The relationship chrononutrition (meals timing, frequency, and contents), exercise, circadian misalignment, gut microbiota, and type 2 diabetes mellitus

Table of contents:

Summary

Diabetes mellitus

The effects of exercise and diet

Circadian preference, and circadian misalignment effect on meals, body weight and type 2 diabetes mellitus

The effects electrical light on sleep, the circadian clock, melatonin, and depressive symptoms in type 2 diabetes

Lifestyle intervention programmes

Conclusion

Recommendations

Abbreviations

References

Book summary:

The current books highlights the importance of diet and exercise on diabetes mellitus, it also touched the effects of morningness-evenenigness on the development and glycemic control of diabetes. In addition, the book discussed the concept of chrononutrition (meal timing, contents, and composition), its impacts on diabetes, body weight, and psychiatric disorders including depression. A broader insight towards meal and exercise timing, relationship between daylight, psychiatric disorders, body weight, and diabetes. The book included a section regarding diabetes prevention programs.

Diabetes mellitus:

Diabetes mellitus is a global health burden; it is increasing alarmingly across all age groups. Worldwide 6% are affected by this morbid disease. Currently, 285 million are suffering from the disease and the projection for the year 2030 is 438 million. Diabetes mellitus is largely unseen disease, and with every diagnosed patient there is another person undiagnosed, so the number is doubled. The vascular complications of diabetes (macrovascular including myocardial infarction, stroke, and peripheral arterial disease and microvascular including nephropathy, neuropathy, and retinopathy) are the principal causes of morbidity and mortality (1-3). DM has a high mortality and morbidity, and the cost of its treatment creates a huge financial burden on the community. In spite of advanced therapies, many patients develop complications like myocardial infarction with lethal consequences and poor quality of life (4-6).

The plasma sugar is increasing at a continuum, and a person with plasma sugar ≥106mg/dl is at higher risk of macrovascular complications and those with prediabetes had 3-4 times the risk of myocardial infarction. The intermingling of lifestyles and genes are the major factors in the etiology of type 2 diabetes. Thus lifestyle management is crucial for the prevention and treatment of type 2 diabetes. Nutritional therapy is an integral component of type 2 diabetes management and every patient should receive an individualized nutritional therapy. Nutritional therapy had been shown to reduce the glycated hemoglobin by 0.5-2% (7).

Physical activity can significantly improve both the fasting and postprandial plasma sugar in patients with type 2 diabetes regardless of weight loss (8). Furthermore, walking and running have been shown to reduce all-cause mortality, cardiovascular disease mortality, sepsis, influenza, pneumonia, and chronic kidney disease mortality among patients with diabetes (9). The American Diabetes Association recommended 150 minutes/week moderate-intensity exercise plus flexibility and strength training (3).

Many studies including the United Kingdom Prospective Diabetes Study Group (UKPDS) showed that intensive blood glucose control in patients with type 2 diabetes reduce both the time free of complications and the cost of complications but significantly increase treatment cost (10).

Physical activity and a friendly diet are cost-effective for the prevention and management of type 2 diabetes. The lifestyles although crucial in the management are usually ignored. In this survey we thought to answer the following questions:

- The best time of exercise concerning meal timing.
- The effect of meal content, timing and skipping on plasma sugar
- The association of red meat with insulin resistance
- The various vegetarian types and their impact on patients in term of obesity and insulin resistance
- The beneficial effects of whole grain, fruits, and vegetables
- The short and long term effects of breakfast skipping in teenage, adolescence and young adults
- Risk factors for obesity/overweight
- The chronotype and circadian misalignment effects on meal pattern and plasma sugar.
- The growing role of the intestinal microbiota in the face of circadian misalignment
- The increasing awareness about the bacteriotherapy (fecal transplantation) in the field of diabetes mellitus
- The consequences of continuous artificial light exposure in chronotype and shifting work
- The association, between depression and late chronotype and the effects on glycemic control.
- The efficacy of a multicomponent diabetes prevention programme including depressive symptomalogy
- Diabetes prevention programe and barriers to its implementation

Chapter (1) : The effects of exercise and diet

The exercise timing to meals and its effects on fasting and postprandial plasma sugar:

Animal studies (11-13) concluded the beneficial effects of exercise on oxidative stress. The previous literature stated the usefulness of exercise on affect and psychological well-being (14) that can positively affect the diabetes control and self-management in addition to its favorable effects on plasma sugar and lipid profile. The studies agreed about the preference of exercise after meals and restricting high-fat diet to the inactive periods. One study pointed that eating in the morning and exercising in the evening is more beneficial. A recent crossover controlled trial showed that a continuous-single isoenergetic exerts its effect over the 24 hour period and two sessions of exercise pre and post lunch affects mainly the glycemic response to lunch (15). Thus individualized exercise may be used according to the sugar profile of the patient to target either fasting or pre-meal plasma sugar.

