Saturday, June 01, 2024

Protons (73) Spanish vs Canadian studies or 3% LA vs 10.3% LA

I hope no one has forgotten the "Spanish Study"

Distinctive postprandial modulation of beta cell function and insulin sensitivity by dietary fats: monounsaturated compared with saturated fatty acids

which was very, very carefully set up to demonstrate post prandial insulin resistance following the ingestion of the saturated fats from butter while also demonstrating a progressively improving insulin sensitivity using oils with increasing content of (mostly) linoleic acid.

A brief look at reference 15 methods section confirms they measured the test meal lipids by gas chromatography.

Obviously, to anyone lacking the Protons perspective, the clear cut message is that saturated fat causes insulin resistance. Insulin resistance is BAD. Saturated fats are BAD.

What Protons actually predicts is that resisting insulin by ingesting saturated fats limits insulin-facilitated obesity, so eliminates the subsequent adipocyte distension derived release of FFAs (which cannot be suppressed by insulin), which would lead to metabolic syndrome.

Resisting insulin prandially resists obesity and so resists obesity-derived insulin resistance. Read that very carefully.

Aside: Resisting insulin in the immediate post ingestion period is a short term effect for a few hours. It's physiological. Constant presence of FFAs secondary to increased basal lipolysis from distended adipocytes is present 24/7 irrespective of what you eat. These fatty acids supply calories and if you are eating carbohydrate then you must resist cellular glucose ingress to take in to account that FFA supply of calories. This insulin resistance is different (still the correct physiological response to FFA availability) because it follows on from pathology related to adipocyte lipid droplet size. The third type of insulin resistance is much more complicated. So is the fourth. Here is not the place to discuss them. End aside.

Sooooo. I really, really like this:

This is *not* demonstrating saturated fat induced pathological insulin resistance. Here the insulin "resistance" will simply stop you getting fat. I would define this as the "normal" response to an high fat meal, assuming a low linoleic acid based fat.

What it *is* demonstrating is pathological insulin sensitivity following the ingestion of 10.3% (actually slightly under this but close enough) of calories as linoleic acid. Here as little as 140pmol/l of insulin will rapidly clear your plasma of calories and leave you hungry. The meal is largely lost in to your adipocytes. You WILL want to eat again, and soon.

This is fundamental and simply falls out of the Protons hypothesis.

Now, there are problems with the study and the authors are to be congratulated on the result generated (though not on their conclusions of course), especially the composition and size of the meals they had to design to get there. But here we are looking at a dynamic response to a single meal. Is it possible to examine their important findings under more steady state conditions? Would the relationship of PUFA ingestion to pathological insulin sensitivity still hold?

What would we find if we kept plasma FFAs forcibly elevated for 24h using repeated small oral fat loads supplying 2430kcal over a 24h period (but no other food) instead of a single oral ingestion of 800kcal as one mostly fat meal?

Then, instead of tracking the insulin response to a small amount of starch/protein along side the fat of the 800kcal meal, we could assess insulin sensitivity during an hyperglycaemic clamp at 20mmol/l of glucose in plasma. The more glucose needed to achieve this level, the greater the insulin sensitivity.

We are now well away from normal physiology but we are asking essentially the same question under more constrained conditions.

I'm assuming people have realised that I'm now describing Xiao's study from the last post

which produced this chart from the above protocol:

To me, the results of Xiao's study and the Spanish study concur beautifully.

Not everyone will agree with me that these reflect a core reality, I wouldn't expect that. But in my NSVHO this is how physiology works. Linoleic acid is insulin sensitising.

However, when you have confirmation bias as badly as I do, and you find two non related studies which neatly corroborate each other while confirming your biases, you know you are trapped. That's me.

You have been warned.


Addendum: Obviously palm oil at around 8% of calories as LA is already insulin sensitising, it's in the same ball park as the 10.3% LA arm of the Spanish Study. A true SFA arm to the study would need to have LA at around 2% of calories and I would predict a GIR well under 40μmol/kg/min.


mct4health said...

