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Three years. It has been three years since starting my study on Intermittent Fasting (IF) and its proclaimed health effects. I am finally ready to go public. A quick background story… Why IF? Because for almost a decade I’d been interested in the subject. Can we really lose weight, improve health and even live longer by staring at an empty plate every now and then? It was against everything I’ve learned, in the gym, in bars, even in med school. Seemingly, there was a lot of confirming evidence to be found online, showing amazing body transformations and improved health for many individuals. I spoke with many of those people. – Wow, to hear the stories was such an inspiration. But from a scientific standpoint the stories were highly biased and not doing much to further improve our knowledge. You think anyone ever changed their feeding frequency and kept all other things equal? Of course not. How than can we know what Really improved their life? IF or the fact that they also changedtheir training routine, stopped smoking and started to walk to work? Or a combination? I wanted to see what we knew at this point. How much was the subject really studied and what did the evidence say? I finished the work in about one year and the result was awesome. The audience loved it. I got my MD and felt on top of the world. But where do I go next? First, the idea was publication in a scientific magazine.  For many reasons, taking time from becoming a good clinician being the most important, but far from single one, I eventually decided not to go that route. Ambivalentia led me to sit on it for way too long, sharing it only with personal friends and people I respect…but not much more. I just could not decide what I wanted to do with it. Since finishing it I’ve had several offers from various ‘important’ people wanting to use my paper. The problem was always integrity. This is my baby. I’m not interested in other people making a quick buck on something that was my life for over ayear and giving me a piece of the cake. Finally, after some recent online pressure – I decided to give it away for free – right here. There is no use in it sitting on my dropbox-account. Please show your appreciation for the enormous work that this required from me, a hyperactive person that normally can’t sit for more than 10 minutes. And the fact that you are getting it for free, on a sliver plate, without having to spend 300 nights, bent over scientific papers, pulling your hair out. Share it with your friends – the social media buttons are on your left. If you like it, please drop a comment below, let me know. Don’t be anonymous. If you want to know more about IF I’d recommend you to buy Brad Pilons book .  The book, in my opinion, is not perfect, and I don’t agree with all the conclusion drawn in there – but it is by far the most complete recourse available for purchase out there with practical implications for anyone interested in the IF lifestyle, and it has helped many peopleget leaner and healthier with a relaxed mindset. Without hesitation the best online recourse on the topic is my dear friend Martin Berkhan’s . Martin is the original popularizer of the IF method  and has researched the subject extensively. He also helped me get the project started with some pointers and connections.  What’s more, he is a great dude and I made a friend in the process, and that I am very grateful for. He is a guy I’d share my last beer with. Martin, I know you’re reading this so thanks, bud. Now, grab a (big) cup or coffee and enjoy the read. Your friend, Bojan The effects of intermittent fasting on human and animal health – a systematic review Thesis January 2012, University of Lund by Bojan Kostevski Center for Primary Health Care Research, Lund University, CRC, SE-205 02 MALMÖ, Sweden Supervised by: Bengt Zöller, Staffan Lindeberg Examination: Daniel Arvidsson Keywords: intermittent fasting, calorie restriction, obesity, aging, cardiovascular health, glucosemetabolism, cancer, neurodegenerative disease.   