BECOMING METABOLICALLY HEALTHY

Keeping blood glucose in a healthy range is a cornerstone of ensuring a healthy future. Yet 52% of Americans are diabetic or prediabetic, and only 12% are totally metabolically healthy.

This week’s topic comes in two newsletters. This first one explores the latest information based on emerging research. Hat tip to Drs. Peter Attia and Ralph DeFronzo for an informative podcast (February 2025) that inspired me to dive into this topic.

Next week’s newsletter will provide more background on glucose regulation. Both newsletters will list actionable and accessible practices that are safe for you to explore.

In Dr. DeFronzo's framework for elevated blood glucose, at least 8 separate organ systems conspire to elevate glucose: the pancreas (2 ways), liver, muscle, kidneys, brain, fat cells, and gut. This situation has been dubbed "the ominous octet." Each person may have a different array and importance of these 8 factors.

We have medications to address these dysregulations, especially when they result in type 2 diabetes. However, before this happens, what might we do to prevent it? Which specific early problems does each person have, and which ones respond to which practices?

Quick takes

How do you know if you have some of these issues?

Consider these questions:

• Can you space meals without becoming weak, lightheaded, or “hangry"?

• Do you get hungry even when you know you’ve had enough to eat? This is likely brain metabolic dysfunction, or a problematic response to gut hormones.

• Do you feel fatigued after meals? Fluctuating blood glucose can play a role.

Look at your lab results:

• Is your Hemoglobin A1C above 5.4%?

• Is your fasting glucose above 100 mg/dL?

• What is your total cholesterol divided by HDL? A ratio <3 is ideal; <4 is good;

• What is your triglyceride divided by HDL? A ratio of < 1 is ideal; < 2 is good;

• What are your AST/ALT levels? Values over 20-25 suggest that liver health is not optimal

• What is your ferritin level? Values over 100 for men, over 80 for women suggest inflammation, possible liver problems, muscle insulin resistance, and other issues.

Here are 8 major systems that impact metabolism:

1. Pancreatic β-cells: insulin supply not keeping up with demand

2. Pancreatic α-cells: too much glucagon released (a hormone that raises blood glucose)

3. Muscle fibers: too little glucose taken up

4. Liver: producing and releasing too much glucose

5. Kidney: retaining too much glucose rather than excreting it

6. Gut hormones: altered response to incretin hormones in the stomach

7. Brain: driving you to eat when you don't need further calories

8. Fat cells: releasing excessive free fatty acids, which are toxic to other organs and increase disease severity

Different Interventions Target Different Systems:

Exercise addresses:

• Muscle insulin resistance

• Liver glucose output

Fasting, or the Fasting-Mimicking Diet© addresses:

• Pancreatic dysfunction

• Fat cell dysfunction

• Incretin (gut hormone) function

• Brain insulin resistance

• Muscle insulin response

Stress reduction (decreasing cortisol) improves:

• Muscle insulin resistance

• Pancreatic α-cell dysfunction

• Other metabolic parameters

The following address all components of the ominous octet:

• Avoiding or efficiently removing an array of toxins

• Weight loss of at least 7-10% of total body weight

• Improving intestinal barrier function (sometimes called “leaky gut repair,” or reducing intestinal permeability)

Favorite Finds

• Evaluating what is going on is often best done with a continuous glucose monitor such as Stelo;

• You can reduce glucose absorption from food by drinking 1 tablespoon of apple cider vinegar (mixed in water) before meals (if it doesn’t cause adverse symptoms);

• The Fasting-Mimicking Diet© improves not only several aspect of metabolic dysfunction but also autoimmune disease and probably cognition;

• The Tapping Solution (also an app on your phone) is one of my favorite short interventions for reducing stress;

• A healthy diet as we explored last week and in my workbook plays an important role in detoxification, lowering inflammation, reducing harmful impact of the diet on the pancreas;

• Sleep is another critical piece of metabolic health, as is limiting the “eating window” to the earlier part of the day. See past newsletters.

Deep Dive

Many Systems Go Wrong As Metabolic Health Declines

Modern research reveals an increasingly complex picture leading to metabolic dysfunction. We're familiar with insulin resistance as the inability of muscles to properly take up glucose from the bloodstream. However, muscle insulin resistance is only one of several disruptions that occur as glucose regulation deteriorates.

PANCREAS

If insulin resistance were the only issue, the pancreas would simply produce more insulin to control blood glucose. Unfortunately, the pancreas itself can become affected in two critical ways:

1. It produces more insulin, but is not able to keep up with the demand for insulin

2. It begins to produce excessive amounts of glucagon - a hormone normally released when we eat protein and actually raises blood glucose

This pancreatic dysfunction typically occurs because the organ is inflamed, and/or affected by oxidative stress.

LIVER

The liver represents a third major factor in this metabolic cascade. Normally, the liver stores glucose as glycogen, releasing it only when blood glucose drops or during stress responses. In metabolic dysfunction, the liver inappropriately releases glucose into the bloodstream when it's not needed. While high insulin should signal the liver to retain glucose, as the body becomes insulin resistant, so does the liver.

The real tragedy unfolds as additional organs join this metabolic disruption:

FAT CELLS

Fat cells, which normally respond to insulin by storing fat after meals, become insulin resistant and inappropriately release free fatty acids. These fatty acids travel to the liver, pancreas, muscles, and kidneys, causing inflammation and damage, and further dysfunction.

BRAIN

The brain becomes affected by the spreading inflammation. Normally, insulin should help suppress appetite after adequate food intake. However, food cravings may arise despite high insulin levels: they represent an abnormal response. This includes disrupted responses to gut hormones like incretins, which normally interact with GLP-1 receptors. These receptors have recently gained fame through GLP-1 agonist medications that help people lose significant weight partly by improving the brain's satiety response.

KIDNEYS

Finally, the kidneys show abnormal glucose handling. Instead of efficiently removing excess glucose from the body, kidneys affected by insulin resistance and metabolic dysfunction reabsorb more glucose than they should. This dysfunction stems from toxicity, inflammation, and poor vascular health.

SOLUTIONS

Addressing this complex metabolic disruption requires a multifaceted approach. Toxicity can play a role in all 8 of these systems. This highlights the importance of strategies such as:

• Avoiding heavy metals, industrial chemicals, pesticides, microplastics, etc.

• Reducing the body’s inflammation to improve its detoxification capacity;

• Hydrating well to eliminate toxins that exit through the urine;

• Following a nutrient-dense diet rich in protective compounds;

• Implementing stress reduction practices;

• Cultivating a healthy gut ecology, which play an important role in removing toxins.

This systems-based understanding of glucose dysregulation explains why comprehensive lifestyle approaches often succeed where single interventions fail. By addressing multiple components of the "ominous octet" simultaneously, we can work toward restoring metabolic harmony.

NEXT WEEK’S NEWSLETTER will dive into more details regarding solutions, and link to a workbook (in development!) that will help identify which parts of the octet are most prominent in different people. This will allow each person to prioritize what they need to do to keep their glucose in an optimal range, and to reverse or prevent metabolic dysfunction.