Yes, agree, thank you Peter. There is only question why. Here is interesting paper about insulin secretion, there are at least three components. Glucose stimulated IS, ROS stimulated IS, FFA stimulated IS and GPR40 stimulated IS (LCFA). And I think there is also GPR41/43 stimulated IS (SCFA) not described there.

And although you don't agree with HIF1alpha involvement, if somebody is interested how I see it, I'm explaining it here

But IR is only rescue mechanism. I now see the main cause of problems in partly reversed TCA cycle and ammonia poisoning from glutamine metabolism activated by DNL. That's probably too far for to be widely accepted. But all insulin resistance problem is only adaptation to this state.

Peter said...

Ultimately I suspect, whatever the trigger/mechanism, insulin resistance is (almost) always adaptive.


karl said...

Insulin also controls LPL and HSL thus a regulatory input of the assembly and disassembly of FFA thus controlling FFA. Is this regulation more important than regulating glucose? Which has priority?

Insulin sensitivity is defined via glucose - but regulating FFA might dominate the nested control loops?

T2D appears to be permanent damage - I'm still not sure which tissue is damaged - My hunch is the liver - but could be pancreas, muscle, adipose. Transplant data in humans doesn't clear this up.

Sometimes I think the studies are designed to NOT provide definitive answers. They used to do chemically defined synthetic diets where you could truly have a single variable.

Gyan said...

Yet apparently Taubes in his latest book "Rethinking Diabetes: what science reveals about diet, insulin and successful treatments" calls T2D as disease of insulin resistance and thus of insulin excess. Although his prescription may work --he favors carb restriction though not PUFA restriction (PUFA being better for cardiovascular risk factors aka cholesterol than saturated fats).

So, the concept of physiological insulin resistance is even now not generally accepted (or even generally known) within the dissidents, never mind the establishment.

Peter needs to write journal papers, there is no other way out to get his important analysis out.

Peter said...

Gary has been more than a little influential w/o having a manuscript maligned by successive rounds of peer review to try to get a message out in to the mainstream technical publications.

I find it sad that I disagree with him today about the fundamental process and I was absolutely on the same page as him before I started the thought train which led to Protons.

Which gave me absolutely no inkling at the time that it was going to lead me to where I am now.

That's life.


Tucker Goodrich said...

"Constant presence of FFAs secondary to increased basal lipolysis from distended adipocytes is present 24/7 irrespective of what you eat."

It's still what you eat.

"Prevention of 4-hydroxynonenal-induced lipolytic activation by carnosic acid is related to the induction of glutathione S-transferase in 3T3-L1 adipocytes"

"Indeed, rather than fat mass expansion, per se, dysregulated fat, characterized by reduced adipogenesis with enlarged adipose cells (hypertrophic obesity) in the subcutaneous (sc) abdominal adipose tissue (AT), appears to be a key determinant of the obesity-associated derangement of glucose homeostasis."

"Accumulation of 4-Hydroxynonenal Characterizes Diabetic Fat and Modulates Adipogenic Differentiation of Adipose Precursor Cells"

mct4health said...

It's strange how nobody even notest that sodium acetate or triacetin can in one week restore fat and glucose metabolism of obese mice or rats on HF diet. Even with PUFA content. No discussion, no interest. Too simple? How to phosphorylate ACC1 and switch HIF1alpha off and why it works?

karl said...


So you think dietary glutamine is the problem? Glutamine is common in many of the historical foods before the T2D problem appeared?

It seems to me it is better to eliminate the cause rather that to take some drug (this time sodium acetate).

On the other hand - it is interesting that lowcarb + DON is now being used to treat previously untreatable cancers. (DON mucks up glutamine metabolism).

So what is your narrative of the cause of the T2D pandemic?
(I'm making a list of all the hypotheses).

mct4health said...

