The ultimate Guide to Insulin, Insulin resistance and more…
Table of Contents
What is insulin?
Insulin is a hormone, a very old one. It’s about 550 million years old! It’s found in nearly all organisms, from the microscopic worm called c. elegans all the way to humans. It doesn’t have a great reputation in the keto world, in the sense that ketogenic diets aim to keep insulin levels low.
These low levels are how we evolved to handle it and how we stay sensitive to it. Insulin isn’t bad per se but too much of it is very, very unhealthy. We’ll cover this in more detail below.
Insulin is the master regulator of metabolism
What does insulin do?
Most people think ‘blood sugar control’ when hearing about insulin. Indeed, high levels of sugar in the blood stimulate the pancreas to release more insulin. The insulin then helps cells to take up glucose from the blood. However, insulin isn’t all about handling blood sugar, it also manages fats, amino acids (from protein) and many other elements .
Insulin is a storage (anabolic) hormone
Amino acids (protein)
Insulin facilitates the uptake of amino acids into cells. This is why insulin is said to have an anabolic effect: the amino acids can be used to build protein, an essential step in the muscle building process. For this reason, some bodybuilders follow a targeted ketogenic diet or a cyclical ketogenic diet instead of a standard ketogenic diet, where carbs are always kept low.
A targeted ketogenic diet includes a small carb bolus shortly before or after exercising. A cyclical ketogenic diet involves days where lots of carbs are consumed to take you out of ketosis.
Research suggests, however, that ketogenic diets don’t impede normal muscle growth . Protein also provokes normal insulin release, so even a very-low-carb ketogenic diet is not insulin-free – you wouldn’t want it to be!
Fats and carbs
An essential but frequently overlooked function of insulin is to store fat and carbs (as glycogen). When we eat a meal, we usually take up more energy than we strictly need, giving ourselves a margin of safety in a sense. Our fat stores act as energy buffers. When our tissues respond to insulin normally, we can release those fuels, use them efficiently and continue with our day with stable energy levels and a normal appetite.
Insulin promotes the uptake of fats into fat cells. The primary function of fat cells is to store energy, anticipating drops and surges of energy to cells. At the same time, insulin inhibits the release of fats from fat storage. This only makes sense: insulin is high when glucose levels are high. As long as there is plenty of glucose that can be used for energy, it would be counterproductive to release lots of fatty acids into the blood.
When insulin levels drop below a certain threshold, stored fats are released from fat cells to be used as fuel. One way to encourage this is to drop your daily net carbs below 50 g. This moves you into the low-carb to ketogenic range, particularly helpful for losing excess body fat. In large part this can happen because you lower your insulin levels enough so that more fat is free to be used as fuel .
The liver can also take up sugars and store it as glycogen, even though the storage space is much more limited than fat tissues. When insulin levels drop, it’s counter-regulatory hormone glucagon is secreted to break down the stored glycogen which is then released into the bloodstream as glucose. This ensures a steady stream of energy supply as soon as blood sugar levels drop.
The liver can participate in energy storage in another way, via de novo lipogenesis (DNL). When glycogen stores are full but more carbs are still coming in, insulin remains high and allows the additional glucose to be converted into fat. This is somewhat normal, but when pushed too far, will eventually lead to fatty liver disease (also known as non-alcoholic fatty liver disease or NAFLD). The world is suffering from a NAFLD epidemic, especially young children.
Side effects of high insulin levels
High insulin levels, also known as hyperinsulinemia when chronically elevated, are ultimately responsible for the devastating condition that is metabolic syndrome. To be clear, some will argue that “excess calories” cause metabolic syndrome but this is wrong. The caloric excess is the consequence, not cause, of metabolic syndrome.
We have seen that insulin has many important functions in the body. So, what is the problem with high insulin levels? For one, your body stops ‘listening’ to insulin well, cells become resistant to insulin. So you produce more and more of it to achieve a given effect. Insulin resistance is the opposite of insulin sensitivity. This means that reversing insulin resistance makes you insulin sensitive.
