Intermittent fasting has become increasingly popular over the past couple of years, as a means not only of helping weight loss, but also for touted benefits of favorably influencing our genes to reduce aging, reducing inflammation (the root cause for most chronic diseases), and increasing cellular repair through a process called autophagy (when cells remove dysfunctional intracellular proteins that have accumulated) .
Does scientific evidence support these claims?
What Happens When We Eat?
Every time we consume food, our body breaks down the protein, carbohydrates, and fats into amino acids, sugars, and fatty acids, respectively. While refined carbohydrates (not whole-food carbohydrates) tend to raise blood sugar and insulin levels, proteins and fats have little effect.
Once the body detects glucose (sugar) in the blood, insulin is secreted by the pancreas and stores excess in the liver as glycogen (long chains of glucose are strung together in a process called glycogenesis). The liver has limited storage space for glycogen, however, and any additional glucose floating around the bloodstream is turned into fat (by a process called de novo lipogenesis).
When we are not eating, and our bodies need glucose for energy, the liver breaks down readily available glycogen stores to convert it back to glucose. This process can begin a few hours after we have finished eating and commonly occurs during overnight fasting. During longer periods of fasting, our bodies utilize fat to make more glucose through a process called gluconeogenesis.
A good analogy is to think of glycogen like a wallet and fat stores as a bank. Glycogen provides a limited amount of readily available glucose and fat stores can provide a greater amount that is more difficult to access. (2)
What contributes to weight gain (or lack of weight loss) for many people, is that once glycogen stores are depleted, and before we access fat stores, we eat again. There’s never enough time for the fat stores to be converted to energy.
The Role of Insulin
Insulin is known to directly cause weight gain, but also reset the weight “thermostat” in the hypothalamus of the brain. Repeatedly exposing the body to insulin without prolonged fasting intervals (such as eating every 2-3 hours, particularly with consumption of refined carbohydrates) leads to persistently elevated insulin. This promotes greater storage of consumed calories and contributes to insulin resistance. When our bodies are continuously exposed to high levels of insulin, they develop somewhat of a tolerance, which requires progressively greater amounts of insulin to store our consumed calories. This becomes a vicious cycle: higher weight thermostat set points, greater insulin secretion, and more insulin resistance.(2)
The Role of Fasting
With fasting, blood glucose levels drop, insulin and IGF-1 (insulin-like-growth factor-1) levels are reduced, glycogen stores in the liver are consumed, and our bodies begin to produce glucose from fat stores via gluconeogenesis.
Our bodies break down triglycerides (the storage form of fat) via a process called lipolysis into glycerol (used for gluconeogenesis) and free fatty acids. Free fatty acids are converted in the liver to beta hydroxybutyrate (BHB) and acetoacetate (ketone bodies), both of which are released into the blood and used as an energy source for cells including the brain. This is the process of ketosis which occurs in those following a ketogenic diet.
With very prolonged fasting (more than 5 days), levels of growth hormone increase to maintain muscle mass, and adrenalin increases to maintain the basal metabolic rate.
Fasting, by lowering basal insulin levels, can lower the weight “thermostat” in the brain, and break the vicious cycle of high insulin/insulin resistance that prevents breakdown of fat and weight loss. Remember, if you’re not eating, you’re not secreting much insulin. (2, 1)
What is Intermittent Fasting?
One of the reasons intermittent fasting (IF) has gained popularity is that it is felt to be less restrictive than traditional reduced-calorie diets. There are two major varieties of IF: time-restricted feeding (TRF) and intermittent calorie restriction (ICR) with 5:2 or 4:3 fasting. (1)
The most common form of TRF is to fast for 16 hours (oftentimes 8pm one evening to 12pm the following day) and consume all calories for 8 hours (12pm to 8pm). This is referred to as the 16/8 variant, however benefits of fasting can be seen with even a 12 to 14 hour fast. The fasting duration can also be long as 20 hours, narrowing the eating window to only 4 hours. With TRF, blood glucose is elevated during and 6-8 hours following a meal, but then remains low until the fast is broken. Once glucose levels return to normal, glycogen stores in the liver are initially used to produce glucose, but fatty acid and ketone levels ultimately rise as fat begins to be metabolized for energy. This process is called intermittent metabolic switching (glucose to ketone or G to K).
Fasting can also be based on a 5:2 or 4:3 weekly schedule, where calorie restriction takes place 2-3 times a week, and a regular (ideally whole food, plant based, low saturated fat) diet is consumed the other 4-5 days. The “fasting” days can include consumption of up to 400-600 calories.
Alternate Day Fasting (ADF) varies normal feeding days with consumption of up to 25% of usual caloric intake or just calorie free liquids (coffee, tea, water) and veggie broth. Fasts can be for 24 hours (6pm to 6pm) or extended to 36 hours (dinner one evening, followed by breakfast 2 days later).
What is the Data on Intermittent Fasting in Cardiovascular Disorders?
Many studies have been performed to evaluate the various methods of IF, both in rodents and humans. The brief reviews below will focus only on human studies, although rodent studies appeared to show consistent favorable benefits.
TRF has been touted to be beneficial in physically active people due to purported maintenance of muscle mass despite weight reduction. A study on 34 resistance-trained males who were assigned to TRF over an 8-hour window versus normal feeding showed that after 8 weeks, the TRF group had reduced fat mass with equivalent muscle area. (4)
A 2016 study (3) found that a 5:2 IF program was as effective for weight loss and glycemic (sugar) control as a calorie restricted diet over a 12-week period, especially if patients found daily calorie restriction difficult.
A study by Bhutani et al. (6) showed that ADF for 2-3 weeks reduced body weight by 3% which was increased to 8% over a longer time period. Additionally, total cholesterol, LDL (bad) cholesterol, and triglyceride levels were reduced, all of which can reduce the risk of developing coronary artery disease.
Other studies (below) have also demonstrated a favorable effect of IF on cholesterol parameters.
Inflammation plays an important role in the development of cardiovascular disease. Pro-inflammatory factors such as CRP, IL-6, and homocysteine have been found to be contributory. A study by Aksunger et al. (7) demonstrated the effect of an IF diet on reducing the concentration of these factors. Further studies have confirmed these beneficial effects (below).
Adiponectin is a plasma protein secreted by adipocytes. Levels are ironically low in those with visceral (abdominal obesity), the more dangerous type that is associated with diabetes, insulin resistance, high cholesterol, and cardiovascular disease. Low levels are associated with elevated markers of inflammation, and adiponectin has both anti-atherosclerotic ad anti-inflammatory effects. Previous studies have demonstrated that weight loss through diet, exercise, medications, and surgery can increase adiponectin levels. Some studies have also shown that IF can increase adiponectin secretion from adipocytes, thus raising levels in the blood. (8) As a result, this can improve insulin resistance (insulin sensitizing effect), positively affect cholesterol levels (raising HDL/good cholesterol and lowering triglycerides) and lower the risk of coronary disease.
Leptin, another hormone produced by fat cells, reduces the sensation of hunger by sending a signal to the hypothalamus in the brain (opposing a hormone called ghrelin, which increases hunger). Leptin levels are higher in those with more fat. While theoretically higher leptin levels should reduce weight by causing people to feel full, obesity can lead to leptin resistance, where the brain does not respond normally to the leptin stimulus. Studies show that IF can reduce leptin secretion, resulting in weight loss (possibly by reducing leptin resistance in the brain), reduce blood stickiness (platelet aggregation), and reduce inflammation of the blood vessels. (9)
High blood pressure is a major contributor to the development of cardiovascular disease. IF has been shown to lower blood pressure in a German study of 1422 people followed for one year. (5) Blood pressures returned to baseline once patients stopped the IF diet. Other studies have shown consistent short-term results (see below). One proposed mechanism is by IF leading to elevated levels of BDNF (brain derived natriuretic factor) which can lower blood pressure and heart rate through activation of the parasympathetic (involuntary) nervous system.
Over two-thirds of the US population is overweight or obese, another major contributing factor to diabetes, insulin resistance, and cardiovascular disease.
A 2017 study (10) showed similar benefits over 1 year between ADF and daily calorie restriction in terms of weight loss and other parameters including changes in blood pressure, fasting levels of glucose and insulin, triglyceride levels, and CRP (a marker of inflammation).
A 2018 study (11) of 150 overweight and obese patients showed that over a 12-week period, an ICR 5:2 diet was superior to a continuous calorie restriction diet and a control group for weight loss (-7.1% versus -5.2% versus -3.3%). There was little difference in weight between the calorie restriction and ICR diet after a 1-year period, however (12 weeks of maintenance and 26 weeks of follow-up followed the 12-week intervention).
IF resulted in weight loss in diabetic patients enrolled in the DiRECT trial (Diabetes Remission Clinical Trial). (12) This improved fasting blood glucose, reduced levels of Hgb A1C (a marker of blood sugar control over a 3-month period), and increased insulin sensitivity. The mechanism of benefit from IF was felt to be related to the insulin receptor being more sensitive (responsive) to insulin, thus stimulating rapid glucose uptake by the muscle cells and liver. (13) Autophagy (cell cleaning) in the pancreas, leading to increased insulin secretion in response to glucose, is another proposed mechanism by which IF can improve diabetes.
In summary, clinical studies have demonstrated many favorable metabolic effects of the various forms of IF, both in animals and humans. These can ultimately result in a reduced incidence of cardiovascular disease.
