A bit speculative here, read with caution!
How do we lower free fatty acids? Obviously, with nicotinic acid. What does this do to insulin secretion in response to a glucose challenge? I'll just work through this figure from the same paper which gave us the insulinotropic effects of various FFAs a couple of posts ago.
Section A is very simple, it just shows that they succeeded in clamping glucose at just over 200mg/dl, about 12mmol/l, ie just in to supraphysiological levels.
Section B shows FFA levels, which they manipulated very carefully. All rats started at about 0.6mmol/l. Nicotinic acid lowered FFA levels to 0.1mmol/l. These are the black squares. Two other intervention groups were included. The white triangles had their lipolysis shut down using nicotinic acid but then had FFAs clamped back up again using a soyabean oil infusion (mostly omega 6 PUFA) and the black triangle group had an infusion of lard based lipids (a mix of lipids but with a significant palmitic acid content) to restore and hold FFAs at about 0.8mmol/l.
The nicotinic acid group, with FFAs of 0.1mmol/l, cannot secrete insulin in response to glucose. Flat line at the bottom of graph C.
The open squares are the control group. These rats show the normal response to an hyperglycaemic clamp. They reduce FFAs in response to the inhibition of lipolysis from secreted insulin, down to 0.2mmol/l. Insulin inhibits lipolysis. But the reduced FFAs also reduce insulin secretion. There is a balance struck with only a modest rise in insulin, sustained throughout the clamp. You can see this in section C, open squares.
The two lipid infused groups have clamped glucose and clamped FFAs. They secrete insulin in proportion to the amount of palmitate in the lipid infusion. A bit extra over control if you use low F:N ratio omega 6 PUFA, a ton extra when you include some palmitate. Section D is simply a summary of this.
Step by step at the mitochondrial level: The lower fatty acid supply results in decrease reduction of the CoQ couple in beta cells. This reduces the reverse electron transport and associated superoxide triggered by glucose as it feeds NADH in to complex I, so limits insulin secretion. You can virtually ablate the insulin response to glucose by eliminating beta cell fatty acid supply.
Now, nicotinic acid is one way of reducing FFAs. There have to be other, perhaps more physiological, methods. Maybe we could use insulin per se? From food perhaps? Let's try eating around 40g of carbohydrate and look at the Spanish study graph again. Insulin rises from 50pmol/l to 75pmol/l. This is enough to reduce FFAs from 0.5mmol/l to just over 0.1mmol/l. Look at the FFAs, especially the circles between 120 and 300 minutes:
Now (again, sorry!) look carefully at the insulin levels after the small carb load, bottom circles.
By 180 minutes insulin is actually lower than fasting, and FFAs are still well below fasting levels too. The rat model appears to hold in humans, not what the study was looking at, and a small effect. But I think the effect is real.
How about scaling this up to a massive dose of potato induced insulin and limiting dietary fat? Severely limiting dietary fat. And never mind pussy footing around at 40g of mixed carbs and protein. There is a limit to how low FFAs can be driven, and it seems safe to assume that a baked potato or three might just inhibit lipolysis maximally and keep it that low for rather a long time. But if you deprive beta cells of free fatty acids you blunt their ability to secrete insulin. Very, very high carbohydrate diets really ought to be able to inhibit lipolysis to the point where the knock on effect is the inhibition of insulin secretion, provided you don't supply exogenous fat. Look at the nicotinic acid treated rats...
Once you get FFA levels low enough to inhibit insulin secretion you will start to move in to the sort of territory where insulin secretion might be blunted enough to allow hyperglycaemia. But the feedback effect of reduced insulin levels is also the re commencement of lipolysis. This will restore enough FFAs to maintain functional insulin secretion and so avoid potential hyperglycaemia, which the body tries to avoid. Of course you have to throw in the increased insulin sensitivity of muscles deprived of exogenously supplied FFAs too.
So is it possible to eat an ad lib, calorie unrestricted diet based on near pure carbohydrate and lose weight? Working from the premise that lowered insulin is a pre requisite for hunger free weight loss, as I always do, the answer is possibly yes. We all remember Chris Voight on his all potato diet (plus 20ml of olive oil, low in palmitate, per day) who lost a great deal of weight over a few weeks, the rate of weight loss accelerating as the weeks progressed? I had a think about it here, well before I had any inkling as to what might be happening in the electron transport chain.
We need to know what the interaction of insulin and FFAs was during this particular n=1 self experiment, and we don't. The rats suggest to me that insulin levels were initially raised post prandially and FFAs were not then available from peripheral adipocytes. Assuming the fall in lipolysis persisted in to the post-absorptive period (the primary function of insulin, especially at low levels, is the inhibition of lipolysis rather than facilitation of glucose diffusion, we've all read Zierler and Rabinowitz) we have a method for limiting insulin secretion late post prandially using reduced free fatty acid levels.
As an aside I personally wonder it might be the ectopic lipid supplies typically found in muscle, liver and visceral adipocytes which might still be available for metabolism by the tissues when exogenous supplies are shut down. It reminds me of how metformin most likely depletes ectopic lipid to improve insulin sensitivity, despite having complex I inhibition as its primary action. You need lipid from somewhere. So reducing FFA supply by inhibiting systemic lipolysis may well be a route to lower fasting insulin levels. Especially if you are not far in to metabolic syndrome.
Once ectopic lipid becomes depleted then lipolysis would accelerate in peripheral adipocytes as systemic insulin resistance falls and fasting insulin levels too, which might be what was reported as progressively increasing weight loss by Chris Voight. Insulin levels would be low, especially during fasting, and appetite low at the same time due to hypoinsulinaemia facilitated lipolysis, much as appetite is low under LC induced hypoinsulinaemic eating. There is more than one way to skin a.... Oops let's not complete that phrase!
What would happen to a healthy person under these conditions, long term, is anyone's guess. Chis Voight gave up after a few weeks when weight loss became alarmingly rapid. But we know from the crucial study by the vegan apologist Barnard that, for diabetic people at least, that a long term, whole food, low sucrose and low fat diet is a complete disaster, once the initial weight loss ceases.
This is playing with fire (possibly near literally, at the mitochondrial level) if you are a diabetic. Please don't go there.
But the physiology of weight loss on ultra low fat diets is basically comprehensible, especially once you look at lipids and superoxide at the ETC level, and what the body needs to function effectively. Running your metabolism on pure glucose would induce, theoretically, an infinite glucose sensitivity and low fasting insulin. If we do reductio ad absurdum you would end up with no fat stores and experience death from hypoglycaemia if you ever depleted your glycogen stores. Mitochondria like (saturated) fatty acids. Fatty acids keep them in control.
I think someone in obesity research used Chris Voight's experience to support some cock and bull story about food reward and a set point of body fat. We can wait for the recant on that one, if you could care less about it. The biochemistry is, as always, the fascinating stuff.