Accepted Manuscript Effects of Coffee on Type 2 Diabetes Mellitus Muhammad Sajid Hamid Akash, Kanwal Rehman, Shuqing Chen PII:

S0899-9007(13)00548-0

DOI:

10.1016/j.nut.2013.11.020

Reference:

NUT 9173

To appear in:

Nutrition

Received Date: 15 September 2013 Revised Date:

5 November 2013

Accepted Date: 8 November 2013

Please cite this article as: Hamid Akash MS, Rehman K, Chen S, Effects of Coffee on Type 2 Diabetes Mellitus, Nutrition (2014), doi: 10.1016/j.nut.2013.11.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Effects of Coffee on Type 2 Diabetes Mellitus Muhammad Sajid Hamid Akash1,2, Kanwal Rehman1, Shuqing Chen1,* 1

Institute

of

Pharmacology,

Toxicology

and

Biochemical

Pharmaceutics,

College

College of Pharmacy, Government College University Faisalabad, Faisalabad, 38000, Pakistan.

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*Address for Correspondence

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Running Title: Coffee and T2DM

Muhammad Sajid Hamid Akash

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Email: [email protected]

Shuqing Chen Email: [email protected]

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Pharmaceutical Sciences, Zhejiang University Hangzhou, 310058, China.

of

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Abstract This article provides the epidemiological and research evidences documenting the effects of coffee consumption on type 2 diabetes mellitus (T2DM). We have focused on to summarize the literature on the effects of coffee consumption on different mechanistic factors involving in pathogenesis of

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T2DM such as glucose tolerance, insulin sensitivity, insulin resistance, glucose-6-phosphatase, intestinal glucose absorption, antioxidant activity, inflammatory biomarkers, NF-κB inhibition, glucose uptake, glucose homeostasis, glucose metabolism, and insulin secretion. These factors play their crucial role to influence the normal levels of glucose in blood. Overall, the experimental and

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epidemiological evidences presented over here elucidate the protective effects of coffee consumption in T2DM indicating the possible multiple preventive mechanisms for T2DM. Despite

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of the firm evidences available via growing literature, it is still uncertain that whether the use of coffee should be recommended to the diabetic patients as a supplementary therapy for the prevention of T2DM or not.

Keywords: Coffee Consumption; Diabetes Mellitus; Glucose Homeostasis; Inflammatory

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Biomarkers; Insulin Sensitivity; Chlorogenic Acid.

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Introduction Coffee is among the most widely used beverages worldwide. Coffee contains several substances that may affect glucose uptake and metabolism. Coffee is obtained from the tea leaves, guarana and cola plant seeds [1]. Other sources of coffee are black tea, green tea, white tea and herbal teas.

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Numerous epidemiological, clinical and/or experimental researches have been conducted on coffee to investigate its effects on cardiovascular diseases [2,3], cancers [4], cholelithiasis [5], neurological disorders [6], endocrine disorders [7-9], kidney stones [10] and T2DM [11-13].

Diabetes mellitus is an auto-inflammatory syndrome which is a collection of many disorders

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such as hyperglycemia, dyslipidemia, insulin resistance, impaired β-cell functioning and insulin secretion [14-17]. It is considered among major life threatening diseases worldwide particularly in

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developing countries. There are various ways to treat T2DM such as medication, life style modification and dietary supplementation. Traditional anti-diabetic agents may cause some potential hazardous effects [14,18] however, there are some naturally occurring anti-inflammatory agents that may have anti-diabetic effects against T2DM [19-22] but these anti-inflammatory agents have some limitations due to short biological half-life [14,22-24]. Dietary supplements are one of the best choices that are known to have nature gifted anti-diabetic properties against T2DM [25-29].

