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SYMPOSIUM / SYMPOSIUM
Coffee, glucose homeostasis, and insulin
resistance: physiological mechanisms and
mediators
Jasmine M. Tunnicliffe and Jane Shearer
Abstract: Epidemiological studies show coffee consumption to be correlated to large risk reductions in the prevalence of
type 2 diabetes (T2D). Such correlations are seen with decaffeinated and caffeinated coffee, and occur regardless of gen-
der, method of brewing, or geography. They also exist despite clear evidence showing that caffeine causes acute post-
prandial hyperglycemia and lower whole-body insulin sensitivity. As the beneficial effects of coffee consumption exist for
both decaffeinated and caffeinated coffee, a component of coffee other than caffeine must be responsible. This review ex-
amines the specific coffee compounds responsible for coffee’s effects on T2D, and their potential physiological mecha-
nisms of action. Being plant-derived, coffee contains many beneficial compounds found in fruits and vegetables, including
antioxidants. In fact, coffee is the largest source of dietary antioxidants in industrialized nations. When green coffee is
roasted at high temperatures, Maillard reactions create a number of unique compounds. Roasting causes a portion of the
antioxidant, chlorogenic acid, to be transformed into quinides, compounds known to alter blood glucose levels. Coffee con-
sumption may also mediate levels of gut peptides (glucose-dependent insulinotropic polypeptide and glucagon-like
peptide-1), hormones intimately involved in the regulation of satiety and insulin secretion. Finally, coffee may have
prebiotic-like properties, altering gut flora and ultimately digestion. In summary, it is evident that a better understanding
of the role of coffee in the development and prevention of T2D has the potential to uncover novel therapeutic targets and
nutraceutical formulations for the disease.
Key words: diet, caffeine, type 2 diabetes, nutrition, beverage.
Re
´sume
´:Des e
´tudes e
´pide
´miologiques associent la consommation de cafe
´a
`une importante diminution de la pre
´valence
de diabe
`te de type 2 (T2D). Cette corre
´lation s’ave
`re valable pour le cafe
´avec ou sans cafe
´ine peu importe le genre des
personnes, leur lieu de re
´sidence et la me
´thode d’infusion. Pourtant, des e
´tudes re
´ve
`lent que le cafe
´suscite une hyper-
glyce
´mie postprandiale de bre
`ve dure
´e et diminue la sensibilite
´de tout l’organisme a
`l’insuline. Si les effets de la consom-
mation du cafe
´demeurent qu’il soit de
´cafe
´ine
´ou non, il doit y avoir un autre ingre
´dient en cause dans le cafe
´. Cet article
fait le tour des composantes spe
´cifiques du cafe
´ayant un effet sur le T2D et en analyse le me
´canisme d’action potentielle
dans l’organisme. D’origine ve
´ge
´tale, le cafe
´contient beaucoup de composantes retrouve
´es dans les fruits et les le
´gumes
dont les antioxydants. De fait, le cafe
´est la plus grande source d’antioxydants alimentaires des pays industrialise
´s. En tor-
re
´fiant les fe
`ves de cafe
´vert a
`haute tempe
´rature, les re
´actions de Maillard aboutissent a
`un certain nombre de compo-
santes particulie
`res. La torre
´faction transforme une fraction de l’acide chloroge
´nique, un antioxydant, en quinides qui,
selon la litte
´rature scientifique, modifient la glyce
´mie. La consommation de cafe
´conditionne aussi le taux intestinal de
gluco-incre
´tines GIP (« glucose-dependent insulinotropic polypeptide ») et GLP-1 (« glucagon-like peptide-1 »), des hor-
mones e
´troitement associe
´es dans la re
´gulation de la satie
´te
´et de la se
´cre
´tion de l’insuline. Finalement, le cafe
´aurait des
proprie
´te
´s analogues aux pre
´biotiques, car il modifie la flore intestinale et, au bout du compte, la digestion. Bref, une meil-
leure compre
´hension du ro
ˆle du cafe
´dans le de
´veloppement et la pre
´vention du T2D me
`nera fort probablement a
`la de
´cou-
verte de moyens the
´rapeutiques et nutraceutiques pour lutter contre cette maladie.
Mots-cle
´s:die
`te, cafe
´ine, diabe
`te de type 2, alimentation, boisson.
[Traduit par la Re
´daction]
Received 5 February 2008. Accepted 13 June 2008. Published on the NRC Research Press Web site at apnm.nrc.ca on 6 December 2008.
Abbreviations: ALT, alanine aminotransferase; CGA, chlorogenic acid; G-6-Pase, glucose-6-phosphatase; GIP, glucose-dependent
insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; T2D, type 2 diabetes
J.M. Tunnicliffe1and J. Shearer. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Faculty of Kinesiology,
University of Calgary, AB T2N 4N1, Calgary.
1Corresponding author (e-mail: jmtunnic@ucalgary.ca).
1290
Appl. Physiol. Nutr. Metab. 33: 1290–1300 (2008) doi:10.1139/H08-123 #2008 NRC Canada
Introduction
Type 2 diabetes (T2D) is characterized by either a lack of
sufficient insulin production or an inability of the body to
utilize insulin produced. In both situations, an insufficient
insulin response results in elevated blood glucose that, in
the long term, can lead to health complications, including
cardiovascular disease, kidney disease, blindness, and nerve
damage. T2D is associated with a lower quality of life, as
well as significant healthcare and economic burdens. In the
years ahead, the number of individuals affected by T2D will
reach epidemic proportions worldwide. The problem will be
so severe that current statistics predict that 1 in 3 individuals
born in the year 2000 will develop T2D in their lifetime
(Narayan et al. 2003). Treatment options include lifestyle
changes, drug therapy, and (or) insulin injections. The most
commonly prescribed medications have negative side effects,
and some have serious contraindications (Canadian Diabetes
Association 2003). As such, inexpensive, readily available,
effective methods of glucose management are of interest.
Coffee is a widely consumed beverage around the world,
brewed and ingested in a variety of forms. It is estimated
that >50% of adults in the United States consume coffee on
a daily basis. American adults drank a daily average of
340 mL of coffee from 1999 to 2002, while coffee drinkers
in Canada consume a daily average of 650 mL (Coffee As-
sociation of Canada 2003; Storey et al. 2006). Recent epide-
miological studies have shown coffee consumption to be
correlated to large risk reductions in T2D. van Dam and Hu
(2005) systematically reviewed all cohort and cross-sectional
studies on coffee and (or) caffeine and T2D. They found a
relative risk reduction for T2D of 0.65 with the consumption
of 6–7 cupsday–1 of coffee for cohort studies, and a
summary odds ratio of 0.48 with consumption of more than
5 cupsday–1 of coffee for cross-sectional studies (95% CI)
(van Dam and Hu 2005). Such correlations are dose-
responsive, are seen with both decaffeinated and caffeinated
coffee, and occur regardless of gender, method of brewing,
or geography (Salazar-Martinez et al. 2004; Soriguer et al.
2004; van Dam and Hu 2005). In small-scale clinical trials,
coffee consumption has also been linked to lower fasting
glucose concentrations, an indicator of improved insulin sen-
sitivity (Naismith et al. 1970). Besides lowering disease in-
cidence, coffee consumption may limit the progression of
T2D. Examination of coffee consumption in individuals
with impaired fasting glucose (6.1 mmolL–1 £fasting
plasma glucose (FPG) < 7.0 mmolL–1 and postchallenge
glucose (PCG) < 7.8 mmolL–1) or impaired glucose toler-
ance (FPG < 6.1 mmolL–1 and 7.8 mmolL–1 £PCG £
11.1 mmolL–1) showed a reduced risk of incident diabetes
with reductions in odds ratios of 0.31 and 0.36, respectively,
among past and current coffee consumers (Smith et al.
2006). In addition to T2D, habitual coffee consumption may
delay the development of symptoms associated with the
metabolic syndrome. Hino and colleagues (2007) found that
the frequency of the metabolic syndrome decreased with in-
creasing coffee consumption. Specifically, coffee consump-
tion was correlated to lower waist circumference, blood
pressure, triglycerides, and fasting plasma glucose levels.
Of note, these are also risk factors for the development of
T2D. A comprehensive review of coffee’s health effects can
be found in the review by van Dam (2008) in this issue.
Given that coffee is already a popular, readily available,
and inexpensive beverage, its use in preventing and (or) re-
ducing T2D has widespread health implications. The objec-
tive of this review was to explore the physiological effects
of coffee constituents in relation to T2D. Understanding cof-
fee’s mechanisms of action, as they relate to glucose man-
agement and insulin sensitivity, will lead to an increased
understanding of how this and other dietary factors alter
T2D disease risk. Such information is useful in the develop-
ment of dietary guidelines and the discovery of novel thera-
peutic targets and nutraceutical formulations.
Constituents of coffee
Prior to exploring the physiological effects of coffee as
they relate to T2D, a brief review of coffee constituents is
of value. Coffee beans contain thousands of constituents, in-
cluding lipids, proteins, carbohydrates, vitamins, and miner-
als. Given this, isolating specific compounds responsible for
the protective effects of coffee on T2D is difficult. To date,
the majority of research on the biological activity of coffee
has mainly focused on caffeine. More recently, the acknow-
ledgment that coffee and caffeine are not physiologically
equivalent has increased the exploration of other coffee con-
stituents (Farah et al. 2006; Johnston et al. 2003; McCarty
2005; Nunes and Coimbra 2007; Shearer et al. 2003). A
general overview of the nutritional profile of caffeinated
and decaffeinated coffee is shown in Table 1. It is evident
that the contribution of coffee to the daily recommended in-
take (DRI) of both macro- and micronutrients is minimal.