Not about dietary glutamine.The problem I see when glutamine has to enter TCA cycle and is deaminated. And that has to be done when DNL is active and fat and carbs are burned simultaneously. This release ammonia and that cause suppression of OXPHOS and tendency to activate pseudohypoxia in adipocytes and fattening. If citrate doesn't go to DNL, it can restore level of cytosolic acetyl-CoA and deactivate pseudohypoxia. I don't know if supplementation of acetate is a good idea. What surprises me is ignorance, acetate flow is NEVER measured in dietary papers. The most influential stuff is not watched. So there is lack of good papers.

Epidemic cause? Lack of SCFA in seed oils, from intestine microbiome, from liver. Lack of vinegar...

mct4health said...

As you can see, in high FFA environment insulin resistance prevents burning glucose. Insulin sensitivity promotes simultaneous burning of fats and glucose so if DNL has been already activated, ammonia does it's bad work.

How glutamine triggers normoxic HIF1

My layman's analysis of how antiporters and DNL drive glutamate into mitochondrion and into TCA cycle, but not when only glucose is burned.

mct4health said...

Sorry, this is about HIF1

Gyan said...

Taubes is smart and through, able to pick over a research paper. Thus it is mystifying how he accepts mainstream epidemiology enough to commit himself to the statement that the preponderance of evidence is towards replacement of saturated fats with polyunsaturated fats, It implies he buys into the lipid hypothesis, LDL and cholesterol hypothesis for cardiovascular diseases.

Passthecream said...

Dang that's a good paper. Will take me a few weeks to dig through in detail.

Q: how much is too much?

Passthecream said...
This comment has been removed by the author.
Passthecream said...
This comment has been removed by the author.
karl said...

So - I know T2D was rare when I was a boy - suggesting that some change in the diet or environment changed things. So your hypotheses of the cause is a lack of dietary Short Chain Fatty acids? (FFA is increased via fructose - but counter examples exist).


Which paper?

A couple of data points:
Rates of T2D in Amish and Mennonites is lower (about 1/3) - but still higher than it was in the 1950-1960's

The rate of T2D was already something like 1.4-2% by 1965 - compared with over 10% today. Which change(s) in environment/diet is the cause? (And why is the research so poor that we can't know for sure today?)..

I have my own pet hypotheses - but I'm trying to collect a list of all the narratives.

Passthecream said...

The second paper that Tucker quoted.

Gyan said...

I subscribe to Dr Eades's weekly newsletter. Today he is writing about how visceral fat, as opposed to subcutaneous fat, is a major driver of inflammation:

"Fat stuffed into the viscera is like having a big splinter or some other kind of foreign body embedded there. Since it doesn’t belong, the body regards it as an invader and mounts an immune response against it. Macrophages flood to the area and worm their way in between and among the fat cells. And as is the wont of macrophages, they send out signals to draw other macrophages t1o the area. Ultimately, macrophages can occupy 50-60 percent of the volume of visceral fat."

I wonder if it is correct. Does body actually regards visceral fat as an invader. I once asked Peter and his view, as far as I could understand, was that it was an older view acceptable 15-20 years ago. Presence of immune cells among visceral fat is explained as response to ongoing death of overextended fat cells.

mct4health said...
This comment has been removed by the author.
mct4health said...

Fructose ends up in the same ammonia toxicity as lack of SCFA in mixed carbs+fat diet. So it adds to it, the same partly reversed TCA cycle and activated HIF1 (pseudohypoxia). It's interesting, fructose activates AMPK and phosphorylates ACC1, but ammonia from AMPD2 erases this SCFA-like effect.

Lev said...

If I eat palm oil containing snacks, I get weird red bumps all over my forehead.
PUFA always caused me acne, and in Israel, sunflower seeds are well known to cause acne breakouts in teens. How nobody made the connection is odd.
Something something IGF1 and insulin sensitivity.

karl said...

