At the 7th World Congress of Diabetes Prevention and Its Complications, ISIC sponsored a session entitled, Good things in life: Can coffee help in diabetes prevention? Speakers at the conference session included Dr. Nathan Matusheski - Associate Principal Scientist, Mondelēz International. See presentation for details

1. Mechanistic hypotheses for
the prevention of diabetes by
coffee
Nathan V. Matusheski, Ph.D.
Mondelēz International, East Hanover, NJ, USA
7th World Congress on Prevention of Diabetes and its Complications
November 12, 2012
Madrid

2. The coffee conundrum:
Coffee consumption has been associated with
decreased diabetes risk – but why?
What is the physiology?
• Energy expenditure?
• Glucose metabolism?
• Insulin sensitivity?
• Caloric displacement?
What is the “food substance”?
• A known bioactive?
• An unidentified bioactive?
• A nutrient?
• Caffeine?
• The absence of substance?

3. Let’s speculate together…
• Which are the most biologically plausible
mechanisms?
• Where do we go from here?

4. Energy Expenditure Hypothesis
Caffeine has been shown to increase energy expenditure
Physiology:
• Caffeine antagonizes the adenosine
receptor1
• Increased cAMP concentrations are
observed2
• Basal metabolic rate is transiently
increased3
• Net increases of up to 150 kcal/day4
Experimental data:
• High amounts (~600-1200 mg/day) are required
• Coffee contains only about 100 mg caffeine per cup
1Nawrot et al. Food Additives and Contaminants 20, 1–30 (2003).
2Fisone et al. Cell. Mol. Life Sci. 61, 857–872 (2004).
3Acheson et al. Am. J. Clin. Nutr. 33, 989 (1980).
4Dulloo et al. Am J Clin Nutr 49, 44–50 (1989).

5. Carbohydrate Metabolism Hypotheses
Glucose kinetics or glucose homeostasis may be acutely
influenced by chlorogenic acid
Physiology: 40.0#
Incremental*Blood*Glucose*(mg/dL)*
35.0#
• Chlorogenic acid (5-caffeoylquinic acid)
30.0#
25.0#
may inhibit carbohydrate digestion or 20.0#
glucose absorption1 15.0#
10.0#
• Decreased hepatic glucose output 2 5.0#
0.0#
• Modified incretin responses3 0# 20# 40# 60# 80#
Time*(min.)*
100# 120# 140#
Experimental data:
• Mixed results from acute crossover studies4
• In vitro results suggest effective concentrations may be
approached in the intestine but plasma concentrations are far
lower 1Naritaand Inouye. J. Agric. Food Chem 57, 9218–9225 (2009).
2Bassoliet al. Cell Biochem. Funct 26, 320–328 (2008).
3Johnston et al. Am. J. Clin. Nutr 78, 728–733 (2003).
4Matusheski et al. Ch. 8 in Coffee: Emerging Health Effects and
Disease Prevention. Wiley-Blackwell: 2012. pp. 161-163.

6. Insulin Sensitivity Hypotheses
A sub-set of mechanisms has emerged that may explain an
improvement in insulin sensitivity
• Anti-inflammatory effects?
• Anti-oxidative effects?
• Hormonal effects, e.g.
glucocorticoid?
• Chelation of iron?

7. Insulin Sensitivity: Inflammation
Coffee contains components that may modulate
inflammatory pathways, leading to improved insulin
sensitivity
Physiology:
• Caffeic acid phenethyl ester, diterpenes
or 3-methyl-1,2-cyclopentanedione may
regulate inflammatory pathways1,2,3
• Decreased inflammation (e.g.
downregulation of NFκB) may improve
insulin sensitivity4
Experimental data:
• Some promising indications from clinical research5
• Limited epidemiologic associations
1Chung et al. J. Agric. Food Chem. 55, 6787–6792 (2007).
2Kim et al. Toxicol. Appl. Pharmacol 217, 332–341 (2006).
3Feng et al. J. Biol. Chem 280, 27888–27895 (2005).
4Goldfine et al. Clin. Chem. (2010).
5Kempf et al. AJCN 91, 950 –957 (2010).

8. Insulin Sensitivity: Mediation of Oxidative Stress
Coffee contains components that may modulate redox
pathways, leading to improved insulin sensitivity
Physiology:
• Chlorogenic acid and/or N-methylpyridinium
may regulate redox pathways leading to
activation of ARE/XRE-mediated responses1
• Mediation of oxidative stress may positively
impact insulin resistance or complications of
diabetes2
Experimental data:
• Mainly pre-clinical and in vitro research
• Reduction in 8-isoprostanes in one clinical intervantion3
1Boettler et al. J. Nutr. Biochem 22, 426–440 (2011).
2Liet al. Exp Diabetes Res 2012, 216512 (2012).
3Kempf et al. AJCN 91, 950 –957 (2010).

9. Insulin Sensitivity: Hormonal
Coffee contains components that may interact with cortisol
metabolism, leading to improved insulin sensitivity
Physiology:
• Undetermined bioactive component(s) may
inhibit 11β-hydroxysteroid dehydrogenase
type 1 (11β-HSD1)1
• Decreased tissue-specific cortisol
concentrations may improve insulin
sensitivity2
Experimental data:
• Mostly in vitro
• 11β-HSD1 remains a drug development target
• Interesting recent results with green coffee bean extract3
1Atanasov et al. FEBS Lett 580, 4081–4085 (2006).
2Tomlinson and Stewart. Best Pract. Res. Clin. Endocrinol. Metab
21, 607–619 (2007).
3Al-Dujaili et al. Steroids 77, 703–709 (2012).

10. Insulin Sensitivity: Iron Chelation
Coffee contains components that chelate iron, which may
be beneficial for insulin sensitivity
Physiology:
• The phenolics and melanoidins in coffee may
chelate iron1,2
• Decreased iron stores may improve insulin
sensitivity or cardiovascular health2
Experimental data:
• Mostly epidemiologic associations
• More clinical research is warranted
1Mascitelli
et al. Arch. Intern. Med 167, 204–205; author reply 205 (2007).
2Morck et al. Am. J. Clin. Nutr 37, 416–420 (1983).
3Rajpathak et al. Biophysica Acta 1790, 671–681 (2009).

11. More Possible Mechanisms Still…
Activation of AMP-activated protein kinase?1
Downregulation of SREBP-1c?2
PPAR-γ agonism?3
Alleviation of magnesium insufficiency?4
Anti-glycation?5
1Lee et al. Biochem. Biophys. Res.Commun. 361, 854–858 (2007).
2Murase et al. J. Physiol. Endocrinol. Metab 300, E122–133 (2011).
3Choi et al. Biochim. Biophyis. Acta 1770, 1612–1619 (2007).
4Mooren et al. Diabetes Obes. Metab. 13, 281–284 (2011).
5Verzelloni et al. Food Chemistry 124, 1430–1435 (2011).

12. Where do we go from here?
Apply your best “plausibility filters”
• Is the coffee composition under study well
characterized?
• If it’s a bioactive – what concentration is required at
which tissue site?
• Which mechanisms are most likely to truly impact
human physiology?
• What are the most appropriate biomarkers to track in
humans?
• What confounding associations might confuse the
issues?

13. Rationale for future research:
Diabetes is one of the world’s most important health
concerns
Coffee is one of the most widely-consumed beverages in
the world
People who consume large amounts of coffee seem to
have only about half the diabetes risk of non-consumers in
some studies
If coffee consumption is a lifestyle behavior that’s
protective against diabetes, we should understand why
?