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The purpose of our present article is to explore and summarize the current scientific literature on the potential effects of coffee consumption on T2DM. PubMed, Medline, ScienceDirect and/or Scopus were searched using the following keywords; coffee, caffeine, diabetes mellitus, insulin sensitivity, glucose-6-phosphatase, inflammatory biomarkers, glucose metabolism,

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chlorogenic acid and glucose absorption. General Properties of Coffee

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Coffee is a mixture of many chemicals such as carbohydrates, lipids, vitamins, nitrogenous compounds, isoflavonoids, micronutrients etc. The major components of coffee are caffeine, cafestol and kahweol, chlorogenic acid (CGA) and micronutrients [30]. Caffeine is rapidly absorbed from gastrointestinal tract and distributes rapidly [31] in all tissues including brain. Pharmacologically, caffeine exhibits its antagonistic effects via A1 and A2A subtype adenosine receptors [32] in which are responsible for stimulatory effects. Coffee exhibits its beneficial effects in both withdrawn and/or non-consumers by improving mood, cognitive performance and endurance during prolonged, exhaustive exercise [33,34]. It is used as an ergogenic aid in sports and is also useful for competitive and recreational athletes who 3|Page

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perform resistance training. Athletic performance has also shown to improve significantly with consumption of coffee [35,36]. Coffee is also associated with increased subjective alertness, improved reaction time for both visual and auditory stimuli and improved performance of manual task such as driving and encoding of new information [37]. Several components of coffee may

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ameliorate the symptoms of T2DM by affecting glucose regulation, such as CGA on glucose-6phosphatase, antioxidant activity of poly phenols on α-glucosidase and caffeine on insulin secretion [38].

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Epidemiological Studies of Coffee Consumption on T2DM

Various epidemiological studies have been conducted to investigate the hypoglycemic effects of coffee against T2DM. The first study was conducted to investigate the effects of coffee

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consumption on T2DM [39] and found that the increase consumption of coffee reduced the plasma levels of glucose. Afterward, this investigation was confirmed by another study that was conducted on Japanese population [40]. To date, many meta-analysis and prospective studies have proven that regular intake of coffee may reduce the risk of T2DM [14,38,41-44]. Many epidemiological studies related to coffee consumption have been conducted in different regions of the world in different ethnic groups including European [14,38,45-50], American [51-56] and Asian peoples [57-61]. In

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all studies except few [45,48,57], it has been concluded that there is an inverse association between the coffee consumption and risk of T2DM. On the basis of these epidemiological studies, it had been found that consumption of high doses of coffee for long term may reduce the risk of T2DM more significantly as compared to that of acute consumption of coffee with low doses [62,63]. On

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the basis of these findings, another study was also conducted to differentiate the significant effects between coffee and caffeine [53]. In this study, it was found that the protective effects did not

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depend on caffeine intake and the association was stronger with decaffeinated coffee as compared to that of regular coffee. The hypoglycemic effects were because of presence of several other components inside the coffee along with caffeine. Effects of Coffee Consumption on Risk Factors of T2DM It has been obvious that T2DM is the collection of various risk factors that collectively provoke the progression of T2DM [14,16,17,64]. From various studies; it has been found that coffee consumption reduces the risk of T2DM by directly affecting those risk factors as discussed in upcoming sections. 4|Page

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Effects of Coffee Consumption on Impaired Glucose Tolerance and Insulin Sensitivity Impaired glucose tolerance (IGT) is a condition of hyperglycemia in which resistance to insulin sensitivity is increased within peripheral tissues in response to glucose [19,20]. Several studies have been conducted to investigate the effects of acute and long term administration of coffee and/or

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caffeine on glucose tolerance. In some studies, it was found that glucose tolerance was impaired after acute ingestion of coffee [34] and/or caffeine [65-66] but in several studies, it has been found that coffee has ability to increase glucose tolerance [34,67-71]. Acute administration of coffee may impair the insulin resistance and glucose tolerance by blocking the effects of adenosine A1 receptor

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relating glucose uptake in skeletal muscles [45] but from the results of several epidemiological studies, long term and habitual use of coffee may help maintain normal glucose tolerance and

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improve insulin sensitivity [53,67-71].

