The Paleo Advantage - Insulin Resistance

The Paleo Advantage in T2DM and the Obesity Epidemic – Lessons in Human Metabolism

By Dr. Chrystyne Olivieri February 2019

Diabetes has become a major health epidemic around the world, accelerating in numbers in recent years. Based on the CDC in 2017, more than half the U.S. population has diabetes or prediabetes.  The most recent data from the CDC National Diabetes Statistics Report of 2017 states that 84 million Americans over the age of 18 (34% of the U.S. adult population) have prediabetes with about 90% being unaware 1. 

This CDC report states that over 30 million Americans of all ages (9.4% of the U.S. population) has diabetes in 2015. This data also reflects that 12.2% of American adults have diabetes, of which 7.2 million (23.8%) remain unaware. Cases of diagnosed diabetes in the United States have increased from 5.6 million persons in 1980 to 23.1 million in 2015. In the 65 year old and older group, over 25% have diabetes as this disease increases in prevalence with age. There is a higher prevalence among non-Hispanic black, non-Hispanic Asian and Hispanic individuals 1. Unfortunately, the incidence of American adults with diabetes has continued to climb for decades and is expected to reach 1 in 3 Americans (33%) by 2050 2. 

There is so much conflicting data and information in the fields of weight loss, obesity and diabetes. It has been difficult for APRNs to really know what a healthy diet should be for individuals who are obese or have Type 2 Diabetes (T2DM) or prediabetes. There are a multitude of diets on the internet to lose weight. Recently the American Diabetes Association (ADA) changed their focus on nutrition which used to suggest use of the ADA diet to using an individualized approach to dietary needs. This article will discuss some information provided from research over the last 75 years about sugar and fat and the interpretation provided. Much of what is accepted as fact regarding diet and cardiovascular disease (CVD), diabetes and obesity comes from the original research done by Ancel Keys in the 1950’s and his 7 Countries Study 3. However, the information provided by Keys research is questionable due to his misunderstanding of human metabolism as compared to what is known today. Unfortunately, much of this misinformation persists until today.

Among APRNs and other healthcare providers, proper diagnosis and management of diabetes requires a steep learning curve and consumes an exorbitant amount of time spent with patients. Because of that, many healthcare providers do what they can, however it is not enough. The facts surrounding the rise in obesity and Type 2 Diabetes are rooted deep in our misunderstanding of human metabolism. Other diseases also affected by elevated blood glucose include CVD, Non-alcoholic Fatty Liver Disease (NAFLD) and Alzheimer’s Disease (AD) 4,5,6 among others. These diseases are closely related because they are all related to elevated blood glucose.

In the world of Functional Medicine, many agree they are all the same disease; just with different manifestations 7,8. Functional Medicine is an approach to healthcare where the cause of the disease is uncovered and addressed. In contrast, Conventional Medicine has focused on symptom alleviation, usually relegating to a treatment plan utilizing pharmaceutical interventions. The cause of many chronic diseases like T2DM, prediabetes and obesity is often lifestyle choices and requires a more patient focused approach. These are diseases of lifestyle and lifestyle modifications should be the main focus in treatment and management. Because of the traditional approach to patient care, the trends in the rise of obesity and related diseases have been on an upward trajectory for almost 30 years, with no end in sight 9,10.

 Therefore, it makes sense that lifestyle modifications have consistently been associated with significant improvements in obesity, T2DM and CVD 11. The “Framingham Heart Study”, a multi-generational, ongoing observational health and diet research study began looking at diet and subsequent disease development of participants within the town of Framingham, Massachusetts in 1948 12. The objective was to identify common factors and characteristics that contribute to the development of lifestyle diseases such as CVD. It continues to this day to make important scientific contributions to our understanding of the causes of heart disease. The following statement was made by the director of the study after 44 years of scientific observations:

“In Framingham, Massachusetts, the more saturated fat one ate, the more cholesterol one ate, the more calories one ate, the lower people’s serum cholesterol…we found that the people who ate the most cholesterol, ate the most saturated fat, ate the most calories, weighed the least and were the most physically active”.

