Insulin Resistance

Insulin Resistance

    When it comes to weight loss and health in general, the most common advice I’ve heard has to be “eat less” and “exercise more”. If I have learned anything during the endocrine unit of medical school, it is that the biochemistry that governs our metabolism is far more nuanced, and its complexity makes the age-old advice of caloric restriction and hitting the weights lacking at best. Eat less of what? What kind of exercise? What if I’m hungry? What if that advice doesn’t work? Understanding the basics of metabolism, especially as it relates to insulin resistance, is one of the most important health-related topics because good metabolic health is one of the main drivers of maintaining quality of life and staving off diseases like diabetes, heart disease, cancer, Alzheimer's, and so on. By understanding the biochemistry of your metabolism, you will be able to make better, more informed choices regarding your health. 

    In this post, I will discuss several disease-causing metabolic processes, namely insulin resistance. I will also discuss how glucose and fructose are converted into energy by the body and how that can go awry. Lastly, I will discuss how exercise impacts this process. By the end of this article, you will have a greater appreciation for and understanding of your metabolism. As always, I aim to provide information that will empower you to live a healthier life.

    At the end of this post, there is a summary that explains the bottom line of insulin resistance. 

A few key points before beginning:

• There are three main categories of nutrients (i.e. sources of calories) 
• Carbohydrates - this includes all sugars, carbs, etc.
• When carbohydrates are digested, they are broken down mainly into glucose and fructose. 
• The body stores carbohydrates in the form of both glycogen and fat. 
• Think of glycogen as a quick source of fuel during exercise or between meals. It is easy to access and turn back into glucose. 
• Fat is more of a long-term fuel storage. It takes more effort to break it down into a glucose-like substance that can be used as energy for the body.
• Lipids - this includes fats such as triglycerides and cholesterol.
• Proteins 
• Insulin is the hormone responsible for telling your body to process and store calories after eating. It is especially important in telling cells to take glucose out of the blood and to store it as glycogen or fat.
• Glucagon is a hormone that essentially has the opposite effect of insulin. It tells cells to break down glycogen and fat in between meals to keep a steady supply of sugar in the blood to supply organs like the brain. 

How is blood sugar maintained?

    The term “sugar” is often vilified, but it is a crucial nutrient in the body. Let me explain why. The most basic form of sugar is glucose. Almost any source of carbohydrates, whether it is a potato or a Twix bar will be broken down into the simplest building blocks, mainly glucose. Those carbohydrates are absorbed through the small intestine and enter the blood circulation from there. 

    Maintaining a proper level of glucose in the blood is essential for many organs to function properly. If it gets too high, one can become hyperglycemic which causes all sorts of problems. If it dips too low, one becomes hypoglycemic which can be a life-threatening medical emergency. Fortunately, the hormones insulin and glucagon work hard to keep blood glucose within its proper range. 

• After a meal containing carbohydrates, blood glucose rises. 
• This triggers the release of insulin from the pancreas. 
• Insulin lowers blood glucose by telling muscle, adipose (i.e. fat), and liver cells to take up glucose and store it as either glycogen or fat.
• Between meals, when blood sugar falls, the pancreas releases glucagon. 
• Glucagon tells liver and adipose cells to break down glycogen and fat so they can be converted into glucose, keeping the brain and other body tissues fueled.

    So far, this is all looking good, right? What could possibly go wrong?

When things go wrong:

    The typical American diet is rich in sugar, processed carbohydrates, and calorie-rich foods. Highly processed foods are broken down and absorbed by the small intestine much faster than raw foods like fruits, vegetables, and meat, whole grains. For example, if you stick a cracker on your tongue, it will dissolve pretty quickly, like maybe less than a minute. Stick a piece of lettuce on your tongue and it will be there for a while. I’ll get more into the details of why that is later, but know this. Sugar and processed carbohydrates cause a sharp rise in blood sugar. The body therefore has to work harder by releasing more insulin to curb the rise in blood sugar. Higher blood sugar = more insulin. 

