I.

It's a Known Thing in the keto-sphere [ I get the sense that r/saturatedfat is an example of this culture ] that people with metabolic syndrome -- i.e., some level of insulin resistance -- can handle fat or carbs [ e.g. either a ketogenic diet or something like the potato diet ] but can't handle both at the same time without suffering two symptoms:

[ 1 ] gaining weight

and

[ 2 ] suffering fatigue.

This is sometimes called "The Swamp".*

This is a very peculiar way for human metabolism to work. What's more, it only works this way for some people -- centrally, people who have acquired some level of insulin resistance [ "metabolic syndrome" ].

The insulin-resistant population leans not-young and slightly male, and its incidence is only appreciable in locations that have adopted a "Western diet".

The clearest articulation I've ever read of the Taubesian model of insulin resistance is actually a glowfic reply by Swimmer963:

Eat one sugary meal, and a healthy pancreas will groan but put out a flood of insulin; eat a high-sugar diet above the maintenance calorie needs every day for a decade, and the cells will gradually respond with less vigor, even as the overtaxed pancreas starts to fall behind, and fat deposits (fat is far from inert -- it's an endocrine organ of its own, in a way) secretes its own hormones, and baseline blood sugar creeps up and up -- and, again, inflames the lining of blood vessels, gunks up and eventually cuts off circulation to extremities, gradually damages peripheral nerves, and makes a very tempting meal for any bacterial infection that starts to sneak in, ignored by an immune system unable to reach it through those sticky damaged capillaries.

This model has problems.

The most obvious is, "Why weren't the rates of metabolic syndrome high in poor agricultural communities that had to eat almost entirely carbs, then?" The American Heart Association's decision to blame the increasing quantity of fat in the 20th-century American diet for the increased incidence of "diseases of civilization" was, in a sense, perfectly natural, given that . . . that was the change in the American diet that had recently occurred! It's called the "nutrition transition": poor agricultural nations' consumption of carbohydrates decreases significantly when they come into some wealth! Yet their rates of metabolic syndrome generally go up [ if few are quite as high as the American one yet ].

A less obvious problem is -- ancestral humans didn't evolve to eat quite as many carbohydrates as even the modern American currently consumes, no. But they ate Swimmer's "one sugary meal" whenever they found a good payload of fruit! Why is the putative Taubesian pancreas "groan"ing?

A third problem with the Taubesian model of insulin resistance, that you would only notice if you frequently talked to people who get large health benefits from a ketogenic diet, is, it doesn't explain "The Swamp" -- the weight-gain-and-fatigue syndrome that occurs only when people on the insulin-resistance spectrum are eating a diet moderately high in both carbs and fat at the same time, and not when they eat a diet high in fat alone, or a diet high in carbs alone. If carbs are causing the syndrome, then why does eating only carbs alleviate it?

II.

One going hypothesis for what's causing "the Swamp" in those with metabolic syndrome is "the Randle Cycle".

Basically, there are a bunch of factors available in your cells [ such as malonyl-CoA ] which facilitate the metabolism of sugar and the synthesis of fat [ triglycerides ] for storage, which also marginally block the metabolism of fat, and a bunch of reciprocal factors which enable or are correlated with the breakdown of fat, and which marginally block the metabolism of sugar [ glycolysis ].

The theory says that when insulin-resistant people eat an appreciable amount of fat and an appreciable amount of carbs in the same ~24-h period, a self-reinforcing metabolic death spiral occurs between the "fat side" of the "Randle Cycle" and the "sugar side".

The "fat side" factors, activated by the influx of fat, block the breakdown of sugar. Simultaneously, the "sugar side" factors, activated by the influx of sugar, at once throttle the breakdown of fat for energy and facilitate its synthesis and storage.

Well, now there's lots of sugar backed up in the bloodstream, unable to be metabolized [ and probably exhausting the pancreas's ability to produce insulin ]. That sugar is going to keep pressuring the "sugar side" factors, which will block the metabolism of fat even harder. Simultaneously, the fat backed up in the bloodstream [ and, at the same time, the pathological vesicles of triglycerides building up outside the cell from the continued shouting of the "sugar side" factors to store more fat ] will keep pressuring the "fat side" factors, which will continue to block the metabolism of sugar . . .

But, okay, so there's a self-reinforcing metabolic death spiral. The "Randle Cycle" mechanisms for reciprocal inhibition of fat and carbohydrate metabolism must be universally conserved across humans. So why can some people handle a diet simultaneously heavy in fat and carbs for long periods of time without becoming obese, chronically fatigued, and insulin-resistant, while others can't?