Dr. William Castelli, Editorial for the Archives of Internal Medicine, July 1992, pg. 1371-1372 13

Armed with this knowledge, perhaps our current understanding of a healthy diet needs to change. It appears that commonly health beliefs are founded in the information from the American Heart Association (in which Ancel Keys was on the original board) and the U.S. Department of Agriculture “Dietary Guidelines for Americans” which has been updated every 5 years since 1980 14,15. Over the course of the last 35 years, public beliefs and research data about dietary sugar and fat have changed. With the help of new research, the answer lies in understanding how the human body uses the two main fuel sources: sugar (glucose, fructose) and fat (dietary as well as triglycerides) as this is imperative to combating the obesity problem.  

HUMAN METABOLISM: 

Metabolism refers to how the human body uses food for fuel. Basic human metabolism consists of a very specific interplay of hormonal signaling occurring in response to foods consumed. For APRNs, helping patients be successful in long term weight loss requires a more in-depth understanding of specific hormones. Insulin is one of the key hormones involved in weight gain and weight loss. Insulin needs to be addressed when discussing obesity and weight loss. The reason why traditional “low calorie” diets fail is that they do not address insulin. Traditional calorie restriction diets may be effective for short term weight loss, however with these types of diets, the body eventually slows down the basal metabolic rate (BMR) in response to months of calorie restriction. This is a protective mechanism to prevent starvation as the only time humans ever ate less calories was during times of reduced food access. Due to slowing BMR, a plateau of weight loss will soon follow. This often can make an individual stop “dieting” as it can become frustrating when weight loss fails to progress. And what follows is even worse. They often return to prior “high carbohydrate” eating patterns, dumping a lot of carbohydrates into a “damaged” metabolism, causing even more weight gain due to elevated insulin. Short term, low-calorie diets may work for some, but the weight loss doesn’t last for most, and it’s because of insulin 16.

As a hormone, insulin is key in keeping blood glucose within normal limits. It is released from the beta cells of the pancreas and allows muscles, fat and liver cells to absorb glucose that is in the blood. This serves as energy to these cells, but it can also be converted to fat if not needed. Because of this, it is not incorrect to think of insulin as a hormone of fat storage. This has historically been quite successful in the survival of our species. Based on what we know of our ancestors, our human DNA has not changed much in the last 40,000 years 17,18. When pre-agricultural humans ate sugar, mainly from seasonal fruits, they would gorge and hopefully gain 20-40 pounds, mainly abdominal fat accumulation 19. Fruit was about the only carbohydrate available (capable of increasing insulin levels), and is still associated with increased insulin release when over-consumed. But what follows the fruit season is winter. Historically, human beings have ensured their long-term survival with the accumulation of abdominal adiposity from elevated sugar intake and subsequent elevated insulin levels (the hormone of fat storage) which made mid-winter starvation less likely. The individuals who gained more abdominal adiposity had a better chance to pass their genetics on to the next generation. This is the basis for the “Thrifty Gene Theory” 20.  

The “Thrifty Gene Theory”, originally studied by Neel, et al in 1998, discussed evidence that famines and food shortages have historically promoted a natural selection in favor of individuals genetically capable of storing more body fat when exposed to more carbohydrates. This results in higher insulin levels. The theory concludes that fertility is insured with surviving food shortages, hence propagating the species. More current research is being undertaken on a genetic level to provide validity to this theory 21. Unfortunately, the Thrifty Gene Theory has not been part of the mainstream accepted doctrine regarding gaining weight with carbohydrates. 

