Insulin Resistance
Insulin resistance is the main driving factor in the progression from high blood sugar to prediabetes, and then to type 2 diabetes.
Insulin is like a key that cells need in order to open pores, through which glucose can get in from the blood. Without insulin, glucose cannot enter cells, and they cannot use it for making energy. But cells can stop responding to insulin and stop taking in glucose if blood sugar and insulin levels have been too high for some time. This is mainly because high blood sugar levels are toxic, and cause damage to cells that normally respond to insulin. The damaged cells become unable to respond to insulin, and with insulin resistance, sugar remains in the bloodstream as there is little elsewhere else for it to go. At the same time, insulin resistant cells can become starved for glucose and unable to produce energy.
In the early stages of insulin resistance, when the blood sugar level gets too high, the pancreas secretes more insulin to compensate for cell resistance in order to try to lower blood sugar levels. But over time, if the levels remain still too high from overnutrition, the pancreas becomes unable to release extra insulin [1]. This is because high glucose levels also cause damage to the pancreas. In short, insulin resistance is when (1) cells become desensitized to insulin, and (2) the pancreas cannot produce enough insulin to compensate for desensitization.
What’s more, as cells produce less energy, the combination of glucose-starved cells and high insulin levels make the body feel tired, hungry, and crave for sweet and salty foods. This happens because the brain wants to increase glucose supply to cells, regardless of the supply already in the blood. This can result in a cycle of overnutrition, high blood sugar and further resistance to insulin.
In summary, insulin resistance is caused by damage to cells, such that they can no longer take in glucose from the blood. It also involves damage to the pancreas, which becomes unable to produce enough insulin.
How does high blood sugar cause such damage to cells?
Continue reading to find out.
How does Insulin Resistance Develop?
It is not exactly clear how insulin resistance develops when cells are exposed to high blood sugar in type 2 diabetes, but general understanding is that inflammation [2,3,4,5,6] and cellular stress play a major role in the pancreas, muscle, liver and fat tissue. Inflammation and stress (oxidative stress and ER stress) in cells interfere with cells’ ability to perform normal functions, and they are triggered by high levels of glucose (glucotoxicity) as well as excess fat molecules (lipotoxicity) in the blood and organs.
1. Glucotoxicity
High glucose levels trigger different types of stress reactions in the body that lead to cell death or dysfunction [7,8,9].
When cells have too much glucose, toxic substances called Reactive Oxygen Species (ROS) are produced. ROS trigger chemical chain reactions inside the cell that generate abnormal DNA, disfigured proteins and toxic fat molecules. DNA is degraded, cell structures fall apart, and vital functions are disrupted, so that cells no longer can carry out their normal activities. Some cells eventually die. This kind of stress caused by ROS is called oxidative stress.
Glucotoxicity lowers insulin sensitivity
Oxidative stress disrupts insulin receptors in cells so that they cannot receive incoming insulin signals [10,11,12]. This is one way how high blood sugar contributes to insulin resistance in muscle [13,14,15], liver and fat cells [16,17,18].
High blood sugar levels can also stimulate the irreversible production of harmful Advanced Glycation End-products (AGEs) inside the body [19]. AGEs are formed when sugar molecules chemically bind to other types of molecules such as proteins, fat molecules and nucleic acids. AGEs have been suggested to block insulin signaling and reduce glucose uptake, as well as increase ROS and inflammation in cells [20].
Glucotoxicity damages the pancreas
In the pancreas, oxidative stress damages and kills β cells, which are cells that make insulin [8,21,22,23,9,24].
Another kind of stress, called ER stress, may also be involved in the damage to the pancreas [25]. The ER (endoplasmic reticulum) is a specialized compartment inside cells that is responsible for producing properly functioning proteins, such as collagens. Stress on the ER can put a halt on insulin production (insulin is a kind of protein), and also cause β cell death [26,27].
Inflammation and high blood sugar
Oxidative stress and ER stress cause insulin resistance, but inflammation also strikes another blow to body cells and organs that are struggling under high blood sugar conditions.
Our immune system is critical not only for defending against microbial infection, but also against abnormalities that develop internally (for example, cancer). The immune system works by triggering an inflammatory response to fight against these abnormalities, which conversely puts a halt on other normal functions. High blood sugar, an abnormality in the blood, puts our body in a fight with itself.
Inflammation also has a self-propagating mechanism that puts on a bigger and bigger fight until the abnormality gets totally resolved. First, some tissue cells get damaged and release inflammatory signals to ask for help. Then, a small number of white blood cells in the bloodstream detect the signals as they’re passing by. These white blood cells can quickly recruit a flood of more white blood cells into the affected area by sending out inflammatory signals themselves. More cells in the area produce more signals, and the reaction gets amplified. If the abnormality does not get fixed, the organ will be in a constant state of inflammation (chronic inflammation), and it may become permanently weakened.
Inflammation only keeps us healthy when it is kept in check. If the immune system is too weak, it would not be able to fight off infection and abnormalities. But if it becomes hyperactive, it can contribute to diseases such as rheumatic arthritis, Crohn’s disease, atherosclerosis, diabetes, Alzheimer’s, multiple sclerosis, stroke and heart attack.
Consuming sugar and refined carbohydrates have been shown to increase inflammation in the body [28,29,30,31,32,33]. In inflamed cells, inflammatory signals can overwhelm other signals that are normally being passed around to perform cellular functions, such as responding to insulin. In this way, inflammation can contribute to insulin resistance in the muscle, liver and fat tissue [4,34,9,35].
The pancreas also gets inflamed when blood sugar levels are too high. Initially, an immune reaction may be triggered to repair β cells that are damaged by oxidative stress. But if high blood sugar and pancreatic damage persist, inflammation becomes chronic to the point that healthier β cells become collateral damage [36]. Inflammation has been shown to reduce insulin production and promote the death of β cells [37], ultimately causing insulin resistance [38,39].