Despite this, their potential contribution to coffee’s benefi-
cial effects cannot be completely discounted.
Macronutrients
Carbohydrates dominate the composition of green coffee
beans, although most of them are nondigestible fibers (Arya
and Rao 2007; Diaz-Rubio and Saura-Calixto 2007). When
green beans are roasted, 98% of their sucrose undergoes
hydrolysis (Farah et al. 2006), and further degradation reac-
tions occur (Arya and Rao 2007). Less than 30% of the total
carbohydrate in coffee beans is found in brewed coffee
(Arya and Rao 2007). Thus, the digestible carbohydrate
fraction of brewed coffee is negligible. The polysaccharides
found in brewed coffee act as prebiotics and dietary fiber
and, as such, may reduce the risk of colon cancer (Arya and
Rao 2007). Soluble dietary fiber also plays a role in the anti-
oxidant activity of coffee by binding and enabling passage
of these phenols to the brewed beverage (Diaz-Rubio and
Saura-Calixto 2007). Decaffeinated coffee may have slightly
lower levels of carbohydrates than caffeinated coffee, de-
pending on the method used in the decaffeination process
(Ramalakshmi and Raghavan 1999) (Table 1).
Micronutrients
Coffee contains numerous minerals and vitamins in vary-
ing concentrations, depending on the method of preparation.
Generally, the concentration of vitamins and minerals de-
rived from dietary coffee consumption is minimal, represent-
ing a small percentage of DRI. Dry roasted coffee contains
4% mineral constituents by weight (Viani 1993). Primary
minerals include potassium, calcium, magnesium, phosphate,
Tunnicliffe and Shearer 1291
#2008 NRC Canada
and sulphate. Of these, potassium is present in the largest
concentration, with ~2.5% of DRI per cup. Potassium con-
sumption may reduce blood pressure, and supplementation
may be useful in treating hypertension, both complications
of T2D (Haddy et al. 2006). In epidemiological and inter-
vention studies, magnesium has been shown to play a role
in diabetes prevention (Greenberg et al. 2006; Higdon and
Frei 2006; van Dam 2006). However, it only plays a part in
the overall protective factor of coffee against T2D, since
magnesium intake was accounted for in cohort studies look-
ing at coffee intake and risk of T2D (Higdon and Frei 2006;
Salazar-Martinez et al. 2004). For both potassium and
magnesium, levels in coffee are minor compared with other
dietary sources. Dry coffee also contains 0.6%–1.3% trigo-
nelline, a compound that undergoes degradation in the roast-
ing process; some forms nicotinic acid (niacin) (Casal et al.
2000). A single cup of coffee contributes 2.4%–8.8% DRI
for niacin. Trigonelline itself is associated with aroma and
may have a role in glucose management (Farah et al. 2006;
van Dam 2006). Plants high in trigonelline are consumed as
folk remedies for diabetes and have documented hypo-
glycemic effects in alloxan-diabetic rats (Fournier 1948;
Mishkinsky et al. 1967). Administration of 500 mg of oral
trigonelline to patients with diabetes results in transient hy-
poglycemia in 50% of patients for 2 h (Mishkinsky et al.
1967). A single cup of coffee contains 29–103 mg of trigo-
nelline, depending on the origin of the beans and degree of
roast (Minamisawa et al. 2004). Brewed coffee also contains
small amounts of vitamin E (Higdon and Frei 2006). Vita-
min E is a recognized antioxidant; however, coffee contains
minimal amounts, so it is unlikely that this component sig-
nificantly contributes to the antioxidant capacity of coffee
(Higdon and Frei 2006).
Unique coffee constituents
Being plant-derived, coffee contains many beneficial
compounds found in fruits and vegetables. When green cof-
fee beans are roasted under high temperatures, chemical re-
actions between amino acids and carbohydrates, known as
Maillard reactions, create a number of unique compounds.
Coffee is abundant in chlorogenic acids (CGAs), compounds
commonly found in fruits and vegetables. Upon roasting, a
portion of CGAs are unstable and are transformed to quino-
lactones (quinides) (Clifford 1999; Farah et al. 2005). One
of the quinides, 3,4-diferuloyl-1,5-quinide, has been shown
to reduce liver glucose production in rats during a
hyperinsulinemic-euglycemic clamp (Shearer et al. 2003).
Other unique compounds include lactones, which are de-
rived from precursors other than CGAs (Farah et al. 2005).
The specific physiological activities of CGAs are discussed
below.
Caffeine
Caffeine (1,3,7-methylxanthine) has been well studied for
its physiological effects. Information on the specific actions
of caffeine can be found in the other reviews in this issue
(van Dam 2008; Tarnopolsky 2008; Tunnicliffe et al.