When sugar and carbohydrates are consumed, insulin is released in response to elevations in blood sugar. Foods with a higher glycemic index will raise blood glucose higher and faster than those with a lower glycemic index 22. The Glycemic Index is a comparison of carbohydrate foods based on how fast and how high they can affect blood glucose levels. According to the ADA, foods are considered to be “high glycemic” if they rate >50 on a scale of 1-100. These foods are best avoided in a low carbohydrate diet and include most grain products like bread, pasta, cereals, rice, corn and starchy potatoes. The lowest glycemic index carbohydrates include non-starchy vegetables. Consuming a low carbohydrate diet which includes carbohydrates mainly from vegetables such as green beans or broccoli, it will not encourage weight gain compared to a diet high in rice, pasta or bread. And the reason is insulin. Eating foods which require more insulin release like carbohydrates from sugar, fruits, grains and starchy vegetables sends hormonal signals within the body (just like the caveman in the summer) to go into fat-storage. In the modern world, near starvation does not happen yearly, so modern humans stay in elevated insulin levels and subsequent fat storage chronically. This eventually increases the body’s “set-point” of weight, causing weight loss to become even more elusive, leading to insulin resistance.

Resistance is caused by chronic exposure. Whatever the human body is exposed to enough has the ability to cause resistance. Antibacterial resistance, becoming an alarming public health crisis, is now common due to the over exposure to antibiotics in food production and in medicine. It is causing subsequent antibiotic resistance 23. It is now even being seen in other pharmaceuticals like cancer drugs 24. However, this also happens with insulin. Chronic exposure to insulin from over consumption of sugars and high glycemic index carbohydrates promotes abdominal fat development. Eventually, insulin resistance (IR) develops 25. Some humans from specific genetic lines do not even need a lot of abdominal fat to develop IR. An example is Asian Indians with T2DM are often much leaner than their American counterparts 26. If IR goes on unchecked for long enough, T2DM develops. And if T2DM goes unchecked, glucotoxicity can develop 27. The term glucotoxicity refers to the prolonged or repeated exposure to elevated blood glucose and it exerts deleterious or toxic effects on the insulin producing beta-cells of the pancreas. This is when A1c levels rise above 10%, considered well out-of-control T2DM.

However, contrary to popular belief, T2DM is not a disease of elevated blood glucose. Blood glucose can become well controlled with many different pharmaceuticals as well as the use of insulin injections. The reality is that T2DM is a disease of IR with elevated blood glucose simply being a symptom. Therefore, giving a person MORE insulin (or insulin producing medications like sulfonylureas) just compounds the problem of insulin resistance. Since the beginning of the diabetes crisis, medical providers have been addressing the problem of symptom management and not the disease of insulin resistance.

GLUCOSE OR FAT:

As Dr. Peter Attia said in his Ted Talk video:

“You can think of insulin as this master hormone that controls what our body does with the foods we eat, whether we burn it or store it. Once you’re insulin-resistant, you’re on your way to getting diabetes. So, what if we’re fighting the wrong war, fighting obesity rather than insulin resistance?” 28

The answer to this dilemma is NOT necessarily pharmaceutical interventions, although that is sometimes required. The answer is to stop the chronic flow of insulin within the human body. When insulin levels drop low enough, the body switches from sugar metabolism to fat metabolism 29. Burning fat for energy can only take place when insulin levels are very low and after glucose stores have been used up sufficiently. Like a hybrid engine in a car, the human body can use sugar or fat for fuel 30. The body burns fat far more efficiently than carbohydrates (sugar). 

APRNs have long understood that the human diet consists of three macronutrients: Fats, Protein and Carbohydrates. Carbohydrates burn at 4 calories/gram, but fat is burned at 9 calories/gram. That means fat provides 125% more energy than carbohydrates. Protein is the last to be used as fuel, burning at 4 calories/gram, as it is needed for building muscle and bone, producing antibodies, restoring organs, blood vessels and nerves, and creating hormones and neurotransmitters. But calories are not the most accurate measure of energy. Calories must be converted to a more basic fuel source: adenosine triphosphate (ATP).

