Introduction
Today, many American diets continue to follow the traditional pattern of a morning breakfast, afternoon lunch, and evening dinner. However, research suggests the cardiometabolic health outcomes of this pattern of eating may be inferior to other patterns of consumption (6, 10, 11, 13, 15). Intermittent fasting, a time-based diet growing in popularity, is one of these patterns of eating and has been shown to potentially provide significant health benefits against many diseases (6, 10, 11, 13, 15, 19). In this literature review, we will use some of these health benefits as indicators for disease processes to evaluate intermittent fasting’s effectiveness on these diseases. These indicators include weight loss for obesity and the maintenance of cognitive functions such as memory along with the magnitude of amyloid-beta protein build-up for Alzheimer’s Disease. For diabetes type 2, our indicators are insulin use as a medication, insulin sensitivity, glucose homeostasis, and more.
Intermittent fasting (IF) has been done for centuries, typically for religious purposes such as Islamic Ramadan (9). However, today it is used for its health benefits and many different forms of IF exist. The studies analyzed in this literature review used several forms of IF, including alternate day fasting (ADF), where individuals alternate between fasting on one day and eating normally the next, time-restricted fasting, where individuals eat only within a specific time frame each day, and the 5:2 interval, where individuals eat normally for five days before fasting for two days each week (6, 10, 11, 13, 15, 19). This literature review aims to examine the current research on intermittent fasting in relations to obesity, diabetes type 2, and Alzheimer’s disease, respectively, and determine whether IF is a robust therapy to both prevent and treat these conditions. Furthermore, it will discuss the limitations of our current research on intermittent fasting and where further research needs to be conducted before conclusive dietary advice on intermittent fasting can be given.
Intermittent fasting (IF) has been done for centuries, typically for religious purposes such as Islamic Ramadan (9). However, today it is used for its health benefits and many different forms of IF exist. The studies analyzed in this literature review used several forms of IF, including alternate day fasting (ADF), where individuals alternate between fasting on one day and eating normally the next, time-restricted fasting, where individuals eat only within a specific time frame each day, and the 5:2 interval, where individuals eat normally for five days before fasting for two days each week (6, 10, 11, 13, 15, 19). This literature review aims to examine the current research on intermittent fasting in relations to obesity, diabetes type 2, and Alzheimer’s disease, respectively, and determine whether IF is a robust therapy to both prevent and treat these conditions. Furthermore, it will discuss the limitations of our current research on intermittent fasting and where further research needs to be conducted before conclusive dietary advice on intermittent fasting can be given.
intermittent fasting on obesity
According to the National Center for Health Statistics (NCHS), 39.8% of adults in the U.S. were classified as obese (7). Obesity has been linked to many chronic diseases and conditions including all-cause mortality, high blood pressure, type 2 diabetes, stroke, coronary artery disease, cancer and many more (2, 4, 16). This not only constitutes a crisis for the individual, but for the nation, as national medical costs due to being overweight and obese is estimated to be $147 billion dollars annually (5). Caloric restriction is the primary method of obesity intervention and results in many health benefits in obese individuals, such as lowered blood pressure, blood cholesterol, and blood sugars (4).
In a literature review of 40 publications, researchers cited IF as an effective intervention for obesity and weight loss, by measuring BMI, waist circumference, hip circumference, and other indicators (11). Furthermore, to analyze how IF compares to established interventions, the effects of IF were studied in relation to normal dieting (i.e. continued energy restriction not linked to time, such as reducing meal size) to determine if IF has additional benefit in weight loss and the treatment of obesity beyond calorie restriction (11). It was found that the majority of studies did not find a difference in weight loss between the two interventions (11). 12 independent, randomized trials directly compared the weight loss of individuals in IF vs. continuous energy restriction (CER), with nine studies concluding that the two interventions were not significantly different in terms of weight loss (11). One of the studies concluded that CER resulted in greater weight loss while the remaining two studies concluded that IF resulted in more significant weight loss than CER (11). In conclusion, the literature review authors found that IF produced similar results when compared to CER when measuring for reduction of body weight, fat mass, lean mass, and increase of glucose regulation (11). Furthermore, an additional, more recent randomized clinical trial that sought to compare alternate-day fasting (ADF), a type of IF, to CER and a control group reinforces Seimon’s findings, by concluding that mean weight loss was similar between ADF and CER, but significantly greater than the control group (15). Additionally, while this study showed lower levels of adherence to the diet in ADF groups, meta-analysis by Mattson et. al demonstrates a similar level of adherence between IF and CER groups (11, 20).