2008b; Graham et al. 2008; Burke 2008). A single cup of
coffee contains 35%–38% DRI of caffeine. At blood con-
centrations resulting from normal coffee consumption, caf-
feine acts mainly as an adenosine receptor antagonist, as do
its major metabolites (Fredholm et al. 1999; Hetzler et al.
1990). Unexpectedly, this component of coffee is known to
cause postprandial skeletal muscle and whole-body insulin
insensitivity, states that would be expected to precipitate
rather then prevent the onset of T2D (Johnston et al. 2003;
Thong et al. 2002; Vergauwen et al. 1994). Specifically, the
consumption of ~5 mgkg–1 caffeine lowers whole-body glu-
cose disposal by ~20%–25%, and results in exaggerated
plasma insulin levels (Battram et al. 2005; Greer et al.
2001; Keijzers et al. 2002; Lee et al. 2005). It is important
to note that these studies have employed alkaloid caffeine
and not coffee.
Indeed, there appears to be differences in the physiologi-
cal response between caffeine — found in various sources or
alone — vs. an equivalent amount of caffeine consumed as a
part of coffee. This paradox exists even if an equivalent
amount of caffeine is simply added to decaffeinated coffee.
In high-fat-fed rodents, chronic decaffeinated coffee con-
sumption (4 weeks) improves both whole-body insulin ac-
tion and glucose disposal, but these effects disappear when
caffeine is added to the mixture (Fig. 1) (Shearer et al.
2007). Similarly, Battram and colleagues (2006) adminis-
tered 4.45 mgkg–1 body weight alkaloid caffeine, caffei-
Table 1. Nutrient profile of caffeinated and decaffeinated coffee.
Component
Caffeinated
coffee (240 mL) Caffeinated coffee DRI (%)
Decaffeinated
coffee (240 mL) Decaffeinated coffee DRI (%)
Caffeine 130±20 mg 25–38 of suggested maximum 3±2 mg* 0.2–1.2 of suggested maximum
Lipids 5 mg 0.00 5 mg 0.00
Protein 280 mg 0.5 240 mg 0.4
Carbohydrates 75–150 mg 0.2–0.4 75–150 mg 0.2–0.4
Dietary fiber 1.1±0.2 g 2.6 1.1±0.2 g 2.6
Chlorogenic acid 88–250 mg n.a. 79–242 mg n.a.
Magnesium 7 mg 1.7 12 mg 2.9
Potassium 116 mg 2.5 128 mg 2.7
Niacin 0.81–2.0 mg 5.1–12.5 0.38–1.4 mg 2.4–8.8
Vitamin E 0.02 mg 0.1 0.02 mg 0
Note: Percentage daily recommended intake (DRI) for an adult male for each component is shown. Values are based on 240 mL (1 cup = 240 g total =
1.5 g dry weight). Ranges are due to differences in degree of roast, type of coffee bean, method of brewing, etc. Values were obtained from Adrian and
Frangne (1991); Arya and Rao (2007); Clifford (1999); Diaz-Rubio and Saura-Calixto (2007); Farah et al. (2006); Health Canada (2005, 2006a, 2006b,
2006c); McCusker et al. (2006); ESHA Research (2003); and United States Department of Agriculture (2006). n.a., not applicable.
*Found to be as high as 7 mg.
1292 Appl. Physiol. Nutr. Metab. Vol. 33, 2008
#2008 NRC Canada
nated coffee in a volume equivalent to the alkaloid caffeine,
decaffeinated coffee of same volume as the caffeinated cof-
fee, or placebo to human subjects 1 h prior to an oral glu-
cose tolerance test. Results demonstrated that caffeine
elevates blood glucose ~160%, compared with caffeinated
coffee, and ~320%, compared with decaffeinated coffee. In-
sulin was also significantly higher with alkaloid caffeine
than with either placebo or decaffeinated coffee, but not caf-
feinated coffee. Of interest, decaffeinated coffee resulted in
the lowest rise in blood glucose of all the groups (including
placebo), suggesting that a component of coffee other than
caffeine is responsible for its role in preventing T2D. This
may be due to the lactones in coffee. Lactones have been
examined for their ability to counteract the stimulatory ef-
fects of caffeine through adenosine receptors (de Paulis et
al. 2002; Farah et al. 2005).
One attractive hypothesis explaining the dichotomy be-
tween epidemiological and laboratory studies on coffee and
(or) caffeine is that an individual will habituate to the detri-
mental effects of coffee with prolonged consumption. To
test this, Dekker and colleagues (2007) administered caf-
feine (5 mgkg–1) to caffeine-naive subjects for 14 days.
