You’ve probably heard of insulin resistance in the context of type II diabetes. Insulin is a hormone that controls blood sugar levels. When blood sugar rises, beta cells in the pancreas release insulin, which brings blood sugar back down (we’ll discuss exactly how it does this later). If a healthy individual and a person with insulin resistance both eat a meal containing the same amount of carbohydrates, you may know that the blood sugar of the person who is insulin resistant will take longer to fall back to pre-meal levels. But what exactly is going on in their cells to make them insulin resistant? How does insulin resistance happen in the first place, and why is it a bad thing?
Every day, we consume energy in the form of carbohydrates, fats, and proteins. These molecules are broken down, absorbed through our guts, and used by our cells to perform the functions that allow us to live and go about our daily lives. Our intake of food is not constant – we might consume a large amount of calories in one meal, then go for many hours without eating much. In extreme circumstances, humans can even live for months without food. Yet our bodies’ need for energy is constant (though variable) – in particular, we need a constant supply of glucose, as this is the only nutrient that certain parts of the brain can utilise. Because of this, our bodies need to be able to do a few things:
The hormone insulin controls these processes in response to blood sugar (glucose). You can think of it as controlling the flow of energy between glucose and stored energy. Suppose you eat a meal that contains carbohydrates. Those carbs are broken down in your gut and absorbed into the blood as glucose. In response, beta cells in the pancreas release insulin, which has a number of effects:
When insulin levels are low, the reverse effects occur: the lack of insulin lifts the blockage on glucose production in the liver, while glycogen and fat can be broken down to access the energy stored within.
When you think of a person with insulin resistance, your first thought may be of a person who is overweight, is type II diabetic, and has elevated blood sugar unless it is controlled by medication. While this person would certainly be insulin resistant, this metabolic disorder is very common and often asymptomatic, at least initially. Indeed, it is perfectly possible to be insulin resistant and yet have normal or nearly normal blood sugar, and it may be that as many as 50% of Americans who are insulin resistant do not know it. We’ll get to why that is later, but let us first understand what differentiates a person with fully developed insulin resistance from someone with a normal glucose metabolism.
Let’s say we feed a healthy person and an insulin resistant person a carbohydrate-containing meal. In the healthy person, insulin is released by the pancreas in response to the rise in blood glucose. Insulin causes most of that glucose (about 80-90%) to be absorbed by the liver and muscle and converted into glycogen. In the resistant person, however, insulin fails to induce the same level of glucose uptake by the muscle and liver, despite the fact that their pancreas is releasing more insulin in an attempt to overcome their resistance. Meanwhile, insulin fails to block the production of glucose (gluconeogenesis) in the liver. Consequently, they will maintain a higher blood sugar compared to the healthy person.
At least in humans, insulin resistance begins with the muscle tissue. Muscle is significant because it is a major store of glucose in the form of glycogen (remember that most of the carbohydrates we consume are stored as glycogen). We think that the main culprit driving insulin resistance in muscle tissue is fat that builds up inside muscle cells. Using NMR, it has been shown that the presence of fat inside muscle cells is the best predictor of insulin resistance. By raising fatty acid levels for 3-4 hours through intravenous injections, we can also mimic the effects of insulin resistance temporarily. But what’s going on inside muscle cells to make them stop responding to insulin?
Usually, when insulin activates the insulin receptor on the surface of muscle cells, this activates signals inside the cell that lead to the insertion of special proteins, called GLUT4, into the cell membrane. GLUT4 proteins act as openings through which glucose is able to enter the muscle cell. However, when insulin activates the receptor on the surface of muscle cells that are insulin resistant, the resulting amount of GLUT4 being inserted into the membrane is reduced.
When muscle cells have too many fatty acids to metabolise, this leads to a build-up of a specific fatty acid called diacylglycerol (DAG). This DAG then activates other molecules called protein kinases. When insulin binds to its receptor on the cell surface, these protein kinases impede the signals that would normally ensue inside the cell. This means that less GLUT4 is inserted into the cell membrane. The end result is that less glucose is able to move into the muscle cell and be converted into glycogen.