In a literature review of 40 publications, researchers cited IF as an effective intervention for obesity and weight loss, by measuring BMI, waist circumference, hip circumference, and other indicators (11). Furthermore, to analyze how IF compares to established interventions, the effects of IF were studied in relation to normal dieting (i.e. continued energy restriction not linked to time, such as reducing meal size) to determine if IF has additional benefit in weight loss and the treatment of obesity beyond calorie restriction (11). It was found that the majority of studies did not find a difference in weight loss between the two interventions (11). 12 independent, randomized trials directly compared the weight loss of individuals in IF vs. continuous energy restriction (CER), with nine studies concluding that the two interventions were not significantly different in terms of weight loss (11). One of the studies concluded that CER resulted in greater weight loss while the remaining two studies concluded that IF resulted in more significant weight loss than CER (11). In conclusion, the literature review authors found that IF produced similar results when compared to CER when measuring for reduction of body weight, fat mass, lean mass, and increase of glucose regulation (11). Furthermore, an additional, more recent randomized clinical trial that sought to compare alternate-day fasting (ADF), a type of IF, to CER and a control group reinforces Seimon’s findings, by concluding that mean weight loss was similar between ADF and CER, but significantly greater than the control group (15). Additionally, while this study showed lower levels of adherence to the diet in ADF groups, meta-analysis by Mattson et. al demonstrates a similar level of adherence between IF and CER groups (11, 20).
intermittent fasting and type 2 diabetes
In 2015, 30.3 million or 9.4% of Americans were estimated to have diabetes with 90-95% of these individuals having type 2 diabetes (T2D) (3). Diabetes type 2 is a chronic disease caused by both environmental and genetic factors that arises due to cellular resistance to insulin and lowered levels of insulin and glucagon secretions (6, 18). Although there is practically no research on IF and its use as a cure for T2D to reverse insulin use, two recent studies addressed the direct effect of diet on T2D remission (6, 10). Both studies demonstrated that diet can be an effective therapy for the remission of T2D, although they had different interventions. In the first study, a randomized trial from 49 different clinics and 306 individuals, weight loss itself rather than IF was the primary correlate to regression of T2D (10). They found that the percentage of individuals experiences T2D regression correlated strongly with their weight loss (10). In the second study, a clinical trial of three individuals with chronic T2D of 10-25 years with a multitude of medications including insulin anti-hypertensive drugs, clinicians studied the effects of supervised ADF fasting on various indicators of metabolic health (6). They found that IF was a sufficient intervention to allow patients to fully stop the use of insulin within 5-18 days and two of the three patients were able to stop use of all medications, while maintaining proper glucose homeostasis (6). Furthermore, patients improved several additional indicators of health, such as lowered HbA1c levels, weight loss, and waist slimming and reported improved mood and energy during fasting days (6). Obvious limitations of this study include the small sample size and more research must be conducted to further establish the use of IF as a therapy for T2D.
While the previous two studies indicate a direct correlation between dieting and both the regression of T2D along with the improvement of metabolic indicators, it is not clear if these effects are solely due to weight loss or if IF itself plays an important role in the treatment of T2D. A study by Sutton et. al looked to see whether a specific type of IF that restricted eating from 9am-3pm, called early time-restricted feeding (eTRF), would improve cardiometabolic health even when accounting for weight loss (13). Early IF was demonstrated to improve many factors influencing the development of T2D, including cellular sensitivity to insulin and beta cell function, lowered blood pressure, lowered oxidative stress, and lower evening appetite, thus demonstrating that weight loss itself is not the primary mechanism for regression of T2D and improved cardiometabolic health during IF (6, 10, 13).
While the previous two studies indicate a direct correlation between dieting and both the regression of T2D along with the improvement of metabolic indicators, it is not clear if these effects are solely due to weight loss or if IF itself plays an important role in the treatment of T2D. A study by Sutton et. al looked to see whether a specific type of IF that restricted eating from 9am-3pm, called early time-restricted feeding (eTRF), would improve cardiometabolic health even when accounting for weight loss (13). Early IF was demonstrated to improve many factors influencing the development of T2D, including cellular sensitivity to insulin and beta cell function, lowered blood pressure, lowered oxidative stress, and lower evening appetite, thus demonstrating that weight loss itself is not the primary mechanism for regression of T2D and improved cardiometabolic health during IF (6, 10, 13).