Oral glucose tolerance tests were performed at 0, 7, and
14 days. Following 14 days of exposure, fatty acid and cat-
echolamine levels were reduced, but insulin resistance and
glucose responsiveness were not. Given this, it is clear that
while habituation may occur to some of caffeine’s physio-
logical effects, others do not. The ability of caffeine to
lower insulin sensitivity, albeit reduced, still exists.
Physiological mechanisms and mediators
The potential mechanisms by which coffee exerts its ef-
fects on the development of insulin resistance and T2D are
diverse. While many of the mechanisms below have been
shown in vitro or in animal models, well-controlled human
studies are lacking. Human studies examining the specific
effects of chronic coffee consumption on T2D are difficult,
given the diverse etiology and time course of this disease.
Weight loss and thermogenesis
One hypothesis explaining how coffee alters T2D risk in-
volves weight management and body composition. Individu-
als who consume coffee on a regular basis would be
expected to have a lower body mass, a factor that would
lower T2D risk. Caffeine contained in coffee has been
shown to induce thermogenesis, lipolysis, fat oxidation, and
insulin secretion in both nonobese and obese individuals
(Astrup et al. 1990; Bracco et al. 1995; Greenberg et al.
2006; Greer et al. 2001). In fact, the consumption of 6 cups
of coffee would be expected to induce a 100 kcal increase in
energy expenditure (Dulloo et al. 1989). The effect is dose-
responsive and due solely to caffeine, not coffee components
(Horst et al. 1936). To date, there is little evidence that cof-
fee consumption promotes significant weight loss or causes
alterations in body composition. Again, this appears to be
due to habituation to caffeine-induced catecholamine re-
sponses and lipolysis with prolonged use (Dekker et al.
2007). Isolated adipocytes from caffeine-treated rodents
show increases in adenosine receptors (A1) and ~30%
reductions in lipolytic sensitivity, compared with controls
(Cheung et al. 1988; Fredholm 1982; Zhang and Wells
1990).
A large prospective study found that increased caffeine
intake correlated with lower weight gain (Lopez-Garcia et
al. 2006); however, the amount was only ~0.5 kg over a
12 year period. A similar effect was seen in decaffeinated
coffee drinkers. Such a small weight differential would not
be expected to alter T2D disease risk. In the laboratory,
studies have also demonstrated caffeine consumption to be
ineffective during and following weight-loss programs.
Astrup and colleagues (1992) examined the effect of a
calorie-restricted diet over 24 weeks on weight loss with
and without the addition of 600 mgday–1 caffeine. In this
double-blind study, they demonstrated no difference be-
tween the caffeine or placebo groups. Similar results have
also been demonstrated following weight loss. Examination
of weight regain following a 13 week calorie-restricted
weight loss diet resulted in no difference between individu-
als who consumed caffeine and those who did not (Kovacs
et al. 2004).
While caffeine and roasted coffee may not be useful in
promoting weight loss, green coffee extract high in CGAs
may be beneficial when consumed as a part of a weight
loss program. Green bean coffee supplements are currently
on the market under the trade name Svetol, and contain
200 mg of CGAs per capsule. In a study examining the ef-
fectiveness of this supplement, participants ingested either
placebo or 2 Svetol capsulesday–1 for 60 days. On average,
the control group lost 2.45 ± 0.37 kg and the supplement
group lost 4.97 ± 0.32 kg (Dellalibera et al. 2006).
Similarly, prolonged ingestion of CGA-enhanced coffee
(5 servingsday–1) in overweight adults over 12 weeks re-
sulted in a weight loss of 5.4 ± 0.6 kg, compared with con-
trols. Body composition analysis of study participants
showed a significant body fat loss of 3.6 ± 0.3% during this
Fig. 1. Glucose infusion rate during a hyperinsulinemic-euglycemic
(2 mUkg–1min–1) in rats fed water (placebo), caffeinated coffee, or
decaffeinated coffee for 4 weeks in combination with a high-fat
diet (60% kcal from fat). *, Significant differences (p< 0.05) be-
tween treatment groups at individual timepoints. Data represent
means ± SE; n= 8 or 9 animals per treatment. Previously published
data adapted from Shearer et al. (2007). Results show that decaf-
feinated coffee, but not caffeinated coffee, mitigates the effects of
high-fat food on insulin sensitivity.
Tunnicliffe and Shearer 1293
#2008 NRC Canada
period, which translated into 80% of the total weight loss
from this depot (Thom 2007). As such, CGAs may have
beneficial effects on metabolisms that promote fat loss.
Antioxidants
Antioxidants combat free radicals in the body. If levels of
antioxidants are insufficient to control free radical produc-
tion, oxidative stress occurs (Penckofer et al. 2002). Oxida-
tive stress is implicated in the development and pathogenesis
of numerous conditions, including diabetes, neurodegenera-
tion, liver disease, cardiovascular disease, and cancer
(Albano 2006; Butterfield et al. 2006; Davidson and Duchen
2007; Gandhi and Wood 2005; Hwang and Bowen 2007).
