plasma estrogen, plasma estradiol, and sex
hormone-binding globulin levels and inversely related with testosterone among
postmenopausal women.5,6 In addition
phytoestrogens may have beneficial effects in patients with DM. Phytoestrogens
content of coffee and effects of caffeine on hormonal level may explain the
effects of coffee on the risk of diabetes in women. Nevertheless, in most
populations, the prevalence of type 2 DM is lower in women than in men at
premenopausal age.43,44
A limitation of our study was that a glucose tolerance test was not
performed in the baseline and follow-up surveys. Therefore, we could have
missed some cases of asymptomatic and diet-treated diabetes, although the
clinical diagnosis of diabetes from the hospital discharge register may have
in part avoided this potential underdiagnosis. Another source of misclassification
may be that we used self-report for data on coffee intake. However, the misclassification
of exposure is most probably not systematically related to the outcome and
vice versa. Therefore, it should not cause biased results but may only weaken
the observed association. Finally, we cannot completely exclude the effects
of residual confounding due to measurement error in the assessment of confounding
factors and unmeasured factors such as diet (whole grain consumption, intake
of fiber, saturated and polyunsaturated fat, glycemic load of the diet, and
total energy intake). The Finnish population typically drink their coffee
without milk or only add a very small volume of milk.
In conclusion, we found a strong and graded inverse relationship between
coffee consumption and the risk of type 2 DM among Finnish men and women,
a population with the highest coffee consumption in the world. The mechanisms
or process by which coffee contents may exert their beneficial effects on
DM are nevertheless unclear. Several components of coffee may affect glucose
regulation, such as chlorogenic acid on glucose-6-phosphatase, antioxidant
activity of polyphenols on α-glucosidase, caffeine on insulin secretion
on pancreatic beta cells, cumulative effects of phytoestrogens, and magnesium,
which are suggested as the biological basis of our findings. Expanded investigation
is required to explore these mechanisms, including randomized controlled trials.
1.Kleemola P, Jousilahti P, Pietinen P, Vartiainen E, Tuomilehto J. Coffee consumption and the risk of coronary heart disease and death.
Arch Intern Med.2000;160:3393-3400.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11112231&dopt=Abstract
Google Scholar 2.Robertson D, Hollister AS, Kincaid D.
et al. Caffeine and hypertension.
Am J Med.1984;77:54-60.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6377891&dopt=Abstract
Google Scholar 3.Ross GW, Abbott RD, Petrovitch H.
et al. Association of coffee and caffeine intake with the risk of Parkinson
disease.
JAMA.2000;283:2674-2679.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10819950&dopt=Abstract
Google Scholar 4.Zeegers MP, Tan FE, Goldbohm RA, van den Brandt PA. Are coffee and tea consumption associated with urinary tract cancer
risk? a systematic review and meta-analysis.
Int J Epidemiol.2001;30:353-362.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11369742&dopt=Abstract
Google Scholar 5.Ferrini RL, Barrett-Connor E. Caffeine intake and endogenous sex steroid levels in postmenopausal
women: the Rancho Bernardo Study.
Am J Epidemiol.1996;144:642-644.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8823059&dopt=Abstract
Google Scholar 6.Nagata C, Kabuto M, Shimizu H. Association of coffee, green tea, and caffeine intakes with serum concentrations
of estradiol and sex hormone-binding globulin in premenopausal Japanese women.
Nutr Cancer.1998;30:21-24.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9507508&dopt=Abstract
Google Scholar 7.Goodman-Gruen D, Kritz-Silverstein D. Usual dietary isoflavone intake is associated with cardiovascular disease
risk factors in postmenopausal women.
J Nutr.2001;131:1202-1206.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11285326&dopt=Abstract
Google Scholar 8.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;281:2106-2112.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10367821&dopt=Abstract
Google Scholar 9.Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Beverage use and risk for kidney stones in women.
Ann Intern Med.1998;128:534-540.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9518397&dopt=Abstract
Google Scholar 10.Pizziol A, Tikhonoff V, Paleari CD.
et al. Effects of caffeine on glucose tolerance: a placebo-controlled study.