Chronically high levels of insulin is the modern health scourge
It’s not easy to explain what insulin resistance is. It can be bad and it can be good. For example, physiological insulin resistance is good and adaptive. It happens on a ketogenic diet or when fasting, ensuring that your brain gets all the glucose it needs instead of your muscles that can rely on fats instead. Pathological insulin resistance is what diabetics suffer from due to eating a poor diet replete with sugar, flour products and seed oils. These disrupt normal insulin signaling, thus damaging the ability of tissues to respond to insulin normally.
Defining Insulin resistance is hard! It can be a healthy response or a bad one
It is important that insulin levels have time to come down in between meals, or at least overnight. This can’t happen if you’re snacking on the regular. Well-formulated low carb meals cause an appropriately modest increase in insulin, allowing the level to come down soon thereafter. Foods that consist of refined carbs and seed oils, however, cause inappropriately high spikes of blood sugar and insulin. Then, these high blood sugar and insulin levels take too long to come down to normal, basal levels.
Don’t snack to keep your insulin levels low
Insulin stimulates the generation of new fat cells (adipose hyperplasia) and the expansion of existing ones (adipose hypertrophy). With normal insulin levels, these things remain in balance. But with problem with chronically high insulin, we have two problems
Chronically high insulin can leads to diabetes, obesity and more diseases
- it facilitates the storage of fat in fat cells, which will eventually lead to obesity
- it stops fat cells from releasing fat in a timely controlled manner, which will eventually lead to diabetes
Being overweight is, however, not the main problem with high insulin. In fact, obesity is best understood as a sign that you’re body is protecting itself from diabetes by getting fat . It has to do something about all that energy rushing in with every meal and snack, so it’s best to handle it safely in ‘storage’ rather than trying to disperse this food-energy throughout your body’s delicate cellular machinery.
The real trouble starts when fat cells maximally expand and no longer respond to insulin. This leads to fats ‘leaking out’ of fat cells, which raises fasting blood sugars and fasting blood triglycerides above healthy levels. Furthermore, when primary fat stores – the fat stores under you skin (i.e. belly fat) – reach maximum capacity, the fat may then spillover into the fat tissue between your organs (visceral fat).
Fat tissue is an immune organ crucial to your health and metabolism
This fat tissue surrounds organs. You might have heard that a lot of visceral fat is not a sign of good health . Visceral fat has important roles to play with the food you ingest, modulating your metabolism and your immune system (i.e. immunometabolism). The liver and pancreas should not be storing this fat, but this happens with chronically high insulin levels.
Athletes can store lots of fat in their muscles without it being a bad thing. Sedentary people who don’t work and have chronically high insulin levels tend to store lots of fat in their muscles too, but this is a bad thing. Why? Because they can’t ‘access’ that fat easily, unlike athletes. They’re bad fat burners.
When fat is stored in the wrong places, this is called ‘ectopic fat deposition’. Ectopic fat deposition happens in the liver and the pancreas most commonly, where they don’t belong. Ectopic fat in the liver is associated with insulin resistance [6,7]. When the liver stops responding to insulin, it starts breaking down stored glucose (glycogen) into glucose at the wrong time. That means that the liver releases glucose despite their being already plenty of glucose in the blood.
Where you store your fat matters, not just how much fat you store
In the muscle, ectopic fat is also associated with insulin resistance [8,9]. Glucose can be stored in muscle glycogen, and muscle cells may also use glucose as fuel. Once muscle cells become insulin resistant, they refuse to take up glucose more and more. Because muscle cells are such large calorie sinks, when people eat lots of carbs and have insulin resistant muscles, this further exacerbates high insulin levels and makes it difficult to control blood sugars.
We want the right balance of insulin sensitivity (or insulin resistance) according to the tissue and its particular job. Chronically high insulin levels leads to fat storage problems and eventually to increased levels of triglycerides (fat) in the blood.
