To stay up to date on the cutting-edge of health and performance, H.V.M.N. Research Lead Dr. Brianna Stubbs tends to read a lot of scientific literature...a lot. Every month, she will dive into the latest and most exciting research papers by walking us through the experiment process, dissecting the results and implications, and candidly share her own thoughts on the study and subject as a whole.

This month, Dr. Stubbs dives into three papers that studied the effects of different types of fasting.

1. Therapeutic use of intermittent fasting for people with Type 2 diabetes as an alternative to insulin
2. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease
3. Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes

Featured researchers include Dr. Jason Fung, Dr. Valter Longo, & Dr. Courtney Peterson.

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Transcription

Overview

The three papers we'll be discussing today are based around intermittent fasting. Before we dive in, the first thing to note is that intermittent fasting is quite a broad term that covers quite a few different ways of not eating. One would think it would actually be kind of simple, but you can actually make this quite complicated.

First up there's water fasting. This would be the typically way that most people think about fasting. Means that you have nothing that contains calories, you just drink water. Water fast can last any duration, most people start off by following time restricted eating, which we'll discuss in a minute, and then moving to say a 24-hour or 36-hour fast. Some people allow tea and coffee on a water fast, as they don't contain calories, but others think that plant polyphenols and caffeine in these drinks might alter your metabolism enough that they actually would avoid those also. Another popular fasting crutch is bone broth. This contains minimal calories, as fat and protein, as well as electrolytes that you need during fasting. But there is a small amount of calories and a minimal incident response. So, overall, this can help people stick to their fast better, but it's not the same as straight up water fasting. Another crutch that people have been using is exogenous ketones like H.V.M.N. Ketone or ketone salts and this helps them stick to fasting. So there's different flavors of water fasting depending on how strict you want to get. Once you define whether or not you're gonna eat any calories or polyphenols or anything that's gonna alter your metabolism, you can then define your eating window.

Second up, there is alternative day fasting. This means you eat every other day, interspersing a feeding day with a day of fasting. Next up there is a feeding practice called OMAD or One Meal a Day. This means that you fast throughout the whole day and just eat one meal either in the middle or at the end of the day. Some people do a practice called fat fasting, which technically speaking if you're talking about avoiding caloric intake altogether, is not fasting, but these people really struggle not to eat anything at all, so they eat foods that only really contain fat such as bacon or avocados and then that helps them transition into more classical fasting. Whole point of eating mainly fat is that you do not trigger an insulin response with fatty foods. So, you kinda keep your metabolic processes as if you were on say, a ketogenic diet.

Next up, in terms of timing, is time restricted feeding and this means that you keep your food intake within a defined limit of time. So a popular example is 16/8 fasting where you might skip breakfast and eat two or three meals between, say, 12:00 noon and 8:00 PM.

Really, it isn't totally clear yet what metabolically differentiates all these different types of fasting. For example, how long do you need to fast before X benefit kicks in, when does autophagy start, how long does it take to get into ketosis? All of these different things might take different amounts of time for different people and each different process might have a different time scale, so it's difficult to say that you must always fast for 24-hours, or you must always fast for three days for example because we don't really know yet when the body starts to turn into some of these helpful metabolic processes. Also, is there the same benefit if you do consume small number of calories or what about calories as fat that don't spike insulin?

Really we're at quite an early stage with intermittent fasting. There are a number of studies that have been done to date that show a lot of interesting potential for fasting, but we really need to work out how different types of fasting can be used strategically for different end points. But I'm gonna frame up this conversation by saying that I'm quite a strong advocate of fasting because there's good scientific evidence that there are broad benefits for health and there's a very, very low risk and low barrier to entry, so anyone can start experimenting with it without much risk and see how it effects them.

We're gonna talk about three papers that look at different strategies that are related to intermittent fasting. Let's get cracking.

Therapeutic Use of Intermittent Fasting for People with Type 2 Diabetes as an Alternative to Insulin

The first one we're gonna talk about was written by a friend of ours at H.V.M.N., Dr. Jason Fung (check out our podcast episode w/ Dr. Jason Fung), and the paper's title is Therapeutic Use of Intermittent Fasting For People With Type 2 Diabetes As An Alternative To Insulin. Many of our listeners will know Dr. Jason Fung, he is a Canadian nephrologist, which means he specializes in the kidney, and he is a world leading expert on intermittent fasting and low carb, especially for treating people with type 2 diabetes. He's written three best selling health books and he co-founded the Intensive Dietary Management, IDM Program. If you actually listen back in some of our archives, you can hear an interview with Dr. Fung and he discusses all about his work with intermittent fasting and his clinical practice.

