Linking Inflammation, Diabetes, and Breath Analysis. 

Diabetes is as common as it is misunderstood. Perhaps the most common misconception is that 

it’s a consequence of carbohydrate overconsumption. Perhaps the most straightforward proof that diabetes is not a result of carbohydrate consumption is the fact that humans consumed significantly more carbohydrates in previous centuries without triggering anything close to the diabetes epidemic our world faces today. Clearly, the fact that diabetes was practically nonexistent before the 1950s but has exponentially propagated in just a few decades indicates that it constitutes a much more complex metabolic dysfunction that is inextricably linked to our modern way of life. This article explains the pathophysiological origins of diabetes and its link to chronic inflammation and fat accumulation. A comprehensive 7-step overview explores how inflammation causes insulin resistance, leading to fat accumulation, low energy levels, and, ultimately, diabetes. Last, we discuss how the progression of this condition can be monitored reliably through breath analysis.  

Step 1 – Onset of inflammation

Exogenous deleterious factors stimulate the production of inflammatory substances in our body’s response to mitigate the negative impact such factors may induce. 

​​Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), can activate various signaling pathways that interfere with insulin signaling. This disruption often involves inhibiting insulin’s ability to promote glucose uptake and utilization in cells, leading to insulin resistance.

Some of the most prominent inflammatory factors include:

1. Excessive calorie consumption
2. Junk food
3. Lack of micronutrient intake
4. Lack of physical exercise
5. Lack of sleep

In the recent PNOE article about inflammation,” we dive deeper into the exogenous stimuli that trigger our body’s inflammatory responses and the principal prevention mechanisms we can apply daily. 

Step 2 – Inflammation neutralizes our cells’ insulin receptors (Insulin Resistance)

Inflammatory markers exert their detrimental effects on insulin receptors of cells through various molecular mechanisms. These markers initiate inflammatory pathways that interfere with insulin signaling cascades upon activation. This interference includes the increased phosphorylation of serine residues on insulin receptor substrate-1 (IRS-1), diminishing its ability to relay signals downstream in the insulin pathway. Additionally, inflammatory cytokines can directly hinder insulin receptor activity, possibly through receptor internalization or impaired autophosphorylation. Activation of stress-sensitive kinases, such as JNK and IKK, further exacerbates insulin resistance by phosphorylating IRS-1, impeding its interaction with downstream signaling molecules. Furthermore, inflammatory signals disrupt insulin-stimulated glucose transporter type 4 (GLUT4) translocation to the cell membrane, consequently reducing glucose uptake. These molecular disruptions culminate in insulin resistance, a pivotal factor in the pathogenesis of conditions like type 2 diabetes, where chronic low-grade inflammation plays a significant contributory role.

Step 3 – Insulin resistance causes fuel utilization dysfunction

When we consume food, our pancreas responds by secreting insulin, the hormone that enables glucose to enter cells and be oxidized. When cells, including muscle cells, become insulin resistant, there’s an impaired ability to use glucose for energy efficiently. Cellular desensitization to insulin means that they no longer respond to insulin and are thus unable to absorb and utilize glucose. To compensate for this reduced glucose utilization, there is an increased reliance on alternative energy sources, such as fatty acids.

Step 4 – Fuel utilization dysfunction leads to fat accumulation and lower energy levels

In insulin-resistant states, cells, especially muscle cells, enhance their uptake of fatty acids and prioritize lipid storage over glucose utilization. This shift towards increased fatty acid uptake and storage contributes to the accumulation of intramyocellular lipids (i.e., the buildup of fat within our muscles and organs). Essentially, when cells become insulin resistant, they favor fat accumulation because their ability to respond to insulin’s signals for glucose uptake properly is compromised. Since glucose is the primary energy source for cells, their inability to absorb it deprives them of the valuable fuel they need, leading them to develop feelings of fatigue and low energy levels.  

Step 5 – Accumulated fat causes more inflammation and insulin resistance 

Both visceral fat, found around internal organs in the abdominal cavity, and intramyocellular fat, which accumulates within muscle cells, are sources of inflammatory markers. Visceral fat is highly metabolically active and secretes pro-inflammatory cytokines and adipokines such as TNF-alpha, IL-6, and leptin. These substances contribute to chronic low-grade inflammation, a key factor in developing conditions like insulin resistance and cardiovascular diseases. Similarly, intramyocellular fat accumulation disrupts cellular processes and is associated with increased production of inflammatory markers. TNF-alpha, IL-6, and other cytokines released by intramyocellular fat can impair insulin signaling within muscle cells, further contributing to metabolic dysfunction and insulin resistance. Overall, both visceral and intramyocellular fat play roles in systemic inflammation through the secretion of inflammatory markers, which have significant implications for metabolic health and the development of chronic diseases.