intermittent fasting and alzheimer's disease
Alzheimer’s disease is currently the sixth leading cause of death in America but is estimated as the third leading cause of death in older populations (1). The four pillars of Alzheimer’s prevention include diet and supplements, physical and mental exercise, yoga and meditation, and psychological well-being (8). Although substantial research has been conducted on the contents of diet, research is lacking on the effects of the timing of consumption as a preventative measure for Alzheimer’s disease. There is substantial literature on the effects of intermittent fasting and Alzheimer’s disease in animal studies, but Alzheimer’s research is difficult on humans (9, 12, 13, 16)
In mice studies, IF was shown to enhance the brain and heart’s resistance to stress, along with other neurological diseases including Alzheimer’s, Parkinson’s and Huntington’s diseases (20). In mice with induced Alzheimer’s disease (AD), IF slowed the deterioration of cognitive function including an increase in both short-term and long-term memory function by slowing the accumulation of amyloid-beta proteins by increased hippocampal insulin signaling (13). In several mice studies, IF has been established as having protective benefits against AD (19). However, the mechanisms are highly complex and many remain unclear (19). IF has been shown to result in an increase of beta-hydroxybutyrate levels, which has been shown to demonstrate some protection against AD (14, 16). It remains unclear if this is the primary mechanism for IF protection against AD, as researchers have also described another mechanism, where ADF in mice maintains aquaporin-4 polarity, thus maintaining amyloid-beta clearance (19).
In mice studies, IF was shown to enhance the brain and heart’s resistance to stress, along with other neurological diseases including Alzheimer’s, Parkinson’s and Huntington’s diseases (20). In mice with induced Alzheimer’s disease (AD), IF slowed the deterioration of cognitive function including an increase in both short-term and long-term memory function by slowing the accumulation of amyloid-beta proteins by increased hippocampal insulin signaling (13). In several mice studies, IF has been established as having protective benefits against AD (19). However, the mechanisms are highly complex and many remain unclear (19). IF has been shown to result in an increase of beta-hydroxybutyrate levels, which has been shown to demonstrate some protection against AD (14, 16). It remains unclear if this is the primary mechanism for IF protection against AD, as researchers have also described another mechanism, where ADF in mice maintains aquaporin-4 polarity, thus maintaining amyloid-beta clearance (19).
Conclusion
Although there are significant gaps, especially on human clinical trials, in research on IF and its effects on obesity, T2D, and AD, IF is a strong treatment for obesity and may have potential as a powerful preventative measure, and perhaps treatment, for T2D and AD . IF was demonstrated to match CER, the predominant form of dieting, in terms of weight loss, fat mass reduction, and other indicators of obesity regression. Additionally, IF was demonstrated to result in regression of T2D in two, small studies. Thus, it is important for IF to be further studied as a treatment for T2D in order to establish IF as a strong therapy for T2D. IF’s effects on cardiometabolic health are not solely due to weight loss, as eTRF was demonstrated to result in improved insulin sensitivity, pancreatic beta cell responsiveness, blood pressure, oxidative stress, and appetite, even in the absence of weight loss. Finally, IF was shown in various animal studies to prevent the onset of AD, although the mechanisms and whether this information can be further applied to humans remains unclear. Ultimately, further research must be completed to establish IF as a strong therapy for T2D and AD, but there is strong potential for IF as both a preventative measure and treatment for these diseases.
works cited
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2. Bhaskaran, K., Douglas, I., Forbes, H., Dos-Santos-Silva, I., Leon, D. A., & Smeeth, L. (2014). Body-mass index and risk of 22 specific cancers: A population-based cohort study of 5·24 million UK adults. The Lancet,384(9945), 755-765. doi:10.1016/s0140-6736(14)60892-8
3. Estimates of Diabetes and Its Burden in the United States. (2017). National Diabetes Statistics Report.
4. Expert panel report: Guidelines (2013) for the management of overweight and obesity in adults. (2014). Obesity,22(S2). doi:10.1002/oby.20660
5. Finkelstein, E. A., Trogdon, J. G., Cohen, J. W., & Dietz, W. (2009). Annual Medical Spending Attributable To Obesity: Payer-And Service-Specific Estimates. Health Affairs,28(5). doi:10.1377/hlthaff.28.5.w822
6. Furmli, S., Elmasry, R., Ramos, M., & Fung, J. (2018). Therapeutic use of intermittent fasting for people with type 2 diabetes as an alternative to insulin. BMJ Case Reports. doi:10.1136/bcr-2017-221854
7. Hales, C., Carroll, M., Fryer, C., & Ogden, C. (2017, October 13). National Center for Health Statistics. Retrieved from https://www.cdc.gov/nchs/products/databriefs/db288.htm