We mentioned earlier that it was possible to be insulin resistant, yet not suffer from elevated blood sugar. This is possible because most people who are insulin resistant simply produce more insulin. Meanwhile the liver, which has not yet developed insulin resistance, is able to take up the excess glucose that isn’t being stored by the muscle. Unfortunately, the liver has to store some of this glucose as fat, which eventually leads to a similar problem to the one we described in muscle cells – DAG accumulates, and the liver develops insulin resistance. Consequently, the liver increases its production of glucose (gluconeogenesis), and it is at this point that elevated blood sugar (hyperglycaemia) starts to become a real problem.
Insulin resistance is a problem for many reasons. Insulin resistance is a fundamental condition that drives not only type II diabetes, but other major chronic diseases of ageing including fatty liver disease, heart disease and cancer. Even before insulin resistance results in elevated blood sugar, the liver is storing excess glucose as fat. This increased fat production is accompanied by an increase in production of very low density lipoprotein (VLDL), which is a particle that carries fatty acids to tissues. This increases fat deposition in the walls of the arteries, which drives atherosclerosis. The accumulation of fat also sets the liver on the path to fatty liver disease.
The increase in insulin production in response to insulin resistance also causes a number of problems. Insulin is a growth promoting hormone, and as such can promote the growth of cancers. Insulin also promotes inflammation, which is a factor in driving almost all chronic diseases of ageing, including cancer, heart disease, and neurodegenerative diseases.
When insulin resistance results in elevated blood sugar in diabetes, this can cause damage to blood vessels and the nervous system if it persists for an extended period of time. When blood sugar is extremely elevated, the kidneys reabsorb less glucose and consequently less water, which may cause severe (and potentially fatal) dehydration. Because insulin resistance makes it difficult to get glucose from the blood into the cells that could use it, cells may be forced to convert fat into ketone bodies for fuel. If this continues for long enough, these ketone bodies may build up and enter the blood, causing it to become too acidic. This is called diabetic ketoacidosis, and can be life-threatening.
Despite the many dangers of insulin resistance, its cellular mechanism appears to be conserved across species, from humans to fruit flies. Let’s briefly recap on how we think insulin resistance happens. When cells have more fatty acids than they are able to metabolise, this leads to the build up of a molecule called diacylglycerol (DAG). This molecule then activates proteins that block insulin signals inside the cell. The existence of these proteins, and their ability to interact with the insulin receptor, is encoded in our DNA, and this code has been conserved throughout our evolution. Is it possible that insulin resistance might be somehow advantageous?
Today, the ‘overloading’ of cells by fatty acids usually occurs as a result of excessive calorie intake, which is not something that our evolutionary ancestors were likely to have experienced very often. There is, however, another scenario in which cells may metabolise large amounts of fatty acids: starvation.
During starvation, the only source of glucose is from the liver – the liver makes new glucose in a process called gluconeogenesis. Since the brain needs to metabolise glucose, any precious glucose consumed or stored as glycogen in other tissues could be seen as problematic. An adaptation that reduced glucose storage by other tissues during starvation, thereby making more glucose available to the brain, could have been an evolutionary advantage. In line with this theory, mice that have fasted for 48 hours experience an increase in DAG and activation of protein kinases in their livers, suggesting the onset of insulin resistance (in mice, the liver becomes insulin resistant before the muscle).
A final recap of our current understanding of insulin resistance in humans:
Gerald Shulman, M.D., Ph.D.: A masterclass on insulin resistance—molecular mechanisms and clinical implications: https://peterattiamd.com/geraldshulman/
Mechanism of free fatty acid-induced insulin resistance in humans: https://www.jci.org/articles/view/118742
The Links Between Insulin Resistance, Diabetes, and Cancer: https://dx.doi.org/10.1007%2Fs11892-012-0356-6
Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation: https://doi.org/10.1016/j.cell.2017.12.001