Can Hydrogen Sulfide Protect Beta Cells and Heart Cells in Diabetes and Obesity?

This is a loose continuation of the previous post about the effects of hydrogen sulfide (H₂S) on cellular metabolism. This time, we will look at a study related to diabetes, focused on the protection of insulin-producing cells—meaning the protection of pancreatic beta cells from high blood glucose levels. We will see that hydrogen sulfide activates the deacetylase SIRT2, improves antioxidant protection via GSH, reduces the level of aldehydes formed by oxidation of polyunsaturated fats in a high-glucose environment through activation of the enzyme ALDH2, and thus acts in a way that makes beta cells more resilient and able to survive even in unfavorable conditions. In the figure, we can actually see everything we need to know. If I were to follow up on the post where I showed that amino acid deficiency activates the enzyme SIRT2 and suppresses the formation of new fats, here we can see the mechanism more precisely.

ALDA1 is an activator of the enzyme ALDH2, which removes toxic aldehydes formed during peroxidation of omega-6 polyunsaturated oils. We see that ALDA1 activates the formation of H₂S, which in turn activates ALDH2, so they mutually reinforce each other. Supplementation of H₂S (NaHS) increases the percentage of beta cell survival (Cell Viability) under high glucose (HG) conditions by activating the production of NADPH molecules via the PPP pathway (G6PD) and recycling GSH.

In a high-glucose environment, i.e., in diabetes, there is a large amount of oxidative stress. This results in the peroxidation of linoleic acid to the aldehyde 4-hydroxy-2-nonenal (4HNE), which blocks a number of enzymes. 4HNE molecules are removed by the enzyme ALDH2, but at the same time also strongly inhibit its activity. In a high-glucose environment, it practically disappears, and detoxification does not function.

4-hydroxy-2-nonenal (4HNE) suppresses the function of detoxifying/aldehyde-removing enzymes (ALDH2), enzymes responsible for antioxidant protection (G6PD), and enzymes responsible for deacetylation (SIRT2).

Although we do not know whether activation of SIRT2 by hydrogen sulfide also occurs through sulfhydration of certain sites on this enzyme, as in the previous post, we know reliably that hydrogen sulfide produced from cysteine or cystathionine metabolism helps to remove toxic products of linoleic acid peroxidation, such as 4HNE. It is therefore quite likely that the observed effect of protein restriction in the diet—such as thermogenesis and high energy expenditure—is related to this detoxification. Thermogenesis is also regulated, and probably limited, by the quality of antioxidant protection. The faster and more effective the recycling of glutathione, the more heat can be safely produced. This way, enzymes are better protected from damage by molecules like 4HNE, cells can remain highly active, and do not fall into cellular senescence or apoptosis/destruction. Increasing ALDH2 activity is a well-known protective mechanism, which I have already discussed here before.

Let us now look at another study, this time about how H₂S protects against lipotoxicity—against damage to heart cells by fats. Problems with fats are always more complicated to understand and research than problems with glucose or fructose. Fats represent far too many different molecules, each with a different purpose, a different signaling function. Nevertheless, it seems that raising the level of H₂S can protect heart cells from damage by high levels of free fatty acids, which would otherwise cause oxidative stress (ROS), leading to cellular senescence (p21) and loss of the tissue’s regenerative function. Hydrogen sulfide administered as NaHS changes the situation and reduces oxidative stress.

We can also highlight from this work the enzymatic pathways producing H₂S. The substrate is not only the amino acid L-cysteine but also homocysteine.

Since elevated homocysteine levels are associated with metabolic problems, I would venture to hypothesize that restriction of sulfur amino acids changes the balance of enzymatic pathway activity so that homocysteine itself becomes the main substrate for H₂S production, which subsequently also activates the production of glutathione from the same substrate. Excess cysteine apparently suppresses the enzyme cystathionine-γ-lyase (CSE/CGL) simply because the elevated product level suppresses the activity of the corresponding enzyme. This, however, also suppresses H₂S production. The other pathways apparently cannot compensate for the loss of CSE. This creates the paradoxical situation where cysteine deficiency is better for H₂S production than it's excess.


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References:

Mitochondrial aldehyde dehydrogenase-2 coordinates the hydrogen sulfide - AMPK axis to attenuate high glucose-induced pancreatic β-cell dysfunction by glutathione antioxidant system

Hydrogen sulfide (H₂S) attenuates lipotoxicity and cardiac cell senescence by regulating protein acetylation

 

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