Designed By Nature

I am a fan of the ketogenic diet because of all its likely health benefits. Not all of them are proven or necesessarily obtained because of the ketones themselves but a lot of the mechanisms are known and research is really booming. Would it be booming if there is nothing interesting about them?

In any case, some people consider a carnivorous diet and if they are also knowledgeable about the ketogenic diet, they’ll consider it also a type of ketogenic diet. What triggered me to write this post is that, in order for a diet to be ketogenic, you have to be producing ketones. And this ketone production depends largely on 2 factors. 1) The availability of free fatty acids in the liver and 2) low glucose in the liver cells.

It’s the 2nd point that I was wondering about because a carnivorous diet may include too much protein to support ketones. But not just a carnivorous diet, any diet that is high enough in proteins so I’m not being picky on carnivores. So let’s have a look at what research shows us to understand if this is a concern or not when you value ketones.

According to Ben Bikman ( https://www.youtube.com/watch?v=z3fO5aTD6JU), protein raises glucagon and that would lead to raised glucose. And that is exactly what he showed in the following slide from the video.

As you can see on the right side, protein (alanine) does raise glucose but does nothing to insulin. You can also see how alanine triggers glucagon secretion. Glucagon drives gluconeogenesis.

One caveat though, this is done via infusion and we know incretins have a role to play thanks to dr Michael Eades ( https://www.youtube.com/watch?v=qMO-5mq3crU). At least in glucose absorption. It would be great to see if a similar effect takes place on protein. He did not address that in the presentation.

So incretins could be having an effect on protein ingestion and it would be great if we could also have a look at the combination of protein and fat together. The following publication looked at fat separately and protein separately. The protein was an egg and milk type of protein meal, still with some carbohydrate in it.

1. oleic acid (0.88 g/kg body wt; water was ingested after the oil to reach the volume of 400 ml; Casa Oilio Sperlonga, Priverna, Italy);
2. protein dissolved in water [Promax protein 85R (Global, Rødovre, Denmark); 2 g/kg body wt, consisting of milk and egg protein; 4.4% carbohydrate and 2% fat] or;
3. pure water (400 ml) were ingested within 5 min

Test results:

“Incretin and islet hormonal responses to fat and protein ingestion in healthy men.”

https://www.ncbi.nlm.nih.gov/pubmed/18612044 ; https://booksc.xyz/book/43773548/00b179 ; https://sci-hub.tw/10.1152/ajpendo.90233.2008

We see the protein meal brings up insulin and glucagon. The carbohydrates with that meal would equal about 7gr for a 80kg guy so we cannot conclude on the insulin nor on the glucose levels but we see that there is no glucagon lowering effect of any kind which is what we wanted to know. Instead we see a rise in glucagon for a prolonged time, contrary to the Bikman presentation which also showed increase in glucagon but much quicker subsiding glucagon levels. Could this be due to digestion spreading the absorption into the blood over time? Likely. I have seen other research that looked at levels and absorption rate whereby fat was causing a delay and lower levels.

Insulin goes up due to dietary intake of carbohydrates. When the body produces/releases glucose in the blood stream it can still raise insulin but only marginally.

We know that insulin opposes glucagon (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329806/). The following research shows us that, although still a bit artificially composed, the glucagon-stimulating effect of protein is strong enough to oppose insulin’s inhibiting effect on glucagon secretion when you ingest the protein rather than use an isolated amino acid via IV.

The meal was tested in 2 groups, normocholesterolemic and hypercholesterolemic.

components of a 800kcal meal	soy	casein	protein-free
protein	20% (40gr)	20% (40gr)	0% (0gr)
corn syrup solids	60% (120gr)	60% (120gr)	80% (140gr)
soy bean oil	20% (17.7gr)	20% (17.7gr)	20% (17.7gr)

Test results:

“Effect of dietary protein on serum insulin and glucagon levels in hyper- and normocholesterolemic men.”

https://www.ncbi.nlm.nih.gov/pubmed/2645886 ; https://sci-hub.tw/10.1016/0021-9150(89)90193-7

As you can see, glucagon went up for the protein-containing meals while for the protein-free it went down. Glucose went up in all cases. Interesting is that despite the higher glucose content in the protein-free meal, the insulin respons seems to be somewhat lower resulting with higher glucose. Looking only at the normocholesterolemic group, protein and carbs together result in a higher insulin secretion than carbs alone. This matches with the presentation from Bikman.

Glucagon and plasma glucose

It should be clear by now that protein ingestion with or without carbs raises your glucagon levels. OK so does glucagon raises glucose in the blood and does it raise gluconeogenesis? This is actually well established but let’s show it anyway.