Abstract   An increasing number of animal studies have shown altered markers for health in subjects exposed to intermittent fasting, i.e. regularly and repeatedly abstaining from eating during 12-36 hours per period. It has been hypothesized that the reported beneficial health effects from caloric restriction on excess body weight, cardiovascular risk factors, glucose metabolism, tumor physiology, neurodegenerative pathology and life span can be mimicked by alternating periods of short term fasting with periods of refeeding, without deliberately altering the total caloric intake. Therefore, a systematic review of available intervention studies on intermittent fasting and animal and human health was performed. In rodents, intermittent fasting exhibits beneficial effects including decreased body weight, improved cardiovascular health and glucose regulation, enhanced neuronal health, decreased cancer risk and increased life span – some ofthe effects independent of the effects attributed to calorie restriction alone. The human studies performed to date are generally of low-quality design. Beneficial effects such as weight loss, reduced risk for cardiovascular disease and improved insulin sensitivity have been observed, but conflicting data exists. The potential health promoting effects of intermittent fasting in humans and applicability to modern lifestyle are discussed. Introduction Calorie restriction and intermittent fasting Almost a century has passed since Osborne and colleagues in 1917 observed that reducing calorie intake in rats increased the animal’s life span (1). In 1935, McCay et al. were first to describe that calorie restriction – deliberately reducing calories without causing malnutrition – prolongs mean and maximal lifespan in rats compared with rats fed ad libitum (2). Numerous subsequent studies have confirmed that a calorie restriction of 30 to 60 percent of ad libitum intake increases the life spanMice put on a  85% modified alternate-day fast (eating 15% of ad libitum daily energy intake on fasting days) reduced IGF-1 levels and decreased proliferation rates of epidermal, prostate, splenic T and liver cells, despite no weight change (41). In a third study, true but not modified alternate-day fasting decreased IGF-1 levels in mice. Cell proliferation rates were however reduced in both groups, even in the absence of weight loss (38). There is however some conflicting data in regard to intermittent fasting and IGF-1. Two 24 hour fasts/week without overall calorie restriction showed increased levels of IGF-1 and no effects on tumor size or survival in rats with prostate cancer (46). One might suspect that two 24 hour fasts per week would be insufficient to exhibit the anti-carcinogenic effects. However, Anson et al. displayed increased levels of IGF-1 in mice on alternate-day fasting diets with maintained body weight compared to controls, in contrast to mice on daily calorierestriction who showed decreases in bodyweight and decreased IGF-1 (17). The authors suggested a difference in the way intermittent fasting and calorie restriction influence the growth hormone -IGF-1 axis and insulin signaling pathways. The relevance of IGF-1 for tumor growth in intermittently fasted animals, with or without calorie restriction remains thus a subject for further clarification. Recent research has also examined intermittent fasting and its direct effect on tumor development. OF1 is a strain of mice that spontaneously develops age related lymphomas at a high rate. In a 16 week trial, none of the mice of this particular strain fed on alternate days developed lymphomas compared to 33% of mice in the control group fed ad libitum (36). There was no difference in food intake or body weight between the two groups, suggesting that intermittent fasting has a protective effect on lymphoma development in this mouse strain, and that the effect was independent of the total calorieintake. The effect of intermittent fasting on induced hepatocarcinogenesis has also been examined. When rats were put on a 48 hour fasting regimen once per week, they developed less preneoplastic lesions compared to rats fed ad libitum over a 48 week period (55). The effects of shorter, more frequent fasts, such as alternate-day fasting on hepatocarcinogenesis remains a subject for future research. Consequently, studies to date indicate that intermittent fasting hampers cell proliferation rates in a variety of cell types, and that it could potentially protect against direct development of some cancer types.  Life span Two studies looked at survival per se. They propose that animals on alternate-day fasting diets increase life span compared to those fed ad libitum (15,40). The magnitude of life span enhancement seems to be dependent on animal strain and age of initiation (40). Furthermore, in one study, only rats on alternate-day fasting diets survived to 30 months of age compared to amean lifespan of 22-24 months for rats fed ad libitum (20). It is merely speculative if the effect on longevity is secondary to the above described effects such as decreased body weight, improved insulin sensitivity, improved cardiovascular health, decreased tumor growth and improved neuronal health, or if intermittent fasting might have some distinctive effect on the aging process. No study to date has specifically studied the effect of intermittent fasting without calorie restriction on lifespan, although the effects