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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 gender, method of brewing, or geography. They also exist despite clear evidence showing that caffeine causes acute postprandial 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 examines the specific coffee compounds responsible for coffees effects on T2D, and their potential physiological mechanisms 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 consumption 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. ` Resume : Des etudes epidemiologiques associent la consommation de cafe a une importante diminution de la prevalence ` ` de diabete de type 2 (T2D). Cette correlation savere valable pour le cafe avec ou sans cafeine peu importe le genre des ` personnes, leur lieu de residence et la methode dinfusion. Pourtant, des etudes revelent que le cafe suscite une hyper ` ` glycemie postprandiale de breve duree et diminue la sensibilite de tout lorganisme a linsuline. Si les effets de la consom mation du cafe demeurent quil soit decafeine ou non, il doit y avoir un autre ingredient en cause dans le cafe. Cet article fait le tour des composantes specifiques du cafe ayant un effet sur le T2D et en analyse le mecanisme daction potentielle dans lorganisme. Dorigine vegetale, le cafe contient beaucoup de composantes retrouvees dans les fruits et les legumes dont les antioxydants. De fait, le cafe est la plus grande source dantioxydants alimentaires des pays industrialises. En tor ` ` ` refiant les feves de cafe vert a haute temperature, les reactions de Maillard aboutissent a un certain nombre de compo` santes particulieres. La torrefaction transforme une fraction de lacide chlorogenique, un antioxydant, en quinides qui, selon la litterature scientifique, modifient la glycemie. La consommation de cafe conditionne aussi le taux intestinal de gluco-incretines GIP ( glucose-dependent insulinotropic polypeptide ) et GLP-1 ( glucagon-like peptide-1 ), des hor mones etroitement associees dans la regulation de la satiete et de la secretion de linsuline. Finalement, le cafe aurait des proprietes analogues aux prebiotiques, car il modifie la flore intestinale et, au bout du compte, la digestion. Bref, une meil ` ` leure comprehension du role du cafe dans le developpement et la prevention du T2D menera fort probablement a la decou verte de moyens therapeutiques et nutraceutiques pour lutter contre cette maladie. ` ` Mots-cles : diete, cafeine, diabete de type 2, alimentation, boisson. [Traduit par la Redaction]

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. Tunnicliffe1 and 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).

doi:10.1139/H08-123
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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 Association of Canada 2003; Storey et al. 2006). Recent epidemiological 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 67 cupsday1 of coffee for cohort studies, and a summary odds ratio of 0.48 with consumption of more than 5 cupsday1 of coffee for cross-sectional studies (95% CI) (van Dam and Hu 2005). Such correlations are doseresponsive, 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 sensitivity (Naismith et al. 1970). Besides lowering disease incidence, coffee consumption may limit the progression of T2D. Examination of coffee consumption in individuals with impaired fasting glucose (6.1 mmolL1 fasting plasma glucose (FPG) < 7.0 mmolL1 and postchallenge glucose (PCG) < 7.8 mmolL1) or impaired glucose tolerance (FPG < 6.1 mmolL1 and 7.8 mmolL1 PCG 11.1 mmolL1) 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 increasing coffee consumption. Specifically, coffee consumption 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 coffees 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) reducing T2D has widespread health implications. The objective of this review was to explore the physiological effects of coffee constituents in relation to T2D. Understanding coffees mechanisms of action, as they relate to glucose management 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 development of dietary guidelines and the discovery of novel therapeutic 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, including lipids, proteins, carbohydrates, vitamins, and minerals. 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 acknowledgment that coffee and caffeine are not physiologically equivalent has increased the exploration of other coffee constituents (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 intake (DRI) of both macro- and micronutrients is minimal. Despite this, their potential contribution to coffees beneficial 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 reactions 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 antioxidant 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, depending on the method used in the decaffeination process (Ramalakshmi and Raghavan 1999) (Table 1). Micronutrients Coffee contains numerous minerals and vitamins in varying concentrations, depending on the method of preparation. Generally, the concentration of vitamins and minerals derived from dietary coffee consumption is minimal, representing a small percentage of DRI. Dry roasted coffee contains 4% mineral constituents by weight (Viani 1993). Primary minerals include potassium, calcium, magnesium, phosphate,
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1292 Table 1. Nutrient profile of caffeinated and decaffeinated coffee. Component Caffeine Lipids Protein Carbohydrates Dietary fiber Chlorogenic acid Magnesium Potassium Niacin Vitamin E Caffeinated coffee (240 mL) 13020 mg 5 mg 280 mg 75150 mg 1.10.2 g 88250 mg 7 mg 116 mg 0.812.0 mg 0.02 mg Caffeinated coffee DRI (%) 2538 of suggested maximum 0.00 0.5 0.20.4 2.6 n.a. 1.7 2.5 5.112.5 0.1

