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March 8TH, 2021

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

Same as last week. Read to the depth that you prefer. The end has the most important part - the to do!

Recap from last week: 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, further insulin resistance, diabetes and heart disease. We are left with the excesses of our choices damaging our most vital organs.

To understand why the human body would have these pathways in place that seem to be damaging, we again have to look back in time. As stated earlier, humans had frequently experienced starvation and periods of food scarcity leaving them dependent on their body stores of fat to survive the time frame where food was lacking. Thus, during times of plenty the insulin resistance mechanism would have allowed the liver and muscles to store fat for that rainy day. The glycogen stores from glucose uptake and storage are depleted in 1 to 2 days following a prolonged fast, thus, fat is the source of long term fuel. During a prolonged fast, insulin turns off, the mechanisms flip flop whereby fats are broken down for fuel and glucose is produced by the liver through gluconeogenesis. It all makes sense in a historical nutrient normal situation.

What does insulin do to the fat cell found outside of the liver? In this case, insulin blocks the breakdown of the fat cell, a process called lipolyisis. Again, we see the insulin in the fed state acting as a storage hormone. The fasted state will reverse this process breaking down fats in the periphery and liver providing a fuel source for glucose production.

This process keeps us alive and healthful until the ingestion of food returns. No matter what happens during starvation, the body will continue to make glucose from fats and proteins until we die, primarily for brain activity. It will continue to keep glucose available to the brain by shutting off glucose storage as glycogen or fat. Everything in this process happens for a reason. It is an amazingly elegant system until we mess with it.

The rub occurs when we live through an endless summer of caloric availability to our absolute detriment based of the repeated theme of caloric excess in the face of genetic risk, sedentary behavior and toxin exposure. These beautifully elegant pathways then start to work against us.

The next piece of this discussion is the dreaded word, inflammation. Insulin resistance will eventually turn into frank diabetes and other chronic diseases. Inflammation and immune activation are the keys to this next stage after we have eaten ourselves and relaxed ourselves into trouble.

Inflammation is the process by which the body rids itself of pathogens or heals an injured body part. The immune system is recruited to an area based on an injury or pathogen. These cells of varying types will sense a danger and secrete chemicals called chemokines and cytokines that are cell signals for defense and repair. In a normal state, the body recruits immune cells to an area, destroys the damaging event and repairs the damage to a baseline of normalcy.

Now, let us say that the immune cells keep getting called to the same area over and over again. The damage will become persistent and the repair will not have a chance to occur. This is simplistically what happens in prolonged insulin resistance and hyperglycemia. Then, with time, we lose function calling it a disease.

It has become very clear now through scientific discovery that prolonged high fat diets coupled with high refined sugar diets will drive immune cells to become aggressive and pro inflammatory at the targeted tissues. This leads to further insulin signaling defects compounding the effects of DAG on the translocation of the GLUT4 receptor. The immune system through innate immune pathogen sensing mechanisms uses primitive pathogen specific pattern recognition cells called toll like receptors and fire balls called inflammasomes to recognize and kill foreign invaders. These activities are also turned on by saturated animal based fats as well as omega 6 type free fatty acids commonly found in processed foods. The why this occurs is still unknown, however, it does and we have to follow the science. This evolved area of research will eventually find out why certain fatty acids trigger immune activation while others like omega 3 fatty acids, fish oil, do the opposite. To say that this is a complex topic is a serious understatement. Therefore, the complexities of immunity and inflammation as they relate to diet and insulin resistance are beyond the scope of this piece. Suffice it to say, that in a balanced state, the ingestion of fats and sugars are directly tied to how your innate immune system responds to pathogens as well as to your own tissues.

Let us briefly look at fructose or fruit sugar. Glucose and fructose are roughly the same molecule where the difference comes down to a 5 carbon ring for fructose versus a 6 carbon ring for glucose. How they are seen by the body is vastly different. Whereas glucose can be metabolized anywhere in the body, fructose is almost entirely metabolized in the liver. It is primarily metabolized into free fatty acids as soon as the liver has met its energy needs. This happens every day now based on the excess caloric ingestion of the American diet. Thus, fructose ingestion has a special designation as the generator of free fatty acids to package and ship to the fat cells as triglycerides or to stay in the liver and make it fat. Unfortunately, fructose also makes excess DAG further driving the insulin resistance problem.

Evolutionarily, the consumption of fruit sugar, fructose, was a blessing for the all of the reasons discussed. A few times a year, trees and bushes would fruit allowing humans to eat in volume driving fat deposition for storage. Survival of the fit and well fed.

Today, unfortunately, very few Americans are lacking calories. The opposite is true. Many children drink large amounts of fruit juice daily. It takes 4 to 5 apples to make 8 ounces of apple juice. What child eats more than one apple? 8 ounces of juice on the other hand, simple. Too much sugar volume for too long a time frame.

What we know clearly now is that as our diet has become more Americanized with refined sugar and fat bombs like donuts washed down with a frappacino and this change has amplified the inflammatory state of our innate immune system causing it to work against us by promoting insulin resistance in the muscle, liver and fat cells all over the body. The inflammation drives local tissue damage where the immune cells are recruited to. The end result is that over time systemic inflammation will lead to diabetes, heart disease, high blood pressure and metabolic syndrome. Now, the rubber has met the road and we are sick. We can and do eat ourselves into disease.

