March 1st, 2021

It is time for the most important article of the year.

This article is deep and shallow. It is science heavy and straight to the point. It is long and necessary. It is probably the most important piece that I have written in a decade.I hope that you will take the time.
Read it twice.

 What is insulin resistance?

This is a very complex question that needs a nuanced answer versus the theories of old. We will look at this topic in one run over two newsletters as it will be too difficult to break up in to 4 or 5 and understand.

Historically, my early medical education pegged insulin resistance as a problem of over production of the sugar storing hormone insulin in response to excess ingested dietary sugar that was unable to get into our cells because of a defect in glucose sugar transportation. This definition was partially but not completely correct as we will see over the ensuing discussion.

The critical importance of this discussion rests on the fact that when we truly and correctly define insulin resistance, we will see that chronic insulin resistance is associated with all of the chronic diseases of aging including cardiac coronary atherosclerosis, diabetes mellitus, hypertension, cancer and Alzheimer’s disease. Add the current COVID19 pandemic to this list and we see that insulin resistance to some extent is a root cause of most of healthcare’s gross expenditures and human morbidity. The root cause of insulin resistance as we will discuss is a combination primarily of genetic predisposition, dietary influences and lack of physical movement coupled to a lesser extent with chemical exposure and intestinal microbiome dysfunction. We are going to focus on the key cause, FOOD!

Let us just say, and I will come back to this point over and over, that insulin resistance is the beginning of a continuum that ends with diabetes and metabolic syndrome after many years. This continuum starts with insulin resistance which can progress to a non-alcoholic fatty liver, to non-alcoholic steatohepatitis (inflamed liver) and/or to diabetes mellitus which we all know of as the point at which blood sugar rises uncontrollably in our blood stream with or without meals. You will have been insulin resistant for many years before you begin to have signs of persistent elevated blood glucose. Therein lies the conundrum, if you are unaware that your dietary and exercise decisions are leading to massive spikes in insulin to compensate for this behavior, the damage is silent because physicians are only tracking blood glucose which takes a long time to go sideways.

This is a critical point of this whole discussion. Just like with autoimmune diseases, the elevated destructive antibody level pre-disease symptomatology is akin to the elevated insulin level pre chronic hyperglycemia. The early, when detected, elevated insulin level or autoimmune antibody level is the place that we should start the discussion of disease avoidance. To wait until you have autoimmune thyroiditis or diabetes makes little sense to me.

Depending on the study 50 to 80% of Americans are insulin resistant at this moment according to the experts. That is a lot of disease risk burning slowly in humans. It is a large fire that is burning daily. The human body is slowly suffering.

Over the next two newsletters, you will learn that the excess consumption of fats and sugars causes a cascade of events that leads to failure of a glucose transporter to shuttle sugar into the muscle causing it to begin to rise in the blood in turn causing more insulin to be released by the pancreas to dispose of the sugar in fat cells known as peripheral and visceral adipose tissue as well as in the liver. Effectively, this drives fat deposition, inflammation and over a decade or two, diabetes and heart disease. The details are important to me as the why explains the reason to change our behavior before it kills us. If the why is not important to you, skip to the bold sections and the end to do next week. I feel so passionately that this topic is critical to a healthy existence for you and your children.

To discuss insulin resistance at any level, let us define the basics of glucose sugar metabolism. When we consume glucose through carbohydrate laden foods like white bread, the carbohydrates are absorbed in our intestines after they are broken down from complex hydrocarbon structures to the molecule glucose via salivary enzymes, stomach acid, and pancreatic enzymes. The glucose is then absorbed into the bloodstream where it will travel primarily to the brain, muscles as well as the liver. It is burned in the brain and muscles for energy or can be stored in the liver or muscle as glycogen. Glycogen is necessary in humans as a rapid energy source in a storable form for movement and activity.

Insulin is a hormone that has the primary function of transporting glucose into these cells for storage.

Insulin, depending on the cell type it is being used on, will tell a receptor on the cell’s surface to signal the cell to make a glucose transporter, transport it into the cell membrane, open and allow glucose to enter the cell for utilization and/or storage. VIDEO LINK In the case of the muscle and liver cell, they use the insulin to help take up glucose to store it as glycogen. Insulin also signals the liver cell to stop making its own glucose by stopping a process called gluconeogenesis which would otherwise further compound rising blood sugar levels.

If the insulin signal is not received by these cells, these processes break down and we call that insulin resistance. A broken signal will lead to a broken function and then on to disease.

It turns out that the primary driver of the lost signal or insulin resistance is occurring at the muscle cell membrane when the GLUT4 or glucose 4 transporter fails to migrate to the cell surface in response to dietary sugar ingestion and insulin release. The failed migration traps glucose in the blood stream. So, why are we not immediately hyperglycemic or blood sugar full? The simple answer is that for a long while the body over compensates by making ever more insulin hormone to force the sugar into the cells of the liver and fat adipose tissue. Increased blood sugar drives increased insulin release and storage as fat and not as glycogen in the muscle. Insulin causes the liver to take glucose and make free fatty acids out of it which are then packaged in lipoprotein cars for transport that eventually end up as a triglyceride, the storage form of fat.

Here comes the crazy part. It is not the glucose or sugar that is driving the problem per se. It is actually ingested and released fat as fatty acids that causes the GLUT4 receptor translocation to become dysfunctional. Sugar gets trapped in the blood but it is fat that is the root cause of the insulin not working.

Why would this be?