Glucose and fructose molecules produce exactly 36 ATP, medium-chain fatty acids (fats) produce 50 ATP and long-chain fatty acids (also fats) produce 155 ATP 31.  By this measure, fat is a FAR more efficient fuel source than sugar. Also, since most of the fat stored in and on the human body consists of triglycerides (one glycerol molecule and three long-chain fatty acids), every molecule of body fat that is burned can produce 465 units of ATP. Compare that to the measly 36 ATP you get from carbohydrates. This is why switching to a high-fat diet often causes energy levels to soar!

If the human body has become a “sugar burner”, it has been systematically trained to need to refuel often as it becomes reliant on fast-burning fuel. This can affect mood, hunger and energy levels like being on a roller coaster all day long. It also causes chronically elevated insulin levels, chronic fat storage mode, weight gain and tempts T2DM development.

When the human body is trained to be a “fat burner”, historically the human body’s preferred fuel source, overall food intake is eventually reduced. There is also more body fat loss without muscle loss during fat metabolism 32,33. Carbohydrate cravings disappear and chronic hunger diminishes. Since overall food intake is reduced, all food consumed needs to have much higher nutritional value: vegetables, some fruit in season, nuts, healthy fats, animal protein from animals fed a natural diet. The human body can go hours between meals, hunger is low, energy levels are high and there is virtually NO fat storage occurring. 

An Ancestral Diet, or one that mimics our ancestors such as the Paleo diet, includes minimal dietary sugars, lots of vegetables, protein from healthy animals and more healthy fats. Consuming more healthy fat sources is also very anti-inflammatory as it decreases glycation and oxidation of free radicals. Glycation is the non-enzymatic reaction between a protein and a sugar. It is believed that excessive glycation is at the root cause of endothelial damage leading to plaque development and CVD as well as other age-related diseases 34. Eating little to no sugar and more healthy fat also encourages the release of ketone bodies, resulting in ketosis. The Paleo diet can result in ketones, which is very high-quality fuel (this is NOT the same as ketoacidosis, which occurs in the absence of insulin, such as in undiagnosed type 1 diabetes). Studies have shown that the brain works just as well on ketones as it does on glucose 35. This may explain why studies of ketosis on cognitive decline are so exciting as a possible treatment for AD 36. Research on disease prevention and symptom improvement using a keto diet has improved chronic diseases like epilepsy, attention deficit/ hyperactivity disorder, AD, migraines, acne and cancer 37,38,39. In cancer treatment, the keto diet is particularly promising as tumor growth is dependent upon sugar 40,41.

Adopting an Ancestral Diet such as Paleo, is a very healthy option because it is so consistent with our DNA as human beings 42,43.  It is a natural human diet. For over 2.5 million years of human evolution, sugars and high glycemic index carbohydrates were nowhere to be found. Of course, climate dictates food sources and percentages of macronutrients (fats, proteins and carbohydrates) vary. The Paleo diet includes a variety of wild, non-starchy and high-fiber root vegetables daily. Fruit is only eaten seasonally 44. No grain products are consumed as it was not until the agricultural revolution that humans began cultivating grains 45. This started about 8-10,000 years ago. Grains did not make their way around the globe until around 3-4,000 years ago 46. To say that the human body has become acclimated to grains as a fuel source is incorrect.

IN CONCLUSION:

Making lifestyle changes is hard. We become very used to what we are exposed to 

enough and start to believe it is the way it’s always been. Humans have only been eating a diet high in processed foods for 5-7 generations. But when considering lifestyle changes such as diet, where you get your information comes is important. With many diets available, many touting their superiority over the others, addressing lifestyle changes and making them long-term is paramount.

