Sulfur Lies At the Crossroads of Obesity and Diabetes

Is sulfur behind your stubborn fat?

Obesity strongly predisposes to type 2 diabetes. This is not because fat storage promotes diabetes. Rather, it is because running out of room to store more fat causes diabetes.

I explained this in detail in When Fat People Can’t Get Fat Enough and When Lean People Get Fat in All the Wrong Places.

In brief, when a person’s ability to store fat efficiently is maxed out, fat cells start to smoosh together and block the blood supply to the adipose tissue. Energy in excess of this point raises free fatty acids in the blood, which compete with glucose for utilization. Inflammatory cytokines are released to recruit the immune system to come and reorganize the infrastructure of the fat tissue to accommodate new blood vessels. Those inflammatory cytokines impair energy utilization across the body, arguably to reserve energy for the immune-mediated restructuring of adipose tissue.

This is compounded by energy overload at the cellular level, causing the preponderance of cells to reject energy molecules like glucose and fatty acids when the demand placed on them to burn these molecules for energy exceeds what they can burn “cleanly” without undergoing damage to their components from reactive oxygen species.

Adipose cells become hypoxic at this point, and the hypoxia response drives new blood vessel formation to accommodate additional fat storage. To the extent this is successful, it increases fat storage and decreases the risk of diabetes.

One of the principal mediators of the hypoxia response is hydrogen sulfide.

Hydrogen sulfide (H2S) is one of three endogenously synthesized gasotransmitters. These are gaseous compounds that act as signaling molecules, and they include nitric oxide, hydrogen sulfide, and carbon monoxide. All three are lethally toxic in excess, but essential in normal, healthy concentrations.

H2S levels are lower in those with diabetes than those without, and lower in diabetics with poorer glycemic control.

Conversely, H2S is elevated in morbidly obese subjects, and correlates positively across body fat percentages from 15 to 60%.

Within obese subjects, H2S is lower in those with elevated fasting glucose.

A body of work on mechanistic effects of H2S suggests that H2S not only increases the formation of new blood vessels needed to expand adipose tissue, but also broadly sensitizes cells to insulin.

Too much H2S poisons mitochondria. H2S itself binds to complex IV of the mitochondrial respiratory chain, displacing oxygen, and does the same in hemoglobin. H2S is metabolized to sulfite, which inhibits the citric acid cycle and makes mitochondria excessively permeable to substances that can damage it.

But the Goldilocks level of H2S is necessary for insulin sensitivity.

Correlations do not show causation, but mechanistic data from cells and animals demonstrate causation. The correlations imply that the mechanistic data is relevant as a mediator of the divergence between obesity and diabetes in the general population.

That is, for a given excess energy intake, one has two paths: with greater H2S, one becomes fatter and less likely to become diabetic; with less H2S, one becomes less fat but more likely to become diabetic.

This is all about where the marginal amount of excess energy goes: does it get locked up in fat stores so that it does not displace glucose for utilization or overload cells that cannot handle it? Or does it float around in the blood, competing for fuel use all over the place and overloading cells that cannot handle it?

Hydrogen sulfide is derived from the sulfur amino acid cysteine, which we obtain from dietary protein. Generating hydrogen sulfide from cysteine depends on vitamin B6, iron, niacin, magnesium, and zinc.

Randomized controlled trials of relevant dietary factors cannot parse causal mechanisms with this level of granularity unless they were to involve subcutaneous continuous H2S delivery systems.

However, meta-analyses of randomized controlled trials done in type 2 diabetics suggest that high-protein diets lower insulin resistance as defined by HOMA-IR (which uses glucose and insulin levels together); that whey protein supplements, which are especially rich in cysteine, lower postprandial glucose; and that supplemental milk protein, driven mainly by whey protein studies, lowers fasting glucose, insulin, and HOMA-IR.

The primary way to address type 2 diabetes should be to Lose Fat Without Losing Muscle and optimize nutrient status with the Comprehensive Nutritional Screening.

These data suggest that getting sufficient protein, especially from proteins rich in sulfur amino acids (eggs and dairy highest, animal higher than plant) is important to providing the H2S necessary for insulin sensitivity. 0.5-1.0 grams per pound of ideal bodyweight is a good rule of thumb. Getting enough vitamin B6, iron, niacin, magnesium, and zinc is also necessary to generating sufficient H2S. See the Cliff Notes for help getting these vitamins and minerals.

On the other hand, this also implies that excess H2S could play a role in stubborn fat and difficulty with weight loss. As covered in How to Lose Fat Without Losing Muscle, high protein diets actually help in optimizing body composition. So protein restriction is probably not the best approach here. Rather, promoting optimal H2S clearance by removing any bottlenecks in that process may help ease the body’s resistance to fat loss.

For that, see my Sulfur Protocol: