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

The coffee conundrum:

What is the “food substance”? •  A known bioactive? •  An unidentified bioactive? •  A nutrient? •  Caffeine? •  The absence of substance?

Coffee consumption has been associated with decreased diabetes risk – but why?

What is the physiology? •  Energy expenditure? •  Glucose metabolism? •  Insulin sensitivity? •  Caloric displacement?

Let’s speculate together…

•  Which are the most biologically plausible mechanisms?

•  Where do we go from here?

Energy Expenditure Hypothesis

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

Caffeine has been shown to increase energy expenditure

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).

Carbohydrate Metabolism Hypotheses

Physiology: •  Chlorogenic acid (5-caffeoylquinic acid)

may inhibit carbohydrate digestion or glucose absorption1

•  Decreased hepatic glucose output2 •  Modified incretin responses3

Glucose kinetics or glucose homeostasis may be acutely influenced by chlorogenic acid

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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

1Narita and Inouye. J. Agric. Food Chem 57, 9218–9225 (2009). 2Bassoli et 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.

Insulin Sensitivity Hypotheses

•  Anti-inflammatory effects? •  Anti-oxidative effects? •  Hormonal effects, e.g.

glucocorticoid? •  Chelation of iron?

A sub-set of mechanisms has emerged that may explain an improvement in insulin sensitivity

Insulin Sensitivity: Inflammation

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

Coffee contains components that may modulate inflammatory pathways, leading to improved insulin sensitivity

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).

Insulin Sensitivity: Mediation of Oxidative Stress

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

Coffee contains components that may modulate redox pathways, leading to improved insulin sensitivity

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). 2Li et al. Exp Diabetes Res 2012, 216512 (2012). 3Kempf et al. AJCN 91, 950 –957 (2010).

Insulin Sensitivity: Hormonal

Physiology: •  Undetermined bioactive component(s) may

inhibit 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)1

•  Decreased tissue-specific cortisol concentrations may improve insulin sensitivity2

Coffee contains components that may interact with cortisol metabolism, leading to improved insulin sensitivity

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).

Insulin Sensitivity: Iron Chelation

Physiology: •  The phenolics and melanoidins in coffee may

chelate iron1,2

•  Decreased iron stores may improve insulin sensitivity or cardiovascular health2

Coffee contains components that chelate iron, which may be beneficial for insulin sensitivity

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).

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).

Where do we go from here?

•  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?

Apply your best “plausibility filters”

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

?