The decreased insulin sensitivity in response to acute doses of coffee [72-74] is because of caffeine-induced antagonism of adenosine receptor with increased epinephrine levels [12]. On contrary, in several epidemiological studies, it has been found that the long term administration of coffee prevents the symptoms of diabetes and improves insulin sensitivity [13,38,40,42,43,47,75]. The acute effects of coffee may suppress the insulin sensitivity whereas; regular habituation of

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coffee consumption can induce glucose tolerance and insulin sensitivity [69, 76-79]. By habitual consumption of caffeine within a complex mixture such as coffee, the negative effect of caffeine can be modified as positive on insulin sensitivity and glucose tolerance (Figure 1). Effect of Coffee Consumption on Inflammatory Biomarkers of T2DM

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Since T2DM is correlated with and influenced by the activation of various pro-inflammatory cytokines and chemokines [14,16,17], suppression of these pro-inflammatory markers with suitable

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agent having anti-inflammatory properties may stop the overall inflammation in T2DM [14,16,19, 20]. Coffee contains a complex mixture of components other than caffeine such as CGA, cafestol, trigonelline, and kahweol. These components have strong anti-inflammatory properties. The components of the coffee that are usually absorbed after intake have varying impacts on different pro-inflammatory and anti-inflammatory biomarkers of T2DM (Table 1). Various studies that have been conducted on human and different animals proved that habitual consumption of coffee may significantly reduce the levels of pro-inflammatory biomarkers such as IL-1β, IL-6, TNF-α, CRP, MCP-1, VCAM-1, C-peptides, ELAM-1 and IL-18 [69,80-89]. Similarly, in some other studies, regular intake of coffee significantly increased the levels of various anti-inflammatory 5|Page

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biomarkers such as adiponectin, IL-4 and IL-10 [82,87,90]. Habitual intake of coffee assertively blocks the activation of these pro-inflammatory markers, while the levels of anti-inflammatory markers are significantly increased that validate the protective effects of coffee consumption in

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T2DM (Figure 2). Effects of coffee Consumption on Pro-inflammatory Cellular Signaling Pathways

In T2DM, glucolipotoxicity induces inflammation via activation of pro-inflammatory signaling pathways such as nuclear factor kappa B (NF-κB) that stimulate various pro-inflammatory

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biomarkers and once these biomarkers are activated, they induce tissue specific inflammation [16,17,57,91]. Previously, it has been found that CGA has a potential to significantly inhibit the activation of NF-κB in cultured cells [92-94]. The inhibitory effects of CGA in coffee were also

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investigated on TNF-α-induced activation of NF-κB in C2C12 cells that were transfected with a NF-κB luciferase reporter gene [78,95]. CGA in coffee significantly inhibits the activation of NFκB in dose-dependent manner as compared to other components of the coffee. Keeping in view the role of pro-inflammatory biomarkers in T2DM, CGA in coffee may have significant potential to stop the activation of various pro-inflammatory biomarkers via inhibition of NF-κB (Figure 2).

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Effects of Coffee Consumption on Inhibition of Hepatic Glucose Production Glucose-6-phosphatase that is mainly located in the liver regulates the levels of glucose in blood by hydrolyzing glucose-6-phosphate in to glucose and phosphate. Abnormal levels of this enzyme may augment the plasma levels of glucose via increased production of hepatic glucose [96]. CGA, the

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phenolic compound present in coffee [97] rapidly absorbs in intestine [98,99] comparatively more efficiently as compared to that of caffeine [100]. CGA has shown to be a potent inhibitor of glucose-6-phosphatase [101,102]. It significantly reduces the levels of plasma glucose [103,104]

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and hepatic glucose production [101,102,105,106]. Being the second abundant component of the coffee after caffeine, the inhibitory effect of CGA on glucose-6-phosphatase may significantly prevent the production of hepatic glucose and ultimately can reduce the harmful symptoms of hyperglycemia.

Effects of coffee Consumption on Glucose Uptake Impairment of glucose uptake in peripheral tissues increases the plasma level of glucose that ultimately leads to the hyperglycemia [107,108]. Normally, glucose transporter 4 (GLUT4) regulates the glucose uptake in peripheral tissues by transferring glucose to cell via binding to 6|Page

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insulin signaling [109]. Coffee being a main source of phenolic compounds [110] has shown in previous studies that phenolic compounds can significantly stimulate insulin-mediated uptake of glucose via activation of GLUT4 and/or insulin receptor [111-113]. It has also been found that caffeine alone does not stimulate glucose uptake [95,114] suggesting that coffee components other