How does the intestinal microbiome play into all of this? Is it the chicken or the egg? This answer is still hotly debated. To me, it would make the most sense that they are all working in concert. Remember that a pregnant woman at conception will change her microbial intestinal flora to aid in the storage of fat essentially becoming insulin resistant to prepare for child birth and breast feeding. These are not mistakes of nature. There are reams of studies showing that the intestinal florae are altered in the obese and insulin resistant state. There are also reams of studies showing that these altered florae are prone to encouraging human caloric storage and immune inflammatory states. The florae are changed directly by dietary influences. Shocker here, refined carbohydrates and saturated fats promote the type of microbe that promotes hyperlipidemia, hyperinsulinemia and hyperglycemia.

It appears from all of the research that the food source is ground zero for dysfunction. We develop disease through various routes whether they be microbially, inflammatorily or metabolically. The genes that were given to us many years ago to protect us from starvation induced death are now causing us harm primarily because of our dietary choices.

There is one more major piece of the puzzle that we must touch on. Exercise!

The age-old discussion of movement versus sitting as a route to disease is amplified in this case. When we move, we burn energy to activate our muscles via a chemical called ATP or adenosine monophosphate. Exercise has an immediate effect on the enzyme adenosine monophosphate kinase or AMPk which is a master metabolic regulating enzyme that produces ATP for muscle activity and movement. It turns off in the presence of excess glucose and turns on with exercise. AMPk directly increases the translocation of the GLUT4 receptor to the surface of the muscle cells increasing glucose flux into the muscle promoting storage as glycogen and reducing blood glucose levels and insulin need. This is the direct antagonist to the diet induced insulin resistance problem!

The more you move, in theory and in study, the more calories you will have to burn to generate ATP and therefore you will need more GLUT4 transporters to go to the cell surface to allow glucose into the muscle for burning. This is an elegant plan for activity and survival. This process is perfect until we choose to sit all day long while we eat like a king or queen.


How do we reverse or stop this process? The answer is four-fold.

1) The most obvious answer is to change the volume and quality of the ingested food sources. Sugar, flour and saturated fats consumed in high volume are the major triggers of insulin resistance. Returning to a whole food, high fiber diet with no added sugars will profoundly change the inputs that cause insulin resistance. Saturated fat in and of itself is not dangerous in moderation and coupled with fiber and normal whole foods. The anti-inflammatory diet is the perfect place to start your new dietary journey.

2) Secondly, having periods of restriction from calories as a fast or a time restricted feeding pattern will give the system time to heal. Eating in an 18:6 pattern is ideal for individuals past 18 years of age and likely younger as well. This means that you compress your meals into a 6-hour window. This allows for long periods of caloric deprivation pushing the metabolic system to shift into breakdown mode as opposed to storage mode. For younger children, I encourage eating only when they are hungry. Only present high quality anti-inflammatory food types to eat and you are well on your way to health and childhood IR avoidance. Avoid, avoid, avoid sugar beverages as juice, soda, sweet tea, flavored milks, etc…..

3) Thirdly, exercise is a powerful tool to change this IR problem by directly increasing the GLUT4 receptor activity. Move often, daily and with purpose. Not much more to say here other than family-based activities are great for collective encouragement.

4) Learn to reduce chronic mental stress. Stress dramatically affects blood glucose levels raising them due to the release of stress hormones from the adrenal gland. Stress also turns on the inflammatory pathways systemically worsening the insulin resistance issue.

Dr. M

P. S.

What herbs and supplements can be used to augment this process?

a. Omega 3 fatty acids are found primarily in fish oils and other foods like flax seeds. They are a major source of anti-inflammatory compounds called resolvins, protectins and defensins. I encourage small oily fish consumption including mackerel, salmon, sardines and trout. High quality fish oil supplements are also excellent.
b. Polyphenol supplements and foods. Polyphenols are chemicals that are found in berries, green leafy vegetables, nuts, seeds, beans, onions, cocoa and other plants. They are very potent sources of anti-inflammatory compounds and directly work against IR.
c. Curcumin or turmeric is a special herb all on it’s own. It is a very potent anti-inflammatory compound as it blocks NFkB and it’s downstream inflammation. This will be very useful to prevent the progression of IR from the immune inflammatory side of the equation.
d. B vitamin complexes can augment the conversion of fats, sugars and proteins into Acetyl CoA for energy generating ATP. Greens, beans and nuts are great food sources as well.
e. Magnesium is necessary because it promotes tyrosine kinase activity, insulin receptor activity, increased cellular glucose transport, and increased cellular glucose utilization, directly reducing peripheral insulin resistance.
f. Alpha lipoic acid is a chemical that elaborates the activity of genes that counteract insulin resistance by turning off glucose production and turning on utilization.
g. Co Enzyme Q10 is a cofactor used in the energy powerhouse of our cells called mitochondria. It helps to maintain mitochondrial activity which is critical in cell survival throughout the body.
h. Berberine has been shown in quality studies to increase AMPk and GLUT4 receptors counteracting SAD type diets and sloth.

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