This in turn promotes insulin resistance in the whole body. Insulin resistant cells don’t take up glucose easily, which means that more insulin is required. More insulin makes insulin resistance even worse which is why it’s a terrible idea to use insulin injections as a long-term therapy for type 2 diabetes . Thankfully, they can come off it in days to months with a team of medical professionals providing them with well-formulated low-carb or ketogenic diets.
Insulin is a precious and powerful resource, use it sparingly
Because chronically elevated insulin levels and insulin resistance create this big fat storage problems, it is fair to say that hyperinsulinemia is toxic. Insulin toxicity increases the risk of atherosclerosis, cardiovascular diseases, and cancer [11,12,13,14].
It has been believed for a long time that glucose toxicity alone explains the increased risk of these conditions. This isn’t correct, insulin and other factors play a role too . Case in point, controlling blood glucose levels by injecting insulin does not decrease the heart disease risk . In fact, the opposite is true! Increased levels of insulin from injections further increase the net risk, despite lowering blood glucose sugars.
Hyperinsulinemia is toxic
High blood sugar levels can cause damage in many ways: they lead to oxidative stress and the formation of reactive oxygen species, which is a threat to cells. Furthermore, high glucose levels randomly bind to proteins in the blood; a process called glycation. When these glycated proteins connect, they form so-called advanced glycation end-products. When collagen is crosslinked in this way, this leads to vascular stiffening and thereby contributes to the aging process. Dr.Shawn Baker, an experienced orthopedic surgeon, wrote about the devastating effects from high blood sugars on his patients’ joints. See his post for us here.
Poor insulin signaling = glucose toxicity
This increased risk of hyperinsulinemia-associated diseases is often summarized under the term metabolic syndrome. It describes a pathologic metabolic state and is strongly associated with insulin resistance. There is a set of symptoms that is correlated with metabolic syndrome. Metabolic syndrome is diagnosed when three of the symptoms are present:
- Waist circumference: ≥ 102 cm in men and ≥ 88 cm in women
- HDL-cholesterol: < 40 mg/dL in men and < 50 mg/dL in women
- Triglycerides: ≥ 150 mg/dL
- Blood pressure: systemic blood pressure ≥ 130 mmHg, diastolic blood pressure ≥ 85 mmHg
- Fasting plasma glucose: ≥ 100 mg/dL
Mechanisms of insulin resistance
What exact mechanism of insulin resistance can explain all cases isn’t known. However, there are a few mechanisms that we know are important .
- fatty acid (fat) induced insulin resistance
- hormonal/receptor level insulin resistance
- mitochondrial level insulin resistance
One example of receptor level insulin resistance is impaired Glut4 translocation. What is that? It’s when a little molecular machine that transports glucose doesn’t make it to the cell surface to do its job.
A kind of fatty acid-induced insulin resistance is when a fat cell takes up fat to maximal capacity, becoming really huge! If it doesn’t resist insulin’s action it will ‘die’. Some fat cells tend to accumulate many small fat droplets, whilst others store all the fat in one big droplet. Over-enlarged fat cells with one big droplet are the most insulin resistant kind. The droplet seems to cause a remodeling of the cell’s internal architecture (cytoskeleton). This interferes with Glut4’s ability to make it to the cell surface to suck in glucose, which is its job.
Then there’s insulin resistance at the mitochondrial level, the many little engines in your cells. You feed them fats, carbs and proteins which they handle in a variety of ways. At its heart, each mitochondrion has an electron transport chains (ETCs). The ETC produces a certain amount of reactive oxygen species (ROS), a byproduct of producing cellular energy (ATP). High levels of superoxide, for example, a kind of ROS, can stop our friend Glut4 from doing its job. This results in insulin resistance .