Dr. Fung, he's done the round on podcasts, he writes very popular blog on media and he's been very outspoken about the results that he's had in his clinic and the number of successes. But up until now, he's had a lot of skeptics really bashing him for not having had his results published in peer review journals and they ask him for his evidence, so this is actually the first time I've seen a case study published from Dr. Fung's IDM clinic. So I really wanted to share this with you because the results are really encouraging and really in keeping with everything that he's been talking about in his years of speaking about the topic.

I think one important thing that Dr. Fung talks about in the introduction to his paper is he points out the difference between fasting and starvation. He says that fasting is deliberate and controlled whereas starvation is not, and that really answers a common question I think that a lot of skeptics again raise like 'What's the difference between fasting and starvation?' This is a very planned out and very closely monitored protocol. He also highlights that fasting could be really important because insulin treatment has a very big financial burden on the people who have to buy and inject insulin daily and then also the lifestyle burden of having to constantly measure blood glucose and tailor your insulin and make decisions about your insulin dose based on your glucose every day for people who are using insulin.

This is a case study, which means it was not a full scale randomized and blinded clinical trial, so you do need to keep that in mind when we interpret the results that are discussed here. The paper describes the management of three patients at Jason Fung's clinic at the IDM. He had two patients who did 24-hour alternate day fasting, so 24-hour fast, 24-hours feeding, and one patient who did three days a week of 24-hour fasting, so it's not really that different. I suppose it's just one patient two consecutive days of feeding and the others were consistently alternate day fasting.

Now on their fasting days, all of the patients described were allowed to consume low calorie fluids, and also to eat a low calorie, low carbohydrate dinner. So on fasting days, the patients consumed only dinner, and on non fasting days, the patients consumed lunch and dinner. Note that they did also skip breakfast. Low carbohydrate meals were recommended for meals generally so they're not on a pure ketogenic diet, but they're being advised to cut down on their carbohydrate intake.

Throughout this study, the patients daily blood sugar diaries were reviewed, and they made adjustments to their medications in conjunction with a medical doctor. That's a really important thing to note, the patients did receive regular medical monitoring, which is really important if you're controlling your diabetes with insulin. You need to make sure that you're getting supervision as you try and make changes to your regime.

The key result that the author was most excited about was that in all three patients, they were able to completely discontinue insulin therapy, which to go back to what we were saying earlier represents a huge relief of the financial burden of having to purchase insulin, and also the lifestyle burden of having to inject it. What's more, clinical studies that have looked at very intensive insulin therapy compared with no insulin therapy have shown that how intensively managing blood sugar with insulin can cause more negative side effects and poorer outcomes along the line. Two of the three patients discontinued all of their medications, and one discontinued three out of four of their medications. This is very similar to results shown by Virta Health, who managed to really really reduce the number of diabetes medications the patients were on through following a low carbohydrate ketogenic diet.

It's a good sign that there's consistent findings that we can actually get people off diabetes medications, and that's really exciting because diabetes is traditionally been thought to be a chronic condition, and once you're diagnosed you're gonna be on insulin for the rest of your life. The sub-headline results looked at body weight, which improved, people lost weight on this trial, they also looked at glycolate hemoglobin, which is a marker of long term blood glucose control, that was improved in the patients fasting. BMI was improved, so broadly across the board here we're seeing that people are getting healthier.

This is in a chronic condition, diabetes again, to say again, that people have not really regarded as treatable at this point, people don't think about reversing or curing diabetes, and they actually focus treatments on controlling blood glucose with insulin. Most people focus on the high blood glucose because high blood glucose is what causes a lot of the very obvious effects, so problems with he kidneys, problems with the eyes, microvascular damage, thing like that. But in reality a key driver of the disease is the insulin as well as the sugar, so being able to cut down on insulin is a big deal for these people.

The findings from this paper actually link really nicely into another paper I was reading recently which looked at the ability of the pancreas to recover beta cell functions, so people often think that part of the reason why you need to inject insulin in type 2 diabetes is that the pancreas gets unable to produce sufficient amounts of insulin and this is called beta cell exhaustion. But this paper showed that if you catch it within six years or so, you can actually recover some function of the beta cells. The patients in this case study that Dr. Fung has written here, were 10, 15, and 25 years post diagnosis. So there's actually some hope that the pancreas function can recover sufficiently to provide blood glucose control on the background of fasting and lowering carbohydrate intake. Really we're starting to see a paradigm shift in how people should look at diabetes. The conclusions of this paper are that they advocate strongly for the inclusion of fasting and those toolkits of those working with diabetic patients.