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than caffeine may confer the stimulation of insulin-mediated glucose uptake [46,67,95,115] in peripheral tissue and regulate the level of plasma glucose. On contrarily, in some other studies, it has also been investigated that caffeine may also stimulate glucose uptake via activation of AMP-

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activation of protein kinase [116-118]. Effects of Coffee Consumption on Intestinal Glucose Absorption

Gastrointestinal peptides such as gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1

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(GLP-1) are the hormones that are secreted in response to glucose absorption [119,120] and are also known for decreasing glucose absorption [121]. Intake of coffee modulates GIP and GLP-1 that are secreted in response to glucose absorption and decreases the absorption of glucose in small intestine [78,121] by shifting the absorption of glucose in distal region of the gastrointestinal tract [87] (Figure 1).

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Effects of Coffee Consumption on Glucose Metabolism

Caffeine is the main component of coffee. Its acute administration impairs glucose metabolism and insulin sensitivity [11,12,66,114,122] which is mediated by increased plasma concentration of epinephrine [12,72]. CGA which is the second abundant component of coffee regulates the glucose

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metabolism in diabetic patients [123]. These phenolic compounds present in coffee antagonizes the negative effects of caffeine on glucose metabolism by increasing insulin sensitivity in peripheral tissues [68,77,100,124], reducing insulin resistance [47,125] and fasting plasma glucose level

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[93,94,126], inhibiting glucose absorption in gut [78], preventing the action of α-glucosidase [127], GLUT4 [128] and glucose-6-phosphatase in liver that ultimately leads to the reduction of plasma glucose levels [46,48, 93,115,124,129]. It has been shown that iron also regulates the metabolism of glucose and is directly associated with T2DM [130]. Phenolic compounds present in coffee significantly inhibit the absorption of iron that ultimately results in protective effects of coffee consumption on glucose metabolism [131]. Effects of Coffee Consumption on Glucose Homeostasis

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Plasma level of glucose is maintained by the interaction of insulin- and non-insulin-dependent processes that together endeavor to regulate plasma glucose level within in the narrow range. This phenomenon is known as glucose homeostasis. In insulin-dependent process, glucose is transported across the cell membrane via protein that is known as glucose transporter whereas; insulin-

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independent process involves brain and nervous system for the transportation of glucose at its target site. Previously, experimental studies found that caffeine might cause acute alteration in glucose homeostasis [132,133] but CGA, the second most abundant component of coffee may antagonize the acute effects of caffeine on glucose homeostasis [77,78,113] by delaying glucose metabolism

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and hepatic mobilization of glucose, and increasing peripheral uptake of glucose [46,67,115] via inhibition of Na+-dependent glucose transporter [123] and glucose 6-phosphatase [101,105,106].

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Effects of Coffee Consumption on Hypomagnesemia in T2DM

Diet along with life style modification is believed to play an important role in the management of T2DM [134,135]. Magnesium is an important micronutrient of coffee (11mg/100g of dry coffee) and/or each cup of coffee contains 7 mg of magnesium [136,137]. Magnesium is an essential cofactor for multiple enzymes that are involved in the metabolism of glucose [138] and plays its role for the regulation of glucose homeostasis, improves insulin sensitivity and prevents T2DM

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[136,137,139-141]. T2DM develops hypomagnesemia [142] and deficiency of magnesium has been considered as biomarker for T2DM [143]. Animal studies confirmed that deficiency of magnesium may induce T2DM [144] and magnesium supplementation has beneficial impacts on glucose homeostasis and insulin action [145,146].

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Long term consumption of coffee significantly increased the serum levels of magnesium with reduced risk of T2DM [43,44,50,53,61,147]. Lin et al [61] also found that subjects without

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diabetes had greater serum levels of magnesium than subjects with diabetes. Magnesium is a component of coffee, and a higher magnesium intake from food can improve insulin sensitivity, glycemic control and reduce the risk of T2DM. Effects of coffee Consumption on Oxidative Stress Oxidative stress induced by chronic hyperglycemia and dyslipidemia plays an important role in the process that leads to the dysfunctioning of pancreatic β-cells followed by reduced production and secretion of insulin from β-cells of pancreatic islets [14,16,17,148,149]. Oxidative stress that is produced in T2DM can be prevented by long term intake of coffee as it contains powerful 8|Page