The ancestral diet was moderately heavy in both fat and carbs [ yes, they ate lots of protein, but the Inuit invented the term "rabbit starvation" for a reason -- if you only eat protein, your body eventually stops being able to extract any calories out of it at all ]. So surely there's something additionally taxing about the diet of people who develop metabolic syndrome, beyond just "moderately high in both fat and carbs".

What changed, to spike the rate so wildly between ~1940 and ~1990, in "the West"?

III.

Lipids are a large family of compounds, and some are much more oxidizable than others. Unfortunately for us, the characteristic that makes lipids particularly oxidizable is one that we cannot do without, because membranes need lipids of that type in order to maintain physical integrity in vivo. This characteristic is the possession of carbon chains with C=C double bonds spaced at a particular distance, as shown in Figure 3.3. The circled hydrogen atoms, attached to the carbon in the middle, are called doubly allylic, or bisallylic: they are particularly susceptible to removal by oxidizing LECs [ lonely electron carriers, usually called free radicals ].

[ . . . ]

[I]f one of the chains is polyunsaturated (contains two or more C=C double bonds) then the molecule takes up more room, so a membrane with large amounts of that type of phospholipid is more fluid than otherwise [ . . . ] There is a trade-off here with regard to oxidizabillity [ . . . ]

-- Aubrey de Grey, The Mitochondrial Free Radical Theory of Aging

[ source: Wikipedia ]

Different fats are shaped differently.

Saturated fats are shaped like a straight line.

Monounsaturated fats are shaped like a kinked pipe.

Polyunsaturated fats, like the ones in "seed oils" -- rapeseed/canola oil, soybean oil, palm oil, etc., with the notable exclusion of olive oil [ for the most part ] and coconut oil -- are shaped like a U, and as de Grey says, have multiple C=C double bonds, which are very volatile when your mitochondrion attempts to metabolize them.

It's usually best for animals to use saturated fats, because they're the least volatile -- but if you're a cold-water fish or you need extra fluidity in your cell membranes for some other reason -- or if you're a seed and you want to be light so you can spread and you don't really care about volatility -- then lots of [poly]unsaturated fats will help, because the molecule takes up more space for the same number of atoms.

What would happen if you evolved to eat a low rate of polyunsaturated fatty acids, but instead your body found itself consuming a very high rate?

IV.

A class of reaction that LECs [ lonely electron carriers, usually called free radicals ] are very prone to undergo [ . . . ] starts with one LEC and one non-LEC and transfers one electron between them, so that the LEC becomes a non-LEC but the non-LEC becomes a LEC [ . . . ] This is therefore a chain reaction, "passing the parcel". But of course one can't get this chain reaction until one has a LEC in the first place.

.

Unfortunately, there is a way that LECs can, and often do, arise de novo inside cells. In principle, one could create two LECs from none, by taking a molecule all of whose electrons are happily paired and splitting it in two, partitioning the electrons so that there is a lonely one on each side. Equally, the starting point could be two or more atoms or molecules, none of which had any lonely electrons. In general, processes of either of these types do not occur to a significant degree in the body, but there are exceptions.

.

By far the most prevalent exception: OXPHOS [ oxidative phosphorylation, the production of ATP in the electron transport chain ] itself. The oxygen that is consumed by OXPHOS is turned into water; each oxygen molecule thus becomes two molecules of water by the addition of four protons and four electrons. [T]he protons and the electrons reach their target by completely different routes. The electrons, in particular, are painstakingly carried, one by one, along a chain of molecules [ mitochondrial Complexes I-IV ], three of which remove a little of the electron's energy and use it to pump protons out of the mitochondrion. The fact that it is one by one, rather than two by two, is the problem: the atoms and molecules that do the carrying are turned into LECs for part of the time. If they can pass their lonely electron on to the next carrier, no harm is done; but this is somewhat error-prone [ . . . ], and a few percent of the electrons are "fumbled" at some stage in the chain. These electrons are annexed by free non-LECs (that is, ones which are not in the [electron transport] chain) to make free, potentially toxic LECs. [ . . . ] [I]t is generally found that production of superoxide [ a simple free radical ] rises with age, and is also unusually high in the affected tissues of sufferers from genetic defects of the respiratory chain [ the electron transport chain ]. Since LECs are able to damage all classes of macromolecule, including nucleic acids, it seemed clear that the rate at which mtDNA mutations occurred would rise as the production of superoxide rose. [ . . . ] [T]he free radical theory [ . . . ] implicated mtDNA mutations as the cause of the rise in superoxide production with age. If they were both its cause and its consequence, one had a vicious cycle which would cause exponential increase in both -- which was exactly what was seen.**
 

-- de Grey, The Mitochondrial Free Radical Theory of Aging

Your body's rate of "oxidative stress" from free radicals produced by oxidative phosphorylation in the electron transport chain, would go way up. This would damage your mitochondria. And damaged mitochondria damage mitochondria. The efficiency with which your body was able to do OXPHOS would decline, in a vicious cycle.*** Markers of oxidative stress would correspondingly go up in all your tissues.

