Review pubs.acs.org/JAFC
Diabetes and Chocolate: Friend of Foe? Duane D. Mellor* School of Biosciences, University of Nottingham, Loughborough, United Kingdom
Thozhukat Sathyapalan Hull York Medical School, Hull, United Kingdom
Eric S. Kilpatrick Hull and East Yorkshire Hospitals NHS Trust, Hull, United Kingdom
Stephen L. Atkin Weill Cornell Medical College Qatar, Doha, Qatar ABSTRACT: Polyphenols and other compounds found in cocoa and chocolate have therapeutic potential in the management of diabetes in humans. Polyphenol benefits have been proposed supported by in vitro studies, animal work, and clinical trials, which have been conducted mostly in healthy volunteers. The energy-dense formulations of many cocoa and chocolate products, which can be up to 50% sugar by weight, have given the perception that chocolate may be harmful through its contribution to obesity. A review of both clinical trial databases and published literature yielded 15 registered trials and 7 published studies. The published data interventions reported are diverse and vary widely in quality, including poor selection of control products or inadequate blinding procedures. There are also inconsistencies in reporting of data with limited information on the effect of cocoa and chocolate supplementation on weight and glycemic control despite the potential benefits reported with respect to the cardiovascular risk factors of endothelial function and lipids. More studies are required powered for primary clinical outcomes together with the development of standardized product formulations that optimize the dose of polyphenols within a palatable and energy-restricted product. KEYWORDS: cocoa, diabetes, polyphenols, endothelial function, cardiovascular risk
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studies, have culminated with a series of meta-analyses.3−8 These reviews have consistently supported the theory that cocoa and chocolate have beneficial effects upon blood pressure, lipid profile, and endothelial function, but less consistently with respect to insulin resistance. However, the beneficial effects of chocolate and cocoa in individuals with diabetes have largely been postulated following studies in healthy volunteers; to date, very few studies have been undertaken in people with diabetes.9−13 This paper aims to review our group’s data from human clinical trials of people with type 2 diabetes in the context of the mechanistic potential of cocoa and chocolate to be beneficial,2 including the methodological challenges in interpreting in vitro work through to formulation of cocoa and chocolate products
INTRODUCTION The concept of chocolate having potential therapeutic benefits for people with diabetes mellitus, especially type 2 diabetes mellitus, presents a number of intellectual challenges, from both clinical and sociological perspectives. It seems almost counterintuitive to suggest an energy-dense food that is high in sugar, and often seen as a treat or a “dietary sin”, could offer such promise. However, a large volume of mechanistic and animal model studies has been undertaken demonstrating the potential benefits of cocoa and chocolate for both glucose regulation and modification of complications associated with diabetes. Cesar Fraga in the American Journal of Clinical Nutrition first proposed the potential of chocolate for people with diabetes in 2005. It was suggested that we should consume more cocoa and chocolate to reduce the burdens of hypertension and diabetes.1 Grassi and colleagues2 further reinforced this potential for its antihypertensive and insulin-sensitizing effect with the mechanistic data. However, the hypothesis of chocolate having a beneficial effect remains counterintuitive to the average consumer and has yet to gain support among the wider medical and healthcare community. Data from clinical trials have been accumulating over the past decade, which along with a significant body of epidemiological © XXXX American Chemical Society
Special Issue: ISCHOM 1st International Congress on Chocolate and Cocoa in Medicine Received: February 10, 2015 Revised: March 12, 2015 Accepted: March 16, 2015
A
DOI: 10.1021/acs.jafc.5b00776 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
Review
Journal of Agricultural and Food Chemistry
endogenous hepatic glucose synthesis. Insulin resistance with insulin deficiency and obesity leads to raised fasting glucose and the futile metabolite cycling that typifies type 2 diabetes and metabolic syndrome.22 When considering cocoa, it is important to reflect that it is a rare example of a plant-derived source of saturated fatty acids and is consequently suggested as being undesirable from a dietary perspective with an impact on raising serum cholesterol levels leading to increase cardiovascular disease risk. This view has been challenged recently, with questioning of the fat−heart hypothesis that it is rather the type of fat or macronutrient that replaces saturated fat in the diet being more important than simply promoting a reduction in saturated fat intake.23−25 Although there are subtle changes with respect to the views regarding the fatty acid composition of chocolate, the issues around its energy density and sugar content remain. Furthermore, there is evidence emerging that a combination of saturated fatty acids together with sugar may increase levels of hepatic fat,26 which is seen as an early risk factor for diabetes and cardiovascular disease.
that could be compatible with medical nutritional therapy guidelines for people with diabetes.