This paper used a nasal spray for getting glucagon into the blood, probably to test it as a treatment for hypoglycemia. They found a dose response and measured both plasma glucagon and glucose. The liver may be releasing from its glycogen storage so it doesn’t tell us anything about gluconeogenesis.

“Effect of intranasal glucagon on blood glucose levels in healthy subjects and hypoglycaemic patients with insulin-dependent diabetes.”

https://www.ncbi.nlm.nih.gov/pubmed/2898045 ; https://booksc.xyz/book/25633903/acf7d8 ; https://sci-hub.tw/10.1016/S0140-6736(88)92181-2

So how about gluconeogenesis?

Let’s look at this 2018 paper looking at the effects of glucagon.

Glucagon opposes hepatic insulin action and enhances the rate of gluconeogenesis, increasing hepatic glucose output. In order to support gluconeogenesis, glucagon promotes skeletal muscle wasting to supply amino acids as gluconeogenic precursors. Glucagon promotes hepatic fatty acid oxidation to supply energy required to sustain gluconeogenesis.

Enhanced gluconeogenesis induced by glucagon explains the increased urea formation in the liver. The carbon skeletons of amino acids are used to produce glucose whereas the amino groups generate urea.

patients with total pancreatectomy show elevated plasma concentration of most amino acids due to reduced gluconeogenesis associated with glucagon deficiency [4], [43], [54], [56]

Importance of glucagon during starvation in normal humans

Starvation requires adaptive processes that affect glucose, fatty acid, and amino acid metabolism in order to supply endogenous fuel to cells. The rate of hepatic gluconeogenesis increases to provide endogenous glucose to peripheral tissues, such as the brain. The skeletal muscle releases amino acids (mainly alanine) that are used to generate glucose in the liver. The adipose tissue releases free fatty acids that are oxidized in the liver to provide the energy required for enhanced gluconeogenesis. Hepatic oxidation of free fatty acids also produces β-hydroxybutyrate and acetoacetate that are used as fuel by the skeletal muscle. Glucagon secretion is a major driving force to the metabolic adaptation to starvation. Plasma glucagon level increases after 24–48 h of fasting, inducing hepatic insulin resistance that prevents glucose from being stored. Glucagon also promotes gluconeogenesis and ketogenesis [49], [63], [64], [65].

Glucagon contributes to fasting and post-prandial hyperglycemia in patients with T1D and T2D by increasing gluconeogenesis and hepatic glucose output.

Glucagon enhances gluconeogenesis in healthy subjects and patients with diabetes thus increasing hepatic glucose output.

etc…

“Metabolic effects of glucagon in humans”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312800/Conclusion

Insulin goes up in the presence of glucose. And since meat doesn’t raise insulin, the means that your steak does not change into chocolate cake. Gluconeogenesis is therefore a process that happens based on need, not because of the presence of excess protein. In other words, if eating excess protein produces excess glucose, then we would expect increases in insulin – which we do not.

So does insulin go up in the presence of glucose? Dietary glucose, yes but when glucose is produced and released from inside your body then the insulin response is much less, if not absent. This was also clearly shown by dr Michael Eades comparing IV with dietary intake at the beginning of this article.

Protein ingestion triggers glucagon release and glucagon raises gluconeogenesis so is this a process based upon need? No. We see the rise in glucose from Bikman’s presentation and when testing the meals. What need was there for extra plasma glucose?

So eating excess protein DOES produce excess glucose and we do not expect insulin to raise much.

Finally on ketones I have to leave the point open but my guess is that the excess glucose will inhibit ketone production for a while until the glucose is handled. How long that will take I don’t know. Glucagon also triggers the liver to secrete glucose so I’d expect not more than a few hours. It will also depend on how much insulin is activated. You won’t be eating pure protein so there will be at least some fat with it which triggers both insulin and glucagon slightly.

Glucagon also promotes gluconeogenesis and ketogenesis

Finally, keep in mind that this comes from within the context of starvation under which insulin is as low as it can get and gluconeogenesis uses plasma amino acids that are available. Not a 350gr steak. That will make a difference in the ability to promote ketogenesis.

The way to check if it would be interrupting your ketones is of course to measure your blood ketone production. An alternative way could be to measure your glucose. If you are at your baseline glucose then you have too much glucose to reach a decent level of ketones but you need to figure this out by measuring both simultaneously. To produce sufficient ketones (>0.5mmol), your glucose level should be lower than baseline.