In order to work out what is happening with a given child having an episode of hypoglycaemia as a result of having the P479L version of CPT-1a, we need some information.
My thanks to Mike Eades for the full text of the paper on the Canadian Inuit, which does include a certain amount of useful clinical data.
Here is the snippet about a young girl having a hypoglycaemic episode while hospitalised:
“Plasma free fatty acid was 3.8 mmol/L and plasma 3-hydroxybutyrate was 0.5 mmol/L”
Blood glucose was 1.9 mmol/l at the time. An FFA level of 3,800 micromol/l is impressively high. She was generating a small amount of ketones.
No one would argue with intravenous glucose at this point, the question is about how she got here.
So. The problem here does not (as I'd initially thought) appear to insulin induced suppression of FFAs to a level at which beta oxidation fails to support metabolism. FFAs are very high, even for an P479L person after a short fast. With ketones starting to be produced (and low blood glucose) I feel it is reasonable to assume that her liver glycogen is depleted and, while some fatty acids are entering the hepatocytes, not enough of them are being oxidised to support ketogenesis. Glycogen is being depleted to keep liver cells functional. Gluconeogenesis from protein is unable to meet the hepatic (and whole body) demand for glucose calories in the situation of limited access to FFA calories.
However much glycogen derived glucose you consider that the ancestral diet contained I feel it is very, very unlikely to be greater than the glucose and fructose of a modern diet. I feel that getting enough glycogen in to the liver to fully fuel its metabolism in the absence of adequate fatty acid oxidation is a non starter. The P479L mutation was not "permitted" by high oral carb loading, it was permitted by conditions which facilitated fatty acid oxidation. You don't have to agree.
What starts to look much more interesting is what controls CPT-1a activity and how this might vary from the ancestral diet to the modern diet.
The paper makes the point that omega 3 fatty acids appear to up regulate fatty acid oxidation (in rats at least) by the liver. If this is true in humans then a high level of omega 3 fatty acids from marine fats might up regulate fatty acid oxidation to a level which no longer necessitates the depletion of hepatic glycogen derived form oral glucose intake or protein catabolism.
In support of this is that the distribution of P479L within Alaska is not uniform, it's significantly commoner in the coastal regions compared to the inland areas.
"The allele frequency and rate of homozygosity for the CPT-1a P479L variant were high in Inuit and Inuvialuit who reside in northern coastal regions. The variant is present at a low frequency in First Nations populations, who reside in areas less coastal than the Inuit or Inuvialuit in the two western territories"
I'm open to other explanations, there are papers suggesting that the mutation helps to preferentially dispose of omega 6 PUFA, with omega 3 fatty acids as the facilitator.
In summary: Maintaining adequate FFA oxidation to avoid glycogen depletion looks to be the core need in P479L. A high fat diet with a large proportion of omega 3 fats might be a plausible way of maintaining adequate hepatic fatty acid oxidation. Hyperglycaemia (via Crabtree effect) looks to be anathema. Glycogen loading with a normal starch/sugar based modern diet is clearly ineffective to prevent hypoglycaemia for some individuals. Resistant starch as a reliable nightly adjunct to infant feeding seems very unlikely in the ancestral diet. Repeated periods of fasting were probably routine when hunting was poor and does not appear to have selected against P479L in weaned children. Unweaned children are unlikely to be exposed to fasting, provided milk was available from lactation.
Well, there are some more thoughts on the biochemistry.
People clearly have very differing ideas of what the Inuit did or did not eat as an ancestral diet. The P479L gene eliminates the need for source of dietary glucose to explain very limited levels of ketosis recorded in the Inuit. While it is perfectly possible to invoke a high protein diet to explain a lack of ketosis in the fed state this goes nowhere towards explaining the limited ketosis of fasting. P479L fits perfectly well as an explanation.
I have some level of discomfort with using the Inuit as poster people for a ketogenic diet. That's fine. They may well have eaten what would be a ketogenic diet for many of us, but they certainly did not develop high levels of ketones when they carried the P479L gene.
However. Over the months Wooo and I seem to have come to some sort of conclusion that, while systemic ketones are a useful adjunct, a ketogenic diet is essentially a fatty acid based diet with minimal glucose excursions and maximal beta oxidation. Exactly how important the ketones themselves are is not quite so clear cut. From the Hyperlipid and Protons perspective I would be looking to maximise input to the electron transport chain as FADH2 at electron-transferring-flavoprotein dehydrogenase and minimise NADH input at complex I. Ketones do not do this. Ketones input at complex II, much as beta oxidation inputs at ETFdh, but ketones also generate large amounts of NADH in the process of turning the TCA from acetyl-CoA to get to complex II, which ETFdh does not. I'm not a great lover of increasing the ratio of NADH to NAD+. These are my biases.
Confirming that the Inuit are not poster boys for ketosis is a "so what?" moment for me. Using their P479L mutation to argue against ketogenic diets is more of a problem. It's a massive dis-service to any one of the many, many people out there who are eating their way in to metabolic syndrome to suggest that a ketogenic diet is a Bad Thing because no one has lived in ketosis before. Even the Inuit didn't! My own feeling is that everyone comes from stock who occasionally practiced and survived intermittent fasting so we are should be adapted to this. I'd guess that if you are of Siberian, Inuit or First Nations extraction you might benefit from Jay Wortman's oolichan oil as part of a ketogenic diet.
I'm always amazed by the concept that a ketogenic diet might be temporarily therapeutic but must be discontinued because it eventually becomes Bad For You. It reminds me so much of the converse concept that low fat diets, which might worsen every marker of health which people may care to look at, will deliver major benefits at some mythical future date.
Ultimately, point scoring on the internet about what the Inuit did or didn't eat shouldn't destroy people's chances of health. Destroying a circular argument about Inuit diets may may the destructor feel good. Destroying the feet, eyes and kidneys of a person with type 2 diabetes, who need a ketogenic diet, as a spin off from that victory must be difficult to live with. I don't know how anyone can do this.
I think that's probably all I have to say for now.