The Pathophysiology of Metabolism and Mental Health

Hey team,

In my last post, I introduced the work of Dr. Chris Palmer, who views and treats mental illnesses as metabolic disorders, delving into the information he presents in his book “Brain Energy”. Since then, I have continued to engage in this space and recently finished reading “Change Your Diet, Change Your Mind” by Dr. Georgia Ede and “Metabolical” by Robert Lustig MD. Today, I want to break down the pathophysiology of metabolism, including the sites of damage, causes, and consequences. I hope you find this both informative and engaging.

Life runs on energy, and for biological organisms like us, this energy comes from the food we eat. Sugars (carbohydrates), fats, and proteins are the macronutrients our cells use to create energy. Essentially, we derive energy from electrons that hop from one molecule to another in a series of reactions, yielding substrates like NAD, FAD, and pyruvate. Our cells break down food into smaller components, such as glucose, fatty acids, and amino acids, which are then used in these reactions to produce energy. For instance, our cells can’t directly use a black bean; it must be broken down by enzymes in our GI tract before being absorbed into the bloodstream as smaller molecules of amino acids, sugar, and fats.

There are two main ways our bodies produce energy from food: aerobic (with oxygen) and anaerobic (without oxygen). These processes often work together for maximum efficiency. Aerobic respiration utilizes mitochondria to produce ATP (energy) and is far more efficient, yielding approximately 38 ATP per glucose molecule compared to just 4 ATP from anaerobic glycolysis. Mitochondria, often described as "insane in the membrane," are unique organelles with their own DNA, separate from the nuclear DNA, and are crucial for energy production. However, this makes them uniquely vulnerable to damage as this separate DNA is not protected like nuclear DNA is. This is on top of being tiny little nuclear reactors producing free radicals every moment that run a muck unless properly cleared.

So where do things go wrong? Essentially energy deprivation, not running at full speed or even near. This results from insulin resistance, and persistent hyperglycemia causing damaged and/or insufficient mitochondria and overall cell function. A cell can have tens of thousands of mitochondria, which are particularly prone to damage and require proper maintenance. This maintenance involves clearing out damaged mitochondria (mitophagy) and creating new ones (mitochondrial biogenesis).

The damage often mentioned refers to glycation and oxidative stress. Glycation occurs when excess sugars (glucose) in the bloodstream bind pathologically to proteins, leading to the production of harmful glycated proteins. Our mitochondria recognize these proteins and release oxygen radicals, inducing inflammation. While this response is healthy in moderation, chronic high blood sugar leads to persistent inflammation and cellular dysfunction. An example of a measured glycated protein would be hemoglobin A1C. When sugar is chronically high in the bloodstream it glycates (sugar + protein) the heme protein. A1C indicates how often someone has been in a hyperglycemic state over the past few months as more glycated heme proteins indicated more time spent in a hyperglycemic state. 

Another major issue is insulin and mitochondrial function. Now insulin is a master growth hormone that is all the rage for diabetics. Insulin is an anabolic hormone, meaning growth and building as opposed to catabolic which is burning (equally important). Insulin is also the key that opens the door for glucose to enter the cells. No insulin, no open glucose door. As glucose levels spike and elevate blood sugar levels our bodies uptake and  burn some of it for energy, store some as glycogen (chained glucose) but mostly store the majority excess as triglycerides (fats). These glucose spikes come from carbohydrates. But not all carbs are the same. Some are just simple carbs (ex. fructose, sucrose, glucose from table sugar and soda) which enter the blood steam very quickly and raise blood sugar levels. A step down from that would be something like starch which are large strings of glucose linked together that are absorbed somewhat slower and still raise blood sugar levels. And then there are even more complex carbs like those found in beans, lentils and quinoa which are absorbed even slower and raise blood sugar levels even less. This is along with fruits, vegetables and legumes containing fiber (which is not absorbed but does feed the bacteria in our gut) also slowing down blood sugar spikes even more. Anytime blood sugar spikes you get a comparable insulin rise in parallel. The greater the spike in sugar, the greater the insulin spike as well. If  blood sugars are high enough for long enough (raising insulin ) we build tolerance to insulin, meaning we need more and more to do the same amount of work. And if insulin isn’t working at full strength due to this tolerance/ resistance growth is going to suffer. The process of creating new synapses via dendritic branches and axon terminals is dependent on insulin (because it's about growth after all which is anabolic). Nowhere is this more apparent than the hippocampus which is constantly making new connections to store memories. The brain has a tight system in place to regulate how much nutrients, hormones, and chemicals from the bloodstream enter into “brain circulation” including insulin and to a lesser degree glucose as well. The brain can quickly build resistance to insulin, meaning less will enter the brain from general circulation due to levels being chronically high and the brain needing tight control over how much is allowed in. 

Another major issue is insulin and mitochondrial function. Insulin, a critical growth hormone, facilitates glucose entry into cells. Persistent high blood sugar from frequent carbohydrate intake can lead to insulin resistance, where more insulin is required to achieve the same effect. This resistance hampers growth processes like the creation of new synapses in the brain, particularly in the hippocampus, which is vital for memory formation.

Moreover, insulin resistance disrupts autophagy, the process of clearing cellular waste, which only occurs when insulin levels are low. High insulin levels prevent proper waste removal, leading to cellular dysfunction. Similarly, damaged mitochondria are not adequately cleared, compounding the problem.

Why is the brain particularly affected? Neurons are incredibly energy-dependent, constantly using sodium, potassium, and calcium pumps to create electrical gradients essential for firing. The brain, with its 80 billion neurons firing about 300 times a second, requires immense amounts of energy. Low blood sugar can quickly lead to symptoms like anxiety, confusion, and discomfort, highlighting the brain’s dependency on a constant energy supply. Proper brain function also relies on adequate vitamins and minerals, which are often deficient in modern diets, further impairing mitochondrial function and overall health. 

While I did not go into specific detail around neurotransmitters and specific parts of the brain which we often use to understand the underlying biology of mental illnesses, these problems are clearly downstream of that (ie symptoms of a bigger problem). If and when your brain is nutrient-deprived and insulin-resistant neurotransmitters are no longer the priority so you best believe functional emotional and cognitive circuits are not working. Additionally the more “energy-hungry” a certain brain area is, such as the hippocampus, the more directly it's going to be affected by a deficiency and the harder it is for your brain to functionally grow out of its energy-deprived and rigid state. 

In conclusion, understanding the metabolic underpinnings of mental health provides a clearer picture of how crucial proper nutrition and metabolic function are to our well-being. By addressing these metabolic issues, we can potentially improve mental health outcomes and overall quality of life. Our brains, being energy-hungry and constantly active, need optimal conditions to function well, including efficient mitochondria, balanced blood sugar levels, and sufficient nutrients. By focusing on these areas, we can enhance our mental and physical health, paving the way for a healthier future.