Sleep II: Glucose Intolerance and Hormone Dysfunction

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My introduction to insulin will be important to understand before getting into today’s conversation. We will be discussing sleep, its affect on blood sugar levels, and its affect on serum insulin levels. If you don’t want to spend the five minutes reading the post on insulin, the most important takeaway is that insulin in a ginormous growth signal to the body. When insulin is present in the bloodstream, our ability to break down and burn stored body fat is blocked, while our ability to form and store new fat molecules is amplified. With that brief introduction, let’s dive in.

I don’t think anyone would argue that humans are incredibly diverse and adaptable. We live and learn to thrive in every environment the world has to offer (mostly). Adaptability is no more than responding positively to your environment. It is making subtle changes in your functioning to better facilitate your existence in that environment in the future. A prerequisite to being adaptable is the ability to sense your environment. Before you can begin to optimize outputs, you have to understand the inputs to the system. Sleep is a primary, pivotal, essential, etc., etc., input to our body functioning. The duration and quality of our sleep each night sends a truckload of data to our body. And being the adaptable creatures we are, our system processes that data and makes compensatory psychologic and physiologic changes. One of the huge levers our body can manipulate in response to this input of data is hormonal and metabolic functioning. If you remember from Sleep I, short sleep induces higher levels of ghrelin (a hormone associated with hunger) and lower levels of leptin (a hormone associated with satiety). These changes in chemical concentration lead to an overall subjective feeling of increased hunger. Today’s topic fits right along side this increased sensation of hunger. When we do not get adequate sleep we become less glucose tolerant. Meaning our blood sugar stays elevated for a longer time after eating, as do our levels of insulin. Short sleep leads to more insulin spending more time in our bloodstream.

In this small study participants were put through two different sleep regiments. Initially they were restricted to four hours in bed per night for six nights, and then allowed 12 hours in the bed for the next seven nights. In each condition they they were subject to a glucose tolerance test while also having their insulin levels measured. During the sleep restricted condition, there was a clear impairment of carbohydrate tolerance. Injected glucose was cleared from the body 40% slower after sleep restriction. They also measured the acute insulin response to be 30% lower in the sleep-debt condition. Glucose effectiveness, a measure of ability to dispose of glucose independent of insulin, was also 30% lower in the sleep debt condition. The combination of these outcomes would certainly lead to prolonged blood sugar elevation, and these differences in glucose tolerance are very similar to those seen in a non-insulin-dependent diabetic male compared to a normoglycemic male. Lastly, the researchers also measured glucose levels and insulin response to a 60% carbohydrate meal; opposed to the IV glucose injection which the above results were in reference to. They measured the increase in peak glucose after eating breakfast was higher in the sleep restricted state. However, peak glucose measurements following lunch and dinner did not differ much between the sleep states [1]. This is certainly no evidence of causation, I simply want to point out that there seems to be some level of hormonal and metabolic dysfunction in response to sleep restriction.

In this study researchers were investigating if sleep restriction impairs insulin signaling. In order for insulin to exert its effect at a cellular level, it first binds to a receptor on the outer membrane of a cell. This binding initiates a cascade of events (molecules tagging other molecules, turning them on) eventually resulting in the body’s ability to move glucose from the bloodstream into the cell. The researchers were able to measure a specific molecule in the insulin pathway (phosphorylated Protein Kinase B, aka pAkt) in order to assess insulin sensitivity of individuals in a sleep deprived state and in a well-slept state. They measured the concentration of insulin that was required to stimulate pAkt to adequate levels. In an insulin insensitive state, the amount of insulin required to reach this level of pAkt stimulation would be higher. In this experiment the participants were subjected to four and a half hours in bed to achieve the sleep deprived state versus eight and a half hours in bed to create the well-slept state (four consecutive days in each state). In the sleep deprived condition the amount of insulin required to elicit the desired pAkt response was 3-fold higher [2]. Another significant manifestation of hormonal disruption after short sleep.

There are many more studies out there, but I like to keep these posts relatively short. It is fairly obvious that there is some level of hormonal dysfunction that occurs after less than a week’s worth of inadequate sleep. Admittedly these studies are small, but we have seen some level of evidence for disruptions to ghrelin, leptin, insulin, and glucose tolerance. So for a quick summary of what we have covered so far: short sleep causes you to feel more hungry and less satisfied after a meal. You then have a decreased ability to deliver glucose from your bloodstream into your cells, elevating your blood sugar for a longer period of time. You also have a decreased response to insulin, further inhibiting your ability to remove glucose from the bloodstream and increasing the overall amount of insulin in your body throughout the day. There is certainly some level of a runaway feedback loop here, as prolonged blood sugar elevation further increases the demand for more insulin secretion. And remember, when you have high levels of insulin circulating, you cannot break down fat, but you can certainly build it.

My concern is not with the 40% slower glucose clearance the day after cramming for an exam or finishing a big project. I am concerned with what happens after 25 years of consistently getting 4-6 hours of sleep. What happens when endocrine dysfunction becomes our normal? What happens when our body is forced to adapt to metabolic conditions it would have only seen in the most stressful times in pre-historic life? Of course we will never know a definitive answer to these questions, but when you are dealing with something as ubiquitous as chronic disease, I naturally look at things equally ubiquitous, i.e. sleep, as possible culprits. The idealized, “I can sleep when I die,” needs to go, or those who believe it will surely meet that end sooner than they should have.

Best explorations

-Ryan; 6/5/2020

See Sleep I: An Evolutionary Imperative

References:

[1] Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999;354(9188):1435‐1439. doi:10.1016/S0140-6736(99)01376-8

[2] Broussard JL, Ehrmann DA, Van Cauter E, Tasali E, Brady MJ. Impaired insulin signaling in human adipocytes after experimental sleep restriction: a randomized, crossover study. Ann Intern Med. 2012;157(8):549‐557. doi:10.7326/0003-4819-157-8-201210160-00005

Sleep I: An Evolutionary Imperative

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I think sleep is a crucial part of maintaining health. It is an insurance policy that is too good not to participate in. This will be the first in a series of articles discussing sleep and its importance to our overall well-being. Some of this can be considered anthropomorphizing and certainly hypothesizing, but we learn through stories. So if you would indulge for a story about sleep….

Travel back to our days as hunter gatherers. The rhythms of our day completely controlled by the light and dark cycles orchestrated by our rotation about the sun. As the sun slides down the horizon, it becomes much harder to find food. And in this ancient world of incredible competition for calories, our energy would almost always be best used in search of food. Therefore, when our ability to find food is limited, it would be beneficial to conserve our energy until we are in a situation that can leverage our unique tools developed for calorie acquisition, i.e. day time vision. From this very basic pattern of light and dark, along with a perspective of calorie conservation, we might develop two different modes of being, one of activity, and one of rest and repair.

That being said, sleep’s ability to withstand natural selection is nothing short of a miracle. Sleep is seemingly juxtaposed to many of the behaviors we know to facilitate the passing of our genes into future generations. When we sleep, we are not looking for food, we are not eating food, we are not having sex, we are not looking for a mate, and we are incredibly vulnerable. These are not trivial facts, they are pillars of what we know to be necessary for procreation. So how does something that fails to directly help us in these pursuits, while also making us the most vulnerable of prey, become so prominent in essentially every animal species on this planet? Ockham’s Razor would simply tell us that the benefit must outweigh the harm. Over the long experimental testing grounds of time, mother nature has weighed and measured sleep, and it has proven to be of essential utility. Sleep’s persistence proves its profits exceed its costs. By understanding the magnitude of what we give up through sleep (eating, sexing, security, etc.), we may begin to understand the value we receive through sleep. It simply has to be greater than or equal in value or sleep would not have proliferated.

We don’t know what all the benefits of sleep, and I’m not convinced we ever will. The system-wide effects of something like sleep are hard to tease apart in the discretizing manner demanded by modern science. However, it is being researched more and more and we will be able to increasingly understand the pieces of its puzzle. Our body is able to synchronize different processes through oscillating hormone levels. Throughout the day hormone concentrations rise and fall, creating a rhythmic balance for our cellular operations. There are numerous hormones, and they all have different effects. For example, melatonin ideally starts to increase in the evening, peaks in the middle of the night, and remains low throughout the day. The cyclic variation of hormones act as a internal clock, sending information throughout the body and allowing for different parts of the body to work towards common goals.