8. Khalsa, D., & Perry, G. (2017). The Four Pillars of Alzheimer’s Prevention. Cerebrum.
9. Patterson, R. E., Laughlin, G. A., Lacroix, A. Z., Hartman, S. J., Natarajan, L., Senger, C. M., . . . Gallo, L. C. (2015). Intermittent Fasting and Human Metabolic Health. Journal of the Academy of Nutrition and Dietetics, 115(8), 1203-1212. doi:10.1016/j.jand.2015.02.018
10. Lean, M. E., Leslie, W. S., Barnes, A. C., Brosnahan, N., Thom, G., & McCombie, L. (2018). Primary care-led weight management for remission of type 2 diabetes (DiRECT): An open-label, cluster-randomised trial. The Lancet,391(10120), 541-551. Retrieved May 11, 2019.
11. Seimon, R. V., Roekenes, J. A., Zibellini, J., Zhu, B., Gibson, A. A., Hills, A. P., . . . Sainsbury, A. (2015). Do intermittent diets provide physiological benefits over continuous diets for weight loss? A systematic review of clinical trials. Molecular and Cellular Endocrinology,418, 153-172. doi:10.1016/j.mce.2015.09.014
12. Shin, B. K., Kang, S., Kim, D. S., & Park, S. (2018). Intermittent fasting protects against the deterioration of cognitive function, energy metabolism and dyslipidemia in Alzheimer’s disease-induced estrogen deficient rats. Experimental Biology and Medicine,243(4), 334-343. doi:10.1177/1535370217751610
13. Sutton, E. F., Beyl, R., Early, K. S., Cefalu, W. T., Ravussin, E., & Peterson, C. M. (2018). Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes. Cell Metabolism,27(6). doi:10.1016/j.cmet.2018.04.010
14. Tarasoff-Conway, J., Carare, R., Osorio, R., Glodzik, L., Butler, T., Fieremans, E., . . . Frangione, B. (2015). Clearance systems in the brain-implications for Alzheimer disease. Nature Reviews Neurobiology,457-470.
15. Trepanowski, J. F., Kroeger, C. M., Barnosky, A., Klempel, M. C., Bhutani, S., Hoddy, K. K., . . . Varady, K. A. (2017). Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese Adults. JAMA Internal Medicine,177(7), 930. doi:10.1001/jamainternmed.2017.0936
16. Wang, X., Liu, Q., Zhou, J., Wu, X., & Zhu, Q. (2017). β hydroxybutyrate levels in serum and cerebrospinal fluid under ketone body metabolism in rats. Experimental Animals,66(2), 177-182. doi:10.1538/expanim.16-0090
17. Wilding, J. P. (2014). The importance of weight management in type 2 diabetes mellitus. International Journal of Clinical Practice,68(6), 682-691. doi:10.1111/ijcp.12384
18. Wu, Y., Ding, Y., Tanaka, Y., & Zhang, W. (2014). Risk Factors Contributing to Type 2 Diabetes and Recent Advances in the Treatment and Prevention. International Journal of Medical Sciences,11(11), 1185-1200. doi:10.7150/ijms.10001
19. Zhang, J., Zhan, Z., Li, X., Xing, A., Jiang, C., Chen, Y., . . . An, L. (2017). Intermittent Fasting Protects against Alzheimer’s Disease Possible through Restoring Aquaporin-4 Polarity. Frontiers in Molecular Neuroscience,10. doi:10.3389/fnmol.2017.00395
20. Mattson, M. P., Longo, V. D., & Harvie, M. (2017). Impact of intermittent fasting on health and disease processes. Ageing Research Reviews,39, 46-58. doi:10.1016/j.arr.2016.10.005
2. Bhaskaran, K., Douglas, I., Forbes, H., Dos-Santos-Silva, I., Leon, D. A., & Smeeth, L. (2014). Body-mass index and risk of 22 specific cancers: A population-based cohort study of 5·24 million UK adults. The Lancet,384(9945), 755-765. doi:10.1016/s0140-6736(14)60892-8