I read what Edades is saying as well ( - This is the "fat tissue is what is damaged" to cause T2D hypotheses. What it lacks is if people lose weight - remove the visceral fat - the tenancy to gain weight does not go away. Something about the insulin set point seems to get permanently broken.

- Quoting Eades:
"... it is vastly easier to not become overweight in the first place than it is to deal with being overweight later." This has been explained by a change in the fat tissue - number of cells etc.. Also, Visceral obesity should effect women a lot more - but does it?

'Knowing' which tissue is damaged seems important - but it feels like nailing jello to the wall. Cooked papers - incompetent papers - make the signal to noise really bad - all the water is muddied.

I would also ask the question is the inflammation the cause or the effect? How to test for the arrow of causation?

Also - while I think 'inflammation' is a thing - it tends to not have a consistent definition. Inflammation is well correlated with a bunch of mental illness syndromes - give someone interferon and they get seriously depressed. If we get sick - we have symptoms of depression/anxiety - take the fever away - is that depression? How much of this is possible a metabolic disease?


Trying to nail down what your cause of T2D pandemic is? Is your hypotheses is the increase in fructose and replacement of SCFA with PUFA consumption is the change that caused the T2D pandemic? There is compelling evidence that the combination of LA(a PUFA) and fructose synergistically damage the liver (might damage the pancreas as well?).

"Fructose-Induced Hepatotoxicity in Rats: Role of Polyunsaturated Fatty Acids"** (2006) (in rats) doi: 10.1093/jn/136.2.443

Synergistic Effects of Fructose and Oleic Acid on Lipid Accumulation and Oxidative Stress in Hepatocytes"** (2014) doi: 10.1074/jbc.M114.580164 in hepatocytes

"Fructose-Induced Lipid Accumulation in Hepatocytes Is Enhanced by Linoleic Acid"** (2017) in hepatocytes doi: 10.1016/j.jphres.2017.02.005

So what I am trying to promote is to not have a 'dog in the race' - making a list of all the narratives - trying to find the evidence and the holes.

Peter said...

Tucker, ah, 4-HNE

Orally, generated in situ, parenterally. There is a dose response curve and 0.1μM is very different to 5μM and also different from 25μM. It's almost like superoxide/H2O2...


Peter said...

Lev, hmmm, that's weird.

Gyan, yes, visceral fat is a tricky as insulin resistance.

karl and Jaromir, I absolutely agree looking for causes is fascinating and potentially useful but I have this uncomfortable feeling that acetate or tri-acetin are applying a sticking plaster to a broken metabolic choice...

karl, if you chop out someone's visceral fat it does bugger all in 4/5 studies published. The author of the fifth study, where it worked, has no explanation when asked to comment. Hmmmmm


karl said...


Yes, liposuction fails.

I keep running into the same logical problem - People with T2D have high x - thus x => T2D - yet it could be the other way round that T2D => x.

So what we have is this long list of correlations - and mostly no work on arrow of causation.

Seems there could be experiments to sort this out - transplanted tissue, longitudinal studies - which comes first. After reading so many of these papers, where the logic is flawed, or false high-fat diets etc - I have a sense that there is a thumb on the scales - like some effort to distort the science that has political/monetary power? Is it just me? Do others smell something rotten?

Is the training in epistemology(scientific methods) of bio-researchers so bad that the arrow of causation is so often simply assumed? Even if I ignore the political/monetary biases - why do so many papers demonstrate incompetence? I suppose if you throw out meritocracy - in the end you get BS rather than science.

Another hypothesis - bio accumulation of 4-HNE causes T2D ( levels increase with age). (hard to separate from MT dysfunction that also increases with age).

It is thought that Glutathione and NAC might help remove 4-HNE?

