1. Latest experiences from
coffee intervention trials
Jaakko Tuomilehto
Department of Public Health
University of Helsinki, Finland
Hubert Kolb
Institute of Molecular Medicine
University of Düsseldorf, Germany

2. Epidemiological data
Possible mechanism MEDIACENTER
THE

3. Coffee consumption and
the development of Type 2 diabetes
among the Finns who have
the highest coffee consumption rate in the world
- 11.3 kg/year per capita THE MEDIACENTER

4. Incidence of type 2 diabetes by volume
of coffee consumption
among men
Coffee Age and exam Multivariate
consumption year adjustment adjustment
<=2 cups 1.00 1.00
3-4 cups 0.83 (0.54-1.25) 0.74 (0.48-1.14)
5-6 cups 0.88 (0.60-1.30) 0.71 (0.47-1.10)
7-9 cups 0.86 (0.53-1.39) 0.67 (0.40-1.14)
>=10 cups 0.69 (0.40-1.19) 0.45 (0.25-0.81)
P for trend 0.735 0.121
Adjusted for age, exam year, BMI, SBP, smoking,
education, physical activity, alcohol and tea
consumption

5. Incidence of type 2 diabetes by volume
of coffee consumption
among women
Coffee Age and exam Multivariate
consumption year adjustment adjustment
<=2 cups 1.00 1.00
3-4 cups 0.72 (0.49-1.04) 0.73 (0.50-1.08)
5-6 cups 0.49 (0.32-0.73) 0.40 (0.26-0.63)
7-9 cups 0.47 (0.25-0.87) 0.42 (0.22-0.79)
>=10 cups 0.26 (0.08-0.85) 0.21 (0.06-0.70)
P for trend 0.002 <0.001
Adjusted for age, exam year, BMI, SBP, smoking,
education, physical activity, alcohol and tea
consumption

6. Incidence of type 2 diabetes by volume of
coffee consumption among subjects
by age group
1.0
0.8
0.6
0.4
0.2 Age >50
0.0 Age <50
Coffee (cups) <=2 3-4 5-6 7-9 >=10
Adjusted for sex, exam year, BMI, SBP, smoking,
education, physical activity, alcohol and tea consumption.

7. Incidence of type 2 diabetes by volume of
coffee consumption
among obese and non-obese subjects
1.0
0.8
0.6
0.4
0.2 BMI >=30
0.0 BMI <30
Coffee (cups) <=2 3-4 5-6 7-9 >=10
Adjusted for age, sex, exam year, SBP, education,
smoking, physical activity, alcohol and tea consumption.

8. Coffee consumption is associated with reduced diabetes risk
Summary estimate derived from 25 epidemiological studies:
1-2 cups per day: rel. risk approx. 0.9
3-4 cups per day: rel. risk approx. 0.8
≥ 5 cups per day: rel. risk approx. 0.6
van Dam 2002 Lancet 360:1477, Saremi 2003 Diabetes Care 26:2211, Reunanen 2003 Lancet 361:702,
Rosengren 2004 J Intern Med 255:89, Salazar-Martinez 2004 Ann Intern Med 140:1, Tuomilehto 2004
JAMA 291:1213, Carlsson 2004 Int J Epidemiol 33:616, van Dam 2004 Diabetologia 47:2152, Greenberg
2005 AJCN 84:682, van Dam 2006 Diabetes Care 29:398, Iso 2006 Ann Intern Med 144:554, Pereira 2006
Arch Intern Med 166:1311, Smith 2006 Diabetes Care 29:2385, Paynter 2006 Am J Epidemiol 164:1075,
Schulze 2007 Diabetes Care 30:510, Hamer 2008 Brit J Nutr 100:1046, Odegaard 2008 AJCN 88:979, van
Dieren 2009 Diabetologia 62:2561, Sartorelli 2010 AJCN 91:1002, Boggs 2010 AJCN 92:960, Oba 2010
Br J Nutr 103:453, Goto 2011 Diabetes 60:269, Zhang 2011 Nutr Metab Cardiovasc Dis 21:418, Lin 2011
Eur J Clin Invest 41:659, Hjellvik 2011 22:418.