A diet which mimics that of our ancient ancestors has validity for improved health in our current, modern culture of processed foods, fast foods and artificial foods. Armed with this knowledge, APRNs can help influence their patient’s health and encourage lifestyle modifications towards dietary changes which reflect what human beings have thrived on for tens of thousands of years. Changing from our current culture of poor diet high in processed foods, sugar, simple carbohydrates, artificial sweeteners and other chemicals is not conducive with human health. Health care providers have become too complacent with watching patients getting older and becoming sicker and diet plays a huge part in that scenario.  Any changes in lifestyle should be made incrementally. Small changes made today can translate into more being made in the future, resulting in improved health outcomes. To get started in making lifestyle changes, refer to table 3 which outlines the 12 tenants of a Paleo lifestyle. APRNs can help patients to make some changes today and reserve the more difficult ones for later, always keeping an eye on eventually achieving each one for the best results. 

Human beings are a very successful species. We have been around for 2.5 million years and we now dominate the Earth. We have manipulated our environment to fit our needs in such a short period of time - so much to the point that we no longer live the natural, healthy lives enjoyed by our ancestors. Sugar and salt dominate the American diet rather than vegetables and healthy sources of animal products which are so high in nutritional value. These changes to our environment and food sources have happened so recently and this is in strict contrast to our ancient DNA, which has not yet caught up to our modern lifestyles. As research is ongoing into what constitutes a healthy diet for human beings, certain things have remained constant throughout human history: 

1. We did not eat every day

2. Famine was common

3. Carbohydrates were never a large source of calories

4. A diet high in healthy animal protein and fats carried out species for much of our evolution. 

APRNs are often seeing patient in primary care, making them well suited to providing 

high quality preventative medical advice. Mimicking the diet of our ancient ancestors to the best of our ability in our modern world is a good way to improve our health and avoid the chronic diseases of westernized civilization. 

References

1. CDC.gov/diabetes. National Diabetes Statistics Report Retrieved August, 15, 2018 from https://www.cdc.gov/diabetes/data/stastistics/statistics-report.html 

2. Boyle, J. P., Thompson, T. J., Gregg, E. W., Barker, L. E., & Williamson, D. F. (2010). Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Population Health Metrics, 8, 29-29. doi: 10.1186/1478-7954-8-29

3. Keys, A. (1980). Seven countries. A multivariate analysis of death and coronary heart disease: Harvard University Press.

4. de la Monte, S. M., & Wands, J. R. (2008). Alzheimer's disease is type 3 diabetes—evidence reviewed. Journal of diabetes science and technology, 2(6), 1101-1113. 

5. Martins, I. J. (2016). Type 3 diabetes with links to NAFLD and Other Chronic Diseases in the Western World. 

6. Shah, A. D., Langenberg, C., Rapsomaniki, E., Denaxas, S., Pujades-Rodriguez, M., Gale, C. P., . . . Hemingway, H. (2015). Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1· 9 million people. The Lancet Diabetes & Endocrinology, 3(2), 105-113. 

7. Hyman, M., The Myth of Diagnosis. Retrieved July 25, 2018 from https://drhyman.com/blog/2018/05/04/the-myth-of-diagnosis/

8. IFM.org: Functional Medicine Institute. What is Functional Medicine? Retrieved July 25, 2018 from https://www.ifm.org/functional-medicine/what-is-functional-medicine/

9. Finkelstein, E. A., Khavjou, O. A., Thompson, H., Trogdon, J. G., Pan, L., Sherry, B., & Dietz, W. (2012). Obesity and severe obesity forecasts through 2030. American Journal Of Preventive Medicine, 42(6), 563-570.

10. Ng, M., Fleming, T., Robinson, M., Thomson, B., Graetz, N., Margono, C., . . . Abera, S. F. (2014). Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. The Lancet, 384(9945), 766-781.

11. Liu, G., Li, Y., Hu, Y., Zong, G., Li, S., Rimm, E. B., . . . Shin, H. J. (2018). Influence of Lifestyle on Incident Cardiovascular Disease and Mortality in Patients With Diabetes Mellitus. J Am Coll Cardiol, 71(25), 2867-2876. 