    Insulin resistance begins in the muscles. Remember how one of the tissues that insulin acts on is muscle tissue? Insulin tells the muscles to take up glucose out of the blood and store it as glycogen or fat. (This can later be utilized for energy during exercise). The muscle has a huge ability to store glucose, but under normal conditions, it can only store glucose when insulin tells it to. Below is a schematic of how this works. 

Description of the diagram above:

    Insulin binds to a receptor on a muscle cell. This causes a cascade of different signaling molecules, kind of like a relay race, which eventually ends in a molecule called GLUT 4 being inserted into the membrane of the muscle cell. GLUT 4 is the molecule that removes glucose from the blood and transfers it into the muscle cell. 

    Here is the issue. When too much glucose is taken up by the muscle and its ability to store that glucose is exceeded, the muscle instead begins burning that glucose. You know how fire requires oxygen to burn? Well, it’s the same with burning glucose in muscles. A byproduct of this process is something called a reactive oxygen species (or ROS for short). When the muscle burns a lot of excess glucose, and it is not burning that glucose during exercise, ROSs build up in the muscle. This causes a condition known as oxidative stress. 

    Oxidative stress triggers the activation of several factors within the muscle, namely a protein called JNK. This protein goes and binds to the insulin receptor, lowering its activity. This results in less glucose being removed from the blood. Therefore, excessive glucose in the blood leads to a change in muscle physiology that reduces its ability to respond to insulin and remove glucose from the blood. This is the definition of insulin resistance. 

Fructose:

    Fructose is similar to glucose in that it is one of the simplest forms of sugar. It is found, as its name implies, in fruit. It is also found in sucrose (i.e. table sugar) and high fructose corn syrup. A sucrose molecule is made of one glucose and one fructose. 

    What are fructose’s implications on blood sugar? Metabolizing fructose differs from glucose in that it does not use GLUT 4 transporters. The majority of the fructose that you consume goes directly to the liver where it will either be broken down into energy or converted to triglycerides and stored as fat. Chronic (i.e. long-term) overconsumption of fructose leads directly to a condition known as non-alcoholic fatty liver disease (NAFLD) which increases insulin resistance and causes a whole host of other issues. I will discuss this further down, but fruit (which contains fructose) is okay because contains fiber. Table sugar and high fructose corn syrup do not have fiber and should therefore be consumed in moderation and with good judgment.

When things keep going wrong:

    When muscle becomes insulin-resistant, the liver follows suit. More insulin must be released to keep blood sugar within normal levels. However, adipose (i.e. fat tissue) remains sensitive to insulin, so it will keep gobbling up glucose from the blood, converting it into fat storage. This is why insulin resistance seems to precede obesity and weight gain. 

    This is also why one sign of insulin resistance is increased triglyceride levels in the blood. Adipose continues to crank out triglycerides which are processed by the liver. Eventually, this will lead to non-alcoholic fatty liver disease (NAFLD). The liver will process those triglycerides and send them back out into the blood in the form of VLDL and LDL particles. You can go back to my post about cholesterol to review LDL in more detail. But, in short, elevated LDL levels in the blood lead to plaque formation which increases the risk of cardiovascular disease. 

    To compound the risk for cardiovascular disease, chronically elevated blood glucose, or hyperglycemia, damages the cells that line the blood vessels which are called the endothelium. This makes them a perfect target for plaque formation.

    Once insulin resistance has progressed, the prolonged strain on the pancreas from cranking out extra insulin eventually takes its toll. The pancreatic beta cells (i.e. those that make insulin) begin to burn out and become unable to meet the body’s demand for increased insulin. Insulin levels begin to drop and blood sugar rises. This is the beginning of type 2 diabetes. 

    The good news is that up until this stage, the progression of insulin resistance and diabetes is reversible. Healthier eating, exercise, and medication can change the trajectory of one’s metabolism. Once beta cells that make insulin die from being overused, diabetes moves into its later stages and, to current knowledge, is irreversible.