2. Lipotoxicity
Oxidative stress, ER stress and inflammation are a destructive combination that causes cell damage, death, and insulin resistance. If this sounds bad already, there is more news – all of three these stresses can also be brought on by fat, not just high blood sugar.
Fat has long been implicated in the development of insulin resistance. For one, obesity is a major, known risk factor for insulin resistance and type 2 diabetes.
Fats are stored as triglycerides inside cells. And when cells need to use the fat to generate energy, triglycerides are broken down into free fatty acid (FFA) molecules. Storing too much triglyceride inside, as well as high levels of FFAs in the blood, have been shown to cause harm to muscles, liver, pancreas and fat tissue – particularly when combined with high blood sugar.
Similar to high blood glucose, high fat levels damage cells by causing inflammation. When fat-storing cells are overloaded with triglycerides, white blood cells detect this abnormality and activate an inflammatory response [40,41]. In obesity, as the muscles and liver store more fat, inflammation can block insulin signaling and lead to insulin resistance. Once insulin resistance develops, it can actually cause more fat to build up inside, resulting in a cycle of high fat, inflammation and insulin resistance [42].
High levels of body fat and fatty acids have also been shown to produce oxidative stress. Oxidative stress disrupts insulin signaling and gives rise to insulin resistance in the muscles and the liver [10]. In fact, insulin resistance promotes the production of more fatty acids, because cells that are starved for glucose will break down fats to get more energy. Triglycerides are broken down into FFAs, producing energy while also releasing FFA into the bloodstream. This means that free fatty acids, oxidative stress and insulin resistance form another vicious cycle that propagates insulin resistance further and further.
In the pancreatic β cells, high FFAs cause ER stress and eventually cell death and lower insulin production [43,44,45,46]. People with fatty pancreas often do not produce enough insulin to compensate for insulin resistance [47,48].
Ceramides
Ceramides are another link between fat and insulin resistance. When FFA levels are high, fatty acids undergo chemical changes that produce new kinds of fat substances called ceramides. Increasing evidence suggests that ceramides directly interfere with insulin signaling, prevent glucose uptake into cells, and block the conversion of glucose into glycogen for storage. Ceramides can also activate inflammation. High blood ceramide levels are associated with diabetes [49,50], showing how important fats can be in influencing blood sugar levels and insulin resistance.
Compound cell damage
This section described how inflammation, oxidative stress, ER stress, AGEs and ceramides damage cells of the muscles, liver, fatty tissue and pancreas to cause insulin resistance. However, there is still ongoing discussion about how influential each of these stressors are in the course of developing resistance [51,52]. They may not be mutually exclusive, but together, they produce damaging effects on the body’s ability to control its own blood sugar levels. The main takeaway is that high blood sugar, as well as high body fat, can both damage the body in many ways that result in insulin resistance and the inability to produce sufficient insulin.
Blood Sugar vs. Fat
As shown in the previous section, high blood sugar alone, or high fat alone, individually pose a risk for developing insulin resistance by damaging the muscles, liver, fatty tissue and pancreas. Fat indeed affects how well our body is able to control blood sugar levels. But this is not the whole story, because in fact, high blood sugar itself can also contribute to high body fat.
Glucose (carbohydrates) and fat are the only 2 types of substances that our bodies can use to get energy. According to our diet and the amount of energy we use daily, our body chooses which food to ‘burn’ and get energy from first. When we eat more carbs and more fat than our body needs for energy, the carbs get burned first instead of fat [53]. The excess fat gets stored. In our modern food landscape, leading a sedentary lifestyle means that it is easy to build up body fat.
Also, in extraordinary cases, if carbohydrate intake exceeds around 5,000 calories per day, carbs can be converted into fat (FFAs) by a process called de novo lipogenesis. Although the amount of fat produced may not significantly add to the amount of body fat being stored already, it is enough to promote insulin resistance in the liver [53,54,55].
The facts show that there is a very close relationship between sugar, fat and insulin resistance in our bodies. Insulin resistance can develop when there is constant high blood sugar by affecting fat metabolism in the liver in individuals without overt obesity. And in overweight individuals, the combination of excess fat and high blood sugar have compound effects that multiply in a vicious cycle to significantly increase the risk of insulin resistance. Unfortunately, once resistance does develop, body fat and insulin resistance can continue to build on top of each another so that it gets harder over time to control one’s blood sugar levels.
Disclaimer
This information outlines the general understanding of how insulin resistance develops from the combination of overnutrition and a sedentary lifestyle that leads to excess build-up of sugar and fats in the body. Overnutrition can be avoided by matching the amount of food we eat with the amount of energy we use on a daily basis.
It must also be noted that various other factors influence insulin resistance, such as age, gender, family history and pre-existing health conditions (e.g. high blood pressure, high cholesterol, pregnancy).
Summary
It is important to maintain blood sugar levels within a healthy range to avoid not only diabetes, but also severe complications (e.g. stroke, heart attack, diabetic foot, blindness) that arise due to the toxic nature of high sugar levels all over the body.
In a healthy state, insulin is produced by the pancreas after a meal to bring down sugar levels. Insulin directs muscle, liver and fat cells to burn sugar to generate energy, and to store any remaining sugar as glycogen. In this way, the blood sugar level does not stay high for too long.
Diabetes is when the body cannot lower blood sugar levels by itself, and therefore has chronically high blood sugar levels.
Diabetes develops gradually over time. It begins with insulin resistance and damage to the pancreas.
Insulin resistance and pancreatic damage may be reversed if blood sugar levels are controlled before permanent damage is done.
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