New Cause of Metabolic Syndrome, and How to Treat it.

New data in Nature Metabolism reveals a link between the microbiome, GLP-1 deficiency and metabolic dysfunction, and opens avenues for innovative solutions.

Do you want to understand the root cause of metabolic syndrome and insulin-resistance disorders?

Of course you do! (6 minute video coverage at the end, if you prefer to watch…)

You’re reading my Newsletter after all, so you’re obviously a metabolism nerd like me!

New Data from Nature Metabolism sheds light on the association among GLP-1 deficiency, the microbiome, and insulin-resistance disorders.

Background

GLP-1 agonist medications, like Ozempic, mimic a natural hormone (GLP-1) that is crucial for metabolic health. Interestingly, insulin-resistance disorders, including obesity and diabetes, are characterized by GLP-1 deficiency.

So - at a high level - it makes sense to "replace what's missing" as a form of therapy.

Think about it by way of analogy… if you have hypothyroidism, you treat with thyroid hormone…. if you have adrenal insufficiency… you treat with corticosteroids.

Make sense, right?

But that doesn't answer the question: What is the CAUSE of GLP-1 deficiency in obesity, diabetes, metabolic syndrome and insulin-resistance disorders?

There have been some hand-wavy explanations in the past, like that “inflammation” harms GLP-1 producing L-cells or that inflammatory T-cells “mop up” GLP-1 in the gut, decreasing bioavailability.

But I like precision… causal pathways… specific mechanisms. Now, FINALLY (!) we have at least one…

These New Data…

These data, published in Nature Metabolism, use a mouse model to demonstrate a causal pathway whereby:

• An obesogenic (Westernized) diet increases levels of the gut bacteria Desulfovibrio.

• Desulfovibrio generates hydrogen sulfide in the gut.

• This hydrogen sulfide overwhelms detoxification mechanisms in the L-cells that make GLP-1, leading to damage to the L-cells’ mitochondria.

• The resulting energy (ATP) deficit in the GLP-1 producing L-cells, leads to a GLP-1 deficit.

• The GLP-1 deficit leads to metabolic dysfunction.

Human Relevance

While these sorts of mechanistic studies need to be done in animal models to best prove casualty, this mechanism is likely relevant to humans given that persons with obesity, insulin resistance and metabolic syndrome appear to have higher levels of Desulfovibrio and lower levels of GLP-1.

Solutions

The researchers also found that bismuth subsalicylate, the active ingredient in Pepto Bismol (yes, like that you'd get at your local pharmacy), blocks Desulfovibrio and hydrogen sulfide, increases GLP-1, and protects against fat gain and metabolic dysfunction in an animal model.

Moreover, a specific dietary fiber (inulin), found in artichoke, chicory root, and asparagus, can reduce Desulfovibrio levels in a humen randomized controlled trial, when dosed at 5g/day for 3 weeks.

Concluding thoughts

There data speak to “root cause” physiology. LOVE IT! They also raise questions about other "functional" foods that may impact Desulfovibrio and product microbiome-mediated pathology underlaying metabolic dysfunction.

Watch a 6 minute video covering these data here: