Is gluconeogenesis demand-driven? answer: it depends (#context strikes again!)
Context #1. The easiest way to explain gluconeogenesis (GNG) is how it relates to starvation. If you're not eating food, your brain still needs a steady supply of fuel. Mostly glucose at first (ketones come later), but since you're not eating anything, glucose comes from hepatic GNG (huge potential supply*) or glycogenolysis (limited supply). *One of the precursors for GNG, glycerol, comes from stored fat (which you'll die of something else before you run out of stored fat bc GNG).

In this case, it is mostly true that GNG is demand-driven.

If you're interested in this, more HERE.

Context #2. Protein (which also contains GNG precursors) doesn't acutely increase glucose. But you might think protein does convert to glucose via GNG but protein also induces a splash of insulin which is why blood glucose doesn't rise. Read this blog post at least up to the awesome Fromentin study: "8% of the blood glucose produced under optimal gluconeogenic conditions came from dietary protein." But also check out the Conn & Newburgh studies. And Gannon.

This is usually the reason recreational keto dieters say they can be high protein, which either ends up looking like PSMF or it's probably not very ketogenic (which doesn't really matter in this #context; protein is restricted in therapeutic ketogenic diets).

#BenignDietaryKetosis #BDK

Context #3. the mouse doctor is in :)

I did a stint studying inflammation and diabetes and one of the routine experiments (alongside the hyperinsulinemic-euglycemic clamp, oral/IP glucose tolerance tests, insulin tolerance tests) was a pyruvate tolerance test (PTT).

The theory: a large dose of pyruvate, another GNG precursor, will increase blood glucose in certain animal models. In general, if a mouse has hyperglycemia, unless it's a tissue-specific genetic manipulation or something, it is multi-factorial. So we tried to assess how much hyperglycemia came from impaired disposal (eg, reduced insulin-stimulated glucose uptake in muscle cells), elevated production (eg, increased hepatic GNG or glycogenolysis), etc.

The PTT was specific for hepatic GNG. The problem, is that many times it worked. That is, pyruvate injection transiently increased blood glucose. And when it did, it usually correlated with increased activities of certain GNG enzymes. This is precisely not "demand-driven," it's firmly on the supply-side.

To refute this, in humans, we have Fromentin and Gannon who measured who measured GNG isotopically and found no impact when the supply was amino acids.

But I'm still left wondering what we would've seen if Conn & Newburgh did that... because if anything is gonna show supply-driven GNG, it's gonna be 160 grams of protein. Yes, "grams of protein," not "grams of steak." Blood glucose didn't budge: is that because glucagon induced GNG but insulin got the new glucose cleared away before it had a chance to show a blip on the graph?

Context #3b. Chronic high protein might be different, in theory, because technically we don't store protein (some fringe theories, but that's generally accepted to be the case). Intake in excess of what is needed is oxidized or the carbons go to liver glycogen and the nitrogen disposed via urea cycle. So, in theory, if your liver glycogen is completely saturated (which is rare unless you're long-term carb-loading), then instead of GNG leading up to glycogen, it could chop off that phosphate off of G6P and new glucose released into the periphery. In theory. To my knowledge, this hasn't been tested.

Context #4. Random thoughts on animal foods.

Nutritionally: take a malnourished child who has no animal foods, give a couple servings a week. DRASTIC improvement in health.

Going from moderate intake to high = *meh*

High animal foods likely isn't harmful for 99% of people (Mrs. Spratt LOL), and it's good at displacing other potentially less-healthy stuff and inducing satiety and ramping up amino acid oxidation and improving body composition hahaha

That's all, for now.

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