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Decaffeinated coffee (240 mL) 32 mg* 5 mg 240 mg 75150 mg 1.10.2 g 79242 mg 12 mg 128 mg 0.381.4 mg 0.02 mg

Decaffeinated coffee DRI (%) 0.21.2 of suggested maximum 0.00 0.4 0.20.4 2.6 n.a. 2.9 2.7 2.48.8 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.

and sulphate. Of these, potassium is present in the largest concentration, with ~2.5% of DRI per cup. Potassium consumption may reduce blood pressure, and supplementation may be useful in treating hypertension, both complications of T2D (Haddy et al. 2006). In epidemiological and intervention 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 looking 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% trigonelline, a compound that undergoes degradation in the roasting 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 hypoglycemic 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 hypoglycemia in 50% of patients for 2 h (Mishkinsky et al. 1967). A single cup of coffee contains 29103 mg of trigonelline, 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). Vitamin E is a recognized antioxidant; however, coffee contains minimal amounts, so it is unlikely that this component significantly 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 coffee beans are roasted under high temperatures, chemical reactions 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 quinolactones (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 derived 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 concentrations resulting from normal coffee consumption, caffeine 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 mgkg1 caffeine lowers whole-body glucose 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 physiological 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 consumption (4 weeks) improves both whole-body insulin action 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) administered 4.45 mgkg1 body weight alkaloid caffeine, caffei#

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1293 Fig. 1. Glucose infusion rate during a hyperinsulinemic-euglycemic (2 mUkg1min1) 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) between 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 decaffeinated coffee, but not caffeinated coffee, mitigates the effects of high-fat food on insulin sensitivity.

nated coffee in a volume equivalent to the alkaloid caffeine, decaffeinated coffee of same volume as the caffeinated coffee, or placebo to human subjects 1 h prior to an oral glucose tolerance test. Results demonstrated that caffeine elevates blood glucose ~160%, compared with caffeinated coffee, and ~320%, compared with decaffeinated coffee. Insulin was also significantly higher with alkaloid caffeine than with either placebo or decaffeinated coffee, but not caffeinated 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 effects of caffeine through adenosine receptors (de Paulis et al. 2002; Farah et al. 2005). One attractive hypothesis explaining the dichotomy between epidemiological and laboratory studies on coffee and (or) caffeine is that an individual will habituate to the detrimental effects of coffee with prolonged consumption. To test this, Dekker and colleagues (2007) administered caffeine (5 mgkg1) 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 catecholamine levels were reduced, but insulin resistance and glucose responsiveness were not. Given this, it is clear that while habituation may occur to some of caffeines physiological 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 effects 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 involves weight management and body composition. Individuals 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 doseresponsive and due solely to caffeine, not coffee components (Horst et al. 1936). To date, there is little evidence that coffee consumption promotes significant weight loss or causes alterations in body composition. Again, this appears to be due to habituation to caffeine-induced catecholamine responses 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 mgday1 caffeine. In this double-blind study, they demonstrated no difference between 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 individuals 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 effectiveness of this supplement, participants ingested either placebo or 2 Svetol capsulesday1 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 servingsday1) in overweight adults over 12 weeks resulted in a weight loss of 5.4 0.6 kg, compared with controls. Body composition analysis of study participants showed a significant body fat loss of 3.6 0.3% during this
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Appl. Physiol. Nutr. Metab. Vol. 33, 2008 Table 2. Antioxidant intake. Dietary component Coffee Fruits, berries Tea Wine Cereals Fruit juice Vegetables % of total Norwegian antioxidant intake (entire diet)* 64 11 8 5 5 2 2 % of total Spanish antioxidant intake (beverages only){ 61 n.d. 5 22 n.d. 5 n.d.

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 production, oxidative stress occurs (Penckofer et al. 2002). Oxidative stress is implicated in the development and pathogenesis of numerous conditions, including diabetes, neurodegeneration, 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 vegetable consumption to fight disease, only 13% of antioxidants are consumed from these foods (Svilaas et al. 2004). Analyses 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 antioxidants 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). Casein, a milk protein, has been shown to interact with polyphenols. Adding milk to coffee, as is commonly practiced by coffee consumers, does not significantly alter its antioxidant capacity (Dupas et al. 2006; Richelle et al. 2001). Fujioka and Shibamoto (2006) identified 9 CGAs in coffee 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 ingestion 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 colonic microorganisms. This group also found that 33% of CGAs are absorbed in human subjects without a colon, indicating 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 contains 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. Altering gut microflora may have long-term health implications,

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).

helping to aid digestion, moderate immune responsiveness, and prevent obesity (Cani et al. 2007a, 2007b, 2007c). Several 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 commonly found in the gut, demonstrated that coffee has significant antibacterial activities in vitro (Almeida et al. 2006). Almeida and colleagues (2006) concluded that several of coffees 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). Periodontal disease is also associated with reduced insulin sensitivity, and may play a role in the development of T2D (Mealey and Oates 2006; Pontes Andersen et al. 2007). Conversely, people with diabetes have an increased risk of developing 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 progression 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 1 mmolL1 CGA, ferulic acid, and caffeic acid, respectively. Rats given a CGA dose daily for 3 weeks also showed significantly lower fasting plasma levels of cholesterol and triacylglycerides (Rodriguez de Sotillo and Hadley
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1295 Fig. 2. Blood glucose concentrations of rats after a meal tolerance test with or without chlorogenic acid (CGA) (120 mgkg1; 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 inhibiting intestinal glucose absorption or reducing liver glucose production following a meal.

2002). In humans, the addition of CGAs to regular coffee prior to an oral glucose tolerance test resulted in a 7% decline 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 mgkg1) 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 hormone 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 glucosedependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1) are released in response to nutrient ingestion, and are responsible for 50%70% of insulin responsiveness (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 secreted (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 intestine, 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 attenuated 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 concluded that the GIP-lowering effects of coffee must be attributable to components other than caffeine. In particular, they hypothesized that CGA reduces intestinal glucose absorption, 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 consumption 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 results in slight elevations in GLP-1 levels. Increased GLP-1 causes greater insulin sensitivity, owing to its antihyperglycemic 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 complications 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 addition, 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,
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1296 Fig. 3. Schematic of CGA actions on the liver and gut. CGA is a potent antioxidant and inhibitor of hepatic glucose-6-phosphate translocase (G-6-Pase), the enzyme that catalyzes the terminal reaction of glycogenolysis and gluconeogenesis. Specifically, CGA and its derived compounds inhibit the transporting component (T1), resulting in concentration-dependent declines in net hepatic glucose output in vitro. In addition, CGA is known to alter incretin secretion and glucose absorption in the gut. GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; T2D, type 2 diabetes.

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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 relationship is dose-responsive and, at the highest levels of consumption (>5 cupsday1), reduces disease incidence by ~50%. Because of the wide variation in caffeine content of commercially available coffee and differing individual responses, coffee drinkers may benefit from switching to decaffeinated coffee. Given that T2D is reaching epidemic proportions in populations worldwide, the mechanisms by which coffee exerts its beneficial effects are worth exploring. In this review, both epidemiological and laboratorybased 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 consume decaffeinated coffee. By understanding coffees effects, 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 Association. Grant support is provided by the Canadian Institutes for Health Research and Genome Canada. Advice and editing of the manuscript by Dr. Raylene Reimer (University of Calgary) was greatly appreciated. 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 impact 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). Specific 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 sensitivity 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 predominantly 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.

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