With your body's core metabolic rate reduced, the Randle Cycle mechanisms might appear to become "antsier". A slight lag in the readiness of fat to flush from the bloodstream through the mitochondria would press harder on the "fat side" signaling pathway, while a slight lag in the readiness of sugar to flush from the bloodstream pressed harder on the "sugar side" pathway. Each side would throttle the metabolism of the macro triggering the other, bringing the overall metabolic rate even lower and exacerbating the process until the person had a chronic excess of sugar in the bloodstream, a chronic excess of triglycerides in the fat cells****, and chronic fatigue.

*Aspden describes a mechanism by which PUFAs inhibit glycolysis by downregulating mTOR/LKB1; the usual Randle Cycle mechanism for blocking glycolysis is that a high ratio of acetyl-CoA to malonyl-CoA will inhibit pyruvate dehydrogenase, but I thought the finding that PUFAs could block glycolysis even more strongly [ as I understand it, usually the Randle Cycle can't override mTOR, although the "fat side" "wants to" ] was illustrative, though not load-bearing.

**de Grey later goes on to say that he disagrees with the vicious cycle theory of mitochondrial aging, but this is only true in a very narrow technical sense; he doesn't dispute that the rate of damage to OXPHOS rises exponentially over time in a vicious cycle, he just thinks it's important to recognize that in "healthy aging", the rate of OXPHOS collapse is very uneven between cells.

***This paper directly shows that 4-HNE, an immediate and exclusive product of polyunsaturated fatty acid metabolism, decreases the activity of the electron transport chain in mice. Although this has not been directly shown in worms, outward signs of the electron transport chain slowdown syndrome shown by Chang et al. [ including fat gain ] have also been demonstrated in C. elegans by Singh et al.

****indeed, two types of obesity are recognized among those who study fat cells: "metabolically healthy" obesity, in which fat cells are overproduced and fat is stored normally, and "metabolically unhealthy" obesity, in which the number of fat cells is unaltered, but the individual fat cells hypertrophy from the body's pathological attempts to store more fat.

Appendix: Ancient Indian Seed Oil Consumers: The First Diabetics?

[S]eed oil consumption started in Ancient India around 5,000 years ago as the first evidence we have for domestication, and what's interesting is, shortly after that, we see the first evidence of what we now call chronic diseases or diseases of civilization [ diabetes and prediabetes, collectively "metabolic syndrome" ]

[ source [podcast] ]

[ Goodrich also claims the season of high monongo nut consumption gives the !Kung pot bellies and metabolic syndrome, because of the monongo nut's high linoleic acid levels, but that the low availability of calories is protective; I imagine either or both of "the monongo nut's LA content isn't actually 'Western'-level", or "these were !Kung who were also eating other things", is true, because as far as I understand it, the !Kung at the time they were studied by Western anthropologists in the late 20th century, were getting enough calories, and I doubt a diet of monongo nuts, which seem pretty normal as far as ancestral "reserve foods" go, genuinely gives you diabetes. ]

Gleaning the pages of recorded works of antiquity one comes across references to conditions characterized by polyuria, most of which doubtless answers the description of diabetes mellitus

.

Susruta Samhita -- one of the medical compendia belonging to [ the Vedic ] age [ the period from around 1500 BC to around 500 BC in Indian history ] [ . . . ] was the first [ . . . ] to describe sweetness of urine. Susruta classified this condition broadly into two groups -- one with hereditary background, and the other acquired by non-conducive foods and habits. He also described two types of patients -- one lean and emaciated, and the other obese.

[ source ]

The condition known today as diabetes (usually referring to diabetes mellitus) is thought to have been described in the Ebers Papyrus (c. 1550 BC). Ayurvedic physicians (5th/6th century BC) first noted the sweet taste of diabetic urine, and called the condition madhumeha ("honey urine"). The term diabetes traces back to Demetrius of Apamea (1st century BC). For a long time, the condition was described and treated in traditional Chinese medicine as xiāo kě (消渴; "wasting-thirst"). Physicians of the medieval Islamic world, including Avicenna, have also written on diabetes.

[ Wikipedia ]

[ as far as I know, all these cultures had some incidence of seed oil consumption -- sesame oil in the case of the Ayurvedics and rapeseed oil in the case of the Chinese ]