Step 6 – Insulin resistance leads to elevated blood sugar (Pre-diabetes)

In insulin resistance, cells become less responsive to insulin signals, particularly muscle, fat, and liver cells. Typically, insulin facilitates glucose uptake into these cells by promoting the translocation of glucose transporter proteins, such as GLUT4, to the cell membrane. However, this process is impaired in insulin resistance, resulting in reduced glucose uptake by cells, particularly in muscle and fat tissues. Consequently, less glucose is taken from the bloodstream and sent into cells for energy use.

Step 7 – Pancreas goes on over-drive and ultimately fails (Diabetes)

Initially, the body attempts to compensate for insulin resistance by producing more insulin (hyperinsulinemia) to overcome the decreased responsiveness of cells. This compensatory mechanism helps maintain relatively normal blood sugar levels in the early stages of insulin resistance. However, over time, the pancreas may fail to sustain this increased insulin secretion, leading to a decline in insulin production and exacerbating hyperglycemia.

Breath analysis, an easy and reliable monitoring tool for metabolic function.

As described in the 7-step process above, the fundamental consequence that unilaterally describes metabolic dysfunction is the cells’ inability to metabolize glucose and instead favors nutrient storage overutilization for energy production. Simply put, when consuming food, metabolic impaired individuals store it instead of using it to power the body.

Measuring the Respiratory Exchange Ratio (RER), the balance between carbon dioxide production over oxygen consumption during the post-prandial state (i.e., after a meal), is perhaps the easiest and most reliable method for understanding whether our cells can utilize the food we consume. In metabolically healthy individuals, the respiratory exchange ratio will rise precipitously after food consumption, indicating that cells absorb and use the nutrients ingested.

Conversely, in metabolically compromised individuals, RER will exhibit a blunt increase, indicating that nutrients cannot enter cells, get oxidized, and produce carbon dioxide that would otherwise cause RER to rise.

Breath analysis not only provides a direct measure of the fundamental mechanism defining metabolic dysfunction but also constitutes a non-invasive and easy assessment. This is in contrast to traditionally used methods such as the euglycemic insulin clamp, which requires trained medical professionals to perform blood analysis and be present at a medical facility.  

Nutrition & Mental Health

• A growing number of studies indicate that psychiatric disorders are metabolic disorders of the brain related to the poor mitochondrial function of certain brain cells. 
• Mitochondria dysfunction impairs glucose uptake depriving cells of the energy they need to function correctly. 
• Ketones have shown promise as an alternative fuel that can be absorbed even by metabolically compromised cells and thus restore energy supply and enable their reparation.  

The previous article on metabolism and mental health explored the deep connection binding cellular function with psychiatric dysfunctions. According to the decades-old theory correlating metabolism and mental health disorders, abnormalities in cellular metabolism, specifically mitochondria function, result in abnormal behavior in several physiological mechanisms that control our mood, including neurotransmitter release, hormone release, hormonal resistance, and premature brain cell death. The proposed mechanism linking mental health to mitochondrial health holds great promise not only because it ecumenically explains the complexity of psychiatric disorders but also because it opens up the exciting potential for diet and exercise, the two most potent and accessible drugs known to humanity, as a cure. In this second article of the three-article series, we discuss the influential role that diet and nutrition can play in slowing down and even reversing psychiatric conditions.  

The ketogenic diet, a powerful tool against mental disease

The various factors leading to mitochondrial damage and metabolic dysregulation in the brain ultimately deprive brain cells of their ability to absorb nutrients and convert them into energy. Low energy levels cause premature brain cell death, neurodegeneration, incorrect neurotransmitter signaling, etc. Glucose is the brain’s primary fuel source, which is obtained from the breakdown of carbohydrates in the diet. The brain requires a constant supply of glucose to function correctly, and it cannot store glucose, so it relies on the bloodstream to deliver a steady supply. Ketones can replace glucose as a fuel source for the brain because they can cross the blood-brain barrier and be taken up by brain cells for energy. Ketones are produced in the liver when the body is in a state of ketosis, which occurs when carbohydrate intake is limited, and the body starts to break down fat for energy. While the brain can use ketones as an alternative fuel source when glucose is unavailable, it’s important to note that not all brain cells can use ketones exclusively. Some brain areas or cells require glucose and cannot use ketones, especially when unavailable. That being said, ketones can help provide alternative fuel for metabolically compromised brain cells, such as those affected by neurodegenerative diseases like Alzheimer’s. Ketones can also help improve brain metabolism, alertness, and brain function, making them a promising area of research for various neurological disorders and conditions.