Two specific hormones I would like to discuss here are leptin and ghrelin. When discussing biochemistry, we will have to settle with some simplification. Keep in mind when people say something like “melatonin is the sleep hormone,” there is probably a good amount of truth to it, but there is also a vast complexity going on in the background. So while melatonin is certainly involved in sleep/wake cycles, its role is much more complex.

Leptin is a hormone primarily made by adipocytes (fat cells) and enterocytes (small intestine) that signal satiety. It is a huge part of that “full” feeling we get after eating a meal. Ghrelin is a hormone produced by your gastrointestinal system, closely correlated with our sensation of hunger. These two hormones have opposing effects, and are largely involved in appetite regulation. For example, ghrelin is often at its highest concentration before a meal and at its lowest levels after eating. The opposite is true for leptin, as its concentration is highest after eating.

Let’s look at how these hormones are affected by sleep. One of the most common ways to study something is to remove it, and then observe or measure the effect of its absence. Many studies have shown that when we are sleep deprived, the circulating levels of these hormones are changed. One study took a small group of participants and took them through two different scenarios. In the first part of the experiment the participants underwent two days of sleep restriction, then had blood levels of ghrelin and leptin measured, along with a subjective assessment of hunger. These same participants where then later allowed two days of extended sleep, and the same measurements where recorded. The study showed that after sleep deprivation, levels of ghrelin increased, levels of leptin decreased, and subjective hunger was increased [1]. Another study looked at a much larger cohort of patients over a longer period of time. Here they showed that short sleep duration was associated with higher levels of ghrelin and lower levels of leptin, independent of BMI, age, sex, and other confounding factors [2]. In this review article, researchers looked at the body of evidence regarding sleep loss and its effect on neuroendocrine and metabolic function, concluding short sleep is associated with an up-regulation of appetite, lower leptin levels, and higher ghrelin levels [3]. There are numerous other studies out there, and there seems to be a strong general consensus that shortened sleep is associated with lower leptin, higher ghrelin, and increased feelings of hunger. Obviously this is a bad combination for anyone who is concerned about their weight, and an extremely difficult situation to overcome if one is trying to lose weight.

Allow me to step back from the science, and return to our hunter gatherer ancestors to try and tell a story. I do not think it is a huge leap to assume that sleep was something we engaged in every night, and something we rarely sacrificed. If not for any other reason than our gift of vision was severely limited without the light of day. However, I can imagine at least one scenario when we would sacrifice sleep. Those nights when we were on the verge of starvation, when we had gone many days without food. At that point we had no other option but to continue moving in search of food, or at least significantly shorten the time we spent asleep. So if we were on the search for food, bargaining sleep for more exploration time, how might our bodies help us? We would be at a huge advantage if our appetite was tuned for high caloric intake. That way if we managed to finally come across food, we could fully take advantage of the available calories. We would not want to be forced to stop eating because we felt “full.” In this situation it would be a great development if in response to short sleep, our body increased its signal for hunger, and decreased its signal of satiety. Increased ghrelin and decreased leptin, in order to increase our appetite and ability to intake large amounts of calories. Shortened sleep would increase the instinctual drive to find calorically dense food.

Of course this is not science, the evolutionary story may or may not be true. However, viewing things through and evolutionary lens allows us to expand our thinking to why things might work as they do, and I certainly remember things better in story than factual bullet points. So take the evolutionary part with a grain of salt, but the elevation of ghrelin, reduction in leptin and overall increase in hunger in response to short sleep is well understood. If you or anyone you know is struggling with their weight, sleep is an essential first pillar to attack. Leptin and ghrelin are only part of this story. Short sleep also impairs glucose tolerance and causes other hormonal imbalances. Diet and exercise are what people often jump to when discussing weight control, but I would argue sleep should be the first stepping stone. Without prioritizing sleep you will be fighting an uphill battle. Stay tuned for further exploration of sleep’s wide ranging effects on our health.