Although people are encouraged to increase fruit and vege-
table consumption to fight disease, only 13% of antioxidants
are consumed from these foods (Svilaas et al. 2004). Anal-
yses of dietary records indicate that the majority (>60%) of
antioxidant intake in adults is consumed from coffee (Pulido
et al. 2003; Svilaas et al. 2004). While other plant-based
foods may have higher concentrations of antioxidants, the
frequency and volume of coffee consumption make it the
primary dietary source (Table 2). The predominant anti-
oxidants in coffee are the polyphenolic CGAs, the main one
of which is 5-O-caffeoylquinic acid (Johnston et al. 2003;
Svilaas et al. 2004). Other antioxidants include caffeic acids,
ferulic acids, melanoidins, Maillard reaction products, and
lignans (Fujioka and Shibamoto 2006; van Dam 2006;
Yanagimoto et al. 2004). Caffeine has been shown to have
antioxidant properties, but not at concentrations from normal
coffee intake (Azam et al. 2003; Robinson et al. 2004). Ca-
sein, a milk protein, has been shown to interact with poly-
phenols. Adding milk to coffee, as is commonly practiced
by coffee consumers, does not significantly alter its anti-
oxidant capacity (Dupas et al. 2006; Richelle et al. 2001).
Fujioka and Shibamoto (2006) identified 9 CGAs in cof-
fee with antioxidant activities. CGAs are esters of cinnamic
acids and quinic acid (Clifford 1999) that are thought to be
metabolized significantly, as serum analysis after coffee in-
gestion does not show CGA presence (Natella et al. 2002).
Olthof and colleagues (2003) have identified the colon as
the main site of absorption following CGA hydrolysis by co-
lonic microorganisms. This group also found that 33% of
CGAs are absorbed in human subjects without a colon, indi-
cating that some absorption occurs in the small intestine,
with metabolism occurring in the liver (Olthof et al. 2001).
Metabolites of CGA, such as caffeic and ferulic acid, retain
antioxidant capabilities, although to a lesser extent (Fujioka
and Shibamoto 2006; Olthof et al. 2003). Coffee also con-
tains a number of unique low- and high-weight molecules
with antioxidant properties, some of which develop in the
roasting process because of Maillard reactions (Yanagimoto
et al. 2002, 2004). Lignans, phytoestrogens with antioxidant
activity, are also found in coffee. These compounds are
metabolized in the intestine, and their degradation products
have been implicated in glucose control (Bhathena and
Velasquez 2002).
Antimicrobial and prebiotic activity
It is now recognized that certain dietary components can
help foster the growth of microorganisms in the gut. Alter-
ing gut microflora may have long-term health implications,
helping to aid digestion, moderate immune responsiveness,
and prevent obesity (Cani et al. 2007a, 2007b, 2007c). Sev-
eral coffee constituents, including caffeine, CGA, caffeic
acid, and trigonelline, have antibacterial properties against
pathogenic and cavity-causing bacteria (Almeida et al.
2006; Daglia et al. 2002). Evaluation of the effects of coffee
on 9 strains of enterobacteria, a family of bacteria com-
monly found in the gut, demonstrated that coffee has signifi-
cant antibacterial activities in vitro (Almeida et al. 2006).
Almeida and colleagues (2006) concluded that several of
coffee’s constituents could be used in foods as natural
preservatives to control bacterial growth. Whether similar in
vivo prebiotic-like activities exist in humans with regular
coffee consumption has not been determined.
Beyond its prebiotic properties, coffee extracts are also
known to inhibit the growth of Streptococcus mutans, the
major causative agent in dental caries. Bacterial infection in
the mouth is linked to low-grade systemic inflammation and
conditions such as cardiovascular disease, atherosclerosis,
and obesity (Gibson et al. 2006; Pischon et al. 2007). Perio-
dontal disease is also associated with reduced insulin sensi-
tivity, and may play a role in the development of T2D
(Mealey and Oates 2006; Pontes Andersen et al. 2007). Con-
versely, people with diabetes have an increased risk of de-
veloping periodontal disease, more so if blood glucose
levels are uncontrolled (Mealey and Oates 2006). Given
these relationships, it is not unreasonable to speculate that
the inhibition of bacterial growth by coffee may exert some
of its effects on insulin resistance by mediating systemic
low-grade inflammation.
Gut absorption and incretins
Coffee consumption may prevent the onset and progres-
sion of T2D by altering physiological signals related to
meal consumption. First, CGAs in coffee may act to limit
glucose absorption from the gut by inhibiting Na+-dependent
transport across the brush-border membranes. Welsch et al.