Eur J Clin Nutr.1998;52:846-849.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9846599&dopt=Abstract
Google Scholar 11.Keijzers GB, De Galan BE, Tack CJ, Smits P. Caffeine can decrease insulin sensitivity in humans.
Diabetes Care.2002;25:364-369.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11815511&dopt=Abstract
Google Scholar 12.van Dam RM, Feskens EJ. Coffee consumption and risk of type 2 diabetes mellitus.
Lancet.2002;360:1477-1478.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12433517&dopt=Abstract
Google Scholar 13.Tuomilehto J, Lindstrom J, Eriksson JG.
et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among
subjects with impaired glucose tolerance.
N Engl J Med.2001;344:1343-1350.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11333990&dopt=Abstract
Google Scholar 14.Knowler WC, Barrett-Connor E, Fowler SE.
et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention
or metformin.
N Engl J Med.2002;346:393-403.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11832527&dopt=Abstract
Google Scholar 16.WHO MONICA Project Principal Investigators. The World Health Organization MONICA Project (monitoring trends and
determinants in cardiovascular disease): a major international collaboration.
J Clin Epidemiol.1988;41:105-114.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3335877&dopt=Abstract
Google Scholar 17.Pajak A, Kuulasmaa K, Tuomilehto J, Ruokokoski E. Geographical variation in the major risk factors of coronary heart
disease in men and women aged 35-64 years: the WHO MONICA Project.
World Health Stat Q.1988;41:115-140.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3232405&dopt=Abstract
Google Scholar 18.Vartiainen E, Jousilahti P, Alfthan G.
et al. Cardiovascular risk factor changes in Finland, 1972-1997.
Int J Epidemiol.2000;29:49-56.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10750603&dopt=Abstract
Google Scholar 19.Hu G, Qiao Q, Silventoinen K.
et al. Occupational, commuting, and leisure-time physical activity in relation
to risk for type 2 diabetes in middle-aged Finnish men and women.
Diabetologia.2003;46:322-329.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12687329&dopt=Abstract
Google Scholar 20.Andersen LB, Schnohr P, Schroll M, Hein HO. All-cause mortality associated with physical activity during leisure
time, work, sports, and cycling to work.
Arch Intern Med.2000;160:1621-1628.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10847255&dopt=Abstract
Google Scholar 21.Keys A. Seven Countries: A Multivariate Analysis of Death
and Coronary Heart Disease. Cambridge, Mass: Harvard University Press; 1980.
22.WHO Study Group on Diabetes Mellitus. Diabetes Mellitus: Report of a WHO Study Group. Geneva, Switzerland: World Health Organization; 1985. WHO Technical
Report Series, No. 727.
23.Reunanen A, Heliovaara M, Aho K. Coffee consumption and risk of type 2 diabetes mellitus.
Lancet.2003;361:702-703.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12606198&dopt=Abstract
Google Scholar 24.Aro A. Serum cholesterol levels in Finland and their relationship to changes
in coffee brewing methods. In: Thelle DS, van der Stegen G, eds. Coffee and
Coronary Heart Disease: Special Emphasis on the Coffee-Blood Lipids Relationship. Göteborg, Sweden: Nordiska älsovårshögskolan;
1990:71-75.
25.Pietinen P, Aro A, Tuomilehto J, Uusitalo U, Korhonen H. Consumption of boiled coffee is correlated with serum cholesterol in
Finland.
Int J Epidemiol.1990;19:586-590.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2262252&dopt=Abstract
Google Scholar 26.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.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14706966&dopt=Abstract
Google Scholar 27.Isogawa A, Noda M, Takahashi Y, Kadowaki T, Tsugane S. Coffee consumption and risk of type 2 diabetes mellitus.
Lancet.2003;361:703-704.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12606201&dopt=Abstract
Google Scholar 28.Arion WJ, Canfield WK, Ramos FC.
et al. Chlorogenic acid and hydroxynitrobenzaldehyde: new inhibitors of hepatic
glucose 6-phosphatase.