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THE GLOBAL BURDEN OF DIABETES Diabetes mellitus is the first noncommunicable disease to obtain a United Nations (UN) resolution to grant its own global day, akin to communicable diseases including HIV/AIDS (UN Resolution 61/225).14,15 This was in response to the increasing epidemic of diabetes globally. According to the latest International Diabetes Federation (IDF) Diabetes Atlas,16 diabetes was responsible for 5.1 million deaths worldwide in 2013, or one death every 6 s. Approximately half of these deaths were due to cardiovascular disease, which represents the most common complication of diabetes. This has led to the view that diabetes could lead to a failure to achieve the Millennium Development goals, and that could lead to global failure in public health.15 Therefore, from a public health perspective, type 2 diabetes can be seen as the first global noninfectious pandemic.17 With obesity and lifestyle being seen as major contributory factors to its causality, it is critical that those responsible for the food supply, both manufacturers and developers of new products, are tasked with producing products that moderate rather than add to this disease burden. The primary focus of the management of type 2 diabetes focuses on attempting to normalize glycemia and modify cardiovascular risk factors, typically blood pressure and serum lipids (cholesterol and triglycerides). The predominant method of achieving these reductions has been via a combination of dietary and other lifestyle interventions along with pharmacological therapy. Expert groups undertaking reviews of evidence to formulate dietary guidelines for the nutritional management of type 2 diabetes are generally in agreement in that, although sugar does not need to be eliminated completely from the diet, target levels similar to those recommended by the general population are prudent.18 This suggests that a maximum of 5% of total energy should be derived from “free” or “added” sugar for the populations, with no individuals exceeding 10% of total energy intake from “free sugar”, which is in line with the 10% maximum of total energy from nonmilk extrinsic guidelines that have been in place in the United Kingdom for over 20 years.19 In the United States, although sugar consumption has not been associated with a negative effect in diabetes, Evert and colleagues20 recommended minimizing consumption of sucrose to avoid displacement of nutrient-dense foods in the diet. The primary focus for the management of type 2 diabetes currently is weight management, as 80% of cases are associated with excess body weight, primarily fat. Both Diabetes UK in Europe21 and the American Diabetes Association in the United States20 suggest energy restriction as part of a healthy meal pattern can result in modest weight reduction, which can reduce dysglycemia and other markers of cardiovascular risk and therefore should be the nutritional treatment strategy of choice. Although the consensus guidelines do not recommend absolute abstinence from added sugar based upon the scientific evidence, the public and many clinicians infer that as diabetes is a condition of hyperglycemia and “high blood sugar” (glucose), it is dietary carbohydrate and especially sugars that are responsible for the condition and therefore need to be avoided. This overlooks the underpinning complex pathophysiology of type 2 diabetes, which includes insulin resistance and a relative insulin deficiency, with dietary carbohydrates including sugar contributing to the resultant hyperglycemia exacerbated by
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CLINICAL PERCEPTION OF COCOA AND CHOCOLATE AS PART OF DIABETES MANAGEMENT The clinical perception of the nutritional and metabolic effects of sugar in diabetes has been influenced by the work of Peters and colleagues27 who suggested that an isocalorific substitution of chocolate cake for potato had no effect on glycemia in individuals with type 1 diabetes who are insulin dependent. This led to a trend within clinical practice, which appears to be based on the unsubstantiated extrapolation of this single study and lacking clear experimental evidence or mechanism as its basis. When one attempts to apply it to individuals with type 2 diabetes, it ignores the fundamental differences between the underpinning pathologies of type 1 and type 2 diabetes mellitus. Whereas type 1 diabetes is typified by its absolute deficiency of insulin, type 2 diabetes is an insulin-resistant state with increased counter-regulation (excess glucagon) leading to increased de novo gluconeogenesis.28 This has resulted in a generation of people with type 2 diabetes being advised to eat chocolate only following a meal to reduce any deleterious effects due to the sugar content. This ignores the principle that total carbohydrate load and glycemic index of the foods consumed are more influential than the type of carbohydrate, be it sugar or starch.29 The overall consensus from nutrition therapy guidelines for the management of diabetes suggests that foods based on cocoa and chocolate are unlikely to form a key