The Meals effect on plasma sugar and body weight:

- Meal timing:

The modern life with shifting work and long working hours had substantially changed the meal timing. Two randomized control trials stated that late meal eating especially close to sleep could lead to obesity due to more frequent eating and higher calorie intake. Furthermore, avoidance of large high glycemic index meals later in the evening could prevent type 2 diabetes mellitus and improve postprandial plasma sugar (16,17).

- Meal frequency:

Traditionally people eat three meals with snacks. The effects of meal frequency on body weight is controversial. A recent review stated that reduced meal frequency might show more favorable effects on lipid profile than frequent meals. Another study pointed that, frequent meal ingestion increases postprandial insulin responses. The study concluded that the substitution of carbohydrates with protein in a frequent meal pattern resulted in lower glycated hemoglobin and reduced postprandial insulin response. Care is needed in patients with diabetic nephropathy because a high protein diet may exacerbate it (18,19).A more recent trial found no difference between frequent and infrequent meals regarding glucose, insulin, and lipid metabolism (20).

- Meal content:

The most challenging part of diabetes mellitus is to follow a diet plan and determine what to eat. The diet should be individualized and preferred given by a dietician. No single diet that can fit every single diabetic patient. The Mediterranean Dietary Approaches to Stop Hypertension (DASH) rich in fruits, vegetables, dairy products, and plant-based diets are all examples of healthful eating patterns. A recent literature review concluded that partial replacement of rapidly available carbohydrate with proteins, cereal fibers, and grains at breakfast might be a useful strategy for producing favorable metabolic outcomes. A diet rich in polyunsaturated fatty acids including fish and nuts is highly recommended, while supplementation is of no benefit (3,21). A high glycemic readily available carbohydrate consumption leads to poor glycemic control, while whole grain diet has a potential to prevent diabetes, overweight, and cardiovascular disease. A plausible explanation could be the fermentation of indigestible fiber by the gut microbiota and hence the prevention of low-grade inflammation and endotoxinemia. A randomized cross-over trial (22) investigated the difference between Whole grain rye kernel test bread (RKB)and a white wheat flour based bread provided as late evening meals (as a single evening meal or as three consecutive evening meals) to healthy young adults. The study concluded that RKB based evening meal has an anti-diabetic potential. Furthermore, the improvements of appetite sensation and increased release of satiety hormones could be beneficial in obesity prevention. These effects could be mediated through colonic fermentation. A large longitudinal cohort (4243, 49.1% males) carried in Spain (23) stated that a higher energy intake at lunch is associated with a lower risk of weight gain, a recent cross-over trial (24) examined the carbohydrate and fat distribution throughout the day and concluded the harmful effects of a large carbohydrate-rich dinner especially among patients with impaired glucose tolerance.

Red meat and whole grain diets effects on inflammatory markers, and insulin sensitivity:

The Mediterranean diet rich in whole grain, dairy products is accepted as a friendly dietary approach, randomized cross-over trials are generally supportive.Kim et al. (25) investigated hypothesized that, a diet rich in red processed meat and refined grains The researchers concluded the same in term of . The levels were A previous trial published by Hosseinpour-Niazi (27) and colleagues investigated the substitution of legumes for red meat in a Therapeutic Lifestyle Change among patients with diabetes and concluded the beneficial effects of legume-based diet on lipid profile and glycemic control independent from body mass index changes. The beneficial effects of legume on inflammatory markers were further confirmed by a trial (28) comparing a non-soya based legume versus a legume free diet, the survey observed that Compared with the legume-free diet, the non-soya legume-based diet significantly decreased high-sensitivity C-reactive protein, interleukin-6 (IL-6), and tumor necrosis factor (TNF-α) in overweight diabetic patients. Furthermore, the researchers observed that, the replacement of two servings of red meat by non-soya legumes in the isoenergetic therapeutic life style low diet for a period of three days per week reduced the plasma concentrations of inflammatory markers among overweight diabetic patients, independent of weight change. Ziegler et al. (29) studied the autonomic nervous system (disturbed by diabetes mellitus) that controls both the cardiovascular system and energy balance. The team estimated the heart rate variability, and inflammatory markers during an insulin euglycemic clamp test in a two arms controlled trial (a diet high in cereal fiber, free of red meat, and high in coffee or a diet low in fiber, high in red meat, and coffee free), and showed no significant differences between the two groups.