Whilst the scope of the day to reported here is very limited, only three patients and in a case study, it is consistent with broad anecdotal experiences from other healthcare professionals. That said, I do wanna highlight that not everyone has a smooth experience with fasting. Compliance and tolerance here was really good and it was likely so good because the patients had self selected for this treatment, were it really closely followed, and were very likely to be highly motivated. Therefore it's not clear whether if you just picked a random sample of the population and told them to fast, whether they would be able to adhere or whether they'd get the same results. These people were obviously making other changes to their lifestyle as well.

Really to wrap up this first paper, the findings that Jason Fung describes are not actually that novel. They're in keeping with a lot of things that we've seen in literature to date and anecdotes that people in our community and people share over social media, but it is really great to see more evidence emerging in this literature. I would like to say that it's great that this has been published in medical journal called The BMJ rather than a basic science journal because hopefully this means that the paper will be read more by clinicians, it might get flagged out by people who are actually treating the patients and who might not be reading into Science or Cell Metabolism or these more basic science journals. Hopefully that will start to move the needle in terms of how people actually administer care to patients with diabetes.

Fast Mimicking Diet and Markers/Risk Factors for Aging, Diabetes, Cancer, & Cardiovascular Disease

The next study we're going to look at today was lead by another very well known scientist in the fasting field, Dr. Valter Longo. The paper is called Fast Mimicking Diet And Markers And Risk Factors For Aging, Diabetes, Cancer, Cardiovascular Disease. Quite ambitious title there, and it was published in the Journal Science Translational Medicine, so basic science journal, published in February 2018.

Dr. Longo is a professor of gerontology and biological sciences at the University of Southern California, and he also directs the Longevity Institute there. Much of the work that got us at H.V.M.N. interested in fasting was actually from Dr. Longo's group. He did many of the early studies in animals demonstrating the effects of fasting on cognitive health, performance and longevity. As one of the world leaders in fasting, Dr. Longo has thoroughly characterized the changes in metabolism and bio markers that's seen during a fast. However, he recognized that generally people have quite a hard time not eating decided to design what's called a fast mimicking diet.

The fast mimicking diet is low in calories, low in sugar and low in protein, but high in unsaturated fat. It's designed to achieve fasting like levels of signaling molecules such as IGF-1 glucose and ketone bodies, but also provides some macro and micro nutrients to minimize the burden of fasting and minimize any adverse effects and improve compliance.

Just as a little side note, talking about IGF-1, it's a growth factor that has a role in metabolism and general growth of the body as well as aging and cancer. Generally speaking, lower IGF-1 has better outcome measure for health.

So Dr. Longo's group has designed a fast mimicking diet and now markets it as a formulation called ProLon. ProLon is a meal plan that's vegetable based soups, energy bars, and it's provided in a box. It's not a low carbohydrate diet, it's a 46% fat, 43% carbs and 11% protein, but it's very low calories. The patients would send out the meals, they weren't eaten under supervision, that's a little bit of a limitation there. The protocol with ProLon is that you do five days of this diet each month and in this study here, they did three months, and five day cycles in each month. This was a randomized study where people either completed three months with the fast mimicking diet five days a month first and then had a three month wash out, or where they had a three months period where they followed their normal diet and then three months with the fast mimicking diet.

They lost a few of the people who did the fast mimicking diet first, they didn't get to follow up with everyone, but they had comparisons between normal diet and fast mimicking diets. The people that took part in this study were generally healthy people completing three cycles and the total number of people that completed all three cycles were 71.

Again, the headlines here were pretty impressive. The fast mimicking diet helped to reduce body weight, reduce body fat, lowered blood pressure and also lowered IGF-1. There were no adverse events reported which is great and compliance was broadly good. Compliance was less good in people who had to do the fast mimicking diet second after having three months of their normal diet which is interesting.

It looked at a number of other metabolic markers such as fasting blood glucose, triglycerides, marker of inflammation called C-reactive protein and cholesterol including HDL and LDL, and none of these were effected by the diet. Then that said, the beneficial effects on body, weight, and IGF-1 were still persistent after a three month wash out period in those that did the fast mimicking diet first.

The authors conclude in this paper that these results indicate that periodic fast mimicking diet cycles are effective in improving the level of an array of metabolic markers and risk factors associated with poor health, aging and multiple disease related processes. Certainly there are some encouraging signs here, certainly want to be able to reduce the body weight, lower IGF-1, all of these things are good and it's certainly good to know that fast mimicking diets are a reasonable alternative to straight up not eating anything at all.