9. Coffee consumption is associated with reduced diabetes risk
Is it a cause-effect relationship?
? YES: Drinking coffee protects from diabetes
? NO: Coffee-associated lifestyle is protective,
people drinking coffee are “different”

10. Coffee consumption tested in intervention trials
Single dose: effect on glucose metaboIism?
No beneficial effects in OGTT:
Modestly increased insulin resistance (caffeine!)
Graham 2001 Can J Physiol Pharmacol 79:559, Keijzers 2002 Diabetes Care 25:364, Johnston 2003
Am J Clin Nutr 78:728, Robinson 2004 J Nutr 134:2528, Petrie 2004 Am J Clin Nutr 80:22, Battram
2006 J Nutr 136:1276, Moisey 2008 Am J Clin Nutr 87:1254, van Dijk 2009 Diabetes Care 32:1023,
Moisey 2010 Br J Nutr 103:833, Greenberg 2010 Diabetes Care 33:278, Beaudoin 2011 Crit Rev
Food

12. Possible mechanisms
Chlorogenic acid is found in green coffee:
- An inhibitor of glucose-6- phosphatase
that catalyzes the terminal reaction of
glycogenolysis and gluconeogenesis, the
two glucose-producing pathways in human
liver.
- It also inhibits glucose transporters (Na+
-dependent glucose transporter) at the
intestinal stage and may also inhibit the
action of the α-Glucosidase enzyme.

14. Coffee consumption tested in intervention trials
4-8 weeks coffee: effect on glucose metaboIism?
No !
Kempf, Herder, Erlund, Kolb, Martin, Carstensen, Koenig, Sundvall, Bidel, Kuha, Tuomilehto 2010
Am J Clin Nutr 91: 950-957
Wedick, Brennan, Sun, Hu, Mantzoros, van Dam 2011 Nutrition Journal 10: 93

17. Coffee consumption tested in intervention trials
4-8 weeks coffee: effect on glucose metaboIism?
Kempf, Herder, Erlund, Kolb, Martin, Carstensen, Koenig, Sundvall, Bidel, Kuha, Tuomilehto 2010
Am J Clin Nutr 91: 950-957

21. Coffee consumption tested in intervention trials
4-8 weeks of coffee: adiponectin increased!
Trial Adiponectin (µg/ml serum)
at baseline after 4-8 w coffee
Kempf 2010 (n=47) 7.96 8.42 (p<0.05)
Wedick 2011 (n=45) 7.80 8.24 (p<0.05)
Epidemiological studies
also find higher adiponectin levels with coffee drinking
(Adiponectin is a diabetes-protective factor)
Wiiliams 2008 Diabetes Care 31:504, Imatoh 2011 Eur J Nutr 50:279 (Li 2009 JAMA 302:179)

26. PROTECTIVE MECHANISMS
Caffeine Magnesium
Thermogenesis ↑ Glucose metabolism
Satiety ↑
Insulin secretion ↑
Glucose absorption ↓
Iron absorption ↓
Chlorogenic acid
N-Methylpyridinium (et al.)
Nrf2 ?
Fat: adiponectin ↑ Gut: GLP-1 ↑
Hypothalamus: anorexic peptides ↑
General: anti-oxidant defence ↑
Body weight ↓ Insulin sensitivity ↑ Diabetes risk↓
Westererp-Platenga 2005 Obes Res 13:1195, Kovacs 2004 Br J Nutr:431, Pimentel 2009 Diabetol Metab Syndr 1:6, Boettler 2011
Mol Nutr Food Res 55:798, Bakuradze 2011 Mol Nutr Food Res 55:793, Paur 2010 Free Radic Biol Med 48:1218