that have been described are expected to increase life span. Interestingly, the largest magnitude of life span expansion (25 percent increase in mean life span) is seen in C57BL/6J mice, the same strain that in many of the studies on alternate-day fasting maintain a constant total energy intake and body weight (40). Other effects Some other interesting effects than the primary addressed in this review were observed in various studies. Many strains of laboratory ratsdevelop spontaneous progressive kidney failure with development of proteinuria and glomerulosclerosis. Rats fed on alternate days showed preserved kidney function as demonstrated by preserved glomerular filtration rate and renal plasma flow, compared to rats fed ad libitum (56). Another surprising finding in rats maintained on intermittent fasting is increased testicular mass and testosterone/estrogen ratio compared to control rats or rats on a calorie restriction diet (57). Analgesia, which may be attributed to negative modulation of synaptic transmission in nociceptive neurons in the dorsal horn of the spinal cord, has also been reported in rats maintained on an alternate-day fasting diet (35). This finding opens up the question whether intermittent fasting alone or in combination with a pharmacological agent could serve as a useful new therapeutic approach for treating pain. Human studies The Ramadan fast Fasting is one of the five pillars of Islam. During the holy month of Ramadan,Muslims restrain from fluid and food intake during daytime for the whole month. Worldwide, there are more than one billion Muslims, of whom the majority fast annually (58). The holy month of Ramadan could thus potentially be a good period to study prolonged short term intermittent fasting in humans on a large scale. A total of 17 studies were found. Conclusions are however very hard to draw from these studies. Apart from the obvious difficulties with doing randomized controlled trials there is a number of confounding factors (59,60). Such confounding variables include: Altered food choices and macronutrient distribution during the fasting month Dehydration and the difficulties with reliable lab tests Changes in activity patterns Reduced sleep due to nighttime eating and socializing Differences in fasting length and hydration status in different geographical locations and time of year Furthermore, the studies were generally of poor study design with few participants and lack of controlgroup. As a result the studies are highly inconclusive with the effects on body weight and blood lipids with some studies showing unchanged body weight (59,61) while others show weight loss (62). Therefore, no objective conclusions could be made about this type of short term intermittent fasting and cardiovascular and metabolic risk factors, and further research of higher quality is warranted. In one observational study, young competitive soccer players were sent to a training camp 3 week’s prior to, and during, the Ramadan fast. The fasting participants were compared to the non-fasting participants and all food was delivered from the same kitchen, thus eliminating some of the confounding factors above (60,63). Apart from a small difference in body weight (0,7 kg) that could be explained by hydration status between the two groups, no differences were observed in blood glucose levels, hematocrit, cortisol levels, inflammation markers or physical performance. In another study, fastinghealthy men and women were compared to a matched non-fasting group with regard to inflammation markers and blood lipid status (61). No differences were observed in body weight, total cholesterol, triglycerides or LDL levels. There was however an increase in HDL levels and decreased inflammation – proposing a beneficial effect in the fasted subjects. Thus, there are some data suggesting altered health markers during the month of Ramadan, but more research is needed if any objective conclusions about this type of intermittent fasting and the factors studied in this review ought to be drawn. Alternate-day fasting To date, very few human intervention studies have tried to replicate the reported effects of alternate-day fasting seen in rodent studies. Only six such studies were found, with somewhat disappointing study designs (64-69). The sample size in these studies was rather small, ranging from eight to sixteen participants, and the study period was often very short. Only one trialincluded a control group. The results are summarized in Table 2. In both true alternate-day fasting trials, a decreased body weight was observed (66,67). In modified alternate-day fasting trials, maintained bodyweight was observed in lean (65,69) but not obese (64,68) subjects. In obese subjects, a modified 8-10 