Basically, insulin must respond to how hard your cell’s engines are working to not ‘blow its circuits’ or ‘starve it’. Cells become insulin resistant to not be overloaded with energy. So it’s both a normal mechanism and one that can be pushed to an unhealthy degree. If cells can’t stop taking in fuels this will lead to very high levels of damage. If it doesn’t take in enough fuel, it’ll starve.
Avoiding insulin resistance
This takes many things, many things that would fit into a ‘healthy lifestyle’. It could be anything from not smoking cigarettes to good sleep hygiene and a well-formulated low-carb diet.
The dramatic reduction of carbs in a ketogenic diet limits the amount of insulin secreted from your pancreas. The idea of intermittent fasting is to eat within a particular restricted window of time to keep your insulin low, because when you don’t eat your insulin lowers. Check-out our intermittent fasting post for more information on how to do it right.
Carb quality, carb quantity, when and how often you eat: they all matter!
So while it is possible to somewhat reduce the damage of high insulin levels from a high carb diet with intermittent fasting, there is one hook: most people find it very difficult to skip snacks between breakfast and lunch or breakfast and dinner, especially when the diet is high in carbs. Crucially, the best way to lower insulin (besides fasting) is to remove refined flours and sugars from the diet.
The best option, which is easy on a ketogenic diet, is to combine the two: intermittent-fasting and a well-formulated low-carb or ketogenic diet. Most people automatically skip meals or only occasionally snack, since they usually feel full and on-point. This may largely have to do with our brain’s particular affinity for molecules called ketone bodies that commonly arise on low-carb and ketogenic diets, or when fasting.
Remember, whole-body stores of energy from glycogen are small, but fat stores are enormous (even in lean people). It’s easier to access your fat stores if you keep insulin low.
Increasing insulin sensitivity with Nutrita
Nutrita helps you to avoid insulinogenic foods and choose instead foods that are low on our in-house insulin index of foods but also nutrient dense. A sure-fire way to be keto is to keep your insulin low, so you can use our keto score to choose foods that keep you steadily in ketosis. To keep it simple and clean, Nutrita gives you a simple green, orange or red light for those foods you scan or look up; does this align with the goal I set myself?
Large meals elicit a proportionally lower insulin response than small meals
Intermittent fasting also means that you eat fewer meals. If you’re losing fat/weight they may stay relatively small, but if you’re weight stable or even putting on mass then you will tend to eat fewer but larger meals. That’s actually a good thing, because small meals elicit a proportionally higher insulin response than large meals.
A study in healthy males showed that the consumption of a small 511 kcal breakfast leads to an insulin release that resulted in a drop in blood glucose levels below their fasting baseline. This was not the case with larger (743 and 1,034 kcal) meals . Such a significant drop in blood glucose is a sign of metabolic dysfunction and is associated with cravings and a quicker onset of hunger. It seems refined carbs and sugary foods are particularly hard to resist in these circumstances, so exclude them from your diet.
Meal frequency matters
In another study, 36 lean and healthy men were randomized to eat 40% more than they needed to (hypercaloric) or just what they needed (this isocaloric control group) .
The hypercaloric group was further divided into a high-sugar/high fat (HSHF) group or a high-sugar group (HS). The HSHF group consumed the extra calories in the form of a so-called Nutridrink shake, with 16% of energy coming from protein, 49% from carbs and 35% from fat. This is a typical macronutrient ratio of unhealthy, standard western diets. The HS group drank the extra calories in the form of a sucrose (table sugar) sweetened soft drink. This translates to the enormous amount of 309 g extra sugar!
The groups were further subdivided by meal frequency: they either consumed the HSHF or HS extra calories together with the 3 main meals or as a snack in between meals, resulting in 6 “meals” altogether.
All hypercaloric diets raised the body mass index (BMI) to a comparable extent. However, increasing meal frequency significantly increased intrahepatic triglyceride content. So increasing meal frequency basically gave subjects a fatty liver. This is prima facie evidence of insulin resistance and the metabolic syndrome being affected by eating too often.