27. Nfr2 =
nuclear factor (erythroi

28. Integr Comp Biol. 2010 Nov;50(5):829-43.
Nrf2, a guardian of healthspan and gatekeeper of species longevity.
Lewis KN, Mele J, Hayes JD, Buffenstein R.
Abstract
Although aging is a ubiquitous process that prevails in all organisms, the mechanisms governing
both the rate of decline in functionality and the age of onset remain elusive. A profound
constitutively upregulated cytoprotective response is commonly observed in naturally long-lived
species and experimental models of extensions to lifespan (e.g., genetically-altered and/or
experimentally manipulated organisms), as indicated by enhanced resistance to stress and
upregulated downstream components of the cytoprotective nuclear factor erythroid 2-related factor
2 (Nrf2)-signaling pathway. The transcription factor Nrf2 is constitutively expressed in all
tissues, although levels may vary among organs, with the key detoxification organs
(kidney and liver) exhibiting highest levels. Nrf2 may be further induced by cellular
stressors including endogenous reactive-oxygen species or exogenous electrophiles.
The Nrf2-signaling pathway mediates multiple avenues of cytoprotection by activating
the transcription of more than 200 genes that are crucial in the metabolism of drugs and
toxins, protection against oxidative stress and inflammation, as well as playing an
integral role in stability of proteins and in the removal of damaged proteins via
proteasomal degradation or autophagy. Nrf2 interacts with other important cell regulators
such as tumor suppressor protein 53 (p53) and nuclear factor-kappa beta (NF-κB) and
through their combined interactions is the guardian of healthspan, protecting against
many age-related diseases including cancer and neurodegeneration. We hypothesize
that this signaling pathway plays a critical role in the determination of species longevity
and that this pathway may indeed be the master regulator of the aging process.

29. Integr Comp Biol. 2010 Nov;50(5):829-43.
Nrf2, a guardian of healthspan and gatekeeper of species longevity.
Lewis KN, Mele J, Hayes JD, Buffenstein R.
Abstract
Nrf2 interacts with other important cell regulators
Although aging is a ubiquitous process that prevails in all organisms, the mechanisms governing
both the rate of decline in functionality and the age of onset remain elusive. A profound
such as tumor suppressor protein 53 (p53) and
constitutively upregulated cytoprotective response is commonly observed in naturally long-lived
species and experimental models of extensions to lifespan (e.g., genetically-altered and/or
nuclear factor-kappa beta (NF-κB) and through their
experimentally manipulated organisms), as indicated by enhanced resistance to stress and
upregulated downstream components of the cytoprotective nuclear factor erythroid 2-related factor
combined interactions is the guardian of healthspan,
2 (Nrf2)-signaling pathway. The transcription factor Nrf2 is constitutively expressed in all
tissues, although levels may vary among organs, with the keydiseases
protecting against many age-related detoxification organs
(kidney and liver) exhibiting highest levels. Nrf2 may be further induced by cellular
including cancer and neurodegeneration. electrophiles.
stressors including endogenous reactive-oxygen species or exogenous
The Nrf2-signaling pathway mediates multiple avenues of cytoprotection by activating
the transcription of more than 200 genes that are crucial in the metabolism of drugs and
We hypothesize that this and inflammation, as well as playing an a
toxins, protection against oxidative stress signaling pathway plays
integral role role inof proteins and in the removal of damaged proteins via
critical in stability the determination of species longevity
proteasomal degradation or autophagy. Nrf2 interacts with other important cell regulators
and that this pathway may indeedfactor-kappa master and
such as tumor suppressor protein 53 (p53) and nuclear be the beta (NF-κB)
through their combined interactions is the guardian of healthspan, protecting against
regulator of the aging process.
many age-related diseases including cancer and neurodegeneration. We hypothesize
that this signaling pathway plays a critical role in the determination of species longevity
and that this pathway may indeed be the master regulator of the aging process.

30. IIS: insulin and IGF
signalling pathways
The role of the antioxidant and longevity-promoting Nrf2pathway in metabolic regulation
Gerasimos P. Sykiotis2, Ioannis G. Habeos2, Andrew V. Samuelson1, and Dirk Bohmann1