(1989) isolated rat membrane vesicles in vitro and found
glucose uptake to be reduced by 80%, 38%, and 35% with
1mmolL–1 CGA, ferulic acid, and caffeic acid, respec-
tively. Rats given a CGA dose daily for 3 weeks also
showed significantly lower fasting plasma levels of choles-
terol and triacylglycerides (Rodriguez de Sotillo and Hadley
Table 2. Antioxidant intake.
Dietary
component
% of total Norwegian
antioxidant intake
(entire diet)*
% of total Spanish
antioxidant intake
(beverages only){
Coffee 64 61
Fruits, berries 11 n.d.
Tea 8 5
Wine 5 22
Cereals 5 n.d.
Fruit juice 2 5
Vegetables 2 n.d.
Note: n.d., no data available or not determined.
*Values are based on 7 d dietary records from 61 adults (Svilaas et al.
2004).
{Values are based on daily intake estimates from nationwide surveys
from 6300 households, hotels, restaurants, and institutions in Spain (Pulido
et al. 2003).
1294 Appl. Physiol. Nutr. Metab. Vol. 33, 2008
#2008 NRC Canada
2002). In humans, the addition of CGAs to regular coffee
prior to an oral glucose tolerance test resulted in a 7% de-
cline in glucose response, compared with a control beverage
(Thom 2007). Likewise, a recent study in our laboratory,
evaluating the effects of CGAs on meal tolerance in rodents
in vivo, demonstrated that CGAs (120 mgkg–1) significantly
lower blood glucose responses, compared with placebo
(Tunnicliffe et al. 2008a) (Fig. 2). Besides altering glucose
transport, CGAs may also alter patterns of intestinal hor-
mone secretion.
Gut peptides are secreted from the gastrointestinal tract
and help regulate energy intake with hunger and satiety
cues (Murphy et al. 2006). The incretin hormones glucose-
dependent insulinotropic polypeptide (GIP) and glucagon-
like peptide-1 (GLP-1) are released in response to nutrient
ingestion, and are responsible for 50%–70% of insulin re-
sponsiveness (Baggio and Drucker 2007; Johnston et al.
2003). GIP is a gut peptide secreted predominantly from the
proximal intestine in response to nutrient absorption; the rate
of glucose absorption determines the amount of GIP se-
creted (Baggio and Drucker 2007; Johnston et al. 2003).
The primary function of GIP is to induce insulin secretion.
GLP-1, like GIP, activates b-cell receptors in the pancreas
to increase insulin secretion (McCarty 2005). Although both
of these gut peptides can be secreted along the entire intes-
tine, GLP-1 is secreted to a greater extent from more distal
segments of the gut (Baggio and Drucker 2007). GLP-1 is
released in the intestine in response to glucose presence,
rather than absorption (Baggio and Drucker 2007; Johnston
et al. 2003). As incretin responses are known to be attenu-
ated in T2D, it is possible that coffee ingestion mediates its
beneficial effects on insulin resistance and T2D through this
mechanism (Drucker and Nauck 2006; Toft-Nielsen et al.
2001a, 2001b).
In a study conducted by Johnston and colleagues (2003),
administration of an oral glucose load (25 g) in combination
with placebo, decaffeinated coffee (400 mL), or caffeinated
coffee (400 mL) in human subjects demonstrated that a
component of coffee alters incretin secretion. GIP responses
were lower with caffeinated coffee, and declined further
with decaffeinated coffee. Since the only difference between
treatments was the presence of caffeine, the authors con-
cluded that the GIP-lowering effects of coffee must be at-
tributable to components other than caffeine. In particular,
they hypothesized that CGA reduces intestinal glucose ab-
sorption, resulting in a lower GIP response. This may be
beneficial in overweight people and in those with T2D,
where postprandial GIP levels are increased by the con-
sumption of high-fat diets (Rudovich et al. 2007). In
addition, GIP has protective effects against apoptosis on the
b-cells of the pancreas (Baggio and Drucker 2007). As loss
of b-cell function leads to insufficient insulin release and
impaired glucose tolerance, it is possible that GIP causes its
protective effects by maintaining b-cell mass in the presence
of hyperglycemia and hyperinsulinemia, hallmark features of
T2D (Meece 2007). Unlike GIP, coffee administration re-
sults in slight elevations in GLP-1 levels. Increased GLP-1
causes greater insulin sensitivity, owing to its anti-
hyperglycemic effects, which are, in part, mediated by its
actions of delaying gastric emptying. People with T2D and
those who are obese have lower levels of GLP-1 response
than expected, so the bolstering effect of CGAs in coffee
may combat this (Anini and Brubaker 2003; Vilsboll et al.
2003).