week alternate-day fasting regimen resulted in weight loss, reduced blood pressure and heart rate, and improved markers for cardiovascular health, such as decreased total cholesterol, decreased LDL and triglycerides, increased HDL concentrations and decreased oxidative stress and systemic inflammation, suggesting that alternate-day fasting might be a novel strategy for decreasing body weight and improving cardiovascular health in the obese population (64,68). To examine the effects of alternate-day fasting on glucose metabolism, eight healthy men were maintained on a 20h modified alternate-day fast for two weeks. Despite unaltered body weight and habitual physical activity,insulin dependent glucose uptake increased, and increased adiponectin levels were observed (65). In another trial, the insulin sensitizing effect of true alternate-day fasting was observed through reduced insulin response to a standardized meal in men, but not women – suggesting a potential sex difference in the effect of alternate-day fasting on glucose metabolism (66). Although not demonstrated in all human studies (68,69), these results indicate that alternate-day fasting might mimic the insulin sensitizing effects observed in rodents on alternate-day fasting diet, and that the effect might be due to increased adiponectin levels. Sex differences were also observed in another study where healthy men and women were fasted on alternate days. In this study, HDL levels were increased in women only, and triglycerides were decreased in men but not women (67). Increased insulin sensitivity was suggested by decreased insulin levels with unaltered glucose levels. In this study, blood pressurewas unaltered, but the study duration was merely 22 days. In contrast, one trial showed decreased blood pressure and resting heart rates in subjects on modified alternate-day fasting regimens for 10 weeks, suggesting that longer intervention periods might be needed for this effect to occur (64). There is, however, conflicting data from another study that utilized a two week crossover study design and randomized eight healthy men to a modified alternate-day fasting diet or a standard diet. No differences were observed in body weight, blood lipids, glucose metabolism or hormone levels, and there was a decrease in energy expenditure after the 2 week period in the alternate-day fasting group (69). More controlled studies, with larger sample sizes and longer study durations are thus needed to bring clarification in this matter. No human trial has directly examined intermittent fasting and tumor physiology. A single two day fast increases endogenous GH-production fivefold, reflecting themetabolic adaptation to fasting, including increased hepatic glucose production, lipolysis and nitrogen conservation (70). However no significant changes in IGF-1 are seen after a single fast period in human subjects, suggesting that repeated fasts and longer intervention periods might be necessary to mimic the changes in IGF-1 and altered cancer growth observed in some rat studies. Whether a prolonged alternate-day fasting regimen can alter IGF-1 levels in humans remains an area for future research. Furthermore, no human trials to date have examined the effects of intermittent fasting on neuronal health or life span. Mechanisms of calorie restriction and intermittent fasting The exact mechanism by which calorie restriction and intermittent fasting exhibits its effects on various organ systems remains unknown. The main hypothesis includes a stress preconditioning response mechanism, in which it is believed that periods of nutrient deprivation displays a beneficial mild stress thatresults in molecular adaptive changes in various tissues, which increases the organism’s resistance to bigger stressors such as excitotoxic and oxidative injury, including ischemia (33,71). Alternating periods of anabolism and catabolism during intermittent fasting might further increase the cellular stress resistance. Other displayed effects are increased production of neutrophilic factors and antioxidant enzymes, ketone body formation and altered metabolism enzyme production (5). Potential adverse effects from fasting Blood glucose levels, mood and cognition A variety of questions often arises when discussing intermittent fasting and human health. It is often believed that blood sugar levels will fall to pathological levels if prolonged fasts are implemented. A characteristic decline in mood and energy levels before lunch among humans is often attributed to a drop in blood sugar. However when actually testing blood sugar levels in healthy subjects prone to this phenomena, no actualdecline in blood sugar to pathologic levels was seen during a 24 hour fast (72). In healthy human