The amount of abdominal fat also increased in the high-frequency meal groups. It should also be said that the extent of the fatty liver was much worse in the high-sugar group. Interestingly, a hypercaloric diet with a larger meal size did not cause a fatty liver nor an increase in abdominal fat. It is remarkable that the high-sugar group with a large meal size did not develop a fatty liver. Imagine, 3 liters (!!!) of a sugary soft drink in addition to the main meals.
What does that mean? It means that at least in this short-term setting of 6 weeks, the timing of the meals was more important than the actual macro distribution or amount of sugar consumed. Does that mean that you can eat as much sugar as you want as long as you stick to 3 main meals without in-between snacks? Well, no. First off, all 4 hypercaloric groups showed a tendency towards higher fasting triglyceride levels. The increase was not dramatic, but the effect might potentiate long-term, and it suggests the obvious; 40% extra calories from bad food is a negative metabolic stress.
Moreover, high-sugar foods cause an insulin spike which then soon results in a dramatic drop in blood glucose. These extreme fluctuations make it difficult to stick to main meals without snacking in between. It is doable in the controlled setting of a clinical trial, but as soon as the participants are sent back home, they will eat when they are hungry, no matter the time of the day.
Another study showed that larger meal sizes are also beneficial for patients with type 2 diabetes. Consumption of a large meal resulted in a bigger sensitivity of pancreatic β-cells to glucose than a small meal, resulting in better blood sugar control .
Carbs are best eaten towards the end of the meal
Not only does food quality matter, but so do your macros (fats, carbs, protein), nutrient density and meal frequency. But there’s more! Even the order in which we eat these fats, carbs and protein matters. A study tested the effect of 3 different sequences of giving certain foods on the release of glucose and insulin, all the while keeping the portions of fats, carbs, and protein the same 
Eating carbs after protein (lean meat) and vegetables, resulted in less insulin and glucose release than eating the carbs first, followed by protein and vegetables.
Best = Carbs after lean meat and vegetables
Worst = Carbs before lean meat and vegetables
It is suspected that eating fat and fiber before carbs slows the carb absorption and thereby favorably modulates a family of cells called incretins. These are then capable of moderating the glucose and insulin responses.
The good news: this recommended food order is very close to our traditional way of eating. A salad with oily dressing as a starter provides fat and fiber. This then slows down the absorption of the carbs that come with the main meal. The easily digested carbs in the form of sugar that cause the highest insulin response come last in the desert.
How the quality of sleep affects insulin sensitivity
A poor night’s sleep can reduce insulin sensitivity .Strategies that improve sleep quality may, therefore, reduce insulin resistance. Blue light blocking glasses let you fall asleep faster and enhance sleep quality. The rule of thumb is
- strong sunlight first thing in the morning
- wear blue-light blocking glasses once the sun has set
So take that early morning walk, dim the lights when the sun is down, block out the blue light in the evening with f.lux and by wearing blue-light blocking glasses. A cold room < 19°C (66 F°) is good for sleep and by proxy insulin sensitivity. It is also recommended to go to bed before midnight because the sleep is deepest during these hours. Last but not least, exercise, especially high-intensity training (HIT) is known to improve overall sleep quality [24, 25].
Exercise increases insulin sensitivity
Exercising increases your need for substrates like sugars, fats and amino acids (protein). By exercising you become more sensitive to insulin, the hormone that facilitates the uptake of those substrates into cells. Resistance training is known to benefit people with pathological insulin resistance [26, 27]. However, you cannot out-exercise a poor diet.
Talking about resistance training, nutrition plays an essential role in getting the most out of your efforts at the gym – or in any other physical activity. If you’re trying to gain muscle or simply improve your body composition, this is a goal that you’ll be able to select in our upcoming mobile app Nutrita.
How to measure insulin resistance
Many insulin tolerance tests aim to predict insulin resistance. Even the gold-standard oral glucose tolerance test (OGTT) with insulin has limitations. We introduce here the most reliable tests.