Liver function and metabolism
The liver plays a key role in maintaining blood glucose
homeostasis by regulating glycogenolysis, gluconeogenesis,
and glycogenesis (Nordlie et al. 1999; Weickert and Pfeiffer
2006). In T2D, this regulation is aberrant, with the liver
often producing inappropriate amounts of glucose, resulting
in hyperglycemia (Nordlie et al. 1999; Roden and
Bernroider 2003; Weickert and Pfeiffer 2006). Chronic
hyperglycemia is linked to the development of compli-
cations from diabetes, such as retinopathy, neuropathy,
nephropathy, and cardiovascular disease (Selvin et al.
2004). Lowering blood glucose is therefore desirable, and
several drugs have been developed for this purpose, with
varying success (Canadian Diabetes Association 2003;
Chipkin 2005). Numerous lines of evidence indicate that
regular coffee consumption has beneficial functional and
metabolic effects on this tissue. For example, 13 days of
CGA administration to mice reduced hepatic triacylglyceride
accumulation (fatty liver), while green bean coffee extracts
have been reported to increase carnitine palmitoyltransferase
activity in mice after 6 days (Shimoda et al. 2006). In addi-
tion, regular coffee consumption has been shown to decrease
levels of alanine aminotransferase (ALT), a marker of liver
injury, and to prevent the development of liver cirrhosis
(Casiglia et al. 1993; Corrao et al. 2001; Honjo et al. 1999,
Fig. 2. Blood glucose concentrations of rats after a meal tolerance
test with or without chlorogenic acid (CGA) (120 mgkg–1;n=8
for each treatment). *, Significant difference (p< 0.05) between
treatment groups at individual timepoints. Data represent means ±
SE. Significant difference (p< 0.05) also exists for area under the
curve for CGA and placebo. Adapted from Tunnicliffe et al.
(2008a). These results confirm that CGA may limit T2D by inhi-
biting intestinal glucose absorption or reducing liver glucose pro-
duction following a meal.
Tunnicliffe and Shearer 1295
#2008 NRC Canada
2001; Kono et al. 1994; Ruhl and Everhart 2005; Sharp and
Benowitz 1995; Tanaka et al. 1998; Tverdal and Skurtveit
2003). Whether these liver-specific effects on inflammation
are due to coffee or caffeine has yet to be elucidated.
Metabolically, coffee consumption also has a direct im-
pact on liver glucose production. When blood levels drop,
the liver produces glucose through glycogenolysis and
gluconeogenesis (Hemmerle et al. 1997; Nordlie et al.
1999). In both of these pathways, glucose-6-phosphatase
(G-6-Pase) catalyzes the last step of glucose formation
(Hemmerle et al. 1997; Nordlie et al. 1999) (Fig. 3). Spe-
cific coffee components are known to act on the G-6-Pase
system. In rodents, acute administration of quinides, the
products of roasting CGAs, increase whole-body insulin sen-
sitivity during a hyperinsulinemic-euglycemic clamp
(Shearer et al. 2003). After employing radioisotopes to
quantify glucose metabolism, results showed no effect of
quinides on skeletal muscle, suggesting the effect was pre-
dominantly mediated at the liver. These observations have
been confirmed by in vitro studies, where CGAs and their
related compounds have been shown to directly inhibit a
component of the G-6-Pase system — G-6-P translocase —
thereby reducing both gluconeogenesis and glycogenolysis
(Hemmerle et al. 1997). Controlling the hepatic production
of glucose is yet another mechanism by which coffee may
prevent diabetes.
Conclusions
Epidemiological data indicate that chronic coffee con-
sumption prevents the onset and may limit the progression
of T2D (van Dam 2006; van Dam and Feskens 2002; van
Dam and Hu 2005; van Dam et al. 2004a, 2004b). This rela-
tionship is dose-responsive and, at the highest levels of con-
sumption (>5 cupsday–1), reduces disease incidence by
~50%. Because of the wide variation in caffeine content of
commercially available coffee and differing individual re-
sponses, coffee drinkers may benefit from switching to de-
caffeinated coffee. Given that T2D is reaching epidemic
proportions in populations worldwide, the mechanisms by
which coffee exerts its beneficial effects are worth explor-
ing. In this review, both epidemiological and laboratory-
based research on coffee were examined in relation to T2D.
Taken together, the data show that coffee does not exert its
beneficial effects through a single mechanism or tissue, but
through many. It is recommended that individuals at risk for
the metabolic syndrome, glucose intolerance, and T2D con-
sume decaffeinated coffee. By understanding coffee’s ef-
fects, a picture of how a single dietary component alters
T2D risk can be generated. Such knowledge may lead to
novel treatments and targets for the disease.
Acknowledgements
Salary support for J.S. is provided by the Alberta Heritage
Foundation for Medical Research, the Heart and Stroke
Foundation of Canada, and the Canadian Diabetes Associa-
tion. Grant support is provided by the Canadian Institutes
for Health Research and Genome Canada. Advice and edit-
ing of the manuscript by Dr. Raylene Reimer (University of
Calgary) was greatly appreciated.
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