component of their recommended dietary intake. The challenge of incorporating chocolate as a regular component of the diet is due to its high energy density (at around 4.5 kcal/19 kJ per gram) and high levels of “free” or added sugars (up to 40−50% of chocolate can be sugar) and saturated fatty acids (up to 20% by weight). Sugar is used in cocoa and chocolate products to moderate the bitter flavors of the polyphenols including flavanols, which have been proposed to be the key active component responsible for the associated health benefits. The sugar and fat contents with low water composition are responsible for its high energy density. The saturated fatty acids, which are largely from the cocoa butter, have been historically linked to dyslipidemia and cardiovascular risk but are desirable in chocolate as they are responsible for the mouthfeel and melting qualities associated with these products. The bitterness of the B
DOI: 10.1021/acs.jafc.5b00776 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
USA/ClinicalTrials.gov
UK/ISRCTN
NCT00825695/Jan 2009
ISRCTN25655161/ Sept 2009 ISRCTN35988358/ Sept 2009 NCT01064583/Oct 2009
UK/ClinicalTrials.gov
UK/ClinicalTrials.gov
USA/ClinicalTrials.gov
NCT01654172/July 2012
NCT01671514/July 2012
C
Brazil/ClinicalTrials.gov
UK/ClinicalTrials.gov
USA/ClinicalTrials.gov
Iran/IRCT
NCT01130727/Oct 2012
NCT01754662/Dec 2012
NCT01886989/June 2013
IRCT2014010716123N1/ June 2014
Iran/IRCT
IRCT138812222602N3/ March 2010 IRCT201101265697N1/ May 2011 NCT01617603/June 2012
Iran/IRCT
Germany/ClinicalTrials.gov
UK/ISRCTN
152/double-blind parallel/ cardiovascular risk 60/double-blind parallel/transcranial Doppler 20/double-blind crossover/lipid profile 12/double-blind crossover/endothelial function 62/double-blind paralle/pain-free walking 70/double-blind parallel/lipid markers and glycemia 100/double-blind parallel/ malondialdehyde 60/double-blind three-arm parallel/ insulin resistance 18/double-blind crossover/MRI brain blood flow 60/double-blind parallel/exercise capacity, muscle metabolism 51/double-blind parallel/endothelial function (FMD) 84/double-blind four-arm parallel/ insulin resistance and lipids 25/single-blind crossover/blood pressure 30/single-blind parallel/glucose, lipids, CRP, HbA1c
UK/ClinicalTrials.gov
sample size/design/primary outcome 120/parallel/blood pressure
country/register
Australia/ANZCTR
ACTRN12607000239460/ May 2007 NCT00677599/May 2008
main ID/date registered
chocolate
cocoa extract or green tea extract soy protein with cocoa and soy polyphenols cocoa beverage
chocolate
cocoa
chocolate
cocoa beverage in milk
chocolate
chocolate prior to oral glucose load cocoa beverage
chocolate
pending start
not completed
completed, not published
completed, not published
study ongoing
completed, not published
completed, not published
published: Parsaeyan et al. (2014) DOI: 10.1186/2251-6581-13-30
published: Haghighat et al. (2013) Iranian J. Nutr. Sci. Food Technol. 8 (2), 21−30
completed, not published
published: Mellor et al. (2013) DOI: 10.1111/dme.12030
published: Mellor et al. (2010) DOI 10.1111/j.1464-5491.2010.03108.x
published: Curtis et al. (2012) DOI: 10.2337/dc11-1443; Curtis et al. (2013) DOI: 10.3945/ajcn.112.043745 completed, not published
chocolate with cocoa flavanols and soy isoflavones cocoa
status as of Sept 14, 2014 completed, not published; data considered for Cochrane Review when unpublished
flavanol-rich drink
intervention
Table 1. Summary of Registered Randomized Controlled Trials Using either Cocoa or Chocolate as Their Intervention and Having Participants Defined by Having Been Diagnosed with Diabetes
Journal of Agricultural and Food Chemistry Review
DOI: 10.1021/acs.jafc.5b00776 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
D
12
69
93
93 (35 pulse wave velocity)
Haghighat et al.43
Curtis et al.11
Curtis et al.12
41
Balzer et al.10 (efficacy study)
Mellor et al.13
10
Balzer et al.10 (feasibility study)
100
10
Mellor et al.14
Parsaeyan et al.42
no. of subjects
author and year
cocoa drink made with water 3 × 250 mL drinks per day containing total of 963 mg (treatment) or 75 mg (control) flavanols
21 in treatment and 20 in control glycemia, lipids, blood pressure, FMD, and plasma flavanols
12 months 47 in treatment and 46 in control for PWV 18 treatment and 17 control blood pressure, arterial pressure, augmentation index, PWV
12 months 47 in treatment and 46 in control insulin resistance, glycemic control, lipids and 10 year CVD risk
8 weeks 32 in treatment and 28 control lipids and CRP
8 weeks (4 week washout) lipids, insulin resistance, blood pressure, glycemia, weight
6 weeks (2 weeks for control group) 50 in each group lipids, malondialdehyde, and inflammatory markers
appearance matched chocolate 27 g of chocolate bar with or without 850 mg of flavan-3-ols and 100 mg of isoflavones
appearance matched chocolate 27 g of chocolate bar with or without 850 mg of flavan-3-ols and 100 mg of isoflavones
unmatched chocolate 25 g of chocolate containing 450 mg of polyphenol or similar amount of white chocolate
appearance matched chocolate 3 × 15 g chocolate each providing 16.6 mg of epicatechin (treatment) or