Nowotny et al. (30) included coffee intake in their trial, and observed no significant difference between high cereals, low red meat, and high coffee intake diet compared to a diet low in cereals and coffee and high in red meat in term ofbody weight improvement, visceral fat mass, muscle fat content, and On the other hands Turners et al. (31) investigated a dairy product meal and a lean red meal based one and observed a sex difference. The dairy products meal decreased the insulin sensitivity as measures by The findings were not observed in men. The trial included 47 overweight and obese participants, some of them had prediabetes. The researchers attributed the contradicting findings to the low carbohydrate in the diet used.

Fruits and vegetables:

Fruits are rich in various specific substances including anti-inflammatory and antioxidants that improve endothelial function. Furthermore, fruit intake had been shown to reduce some malignancies and the risk of cardiovascular disease (32-34). Although Fiber-rich diet including fruits is recommended by most guidelines, some health professionals are concerned about the impact of fruits intake on body weight, waist circumference, and glycemic control. Few studies have investigated the consequence of high fruits intake on glycemic control with neutral results (35) or inverse relationship (36). The previous reviews were observational and not conducted on patients with diabetes. A randomized trial (37) with a period of 12 weeks follow-up found no association between poor glycemic control and advising at least two measures (a reasonable size piece) of fruit intake instead of a maximum of two supporting the previous observations. Tanaka et al. (38) published a study in Japan among patients with diabetes mellitus on energy-restricted low-fat diet and stated that: Increased fruit intake in ranges commonly consumed was associated with reduced incident diabetic retinopathy. Another randomized controlled trial (39) conducted in the same country found that achieving a well-balanced diet by the daily consumption of 70 grams of green vegetable, and a total intake of 200 grams or more of vegetable correlated with improved control of HbA1c and triglyceride levels in elderly type 2 diabetes patients. Many guidelines stated they are no upper limit of vegetables, but the recommendations are to restrict the daily intake of fruits to no more than 20% of total calorie due to the association with the metabolic syndrome (40) to which people with diabetes mellitus are more prone.

A guide to estimating your daily calorie:

- Weight reduction desired: Weightx20
- Weight reduction not desired: Weightx30
- A 100 grams piece of bread=9 tablespoon of rice =320 calorie, this complex sugar are advised to constitute from 50-55% of the daily calorie
- A large dish of vegetable=50 calorie, small 25 calorie
- A cup of skimmed milk 130 ml=50 calorie
- A moderate piece o small apple, orange, or mango=1/4 banana=3 dates=20 grapes = 1/2 grapefruits=1/4 medium melon=50 calorie
- A teaspoon of oil=50 calorie
- A tablespoon of honey=24 calorie

N.B: Sweets and Desserts have high calories

- 3 teaspoons = 1 tablespoon, 4 tablespoons = 1/4 cup, 5 tablespoons + 1 teaspoon = 1/3 cup , 8 tablespoons = 1/2 cup, 1 cup = 1/2 pint

The vegetarian diets effects on body weight and diabetes:

Vegetarian diets are not uniform across nations. In South Asians for example, in spite of the high level vegetarianisms, there is a high level of cardio-metabolic diseases compared to other region of the world. The vegetarians in this region more frequently eat dairy, legumes, vegetables, fruit, desserts, and fried foods than non-vegetarians, in other parts of the world like the United States and Canada the vegetarian diets usually contain less refined cereals, desserts, fried foods, fruit juice, and soft drinks in addition to more legumes, fruit, and whole grains than non-vegetarian food. The differences in healthfulness of the vegetarian diets consumed could explain the unexpected discordance in the diet and the highly prevalent cardio-metabolic diseases. The difference in the elements of food consumed and a more healthier vegetarian diet in the United States translates in a lower probability of central adiposity compared with South Asians. The vegetarianisms in both South Asia and United Stated had a lower body mass index than non-vegetarians (41). A relatively small cross-sectional study (42) conducted among Black individuals living in USA examined the association of vegetarian diets with diabetes, hypertension, and lipid profile. The survey showed a lower rate for hypertension, diabetes, high blood total cholesterol and high blood LDL-cholesterol among vegetarians, the survey further concluded that apart from central adiposity and body mass index, the peso-vegetarians were similar to non-vegetarians. A further larger study with two years follow-up (43) (participants, ,15200 men and 26,187 women,17.3% Blacks) conducted across the United States and Canada came to the following conclusions: Vegans, lacto ovo vegetarians, and semi-vegetarians) had a lower risk of diabetes than non-vegetarians. In non-Blacks vegan, lacto ovo and semi-vegetarian diets were protective against diabetes, while among Blacks semi-vegetarian was not protective. The incidence of type 2 diabetes was highest among non-vegans followed by pesco vegetarians, lacto ovo vegetarians and semi-vegetarians respectively. A larger observational study (n=156,317 adults aged 20-49 years who participated in India's third National Family Health Survey (2005-06) carried in India (44) investigated the Association between types of vegetarian diet (vegan, semi-vegetarian, lacto-ovo vegetarian, lacto-vegetarian, pesco-vegetarian, and non-vegetarian). After controlling for for age, sex, rural/urban residence, religion, the level of education, household wealth, caste, television watching smoking, and alcohol, the study concluded that Mean BMI was highest in lacto-ovo vegetarian and lowest in vegans and pesco-vegetarians, furthermore the consumption of a lacto-, lacto-ovo and semi-vegetarian diet was associated with a lower likelihood of diabetes than a non-vegetarian, while the peso-vegans reported the highest risk of type 2 diabetes incidence. From the above, there was an agreement in that diabetes, obesity, and cardiovascular risks were lower among different classes of vegetarian diets with the peso-vegetarian and semi-vegetarians attaining the lowest benefit. The healthier and friendly are the food items included in the vegetarian diets is the highest benefits in terms of cardio-metabolic risk. The above findings may assist in the development of an interventional strategies to address the worldwide growing burden of diabetes and of overweight/obesity. However, prospective studies with better measures of dietary intake and clinical measures of diabetes are needed to clarify this relationship.

Types of vegetarians diets:

Flexitarian = A recent term to describe people who eat a mostly vegetarian diet, but occasionally eat meat

Pescatarian = described those who abstain from eating all meat and animal flesh with the exception of fish

Lacto-ovo vegetarians = People who do not eat beef, pork, poultry, fish, shellfish or animal flesh of any kind, but do eat eggs and dairy products are (“lacto” comes from the Latin for milk, and “ovo” for egg).

Lacto-vegetarian is used to describe a type of vegetarian who does not eat eggs but does eat dairy products.

Ovo-vegetarian refers to people who do not eat meat or dairy products but do eat eggs.

Vegans do not eat meat of any kind and also do not eat eggs, dairy products, or processed foods containing these or other animal-derived ingredients such as gelatin (as opposed to vegetarians, who usually eat dairy products and eggs). Many vegans also refrain from eating foods that are made using animal products that may not contain animal products in the finished process, such as sugar and some wines. There is some debate as to whether certain foods, such as honey, fit into a vegan diet.

Pesco-vegetarians also includes fish and seafood, but not other animals flesh, most of them also maintained a lacto-ovo vegetarian

Luna, Taryn (1 July 2015). "Legal Sea Foods launches 'Pescatarianism' ad campaign" . The Boston Globe