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antioxidants such as caffeine, CGAs, lignan, isoflavonoids and caffeic acid that antagonizes the harmful effects of oxidative stress in T2DM [150-155]. The antioxidant activity of long term intake of coffee has also been confirmed in several animal studies in which the serum levels of antioxidant

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activity was significantly increased with reduced risk of T2DM [153,156-158]. Effects of Caffeine on Insulin Secretion

In addition to exhibit its stimulatory effects on endocrine pancreas, caffeine has also shown to stimulate the secretion of insulin from β-cells of pancreatic islets by inhibiting the antagonistic

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effects of cAMP-phosphodiesterases on insulin secretion [159]. Ryanodine receptors regulate the intracellular calcium concentrations [160] and it has been known that caffeine acts as an agonist of ryanodine receptors in pancreatic β-cells and stimulate Ca2+-induced Ca2+ release which in turn

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mediate insulin secretion in the presence of glucose [161]. Caffeine may stimulate insulin secretion in a glucose-dose-dependent manner which has no effects at low glucose concentrations [161,162], this explains the mechanism of insulin release in response to postprandial glucose and has no effects on fasting plasma glucose concentrations [68].

Effects of Coffee Consumption on Weight Loss in T2DM

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In T2DM, weight gain is one of a major vulnerable risk factor associated with use of anti-diabetic agent as most of the anti-diabetic agents may cause weight gain during treatment of T2DM [17]. Therefore, it has been suggested from the diabetologist to adopt lifestyle modification and dietary supplementation for diabetic patients. Previous studies confirmed that coffee consumption induces

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significant weight loss in rodent models [163-165] and this effect of coffee has also been found to be significant in epidemiological studies [81,166,167].

Coffee causes weight loss in diabetic

patients by increasing thermogenesis [168,169], lipid metabolism [163-165,169-171] and/or

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lipolysis [12,73,171,172]. It has also been verified that consumption of coffee induces the weight loss more significantly in non-obese-diabetic patients as compared to that of obese-diabetic patients [169,170,173,174].

Prevention and/or Treatment of DM with Coffee Consumption All studies that have been mentioned above indicate that long term intake of coffee may result in prevention of the risk factors involved in T2DM except few studies in which it had been noticed that acute intake of coffee might cause the impairment of glucose tolerance and insulin sensitivity [66,133,175]. Long term coffee consumption significantly prevented the insulin resistance [47] and 9|Page

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progression of diabetes was significantly reduced in patients with impaired glucose tolerance [71]. Experimental studies proved that moderate doses of acute caffeine intake helped diabetic patients to prevent and counteract the hyperglycemia [176,177].

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Probable Mechanisms Involve in Prevention of T2DM by Coffee Consumption From the results of several epidemiological and experimental studies conducted on animals, it has been evidenced that coffee consumption has potential to significantly reduce the risk of T2DM in which several possible mechanisms may be involved [31,178]. As coffee is mixture of various

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substances such as caffeine, CGA, isoflavonoids, magnesium etc; all of these might significantly be involved in preventing the harmful symptoms of T2DM via different mechanisms. In short, we may particularly say that these components of coffee are the main contributors for exerting their possible

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beneficial effects in different ways to reduce the risk of T2DM more significantly without inducing any kind of harmful effects on diabetic patients (Figure 2). Caffeine improves glucose tolerance, insulin sensitivity and insulin secretion from β-cells of pancreatic islets via activation of ryanodine receptors. Similarly, CGA antagonizes the effects of glucose-6-phosphatase, GIP and GPL-1. CGA also inhibits the absorption of glucose in small intestine, prevents hepatic production of glucose, and regulates glucose metabolism and homeostasis. Magnesium also contributes in the metabolism

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of glucose, regulation of glucose homeostasis and improves insulin sensitivity. Possible Harmful Effects of Coffee Consumption on Diabetic Patients Although, it has been confirmed from various epidemiological studies and researches that coffee

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consumption reduces the risks of T2DM but still one controversial issue is its harmful effects on diabetic patients. It has also been observed that coffee consumption during pregnancy is associated with modestly low birth weight and high risk of miscarriage [179]. Habitual consumption of coffee

