Thread by @ChrisMasterjohn

@whsource I’ve been saying this for many years, and it’s extremely clear on mechanistic considerations alone. Elevated glucose is only a problem in and of itself when it causes osmotic stress sufficient to induce a coma. That’s rare.

@whsource Dicarbonyls such as methylglyoxal are very strongly implicated in the causal pathway to diabetic complications, and insulin dramatically protects against them through causal pathways that are almost irrelevant to hyperglycemia.

@whsource Such that hyperglycemia should almost be regarded as an incidental correlate of insulin signaling deficiency, where it is the latter that causes diabetic complications.

@whsource And it’s not just via dicarbonyls. Insulin also is critical to antioxidant defense and the poor glutathione status and increased ROS that results from its deficiency are also major contributors.

@whsource Granted, elevated glucose can activate the polyol pathway which saps NADPH from glutathione recycling, but that’s only a secondary contributor to poor glutathione status, and it’s only relevant if hyperglycemia is mainly a supply-push phenomenon where intercellular levels go up.

@whsource If total body glucose is kept the same but hyperglycemia is mainly or purely an uptake problem, intracellular glucose wouldn’t even be elevated.

@whsource And what is glucose going to do in the blood besides be an osmolyte? Well, it can glycate hemoglobin, but we know that’s irrelevant because fructosamine 3-kinase mice have hugely elevated Hba1c but are totally healthy and live normal lifespans.

@whsource So this finding your posted is very cool, but seems very predictable in the lack of diabetic complications.

@whsource Notably, methylglyoxal is derived from both ketones and glucose, but it’s derivation from glucose is downstream from glucokinase, at the level of triose phosphate isomerase. So fuctokinase impairment should actually decrease methylglyoxal.