Some papers that discuss how the body removes 4-HNE:
Kawai M, et al. Detection and quantitation of 4-hydroxy-2-nonenal (4-HNE) in human plasma: implications for oxidative stress markers. J Anal Toxicol. 2018;42(5):261-268. doi: 10.1002/jat.3343
Lee JH, et al. Glutathione and N-acetylcysteine conjugate formation of 4-hydroxy-2-nonenal (4-HNE) as a mechanism for its detoxification. J Biol Chem. 2015;290(25):16,543-16,554. doi: 10.1074/jbc.M115.662114
Li Z, et al. Cysteine conjugate formation of 4-hydroxy-2-nonenal (4-HNE) by human hepatocytes and its role in detoxification. J Pharmacol Res. 2017;143:136-145. doi: 10.1016/j.jphres.2017.03.005

Both NAC and Glutathione appear to help remove 4-HNE AND with insulin sensitivity.

If one stopped eating LA - that would not mean that the accumulated 4-HNE just goes away..

mct4health said...

There will probably not be one cause of diabetes, but all causes (not just diabetes) revolve around a change in metabolism from OXPHOS to fermentation. And since it seems to me theoretically that the change should be a step like a switch, the percentage of cells in one and the other state probably changes. And it also seems to me that in some tissues this switching is desirable, but in adipose tissue it is undesirable, it cannot be switched back.
I don't agree that a healthy fat cell gets bigger and it's only when a large cell becomes problematic. This simply does not fit the HIF1a knock-out model. the conditions for HIFI activation remain, i.e. many ROS, but the cell does not enlarge. It certainly also oxidizes many PUFAs, but nothing negative happens. Mystery? The genes for making new fat just don't turn on. Therefore, it will not start deamination process etc, etc. Does it make sense or not?

Yes, physiological acetate would be better, more trials needed. Is this data deficiency something intended, like Karl asks?

mct4health said...

And one paper what HIF1alpha KO in adipocytes can do in mice

Passthecream said...

Apologies, this is off-topic but I thought it to be a lovely exposition of some immune topics which some may find of interest:

Passthecream said...

Karl, the sort of immune system maelstrom which he is describing is what I think of as inflammation. Bruised fingers and angry fat cells are small potatoes in comparison.

Bob Kaplan said...

karl wrote: "Insulin also controls LPL and HSL thus a regulatory input of the assembly and disassembly of FFA thus controlling FFA. Is this regulation more important than regulating glucose? Which has priority?:

I think this is a really important question. Our equipment essentially defines how we look at things and we assess IR & IS based on glucose clearance...

...but I think it's also important to consider what happens to NEFAs/FFAs. I'll avoid speculating on whether insulin is inhibiting lipolysis or enhancing FFA deposition and assume for the sake of argument that lower postprandial (or last 30 min of an insulin/glucose clamp) FFAS and/or TGs means that adipose tissue appears to be more sensitive to insulin's fat sequestering effects. In Xiao et al., 2006, at day 2 of oral ingestion, NEFAs and TGs are lower in the PUFA group compared to the SFA group (0.73 mM vs 0.85 mM and 1.50 mM vs 1.90 mM, respectively). I may be mistaken, but it doesn't look like Xiao looked at fatty acid levels during the clamp, only glucose. But the Spanish study also shows a similar postprandial trend in FFAs and TGs based on UFAs vs SFAs as well.

Another study I've seen is from Toubro et al., 1994 entitled "Insulin sensitivity in post-obese women." They performed a hyperinsulinemic euglycemic clamp on the entitled compared to controls and concluded "that the insulin sensitivity of glucose metabolism is unaltered in the post-obese state." But they also looked at FFAs during the clamp and found that "at the end of the clamp free fatty acids were lower in the post-obese women than in the control women." They pointed to "an increased antilipolytic insulin action in post-obese subjects, which may favour fat storage and lower lipid oxidation rate post-prandially."