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is directly related to acute myocardial infarction, high blood pressure, increased risk of coronary heart disease and diabetic complications [178,180-182]. Diabetes mellitus itself is a risk factor in heart disease and a J-shaped association is interlinked between coffee consumption and risk of developing acute coronary disease [183,184]. Therefore, it is very important to consider the possible harmful effects of coffee consumption during T2DM treatment in order to avoid any possible complication. Consideration for Future Research

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Before recommendations on coffee consumption for patients with established diabetes can be made, further research should be made to determine the effect of these additional non-caffeine constituents whilst additional studies should be conducted exploring specifically the effects of non-caffeine components present in coffee against T2DM. Additionally, the effect of adding milk or sugar to

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coffee, and the effect of concomitant consumption with a meal should also be studied. Future research will provide valuable insights into caffeine effects on T2DM. Epidemiological studies proved the beneficial effect of coffee on humans but there are still some complications that require more research. These future researches should consider the exact mechanism of actions for the

significantly for prevention and/or treatment of T2DM.

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Conclusion

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prevention of diabetes mellitus and which component of the coffee contributes its part more

To conclude, we have briefly summarized the literature focusing on the epidemiological studies conducted in different regions of the world and experimental studies conducted on animals relating effect of coffee consumption on T2DM. Coffee may directly affect different mechanistic factors that are involved in the pathogenesis of T2DM. From these epidemiological and experimental studies, we cannot certain that whether potential effect of coffee consumption in

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reducing the risk of T2DM is fundamental or not because one controversial issue is its possible harmful effects that have also been observed in few studies. Despite the evidences obtained from epidemiological and research studies, recommendations of coffee consumption for diabetic patients is thought to be indecisive, but studies have shown that coffee consumption does impart

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its significant effects to stop the pathogenesis of T2DM and should be considered as an alternate supplement along with other anti-diabetic agents.

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Conflict of Interest

Authors declare that they do not have any conflict of interest for this article. Acknowledgments

Authors are thankful to Chinese Government to provide scholarships for PhD studies to Kanwal Rehman and Muhammad Sajid Hamid Akash. One of the authors would like to acknowledge Higher Education Commission of Pakistan for the award of partial support for PhD studies abroad to Mr. Akash. One of the authors would also like to admire his wife Mrs. Akash for her motivation and support. Without her, the publication of this article would not have been possible. 11 | P a g e

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Figure 1. Acute and long-term effects of coffee on glucose tolerance and insulin sensitivity. Acute coffee consumption blocks the effects of adenosine A1 receptor decreasing glucose uptake in skeletal muscles which may result in insulin resistance and glucose tolerance. However, long term and habitual coffee consumption can modulate the secretions of gastrointestinal hormones that may result in maintaining normal glucose tolerance and improve insulin sensitivity. Figure 2. Probable mechanisms involve in prevention of T2DM by coffee consumption. The

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major cellular and molecular pathways involve in prevention of T2DM by coffee consumption.

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Table 1. Effect of coffee consumption on inflammatory biomarkers of T2DM.

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Sr.# Biomarkers Effect of coffee Consumption References Pro-inflammatory Biomarkers 1 IL-1β Decrease 85 2 IL-6 Decrease 86 3 TNF-α Decrease 80, 82, 86, 87 4 CRP Decrease 81-84, 89 5 MCP-1 Decrease 85, 86 6 VCAM-1 Decrease 84 7 C-peptides Decrease 77 8 ELAM-1 Decrease 81 9 IL-18 Decrease 88 Anti-inflammatory Biomarkers 1 Adiponectin Increase 82, 90 2 IL-4 Increase 87 3 IL-10 Increase 87 Abbreviations: IL-1β: Interleukin-1beta, IL-6: Intrerleukin-6, TNF-α: Tumor necrosis factoralpha, CRP: C-reactive protein, MCP-1: Monocyte chemotactic protein-1, VCAM-1: Vascular cell adhesion molecule-1, ELAM-1: Endothelial leukocyte adhesion molecule-1, IL-18: Interleukin-18, IL-4: Interleukin-4, IL-10: Interleukin-10.

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