subjects, a 24 hour fast decreases liver glycogen stores no more than 57% and in absence of vigorous exercise does not lead to muscle glycogen consumption, suggesting that liver glycogen stores are sufficient after a 24 hour fast to keep blood glucose levels within normal range (73). Furthermore, a double-blind, placebo-controlled study of two days of calorie deprivation showed no adverse effect on cognitive performance, activity, sleep, and mood, when the subjects were unaware of the calorie content of the treatments (74). Hunger The homeostasis of body weight regulation and hunger signaling is composed of complex circuits of both central signals including orexin, neuropeptide Y, melanin concentrating hormone and alpha-melanocyte, and peripheral signals from the gut and adipose tissue, such as ghrelin, peptide YY and leptin (75). The interplay between these and other endocrine signalingsystems and its effect on body weight regulation and subjective feelings of hunger and satiety remains largely unknown. The hunger response however seems to be highly adaptive in different meal patterns. Ghrelin, a gut derived hormone, is considered a meal-initiation signal. It increases during fasting and usually peaks in concentration before an anticipated meal, paired with increased feelings of hunger, and decreases after feeding. Interestingly, the rise in ghrelin is independent of meal timing as demonstrated by similar peaks before an anticipated meal in various meal frequencies, thus suggesting that subjective feelings of hunger and energy intake is highly dependent on the individual’s preferred meal pattern (76). Increases in subjective feelings of hunger might be the single most important factor to consider when discussing the applicability of intermittent fasting as a therapeutic or preventive intervention in human subjects. In obese patients, a 14 day total fast lead tostrikingly decreased body weights and decreased blood pressure, without causing increased hunger sensations. Thus a hunger suppressing effect of prolonged fasting was demonstrated (77). This anorexic effect might be attributed to the evolutionary purpose of seeking for nutrients in absence of food. The experiment, dating back to 1962, was effective and well tolerated. Only one study has directly examined the feelings of hunger and fullness in non-obese subjects on an intermittent fasting diet, by using a 100 mm visual analog scale (67). The subjects were fasted on alternate days and reported an increased feeling of hunger from 37 to 56 mm and decrease in feeling of fullness from 43 to 23 mm when the dietary intervention was initiated. The magnitude of hunger did however not change during the intervention period as repeated measurements were taken, and feelings of fullness actually increased some over time. The duration of this study was only 22 days and it is still purely speculativewhether and adaptation to the new meal pattern would occur in a longer time span. In contrast, modified alternate-day fasting in obese asthmatic patients did not significantly increase the subjective perception of hunger from baseline during the eight week long intervention period (68). Whether repeated bouts of short term fasting can alter hunger hormone signaling or demonstrate the same anorexic effect as the long term fast described above is highly speculative and an interesting area for future research. Decreased metabolic rate It is commonly believed that multiple small meals increase metabolism and lead to increased overall energy expenditure. Following every meal there is an increase in expenditure due to the processing of the nutrients, commonly referred to Thermic Effect of Food (TEF) (78). A common belief therefore is that increased meal frequency leads to increased TEF and increased overall energy expenditure with multiple meals, and that intermittent fasting accordinglywould decrease metabolic rate and lead to increased fat accumulation and possibly obesity. According to current research though, TEF is proportional to the calorie content and vary with macronutrient composition (with the highest increase in energy expenditure observed with a high protein diet) and not meal frequency per se, as demonstrated by the equal TEF in different meal patterns under iso-caloric conditions (79,80). Furthermore, one study examined alterations in resting metabolic rate in human subjects on alternate-day fasting diets, and found no changes after a 22 day period (67). According to these findings, any potential decreases in metabolic rate would be due to decreased total calorie intake and not fasting per se. Increased stress Increased levels of both ACTH and corticosteroids can be noted in rodents maintained on alternate-day fasting diets compared with rats