2-hour oral glucose tolerance test (OGTT) with insulin
In this test, the subject drinks a solution containing 100 g of glucose. The insulin levels are assessed at baseline, and at 30, 60, 90, and 120 min after the glucose load. The pattern of insulin response overlayed to the glucose response puts you into 1 of 5 so-called Kraft patterns, measuring your insulin resistance. Healthy subjects have fasting insulin below 30 uU/ml and a moderate insulin peak 30-60 min after the glucose load, whereas a peak at 120 min indicates a high risk of diabetes  .
The 2-hour OGTT with insulin is a decent predictor of insulin resistance. The downside is that it requires 5 blood samples over a period of 2 hours – something that most people prefer to avoid.
With this technique, the insulin concentration is raised abruptly and maintained at a stable level by continuous infusion of insulin. At the same time, insulin secretion from your pancreas is suppressed.
A 20% dextrose solution, a type of sugar, is injected into a vein while blood glucose levels are monitored. The amount of infused glucose is variable so that blood glucose levels are kept in the normal range (euglycemic) .Hence, how fast your can ‘dispose’ of the injected glucose determines how much glucose you need to keep blood levels constant.
This technique uses very high insulin levels, completely stopping your fat cells from releasing fat. And the test only measures one of insulin’s jobs, taking up glucose into cells. Despite this limitation, the hyperinsulinemic euglycemic clamp is still seen as a gold standard to assess insulin sensitivity. It is a costly, inconvenient and cumbersome method.
Nutrita’s insulin sensitivity calculator (McAuley index)
The McAuley index is a handy surrogate measure of insulin resistance. It basically estimates rather than measures your likelihood of being insulin resistant.
The beauty of this index is that it is straightforward and easy to do. It only needs 2 things, fasting insulin and fasting triglycerides . Such fasting indexes are usually not very useful because they have a high false-positive rate (i.e. it says you’re insulin resistant when in fact you’re not). However, the McAuley index is an exception to this rule. The problem with most fasting indexes is that they only capture a snapshot: the measurement in this very moment, which can be influenced by many factors, such as quality of sleep the night before or what you have eaten.
The reason why the McAuley index is more reliable is because it includes fasting triglycerides. Glucose and insulin levels don’t directly influence triglycerides, it is rather indirect and delayed in time. The fasting triglycerides value is, therefore, more stable over several hours, which makes it more reliable than standard fasting indexes. It is a shame that it is hardly known and under-used. Nutrita provides you with the best methods we can find, and think the McAuley index is a good way to estimate your level of insulin resistance.
Insulin has many essential functions in the body. For this reason, it is crucial that the hormone can exert its function in a natural manner; spike it with food like berries, meat and nuts, not sports bars, fruit juices and pasta. In simple terms, poor insulin signaling is a state where cells no longer respond to insulin as they should. This factor is a major one in most chronic western diseases, like diabetes, obesity, cancer and Alzheimer’s disease.
But Insulin resistance is not good or bad since per se, since its involved in normal bodily functions and in serious disease. Diabetics are the prime example of pathological insulin resistant. It is therefore crucial for good health to maintain insulin sensitivity by secreting as little insulin as necessary, and a few rather than many times a day.
Low-carb or ketogenic diets are particularly good at keeping your insulin levels low (i.e. in a healthy range). The diet doesn’t change your genetic level of insulin resistance but it can help you reverse pathological insulin resistance, as seen in diabetes. With Nutrita’s in-house insulin index, it’s never been easier to avoid foods producing insulin tsunamis (hyperinsulinemia) while eating those that are both tasty and nutrient dense.
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Written by Raphael Sirtoli, PhD
Raphael Sirtoli has an MSc in Molecular Biology and is a PhD candidate in Neuroscience at the Behavioral n’ Molecular Lab in Portugal. His understanding of metabolism, nutrition and clinical medicine is the base upon which Nutrita’s knowledge derives from. He loves open scientific debate, Crossfit, football, hiking and cold water immersion.