The mechanisms connecting ketones to mental health

By providing an alternative energy source for metabolically compromised cells, ketones trigger a series of positive effects that directly impact our emotions, mood, and psychological state. These include improved neurotransmitter levels, insulin resistance, and reduced brain inflammation. 

Neurotransmitter levels

• The ketogenic diet has been shown to influence neurotransmitter levels, including glutamate, GABA, and adenosine.
• Glutamate is the brain’s primary excitatory neurotransmitter, which promotes brain activity.
• The ketogenic diet has been found to reduce glutamate levels, which can help regulate excessive brain activity and prevent excitotoxicity, a process linked to neurodegenerative disorders.
• On the other hand, GABA is the primary inhibitory neurotransmitter in the brain, responsible for calming and reducing brain activity.
• The ketogenic diet has been shown to increase GABA levels, leading to a more balanced and calm state of mind.
• This increase in GABA can positively affect anxiety, stress, and overall mental well-being.
• Adenosine is another neurotransmitter that plays a role in regulating sleep, energy levels, and mood.
• The ketogenic diet has been found to increase adenosine levels, which can contribute to improved sleep quality and stability.
• Adequate sleep is crucial for mental health, and increasing adenosine may help promote better sleep patterns.
• By influencing these neurotransmitters, the ketogenic diet can help regulate brain activity, promote a balanced state of mind, reduce anxiety, and improve sleep quality. 

Insulin resistance

As discussed above, psychiatric disorders can be considered as the inability of brain cells to secure the required energy from carbohydrates. This phenomenon is not caused by a lack of carbohydrates in blood circulating levels but by brain cells’ inability to absorb circulating glucose molecules. This, in turn, is caused due to brain cells’ failure to respond effectively to circulating insulin, the hormone responsible for transporting glucose from the bloodstream into cells. This condition is also known as insulin resistance. When brain cells become insulin resistant, glucose remains in the bloodstream, leading to high blood sugar levels and insufficient energy supply to cells. The ketogenic diet is a high-fat, moderate-protein, and low-carbohydrate diet that forces the body to use fat instead of carbohydrates as its primary fuel source. By significantly reducing carbohydrate intake, the body enters a metabolic state called ketosis, producing ketones from fat breakdown for energy. In ketosis, glucose levels in the bloodstream are lowered, reducing insulin demand. This glucose and insulin levels decrease can improve insulin sensitivity and reduce insulin resistance. Additionally, the ketogenic diet promotes weight loss, which is beneficial for managing insulin resistance as excess body fat can contribute to insulin resistance.

Brain inflammation & brain cell mitophagy.

Another critical aspect of the ketogenic diet is its impact on mitochondria, which are the energy-producing organelles in our cells. The ketogenic diet stimulates a process called mitophagy, which involves getting rid of old and defective mitochondria and replacing them with new ones. It also stimulates mitochondrial biogenesis, which means that cells in the body and brain will have more and healthier mitochondria. This is crucial because dysfunctional mitochondria have been associated with inflammation in the brain. By promoting the health and function of mitochondria, the ketogenic diet can help reduce brain inflammation.

Overall, the ketogenic diet offers multiple mechanisms through which it can reduce brain inflammation, including changes in the gut microbiome, modulation of neurotransmitter levels, improvement of insulin resistance, and enhancement of mitochondrial health.

Brain Health & Mental Health Summary

Mental health is intrinsically correlated with metabolic health. Mitochondria dysfunction, the birthplace of metabolic disease, can become a significant contributor to the development of psychiatric disorders, which can, in turn, lead to a multitude of chronic physiological conditions. The expected result of such metabolic dysfunction is brain cells’ inability to metabolize glucose. This state exposes them to a low energy state which becomes a cornerstone to mental disorders. Ketones can play a remedial role in replenishing some of this energy deficit, thus providing a viable treatment for several conditions. However, it’s important to note that altering your diet while on psychiatric medication or when suffering from any psychiatric or physiological disorder can be dangerous, and such dietary changes should only be undertaken in collaboration with your doctor. Moreover, even if you decide to follow a ketogenic diet, you should always be aware of its potential side effects, which include possible muscle mass loss and restriction of your gut-microbiota diversity. Despite these side effects, ketogenic diets have shown great promise in overcoming psychiatric diseases and achieve better health.  

This article has been inspired by the work of Chris Palmer, MD. For further information about metabolism and mental health, readers can refer to his book, Brain Energy.