I would say that perhaps a title and the conclusions here are slightly overstated. If you're looking at the data in the paper, you can see that there're a broad number of markers that were not changed by the fast mimicking diet, including cholesterol, and triglyceride. An important point to note here is that the people recruited for this study were classified as healthy. When the researchers pulled out the data from people who already had more elevated risk factors such as higher triglyceride or worst cholesterol, then those markers were improved more and actually improved significantly in people where the risk was high to start with. So I guess what this says to us is that if your risk is already elevated, risk of disease, then fast mimicking diet might achieve more of an improvement in bio markers compared with if you are already healthy and your biomarkers are good.

Early Time Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, Oxidative Stress Even Without Weight Loss in Men with Pre-Diabetes

With that, on to our final paper of the day. We're gonna close up this month with another slightly different strategy for not eating. The title of this paper is Early Time Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, Oxidative Stress Even Without Weight Loss In Men With Pre-Diabetes. It was published in Cell Metabolism in June 2018. The lead author here was Dr. Courtney Peterson. She is an assistant professor in the department of nutrition sciences at University of Alabama Birmingham. I hadn't actually heard about her before, but I was looking up her resume and it's badass. She did a PhD in physics at Harvard looking at the big bang theory before changing disciplines to study nutrition and metabolism at Pennington bio medical research where one of the world leading diabetes metabolism experts called Eric Ravussin, who's also an author on this paper.

They looked at time restricted feeding, so what they're doing here is extending the daily fasting period between dinner and breakfast the following morning. Time restricted feeding can be practiced with or without calorie restriction and weight loss. A normal American eats over a 12-hour period each day, so they've defined time restricted feeding here at least a 10-hour eating window, so 14-hour fasting window.

In an introduction to this paper, they really nicely layout how early animal research that time restricted feeding consistently improved health endpoints in animals, even when food intake was matched and weight loss was matched, or weight loss was not achieved at all. However, they point out that there was a sign in these early experiments that actually the time of day that the eating window fell on might be important.

For example, when the eating window was late in the day, there were mainly null or negative results with time restricted feeding compared with when it was early, whether there were more positive results. Moving the feeding window so it's specifically early time restricted feeding, not just time restricted feeding, is meant to exploit our circadian clock. Circadian clock just refers to the way that many systems in our body fluctuate regularly throughout each day.

For example, the insulin's response to food and the thermic response to food is higher and more optimal in the morning compared with in the evening. They point out that studies where they've looked at people eating in alignment with circadian rhythm, so front loading the day, eating more at breakfast and less in the evening, these studies showed improved glucose control and proved weight loss, lower lipid levels, and hunger reduction. What they're looking to test in this paper is that doing time restricted feedings specifically earlier in the day has more benefits. This study similar to Dr. Jason Fung's study was relatively small with eight people completing the study.

I do wanna highlight though that they talk about in the methods that only 1,000 people expressed interest in participating in this trial, but they couldn't commit to eating the meals under supervision, which is one of the big strengths of this trial. They screened 130 people and of those 18 met the criteria of pre-diabetes as measured by glycolate hemoglobin. Of those 18, 12 were enrolled and eight completed, those that withdrew did so for unrelated medical reasons or changes to their work schedule. Really whilst it does seem like a small study, they did clearly do a lot of thorough marketing and advertising of the study and carefully enrolled and picked their subjects. I guess that could be a strength and a weakness.

The overall study design was a randomized and crossover design. That means that everyone did time restricted feeding and also normal feeding. In the time restricted condition, there were five weeks in condition one, a seven week wash out period and then condition two with order of condition one and condition two time restricted eating or normal eating being random.

For the control group, the feeding window was 12-hours, so a typical day would look like breakfast at 7:00 AM, lunch at 1:00 and dinner at 7:00. For the early time restricted feeding group, the feeding window was only six hours, breakfast at 7:00, lunch at 10:00, and dinner at 1:00. That's quite a lot of eating in six hours given that the calories were much.

So one of the real strength of this study was that the study staff provided all of the foods for the participants and supervised them eating them, so it was really, really good compliance. In fact, compliance was over 98%, and then also they could be 100% sure that in each condition, the same meals were being eaten between the early time restricted feeding and the normal feeding window.

Similarly to Dr. Longo's paper, this wasn't a low carbohydrate diet. 50% of the energy came from carbohydrate, and the typical breakfast would make anyone who was on keto squirm. It was cereal, fruit juice, eggs, milk, butter, and vanilla wafer. The primary endpoints that they were measuring were based around an oral glucose tolerance test which you may have heard us discuss before on the podcast. In this test you drink 75 grams of glucose, and you have regular blood tests to measure the amount of glucose and insulin in your blood, so a healthy person will have a increase in glucose and insulin, a big spike in insulin that will bring the glucose down quickly. If you're less healthy, it will take ... You might have a lower insulin spike, your glucose might stay elevated for longer and take longer to return to baseline, so that's what we're looking at here. From the oral glucose tolerance test, you can calculate some measures of insulin sensitivity as well as measuring insulin itself.