3. Estimates of Diabetes and Its Burden in the United States. (2017). National Diabetes Statistics Report.
4. Expert panel report: Guidelines (2013) for the management of overweight and obesity in adults. (2014). Obesity,22(S2). doi:10.1002/oby.20660
5. Finkelstein, E. A., Trogdon, J. G., Cohen, J. W., & Dietz, W. (2009). Annual Medical Spending Attributable To Obesity: Payer-And Service-Specific Estimates. Health Affairs,28(5). doi:10.1377/hlthaff.28.5.w822
6. Furmli, S., Elmasry, R., Ramos, M., & Fung, J. (2018). Therapeutic use of intermittent fasting for people with type 2 diabetes as an alternative to insulin. BMJ Case Reports. doi:10.1136/bcr-2017-221854
7. Hales, C., Carroll, M., Fryer, C., & Ogden, C. (2017, October 13). National Center for Health Statistics. Retrieved from https://www.cdc.gov/nchs/products/databriefs/db288.htm
8. Khalsa, D., & Perry, G. (2017). The Four Pillars of Alzheimer’s Prevention. Cerebrum.
9. Patterson, R. E., Laughlin, G. A., Lacroix, A. Z., Hartman, S. J., Natarajan, L., Senger, C. M., . . . Gallo, L. C. (2015). Intermittent Fasting and Human Metabolic Health. Journal of the Academy of Nutrition and Dietetics, 115(8), 1203-1212. doi:10.1016/j.jand.2015.02.018
10. Lean, M. E., Leslie, W. S., Barnes, A. C., Brosnahan, N., Thom, G., & McCombie, L. (2018). Primary care-led weight management for remission of type 2 diabetes (DiRECT): An open-label, cluster-randomised trial. The Lancet,391(10120), 541-551. Retrieved May 11, 2019.
11. Seimon, R. V., Roekenes, J. A., Zibellini, J., Zhu, B., Gibson, A. A., Hills, A. P., . . . Sainsbury, A. (2015). Do intermittent diets provide physiological benefits over continuous diets for weight loss? A systematic review of clinical trials. Molecular and Cellular Endocrinology,418, 153-172. doi:10.1016/j.mce.2015.09.014
12. Shin, B. K., Kang, S., Kim, D. S., & Park, S. (2018). Intermittent fasting protects against the deterioration of cognitive function, energy metabolism and dyslipidemia in Alzheimer’s disease-induced estrogen deficient rats. Experimental Biology and Medicine,243(4), 334-343. doi:10.1177/1535370217751610
13. Sutton, E. F., Beyl, R., Early, K. S., Cefalu, W. T., Ravussin, E., & Peterson, C. M. (2018). Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes. Cell Metabolism,27(6). doi:10.1016/j.cmet.2018.04.010
14. Tarasoff-Conway, J., Carare, R., Osorio, R., Glodzik, L., Butler, T., Fieremans, E., . . . Frangione, B. (2015). Clearance systems in the brain-implications for Alzheimer disease. Nature Reviews Neurobiology,457-470.
15. Trepanowski, J. F., Kroeger, C. M., Barnosky, A., Klempel, M. C., Bhutani, S., Hoddy, K. K., . . . Varady, K. A. (2017). Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese Adults. JAMA Internal Medicine,177(7), 930. doi:10.1001/jamainternmed.2017.0936
16. Wang, X., Liu, Q., Zhou, J., Wu, X., & Zhu, Q. (2017). β hydroxybutyrate levels in serum and cerebrospinal fluid under ketone body metabolism in rats. Experimental Animals,66(2), 177-182. doi:10.1538/expanim.16-0090
17. Wilding, J. P. (2014). The importance of weight management in type 2 diabetes mellitus. International Journal of Clinical Practice,68(6), 682-691. doi:10.1111/ijcp.12384
18. Wu, Y., Ding, Y., Tanaka, Y., & Zhang, W. (2014). Risk Factors Contributing to Type 2 Diabetes and Recent Advances in the Treatment and Prevention. International Journal of Medical Sciences,11(11), 1185-1200. doi:10.7150/ijms.10001
19. Zhang, J., Zhan, Z., Li, X., Xing, A., Jiang, C., Chen, Y., . . . An, L. (2017). Intermittent Fasting Protects against Alzheimer’s Disease Possible through Restoring Aquaporin-4 Polarity. Frontiers in Molecular Neuroscience,10. doi:10.3389/fnmol.2017.00395
20. Mattson, M. P., Longo, V. D., & Harvie, M. (2017). Impact of intermittent fasting on health and disease processes. Ageing Research Reviews,39, 46-58. doi:10.1016/j.arr.2016.10.005