fed ad libitum (28,29,42). Apart from the obvious notion that cortisol is one of the major hormones responsiblefor glucose utilization during fasting, the question arises whether the increased stress in any way could be harmful to the human organism. The molecular stress response in intermittently fasted subjects seems markedly different from the one associated with uncontrolled stress. In fasted rodents there is actually a down regulation of glucocorticoid receptors in the brain, with maintained expression of mineralocorticoid receptors, suggesting that fasting might alter the brain’s responsiveness to glucocorticoids (81). In contrast, in uncontrolled stress, down regulation of the mineral corticoid receptor has been noted. Furthermore, deleterious stress responses are associated with a decrease in the expression of brain-derived neurotrophic factor (BDNF), a response quite the opposite of calorie restriction and intermittent fasting, where increased concentrations of BDNF have been observed in numerous studies (4). In conclusion, the controlled stress response from intermittent fasting seemsfundamentally different from the one by uncontrolled physiological and psychological stress. Conversely, In line with the mechanisms described above, the increased stress might be one of the necessary factors for initiating molecular resistance for larger stressors, and thus promote some of the beneficial effects of intermittent fasting. Loss of muscle mass One potential serious side effect of intermittent fasting would be loss of muscle mass. Theoretically, food deprivation would result in depleted hepatic glycogen stores, leading to increased proteolysis and flux of amino acids from skeletal muscle for hepatic de novo gluconeogenesis, to maintain healthy blood glucose concentrations. As discussed previously though, a 24 hour short term fast is insufficient in duration to deplete liver glycogen stores in healthy subjects (73). Up to 40 hours of total fasting does not stimulate catabolic processes and lead to skeletal muscle atrophy (82). Modified alternate-day fasting and loss of leanbody mass was investigated in only one study in the systematic search. No loss of fat free mass in the absence of weight loss was observed compared to a control group fed a standardized diet (69). Furthermore, an increase in ketone body concentrations has been observed in subjects on alternate-day fasting diets in both human and animal studies (17,68). Ketone bodies spare skeletal muscle from breakdown by providing non-glucose energy substrate for various tissues, of which the brain is the most important, and thus decrease the need for protein-derived substrates for gluconeogenetic conversion to maintain glucose homeostasis (83). Available data thus suggests that short term fasting does not deplete hepatic glycogen stores to the extent that markedly increased proteolysis and gluconeogenesis becomes necessary to maintain healthy glucose concentrations. Still this notion needs to be clarified in future research of longer duration. Conclusions Alternate day fasting as a model for calorierestriction Intermittent fasting in the form of alternate day fasting in many instances reduces overall energy intake, with no obvious adverse effects, and thus becomes a model of calorie restriction in both human and animal subjects. Secondary to reduced energy intake and weight loss, effects such as reduced risk factors for cardiovascular disease, and improved glucose metabolism have been demonstrated in both animal and human subjects on true and modified alternate-day fasting diets. In rats, protection against ischemic injury and improved survival has been demonstrated in both myocardial and cerebral ischemic events. Other beneficial effects, such as slowing the neuronal aging process and increasing cognitive functions and memory, have been observed. In line with animal studies on daily calorie restriction, alternate-day calorie restriction has shown beneficial effects in neuronal disorders such as stroke, epilepsy and neurodegenerative disorders, including Alzheimer’s, Parkinson’sand Huntington’s disease. Additionally, calorie restriction can reduce cancer risk and increase life span in rodent models on alternate-day fasting diets. Intermittent fasting and health in the absence of calorie restriction Some effects occur even if the subject maintains body weight, suggesting that the reduced meal frequency or prolonged time in the fasted state might have some additional effects regardless of overall calorie restriction and weight loss. In humans, modified alternate-day fasting diets might be easier to adhere to and they seemingly lead to less pronounced weight loss than true alternate-day fasting. Without causing weight loss, effects