12. Mahmood, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. The Lancet, 383(9921), 999-1008. 

13. Castelli, W. P. (1992). Concerning the possibility of a nut. Arch Intern Med, 152(7), 1371-1372.

14. ODPHP (2015). Office of Disease Prevention and Health Promotion. Food & Nutrition - Previous Dietary Guidelines. Retrieved August 21, 2018 from https://health.gov/dietaryguidelines/

15. Mozaffarian, D., & Ludwig, D. S. (2015). The 2015 US Dietary Guidelines: Lifting the Ban on Total Dietary Fat. JAMA, 313(24), 2421-2422. 

16. Lips, M. A., de Groot, G. H., van Klinken, J. B., Aarts, E., Berends, F. J., Janssen, I. M., . . . Van Dielen, F. (2014). Calorie restriction is a major determinant of the short‐term metabolic effects of gastric bypass surgery in obese type 2 diabetic patients. Clin Endocrinol (Oxf), 80(6), 834-842. 

17. Eaton, S. B. (2006). The ancestral human diet: what was it and should it be a paradigm for contemporary nutrition? Proceedings of the Nutrition Society, 65(01), 1-6. 

18. Krishnaswamy, K. (2012). Evolutionary aspects of diets in the context of current chronic diseases. Bulletin of the Nutrition Foundation of India, 33(1). 

19. Knight, C. (2011). “Most people are simply not designed to eat pasta”: evolutionary explanations for obesity in the low-carbohydrate diet movement. Public understanding of science, 20(5), 706-719. 

20. Neel, J. V., Weder, A. B., & Julius, S. (1998). Type II diabetes, essential hypertension, and obesity as" syndromes of impaired genetic homeostasis": the" thrifty genotype" hypothesis enters the 21st century. Perspectives in biology and medicine, 42(1), 44-74. 

21. Prentice, A.M., B.J. Hennig, and A.J. Fulford. “Evolutionary Origins of the Obesity Epidemic. Natural Selection of Thrifty Genes or Genetic Drift Following Predation Release?” International Journal of Obesity 32 (2008): 1607.

22. Schwingshackl, L., & Hoffmann, G. (2013). Long-term effects of low glycemic index/load vs. high glycemic index/load diets on parameters of obesity and obesity-associated risks: a systematic review and meta-analysis. Nutrition, Metabolism and Cardiovascular Diseases, 23(8), 699-706. 

23. Zahar, J.-R., & Lesprit, P. (2014). Management of multidrug resistant bacterial endemic. Medecine et maladies infectieuses, 44(9), 405-411. 

24. Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. (2013). Cancer drug resistance: an evolving paradigm. Nature Reviews Cancer, 13(10), 714.

25. Shulman, G. I. (2014). Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. New England Journal of Medicine, 371(12), 1131-1141. 

26. Premanath, M., Basavanagowdappa, H., Mahesh, M., & Suresh, M. (2014). Correlation of abdominal adiposity with components of metabolic syndrome, anthropometric parameters and Insulin resistance, in obese and non obese, diabetics and non diabetics: A cross sectional observational study.(Mysore Visceral Adiposity in Diabetes Study). Indian journal of endocrinology and metabolism, 18(5), 676. 

27. Bensellam, M., Laybutt, D. R., & Jonas, J. C. (2012). The molecular mechanisms of pancreatic β-cell glucotoxicity: recent findings and future research directions. Molecular and cellular endocrinology, 364(1-2), 1-27.

28. Attia, Peter, M.D. June, 2013. What if we’re wrong about diabetes? Ted Talk. retrieved from https://youtu.be/UMhLBPPtlrY

29. Cox, P. J., Kirk, T., Ashmore, T., Willerton, K., Evans, R., Smith, A., . . . McLure, S. W. (2016). Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell metabolism, 24(2), 256-268. 