We have to go back thousands of years to answer this question. Unlike today, humans have never had a common and never-ending source of fuel to ingest. They routinely went through periods of feast and famine. Thus, the evolution of our ability to metabolize food led to the storage of excess food for rainy days while always preserving sugar for our brains critical functioning. This is the critical understanding as to the why this insulin resistance problem is occurring. In normal historical times, the genes involved in storing calories as fat in the liver and adipose tissue were advantageous to humans when food was scarce. Now, we are polar bears living in the desert. We are genetically mismatched for the environment and our behaviors within it. Just like human issues around vitamin D development where skin color and sun exposure levels have become mismatched, food excess and our genes no longer play well together.

Here comes the hard science. Skip this section if you just want the Cliffy Spliffy notes.

When we consume large volumes of fat as a dietary calorie source, we begin to store fatty acids as a carbon chain called a triglyceride. It is the main source of energy stored throughout the body. However, under excess fat ingestion conditions, a precursor to the triglyceride called diglyceride or diacyl glycerol, DAG for short, goes up in volume and has a profound effect on cellular metabolism. This is the inflection point at which insulin resistance starts. The DAG molecule causes a local change through a few intermediates known as PKC which turns off the insulin receptor’s activity and turns off PI3 kinase activity stopping the translocation of the glucose transporter 4 to the cell membrane surface. This effectively prevents glucose from entering the muscle cell trapping it in the blood stream. See the drawing.

At this point, the glucose levels in the blood stream begin to rise causing the body to secrete ever more amounts of insulin to try and shove the glucose into a cell and out of circulation. This is known as hyperinsulinemia and brings us to step number two in the damage cycle of insulin resistance.

Insulin travels all over the body to handle the blood stream trapped sugar. The big issue arises when the insulin hormone hits the liver. Under normal conditions insulin has two major roles in the liver. First, it shuts off the liver’s ability to make more glucose via a process called gluconeogenesis. This is useful when you have plenty of glucose on board. Second, it tells the liver to make fat. Therefore, excessive insulin will lead to a fatty liver. Over time the fat cells becomes metabolically and immunologically active leading to hepatic inflammation and possibly cirrhosis/fibrosis. This is the normal physiological response to excess, inflammation and hardening.

Let me recap: Excessive amounts of ingested fats cause the hormone insulin to not be functional at the muscle level leaving blood glucose stranded in the blood stream driving up the production on insulin which in turn causes fat deposition and inflammation in the liver and periphery. This is how the stage is set for chronic disease development.

Now, at this point you can already guess how ingested sugar becomes an exacerbant in this process.

Excessive fatty acid ingestion and production can lead to insulin resistance. This point is solid based on the evidence. What happens when we throw large volumes of sugar into the mix? Sugar laden beverages coupled with refined flour, sugar and fat based processed foods eaten in high volume represent the quintessential American diet. What happens now?

The insulin resistance mechanism as discussed has caused the ingested glucose sugar to stay in the blood stream raising blood sugar levels temporarily until more insulin is made to force the sugar into the fat cells. This process continues meal upon meal. If there is a large sugar gradient based on the high volume consumed, there will be a large insulin volume produced to handle it each and every time. The excess sugar forces the production of free fatty acid, FFA, which is deposited in the liver causing a fatty liver, again the hallmark of insulin resistance. The excess FFA's will also need lots of lipoprotein transporters to move all of the fat to the storage sites throughout the body. This is the point where your doctor tells you that you have high lipids and are at risk for heart disease.

The liver is the chemical factory of the human body. It will do what it has to do based on what we choose to eat. Let us take a closer look at the liver. The muscle’s insulin resistance forced the excess sugar to stay in the blood stream driving up insulin release overall. The blood sugar and the circulating insulin now head to the liver where they have profoundly negative effects. As stated previously, the liver becomes fatty. Why?

In the liver, glucose enters cells independent of insulin through a different glucose transporter called GLUT2. Unlike the muscle cell, glucose is not trapped when it arrives at the liver cell. Normally, insulin’s effect in the liver cell is to store glucose as glycogen, the storage form, and also to turn off any excess glucose production occurring through gluconeogenesis. Normally 83% of the bodies glycogen is found in the muscle. But, in the insulin resistant state, this storage location is lost. Thus, only the liver can handle the excess glucose flux. With the ability to form glycogen lost, the liver turns to making FFA. Compounding this problem is the fact that the liver is also not receiving the signal from insulin to stop making it's own glucose sugar.

The liver is left making it's own sugar in perpetuity while taking in excess sugar from the blood stream. It is all converted to free fatty acids to be packaged as triglycerides in lipoproteins with cholesterol. The lipoproteins are then sent all over the body for storage. Low density lipoprotein or LDL particle number is the biomarker of risk for coronary atherosclerotic heart disease. Therefore, if we chronically over consume fat and sugar food bombs, the liver will make lots of LDL particles to transport the triglycerides. Now we find one great link between diabetes and heart disease, processed food.

So, here we are, over ingested fats are causing insulin to not trigger the signal for glucose to enter the liver or muscle cell to be stored as glycogen and or burned as fuel. The combination of excess sugar and fat ingestion simultaneously has provided a nutrient gradient with glucose levels rising in the blood forcing the pancreas to pump out more insulin which in turn forces the liver to convert the excess sugar into fatty acids which are packaged in lipoproteins and transported to our fat cells driving obesity and heart disease. We are left with the excesses of our choices damaging our most vital organs.

To be continued:

Dr. M

Glass Cell Metabolism
Coughlan J Endo Diabetes Obesity
Lustig Pediatrics
Patel J Obesity
Peterson Physiology Reviews
Peter Attia MD #140/149