- Reduced inflammation (lower IL-6, CRP, homocysteine) which is at the root cause of most chronic diseases
- Improvement in lipid profile by lowering LDL (bad cholesterol) and triglycerides and raising HDL (good cholesterol)
- Increased adiponectin and reduced leptin (both associated with reduced development of plaque buildup in the arteries)
- Lowering of blood pressure
- Reduction in body weight
- Improved glucose metabolism (by increasing insulin sensitivity in tissues and improving insulin secretion from the pancreas), thus reducing diabetes
- Protecting the nervous system from aging (by reducing development of free radicals)
- May initially cause fatigue and dizziness as body acclimates to using ketones rather than glucose for energy
- Should be used with caution in those taking blood sugar lowering medications to avoid hypoglycemia (very low blood sugars that could be fatal)
- Use with caution in the elderly who are more susceptible to low blood sugar and falls
- Should be avoided completely by children and pregnant women
1.Bartosz Malinowski et. al. Intermittent Fasting in Cardiovascular Disorders—An Overview. Nutrients. 2019, 11, 673.
2. Fung, Jason. 2016. The Obesity Code: Unlocking the Secrets of Weight Loss. Vancouver. Greystone Books.
3. Carter, S.; Clifton, P.M.; Keogh, J.B. The effects of intermittent compared to continuous energy restriction on glycaemic control in type 2 diabetes; a pragmatic pilot trial. Diabetes Res. Clin. Pract. 2016, 122, 106–112.
4. Tatiana Moro, T.; Tinsley, G.; Bianco, A.; Marcolin, G.; Pacelli, Q.F.; Battaglia, G.; Palma, A.; Gentil, P.; Neri, M.; Paoli, A. Effects of eight weeks of time-restricted feeding (16/8) on basal metabolism, maximal strength, body composition, inflammation, and cardiovascular risk factors in resistance-trained males. J. Transl. Med. 2016, 14, 290.
5. Toledo, F.W.; Grundler, F.; Bergouignan, A.; Drinda, S.; Michalsen, A. Safety, health improvement and well-being during a 4 to 21-day fasting period in an observational study including 1422 subjects. PLoS ONE 2019, 14, e0209353.
6. Bhutani, S.; Klempel, M.C.; Kroeger, C.M.; Trepanowski, J.F.; Varady, K.A. Alternate day fasting and endurance exercise combine to reduce body weight and favorably alter plasma lipids in obese humans. Obesity (Silver Spring) 2013, 21, 1370–1379.
7. Aksungar, F.B.; Topkaya, A.E.; Akyildiz, M. Interleukin-6, C-reactive protein and biochemical parameters during prolonged intermittent fasting. Ann. Nutr. Metab. 2007, 51, 88–95.
8. Bhutani, S.; Klempel, M.C.; Berger, R.A.; Varady, K.A. Improvements in Coronary Heart Disease Risk Indicators by Alternate-Day Fasting Involve Adipose Tissue Modulations. Obesity 2010, 18, 2152–2159.
9. Bowman, J.D.; Bowman, C.D.; Bush, J.E.; Delheij, P.P.; Frankle, C.M.; Gould, C.R.; Haase, D.G.; Knudson, J.; Mitchell, G.E.; Penttila, S.; et al. Parity nonconservation for neutron resonances in 238U. Phys. Rev. Lett. 1990, 65, 1192–1195.
10. Trepanowski, J.F.; Kroeger, C.M.; Barnosky, A.; Klempel, M.C.; Bhutani, S.; Hoddy, K.K.; Gabel, K.; Freels, S.; Rigdon, J.; Rood, J.; et al. Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese Adults: A Randomized Clinical Trial. JAMA Intern. Med. 2017, 177, 930–938.
11. Schübel, R.; Nattenmüller, J.; Sookthai, D.; Nonnenmacher, T.; Graf, M.E.; Riedl, L.; Schlett, C.L.; von Stackelberg, O.; Johnson, T.; Nabers, D.; et al. Effects of intermittent and continuous calorie restriction on bodyweight and metabolism over 50 wk: A randomized controlled trial. Am. J. Clin. Nutr. 2018, 108, 933–945.
12. Leslie, W.S.; Ford, I.; Sattar, N.; Hollingsworth, K.G.; Adamson, A.; Sniehotta, F.F.; McCombie, L.; Brosnahan, N.; Ross, H.; Mathers, J.C.; et al. The Diabetes Remission Clinical Trial (DiRECT): Protocol for a cluster randomised trial. BMC Fam. Pract. 2016, 17, 20.
13. Sequea, D.A.; Sharma, N.; Arias, E.B.; Cartee, G.D. Calorie restriction enhances insulin-stimulated glucose uptake and Akt phosphorylation in both fast-twitch and slow-twitch skeletal muscle of 24-month-old rats. J.Gerontol. A Biol. Sci. Med. Sci. 2012, 67, 1279–1285.