30. Prentki, M., Matschinsky, F. M., & Madiraju, S. M. (2013). Metabolic signaling in fuel-induced insulin secretion. Cell metabolism, 18(2), 162-185.

31. Lodish, H., Berk, A., Zipursky, S. L., Matsudaira, P., Baltimore, D., & Darnell, J. (2000). Oxidation of glucose and fatty acids to CO2. Chapter 16, Sections 16.1 to 16.16. https://www.ncbi.nlm.nih.gov/books/NBK21624/

32. Rego Costa A.C., Rosado E.L., & Soares-Mota, M. (2012) influence of the dietary intake of medium chain triglycerides on body composition, energy expenditure and satiety: a systematic review. Nutricion Hospitalaria, 27(1). 

33. Wang, Y., Liu, Z., Han, Y., Xu, J., Huang, W. & Li, Z. (2018) Medium Chain Triglycerides enhances exercise endurance through the increased mitochondrial biogenesis and metabolism. PloS one, 13(2), e0191182.

34. Yamagishi, S.-i., Maeda, S., Matsui, T., Ueda, S., Fukami, K., & Okuda, S. (2012). Role of advanced glycation end products (AGEs) and oxidative stress in vascular complications in diabetes. Biochimica et Biophysica Acta (BBA)-General Subjects, 1820(5), 663-671. 

35. Prince, A., Zhang, Y., Croniger, C., Puchowicz, M. (2013) “Oxidative metabolism: Glucose versus Ketones” in Oxygen Transport to Tissue XXXV, pp323-328 Springer, New York, NY

36. Cunnane, S. C., Courchesne-Loyer, A., Vandenberghe, C., St-Pierre, V., Fortier, M., Hennebelle, M., . . . Castellano, C.-A. (2016). Can ketones help rescue brain fuel supply in later life? Implications for cognitive health during aging and the treatment of Alzheimer’s disease. Frontiers in molecular neuroscience, 9, 53. 

37. Fernando, W. M. A. D. B., Martins, I. J., Goozee, K., Brennan, C. S., Jayasena, V., & Martins, R. N. (2015). The role of dietary coconut for the prevention and treatment of Alzheimer's disease: potential mechanisms of action. British Journal of Nutrition, 114(1), 1-14. 

38. Paoli, A., Rubini, A., Volek, J., & Grimaldi, K. (2013). Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. European journal of clinical nutrition, 67(8), 789. 

39. Rho, J. M. (2017). How does the ketogenic diet induce anti-seizure effects? Neuroscience letters, 637, 4-10. 

40. Allen, B. G., Bhatia, S. K., Anderson, C. M., Eichenberger-Gilmore, J. M., Sibenaller, Z. A., Mapuskar, K. A., . . . Fath, M. A. (2014). Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism. Redox biology, 2, 963-970.

41. Seyfried, T. N., Marsh, J., Shelton, L. M., Huysentruyt, L. C., & Mukherjee, P. (2012). Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer? Epilepsy research, 100(3), 310-326. 

42. Carrera-Bastos, P., Fontes-Villalba, M., O’Keefe, J. H., Lindeberg, S., & Cordain, L. (2011). The western diet and lifestyle and diseases of civilization. Res Rep Clin Cardiol, 2, 15-35. 

43. Eaton, S. B., & Konner, M. (1985). Paleolithic nutrition: a consideration of its nature and current implications. New England journal of medicine (USA). 

44. Brand-Miller, J., Mann, N., & Cordain, L. (2009). Paleolithic nutrition: what did our ancestors eat. Selinger A, Green A, editors(2009), 28-42. 

45. Cordain, L., Eaton, S. B., Sebastian, A., Mann, N., Lindeberg, S., Watkins, B. A., . . . Brand-Miller, J. (2005). Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr, 81(2), 341-354. 

46. Cordain, L. (1999). Cereal grains: Humanity s double-edged sword Evolutionary aspects of nutrition and health (Vol. 84, pp. 19-73): Karger Publishers.