Best explorations

References:

[1] Spiegel K, Tasali E, Penev P, Van Cauter E. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med. 2004;141(11):846‐850. doi:10.7326/0003-4819-141-11-200412070-00008

[2] Taheri S, Lin L, Austin D, Young T, Mignot E. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med. 2004;1(3):e62. doi:10.1371/journal.pmed.0010062

[3] Van Cauter E, Holmback U, Knutson K, et al. Impact of sleep and sleep loss on neuroendocrine and metabolic function. Horm Res. 2007;67 Suppl 1:2‐9. doi:10.1159/000097543

-Ryan; 6/1/2020

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Health and Compound Interest: A Mental Model for Building a Lifestyle

Compound interest is the addition of interest to a principal sum. It is interest on interest. It is a principle that allows something to increase at faster and faster rates over time. For those visually inclined it is something like this…

https://www.fool.com/knowledge-center/compound-interest.aspx

Economics lesson over. We will apply the idea of compound interest to our approach to health.

This can take many forms. It can be purely psychological, as in a single good decision today makes me more likely to make a good decision tomorrow, and maybe even two good decisions the following day. Another way to describe this is something like the feeling of momentum. *Before we go any further, we will clarify this vaguery, ‘good decision,’ as anything objectively benefiting your health, ie. eating a serving of broccoli, walking outside for 10 minutes, doing a push-up, etc. This would be specific to you and these are general examples.* The compounding principle can also operate in a purely physiologic realm. If I do a set of push ups today, maybe I am able to build some small amount of muscle. If I build muscle, my body’s ability to dispose glucose is improved. If I can dispose of more glucose, my blood sugar goes down. That muscle it not likely to disappear any time soon, therefore I am better at disposing glucose everyday in the future. My average blood sugar over time (HA1c) goes down.

But here is where it gets fun. That same muscle (built from my push-up) that helps me regulate blood sugar helps me move more functionally, increasing my ability to meet the physical demands of life. It increases my resting metabolic rate, allowing my body to “burn” more calories throughout the day. It will help regulate certain hormones circulating in my body. Hell, doing the push-ups might just make me feel better afterwards. The single ‘good’ decision of doing push-ups generates health benefits in multiple dimensions. And the principle of compounding applies in every dimension! The general idea of health compounding is that no matter how insignificant a single ‘good’ decision today may seem, the majority of its benefit exists in your future. So cherish each and every positive decision you make, you just sacrificed a small amount today for a potential windfall tomorrow.

My favorite example of health investment and compound interest is sleep. I have learned to love sleep. We can view investment in our health through the lens of time. How many hours of the day am I doing something productive for my health versus how many hours I am doing something neutral or even negative? I will be the first to admit how difficult it is to make health conscious decisions in today’s environment. We have endless entertainment streaming right to our favorite device, delicious foods that someone would happily deliver to our very own door, not to mention all the gyms are closed! Needless to say, decisions in the best interest of our health are difficult to make. This is what makes sleep the king (or queen) of health decisions. If you prioritize giving yourself 8 hours in bed each night, you just banked 8 hours of good health decisions! You just optimized one-third of your day. Thankfully our unconscious state during sleep makes it rather difficult to be tempted by those beautiful desserts or “Click to play the next episode.” So from the abstracted point of view of wanting to make more ‘good’ decisions than ‘bad’ decisions throughout our 24 hour period, prioritization of sleep is paramount. In a more concrete view, sleep provides numerous physiologic benefits. Chronic short sleep can promote weight gain, hinder weight loss, dysregulate blood sugar levels, cause hormone imbalances (including those that regulate appetite), to only mention a few manifestations. If you are interested in the science of sleep and its physiologic outcomes, stay tuned.

I don’t want to dive too deep into the science right now as this post is more about the conceptual framework we need to adopt towards our health. Every single decision we make is a node in a network. The output from that decision node affects many other aspects of our life, it compounds. My sleep affects my energy, my energy affects my workout, my workout affects my sleep. My food affects my hormones, my hormones affect my appetite, my appetite affects my food choices. My movement affects my hormones, my hormones affect my energy levels, my energy levels affect my desire to move! Our body is a symphony. Every individual piece playing some minor role in the overall function. Don’t downplay a ‘good’ decision, regardless of how insignificant it may seem. Celebrate eating a serving of vegetables, acknowledge the victory of going for a walk, and throw a party for yourself tomorrow if you give yourself 8 hours in bed.

Best explorations

-Ryan; 4/30/2020