- Breakfast skipping: Breakfast is often thought of as the important meal of the day. It significantly contributes to the daily energy requirement and improves cognition (45). For research purposes, breakfast is defined as "the first meal of the day, taken before or at the start of daily activities (e.g., errands, travel, work), within 2 hours of waking, typically no later than 10:00 am and of an energy level between 20 and 35% of total daily energy needs."(46). Another definition is any food or beverage consumed between 5:00 a.m. and 10:00 a.m. Poor breakfast habits are skipping breakfast or only drinking or eating something sweet. The habit of skipping this important meal is highly prevalent with 12-34% of youth are regular breakfast skippers (skip breakfast for three or more weekdays) (47). Breakfast consumption is protective from diabetes mellitus through decreasing body weight, lesser visceral adiposity, and prevention of low-grade inflammation. Obesity, visceral fat accumulation, and prolonged long-term fasting are strong predictors of insulin resistance (48-53). Moreover, breakfast skipping had been shown to increase postprandial hyperglycemia after lunch and dinner in association with impaired insulin response and lower GLP-1 and hence long-term effects on insulin metabolism that persists throughout the day (54). Diabetes mellitus is largely vascular disease, so a multidisciplinary approach targeting all the vascular risk is recommended (3). A previous study (55) stated that the bad habit of breakfast skipping and smoking are associated with diabetes mellitus prevalence. In contrast, a randomized control trial found that skipping breakfast does not result in accurate compensation at the subsequent meal ending in a lesser energy intake (56). The previous trial was conducted on habitual breakfast consumers, in whom the effect may differ from non-habitual breakfast consumers. Furthermore, the trial did not examine the long-term effects of breakfast skipping like low-grade inflammation that could lead to insulin resistance, diabetes mellitus, and poor glycemic control. The proposed mechanisms for the association of breakfast consumption and decreased body weight and type 2 diabetes incidence is through the release of hormones including cholecystokinin and other incretins that modulate satiation, additionally the consumption of a breakfast high in fiber and cereals (resistant starches) which are susceptible to colonic fermentation and hence high short chain fatty acids resulting in the attenuation of hepatic glucose release, and increasing the glucagon-like peptide-1. The satiety produced by breakfast consumption and the effects of resistant starch fermentation by the microbiota may extend to the following meal (57-59). Low-grade inflammation leading to insulin resistance is an additional proposed mechanism. The habit of breakfast skipping is also associated with late dinner consumption and psychiatric illnesses. A study conducted among students (14880 from different provinces including Urban and rural) in Iran (60) found that the students who regularly consumed breakfast were less likely to experience mental health disorders and violent behavior. A longitudinal study (61) with prolonged follow-up (27 years) assessed the relationship of breakfast at the age of sixteen, then the participants were assessed for the metabolic syndrome. The survey concluded the association of breakfast skipping in early life is associated with central adiposity and high fasting plasma sugar in adulthood. A study conducted in the United States found that leptin which a hormone with diurnal secretion that is lowest in the morning was associated with breakfast skipping after adjustments for various confounding variables including age, race/ethnicity, time of venipuncture, physical activity, alcohol intake, smoking, diabetes and after further adjusting for: dietary factors (62). The following are the risk factors for obesity among South Asian teenage (13-19) years, adolescence (10-18) years and young adult (19-24) years observed by a systematic review (63) of the short and long term effects of nutritional transition on the epidemic of obesity:

- a total vegetarian diet
- Reduced fruit and vegetable intake
- fast food and soft drinks consumption
- and skipping breakfast.

Other contributing factors identified were:

- Adding extra salt to meals
- Eating outside of the home
- Frequent visits to restaurants
- And eating while watching television. On the other hands, the daily milk/yoghurt consumption and a family supper have shown a protective effect against overweight/obesity.

More definitive randomized controlled trials will provide answers to these important public health questions regarding pathways of dietary behaviors, dietary composition, and risk of obesity and related chronic diseases.

- Late dinner intake:

The sympathetic drive and hence plasma sugar are higher at night . Thus meal consumption two hours or less before sleeping especially large high glycemic index may further increase body weight and postprandial plasma sugar (16,17). Furthermore eating a late dinner could lead to breakfast skipping inducing a vicious cycle of higher weight gain and higher postprandial plasma sugar with deleterious consequences. Thus eating late dinner combined with breakfast skipping is poorer than skipping breakfast alone (64). In contradiction to the above, Sandhu et al. (65)who published a recent study in Canada showed no association between the evening meal timing and cardiometabolic risk profile. The study was cross-sectional, conducted among South-Asian Canadian, and the sample size was relatively small. One important factor that should be put in mind is the circadian preference, that is morningness-eveningness (Larks or Owls). Late eveningness people usually eat later at night and skip breakfast. Furthermore, late chronotype had been shown to be associated with poor glycemic control (66). A cross-over controlled trial conducted by Thomas et al. (67) among habitual breakfast skippers and non-skippers obese women concluded that the adverse effects of breakfast skipping were found only among habitual breakfast eaters. The authors explained their finding by the metabolic and behavioral memory for the usual eating pattern, another explanation is that the breakfast skippers could be late chronotype and they usually skip breakfast, so this is their norm. The researchers pointed out that, although the disruption of the usual eating pattern in breakfast eaters lead to adverse effects, this was not observed among non-skippers. A plausible explanation could be the effect of working hours. People may work against their circadian preference. So breakfast eaters may return to be evening chronotype and are used to taking breakfast against their circadian preference due to work obligation and vice versa. Scheduling the working according to circadian preference could illuminate these unwanted metabolic effects.