The secondary measures, the ones that they were looking at along side the most important measures were risk factors associated with cardiovascular disease, inflammatory markers and oxidative stress markers. So what were the results? Body weight was stable, when you consume the same amount of calories, consuming them in a time restricted feeding kind of way didn't appear to affect resting metabolic rate or energy expenditure. Now interestingly the fasting glucose did not change between conditions, and the glucose response to the orals glucose tolerance test was also the same between groups. However insulin did decrease in the time restricted feeding group, therefore the oral glucose tolerance test derived indolent insulin sensitivity were improved. The biggest difference is were in people who had higher levels of insulin at the baseline. This is again maybe some of what we saw with Dr. Longo's paper where people who were already more at risk at the start saw more of an improvement.

Before we get a bit despondent that there's not an improvement in the oral glucose tolerance test, the authors have a few reasons that they've suggested why this might've happened. The key reason that they suggest this might have happened is that the time of fasting was not standardized before each oral glucose tolerance test. What I mean there is that the group who were currently on early time restricted feeding had been fasting for a number of hours more than the group who were on the normal feeding window before they did the oral glucose tolerance test. Research has shown that even 24-hours of fasting can slightly decrease insulin sensitivity, make it worse and increase levels of triglycerides and generally push markers in the short term in the wrong direction. They suggest that that might have been the case here and that might have cause lack of visible improvements to some of the oral glucose tolerance test measures.

In terms of cardiovascular risk, there was a big decrease in blood pressure, and they suggest this might be because of the lower insulin or because of a natural recess which means salt excretion, which is regulated earlier in the day by the circadian system. Otherwise, there were no changes in arterial stiffness or cholesterol. Overall the oxidative stress markers were better with the early time restricted feeding group, although they do note that this was because they actually went up in the control group, so it's more like early time restricted feeding mitigated the diet induced rise in oxidative stress and again inflammation was not changed.

One thing that you might not have expected is that the people who ate the meals earlier in the day had reduced appetite in the evening. For me, it was certainly cool observation that people weren't more hungry later in the evening despite having finished eating up at say 1:00 PM. That said, this particular finding is just one of many conflicting findings in this field. Some people who have looked at time restrictive feeding have found people are less hungry, others have found that it's more hungry, so this is really just another brick in the wall. There's no consistent consensus about whether time restricted eating makes you more or less hungry, but they found less so.

Most of their participants when surveyed reported that it was actually more hard to eat enough calories in six hours than it was to fast for 18-hours. It was easier to fast than it was to stuff themselves.

The authors highlight as the headline finding for this paper the improved insulin sensitivity and beta cell function as well as the lower desire to eat in the evening. In the paper they write, "We speculate that early time restricted feeding by virtue of combining daily intermittent fasting and eating in alignment with circadian rhythms and metabolism will prove to be a particularly efficacious form of intermittent fasting. In the light of these promising results, future research is needed to better understand the mechanisms behind both intermittent fasting and meal timing to determine which form of intermittent fasting and meal timing are efficacious and translate them into effective interventions for the general population."

The authors hit a nice note here, a nice balance between optimism and highlighting the strengths of their results, but also highlighting that more research needs to be done to really answer this question. So I think I'm gonna wrap up here by saying that my takeaway from reading all of these papers is that there are a lot of different ways to do fasting whether it's alternate day fasting like Jason Fung's study, fasting mimicking diets in Dr. Longo's study, or time restricted feeding and then moving the eating window earlier in the day such as in the Peterson's study.

Closing Thoughts

All of these studies are showing that there are some improvements in metabolic parameters that are associated with health. So if you are worried about your risk of metabolic disease and you feel that's it's practical for you building in for you some kind of fasting practices likely to do you good. I think what we've seen today is that really you can pick from a number of different options and find what best suits your lifestyle.

One hopes that as papers like this start to increase in number and reach more people, that fasting will move from the realm of bio hackers and self experimenters into more mainstream medical practice. That said, all of this data is more focused on people with pre-existing conditions, so we can't definitively say whether or not there's a benefit for young, healthy, active people. It's not really clear because there isn't really a burden of disease in this group, it might actually be slow getting an answer to the question of how fasting effects young, healthy people.

That said, I fast myself, trying to do one 24-hour fast a week. The risk-reward profile is balanced enough that fasting regularly is more likely to help you live longer and healthier than it is to do you harm.

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