Apparently there's a kerfluffle between various ancestral health diet blogs about a mutation found in most coastal Inuit and almost no one else, and what its implications are regarding whether the Inuit were in ketosis most of the time, and whether they are a good model for the effects of long term ketosis in people without the mutation. The information is sufficiently interesting that I thought I'd post a summary here.
The mutation is in the CPT1 gene, which is ultimately responsible for oxidation of long chain fatty acids. The associated enzyme activity was reduced by a factor of roughly 17 in people homozygous for the mutation - that is, that had the mutation on both strands of their DNA - and appears to inhibit ketosis on modern diets. Out of 422 consecutive infants screened from one affected region, 70% were homozygous for the mutation and another 24% were heterozygous - had the mutation on one of their two DNA strands. A significant proportion of the affected people are in hypoketotic hypoglycemia - that is, have low blood sugar, but without the normal response of going into ketosis - and there were at least 10 infant deaths out of the 422 screened.http://www.ncbi.nlm.nih.gov/pubmed/19217814
So basically we have a mutation that seems to kill a noticeable percentage of infants, but which has actually been selected for, rather than against, in coastal arctic Inuit populations. The question is, why?
Petro Dobromylskyj, who writes the Hyperlipid blog, has an explanation that hangs together pretty well. He notes that the coastal inuit's precontact diet was extremely high in fat and had virtually no carbohydrate. He argues that with such a diet, the free fatty acid concentration in the body would increase to the point where even the small residual activity from the enzyme from the mutated CPT1 gene would be sufficient to allow adequate levels of long chain fatty acid metabolism. This would explain why the mutation didn't get rapidly selected out of the gene pool, for this population.
There remains the question of why there was selection in favor of the mutation. Dobromylskyj notes that normally, when the energy from oxidative metabolism is no longer needed, the enzyme from the CPT1 gene is inhibited by malonyl-COA. The enzyme from the mutated CPT1 gene is not inhibited by malonyl-COA, so long chain fatty acid oxidation would continue even when the energy was not needed for normal functions: the energy would simply be dissipated as heat when it wasn't powering muscles or other tissue activity. In addition, the increased free fatty acid concentration would mean that this elevated level of metabolism could be sustained for much longer than in people without the mutation. In the arctic areas where the mutation is found, the extra body heat would be adaptive: for example, it could keep you alive through a cold night or rest period where normal humans would die of hypothermia.http://high-fat-nutrition.blogspot.com/2014/11/coconuts-and-cornstarch-in-arctic.html
What does this mean for the paleo diet, and for the argument that the Inuit are a model for a sustained ketogenic diet? Well, it does mean that they metabolized an extremely high fat, virtually zero carb diet slightly differently from most of us. The differences mean that such a high fat diet won't give most of us quite the ability to survive the arctic wilderness that it gave the Inuit. On the other hand, the extra free fatty acid metabolism that the Inuit have on such a diet would mean that they would see a bit more oxidative stress than most of us on such a diet.
Ultimately, though, they were still likely in long term ketosis. And, if anything, a long term ketogenic diet, outside of the arctic wilderness, is likely more healthy for us than for the Inuit, given our lower levels of oxidative stress on such a diet.