Preventing/Reversing Insulin Resistance

• Exercise is one of the best ways to combat insulin resistance. Here is the reason why. Do you recall the drawing of the muscle cell with the GLUT 4 transporter? The only way that the muscle cell can take in glucose is when insulin signals the movement of GLUT 4 transporters into its cell membrane. Well, it turns out that exercise provides two separate pathways to move glucose into muscle cells without the need for insulin. Additionally, exercise reduces the activity of the protein JNK which also allows for more glucose to be taken out of the blood. JNK is not able to inhibit the insulin receptors, so the muscle cells become more sensitive to insulin. Furthermore, exercise depletes the glycogen storage in muscles, allowing for more glucose to be stored in the muscles. Exercise, both aerobic and strength training, plays a crucial role in metabolic health.
• The best time to exercise to lower blood glucose and insulin release is generally within two hours after eating. This is approximately how long insulin remains elevated after eating.
• Studies have repeatedly shown that muscles remain more sensitive to insulin for 48-72 hours after moderate exercise (i.e. getting your heart rate to around 60-70% of its max) [1]. With this in mind, moderate exercise at least three to four times throughout the week should prolong the benefits of exercise in reducing insulin resistance. 
• Diet is also key to metabolic health. It should come as no shock that processed and sugary foods cause a spike in blood sugar and therefore insulin. Foods that take longer to digest like fruits, vegetables, and whole grains generally cause blood sugar to rise and fall more gradually, blunting the release of insulin. 
• Fruit is good! Even though fruit contains fructose, the ratio of fiber to fructose is very high. This means that the fructose sugars will be absorbed much slower from the intestines and the fiber will make you feel more full, generally preventing you from overeating fruit. 
• Avoid high fructose corn syrup. This has no fiber and is therefore digested extremely fast. Because it contains high concentrations of both glucose and fructose, overconsumption drives insulin resistance and fatty liver disease. 
• Cholecystokinin: foods that trigger the release of a hormone called cholecystokinin (or CCK for short) tend to slow the emptying of contents from the stomach into the intestines, further blunting the rise of glucose and insulin in the blood. Foods that trigger the release of CCK are fats, proteins, and fiber. Another benefit of eating foods that trigger the release of CCK is that it triggers satiety, i.e. makes you feel more full [2]. Just writing this is making me want to go eat a handful of almonds and sunflower seeds. Therefore, when eating a meal or snack, it is best to have something containing protein, fat, and/or fiber or at least start with it. For example, you might have a salad before eating a bowl of spaghetti or a slice of cheese instead of instead of just plain crackers.

The bottom line:

    I know this is a long post and I promise that I tried to keep it brief. I’m very passionate about this if you can’t tell. If your eyes started to glaze over and you didn’t understand every detail above, here’s a summary.

    Overconsuming foods that tend to spike blood glucose, like highly processed foods and foods rich in sugar, will make it harder for the body to process carbohydrates in the future. This is insulin resistance, and it tends to shift metabolism more towards storing energy as fat, which leads to obesity and eventually type II diabetes.

    Regular exercise is a great way to improve the body’s sensitivity to insulin, making it easier to metabolize sugars and decreasing insulin resistance. 

    Furthermore, eating more raw, whole foods and foods with more protein and fat blunt the body’s insulin response, reduce spikes in blood sugar, and lend to making you feel more full.

    I hope you have learned something from this post that you can apply to your own life. 

Sources:

1. Venkatasamy, V. V., Pericherla, S., Manthuruthil, S., Mishra, S., & Hanno, R. (2013). Effect of Physical activity on Insulin Resistance, Inflammation and Oxidative Stress in Diabetes Mellitus. Journal of clinical and diagnostic research : JCDR, 7(8), 1764–1766. https://doi.org/10.7860/JCDR/2013/6518.3306
2. Valassi, E., Scacchi, M., & Cavagnini, F. (2008). Neuroendocrine control of food intake. Nutrition, metabolism, and cardiovascular diseases : NMCD, 18(2), 158–168. https://doi.org/10.1016/j.numecd.2007.06.004