Intermittent fasting effects on diabetes:

Intermittent fasting is a new method of obesity management, the optimal diet in this modality of weight management is unknown. Generally it involves extended periods of fasting (e.g. from sixteen to forty-eight hours) with no of little amount of food intake followed by normal eating on a recurrent basis. It is stated that, animals including human evolve in a relatively food deficient environment. The current habit of eating three meals/day and overconsumption of nutrients combined with work involving inactivity often leads to metabolic co-morbidities including visceral fat accumulation (central adiposity) and insulin resistance. Animal studies results were contradicting with some (68) reporting a beneficial effects on a wide range of diseases including diabetes mellitus, neurological disorders such as Alzheimer's disease Parkinson's disease and stroke, and malignancy, while others (69) reported an increased insulin resistance possibly mediated by attenuation of hepatic insulin signaling. The activation of adaptive cellular stress response signaling pathways that enhance DNA repair, autophagy, and mitochondrial health is another proposed mechanism. A pilot trial (70) conducted among overweight and obese patients with type 2 diabetes showed that intermittent energy restriction resulted in glycemic improvement control and weight reduction offering an alternative treatment approach. A further recent three phase observational study (71) showed that a short period of intermittent fasting improved fasting plasma glucose, postprandial variability, and body weight. Furthermore a positive relationship was found between the increased hour fasting and fasting glucose reaching targets. Supporting the beneficial effects of intermittent fasting is a one week fasting pilot study (72). The study which applied the Buchinger method with a nutritional energy intake of 300kcal/day by liquids only and stepwise re-introduction of solid food thereafter, indicated that prolonged fasting is well-tolerated and decreased body mass index, central adiposity, and blood pressure.

A recent insight about the role of antioxidants in diabetes:

Oxidative stress and low grade inflammation are suggested as contributors in the development of type 2 diabetes. The role of antioxidants in the prevention of diabetes is controversial. Some studies have shown that the antioxidant vitamin E may help decrease the risk of type 2 diabetes, other failed to conclude the same for The findings of these studies could be explained by the fact that, the investigators looked only at isolated nutrients. However, Food rich in antioxidants is coffee, fruits and vegetables, wine in moderation, and tea. included 64,223 women who participated in from the large E3N-EPIC prospective cohort study, begun in France in 1990 with the aiming to studying risk factors for cancer and severe chronic conditions in women born between 1925 and 1990. The total antioxidant capacity was calculated after detailing dietary history. The patients were then followed for fifteen years. After controlling for various confounders, women who are ate the most antioxidant showed a 39% lower risk of type 2 diabetes than women who ate the least amount (lowest quartile). Furthermore, the effect plateaued after the consumption of 15mmol of the antioxidants.

Foods contribution to high total antioxidant was as follows:

Fruit (23%), vegetables (19%), alcoholic beverages (15%), and tea and other hot beverages (12%). It is interesting to note that the researchers stress on alcohol in moderation, because consuming high quantities of alcohol, spirit, and peer have been linked to increased diabetes risk. In spite being conducted only among women, and that the dietary habits may change overtime and need multiple assessments, the trial gave an insight and pave the way for future researches to study the mechanism that the antioxidants decreased the risk of diabetes like the effects on insulin sensitivity.

References:

New Study Shows Antioxidant-Rich Foods Diminish Diabetes Risk - Medscape - Nov 10, 2017

- Mancini FR, Affret A, Dow C, Balkau B, Bonnet F, Boutron-Ruault MC, Fagherazzi G. Dietary antioxidant capacity and risk of type 2 diabetes in the large prospective E3N-EPIC cohort. Diabetologia pp 1–9

The positive health effects Coffee intake either caffeinated or not:

Coffee is consumed worldwide, recent studies from the US and Europe have focused attention on the positive effects of coffee in reducing all-cause human mortality. Although the mechanisms are not known, coffee can benefit patients with and without liver cirrhosis by slow formation of liver fibrosis, reduce the risk for hepatocellular carcinoma, and lower overall mortality including mortality from heart disease, circulatory disorders, chronic lung disease, stroke, diabetes mellitus, and kidney disorders. Furthermore, the effect of coffee intake on mortality reduction occurred whether the coffee was exclusively caffeinated or decaffeinated. The effect was evident regardless of whether the coffee consumed contained caffeine or not. The effect on mortality was prominent—four or more cups of coffee daily reduced the death rate from liver disease by 71%. In the European study of all-cause mortality. A recent meta-analysis of 11 relevant publications suggested that coffee consumption can reduce occurrence of metabolic syndrome. The consumption of excess coffee have been questioned in the past, but up to 400 mg (8 ounces cups) of caffeine can be consumed daily without significant risk. The effect of coffee consumption in lung cancer is to be resolved, a controversy exists as some indicated a reduction, others were neutral or associated with an increased risk (73-77).

[...]