such as improved fasting insulin have been demonstrated in both animals and humans. In line with these findings, adiponectin increases in rats and humans on both true and modified alternate-day fasting diets in the absence of calorie restriction. Additionally, in mice, fat redistribution from visceral to subcutaneous stores has beenobserved despite unaltered overall body weight. If this effect proves to be true in human subjects it could propose reduced disease risk despite unaltered body weight. Animal data further indicate some beneficial effects of intermittent fasting diets even without calorie restriction. Neuronal health improvements such as resistance to excitotoxic injury have been observed. Resistance to oxidative stress could be beneficial in the pathogenesis of epilepsy and various neurodegenerative diseases such as Alzheimer’s disease. Alternate-day fasting in animals also leads to improved recovery after induced spinal cord injuries and progressive demyelinating disease of the peripheral nervous system, in the absence of calorie restriction. Furthermore, in animal studies, changes associated with retareded tumorgenesis, such as decreased cell proliferation rates in various cell lines and decreased incidence of lymphoma, have been observed. Whether these observations are valid in human subjects aswell remains an interesting area for future research. Future research is warranted to test whether the health promoting effects described in animal studies have some validity in humans. We are in the very infancy of research on intermittent fasting in human subjects and future studies with larger sample sizes, longer durations and of better study design must be completed before any definite conclusions can be made regarding intermittent fasting and human health and the applicability to modern lifestyle. Acknowledgement My sincere gratitude to Staffan Lindeberg and Bengt Zöller for helping me set up the systematic search, for all the intellectually stimulating discussions and for the guidance in writing this review.   References 1.        Osborne TB, Mendel LB, Ferry EL. The effect of retardation of growth upon the breeding period and duration of life in rats. 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IUBMB life. 2001;51(4):241-247.   Table 1: Used search terms The complete search term used was: (Hunger/physiology[mesh] OR Cholesterol/metabolism[mesh] OR Blood Pressure/physiology[mesh] OR Body Composition/physiology[mesh]OR Blood Glucose/metabolism[mesh] OR Energy Metabolism/physiology[mesh] OR Cardiovascular Diseases/prevention[mesh] OR Diabetes Mellitus, Type 2/prevention[mesh] OR Neoplasms/prevention[mesh] OR Caloric restriction[mesh] OR Caloric restriction/methods[mesh] OR Fasting[mesh] OR Fasting/physiology[mesh] OR Fasting/blood[mesh] OR Feeding behavior[mesh] OR Obesity[mesh] OR Energy intake[mesh] OR diet/methods[mesh] OR eating/physiology[mesh] OR Ghrelin/blood[mesh] OR Ghrelin/metabolism[mesh] OR Glucagon/blood[mesh] OR Glucagon/metabolism[mesh] OR Insulin/blood[mesh] OR Insulin/metabolism[mesh] OR Insulin Resistance/physiology[mesh] OR Leptin/blood[mesh] OR Leptin/metabolism[mesh]) AND (Short term fasting” OR “Short term fast” OR “Intermittent fasting” OR “”Intermittent fast” OR “Periodic fasting” OR “Periodic fast” OR “Alternate-day fasting” OR “Alternate-day fast” OR “Alternate day modified fasting” OR “Alternate day modified fast” OR “Every other day feeding” OR “Reduced meal frequency”OR Nibbling gorging OR Hormesis OR “Omitting breakfast” OR “Omit breakfast” OR “Skipping breakfast” OR ramadan OR fasting refeeding OR Alternate day caloric restriction). Table 2: Alternate day fasting and body weight, glucose metabolism and cardiovascular health in humans Reference Subjects (n) Protocol Trial length Body weight Glucose metabolism Cardiovascular health Soeters et al, 2009 (69) 8, non-obese 20 h mod ADF 2wk crossover - -glucose, -insulin -TG Varady et al, 2009 (64) 16, overweight 75% mod ADF 10wk ↓ Not studied ↓BP, ↓HR ↓TCL, ↓LDL, ↓TG,  – HDL Johnson et al, 2007 (68) 10, overweight, asthmatic 80% mod ADF 8wk ↓ -glucose, -insulin ↓TCL,↑HDL, ↓TG, -LDL Heilbronn et al, 2005a (67) 16, non-obese ADF 22d ↓ -glucose, ↓insulin -BP ↑HDL(women), ↓TG (men) Heilbronn et al, 2005b (66) 16, non-obese ADF 22d ↓ ↑insulin sensitivity (men), -insulin sensitivity (women) Not studied Halberg et al, 2005 (65) 8, non-obese 20 h mod ADF 15d - ↓glucose, -insulin, ↑insulin sensitivity Notstudied Abbreviations: ADF, alternate-day fasting; mod ADF, modified alternate day fasting; BP, blood pressure; HR, heart rate; TCL, total cholesterol; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride. -, unaltered; ↑, increase; ↓, decrease. 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