Arch Biochem Biophys.1997;339:315-322.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9056264&dopt=Abstract
Google Scholar 29.Newgard CB, Foster DW, McGarry JD. Evidence for suppression of hepatic glucose-6-phosphatase with carbohydrate
feeding.
Diabetes.1984;33:192-195.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6319214&dopt=Abstract
Google Scholar 30.Youn JH, Youn MS, Bergman RN. Synergism of glucose and fructose in net glycogen synthesis in perfused
rat livers.
J Biol Chem.1986;261:15960-15969.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3023336&dopt=Abstract
Google Scholar 31.Andrade-Cetto A, Wiedenfeld H. Hypoglycemic effect of
Cecropia obtusifolia on
streptozotocin diabetic rats.
J Ethnopharmacol.2001;78:145-149.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11694359&dopt=Abstract
Google Scholar 32.Johnston KL, Clifford MN, Morgan LM. Coffee acutely modifies gastrointestinal hormone secretion and glucose
tolerance in humans: glycemic effects of chlorogenic acid and caffeine.
Am J Clin Nutr.2003;78:728-733.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14522730&dopt=Abstract
Google Scholar 33.del Castillo MD, Ames JM, Gordon MH. Effect of roasting on the antioxidant activity of coffee brews.
J Agric Food Chem.2002;50:3698-3703.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12059145&dopt=Abstract
Google Scholar 34.Kobayashi Y, Suzuki M, Satsu H.
et al. Green tea polyphenols inhibit the sodium-dependent glucose transporter
of intestinal epithelial cells by a competitive mechanism.
J Agric Food Chem.2000;48:5618-5623.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11087528&dopt=Abstract
Google Scholar 35.Nauck MA, Heimesaat MM, Orskov C.
et al. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide]
but not of synthetic human gastric inhibitory polypeptide in patients with
type-2 diabetes mellitus.
J Clin Invest.1993;91:301-307.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8423228&dopt=Abstract
Google Scholar 36.Meier JJ, Hucking K, Holst JJ.
et al. Reduced insulinotropic effect of gastric inhibitory polypeptide in
first-degree relatives of patients with type 2 diabetes.
Diabetes.2001;50:2497-2504.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11679427&dopt=Abstract
Google Scholar 37.Barbagallo M, Dominguez LJ, Galioto A.
et al. Role of magnesium in insulin action, diabetes and cardio-metabolic
syndrome X.
Mol Aspects Med.2003;24:39-52.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12537988&dopt=Abstract
Google Scholar 38.Paolisso G, Scheen A, D'Onofrio F, Lefebvre P. Magnesium and glucose homeostasis.
Diabetologia.1990;33:511-514.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2253826&dopt=Abstract
Google Scholar 39.Paolisso G, Ravussin E. Intracellular magnesium and insulin resistance: results in Pima Indians
and Caucasians.
J Clin Endocrinol Metab.1995;80:1382-1385.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7714114&dopt=Abstract
Google Scholar 40.Paolisso G, Barbagallo M. Hypertension, diabetes mellitus, and insulin resistance: the role of
intracellular magnesium.
Am J Hypertens.1997;10:346-355.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9056694&dopt=Abstract
Google Scholar 41.Tuomilehto J, Tuomilehto-Wolf E, Virtala E, LaPorte R. Coffee consumption as trigger for insulin dependent diabetes mellitus
in childhood.
BMJ.1990;300:642-643.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2322701&dopt=Abstract
Google Scholar 42.Yoshioka K, Kogure A, Yoshida T, Yoshikawa T. Coffee consumption and risk of type 2 diabetes mellitus.
Lancet.2003;361:703.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12606200&dopt=Abstract
Google Scholar 43.DECODE Study Group. Age- and sex-specific prevalences of diabetes and impaired glucose
regulation in 13 European cohorts.
Diabetes Care.2003;26:61-69.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12502659&dopt=Abstract
Google Scholar 44.Qiao Q, Hu G, Tuomilehto J.
et al. Age- and sex-specific prevalence of diabetes and impaired glucose regulation
in 11 Asian cohorts.
Diabetes Care.2003;26:1770-1780.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12766108&dopt=Abstract
Google Scholar