To me, that sounds a lot like there's greater insulin sensitivity in AT exposed to higher PUFA vs SFA and in post-obese vs normal weight women, which suggests enhanced insulin sensitivty of AT to "trap" or sequester FFAs in the presence of insulin, which may be somewhat independent of glucose clearance rate, but just as, if not, more important in terms of predicting which group you would bet on getting fatter if these results reflect what happens meal after meal (until of course you might reach a point where AT distension resists the sensitizing effects of insulin on FFAs in circulation).

karl said...

@mct4health who said "There will probably not be one cause of diabetes..."

I'm going to disagree - perhaps because I'm older, I remember a time when T2D was just not happening. It seems the best explanation is a change in diet or environment. It could be the PUFA + fructose combo, but it seems far fetched that the majority of people with T2D got it from different things.

@Bob Kaplan who said "Our equipment essentially defines how we look at things..."
Quite true - I think that what drove the cholesterol nonsense at the start was it was an easy test to do - portable.

The narrative that 'insulin is exists to controls BG(Blood Glucose)' is wrong in that it leaves out the long list of other effects. I changed the way I think about T2D - most think of it as elevated BG - re-framing that to thinking in terms of chronically elevated insulin seems to give a clearer picture. (That being said - what really counts is the level PLUS the sensitivity in whatever tissue we are looking at). So we can have adipose tissue storing fat while the liver is being resistant.

I started this quest looking at causes of CVD - and my current thinking is the large correlation with T2D (much larger than high LDL) is due to insulin shutting down autophagy. The arteries near the hear are under a lot of mechanical stress - small - even microscopic tears form clots - if they don't get absorbed, new intima grows over them - what is left of the clot forms a new striation in the plaque.

So to reduce CVD - it seems we need to know what actually causes T2D and thus my current quest of exactly which tissue gets damaged.

Peter said...

Nice find Bob. I'm spending a lot of time on

Fat metabolism in formerly obese women

by the same group. Interesting indeed.


karl said...

@Peter and Bob - RE: formerly obese

Could it be that it is because when people lose weight, they do not lose all types of fatty acids at the same rate. Specifically, there is evidence suggesting that linoleic acid (LA) may be conserved to some extent during weight loss. (Seems that the stored LA - some which would get metabolized - tend to increase insulin sensitivity? )

I've wondered for a long time if stored LA changes the set point.

As LA appears to bio-accumulate - even a small increase from what would be found traditional diets could over time cause a large increase in the amount of LA stored in our fat.

The public rejects things that cause immediate harm - not so much to things that kill us slowly.

mct4health said...

"fat oxidation is subnormal despite higher circulation NEFA levels." in FO.
This means high malonyl-CoA, so hi activity of ACC2 and ACC1. ACC2 is THE SWITCH. That's my conclusion, see my blog.

Captain Sunset said...

I have read a mountain of stuff on LA, and it seems to me that the newer veg margarines could indeed be the culprit. I would like to hear Peters's take on it. Anyway, they all taste bloody awful! Some say it can take 5 years to rid the body of LA. That kinda figures. Uuuuugh. "Margarines were originally obtained from lard and other fat sources, and were widely consumed through the world until the 1970s and 1980s. However the association of saturated fats with coronary heart disease led to the development of new margarine products of vegetable origin. These new margarines, with high-polyunsaturated-fatty-acid content, include soft margarines and diet spreads. Sunflower oil is one of the oils employed in the formulation of fat blends to achieve an adequate product. Typical fat blends for margarines are shown in Table 5."

mct4health said...

If we accept the switch to be ACC, then we can change the threshold and status. By changing type of fats we shift the threshold, but we cannot change status of already switched cells. That can be done only by phosphorylation of ACC by AMPK. This is tricky and diet change have to be much greater then for prevention. And the reset must be repeated many times until the switch is no more activated by diet.

mct4health said...
This comment has been removed by the author.
mct4health said...

You may be interested.
"However, in the presence of elevated fatty acids, the lack of ARNT/HIF1b is protective against HFD-induced diabetes. The current paper suggests that inhibition of ARNT/HIF1b may be a
possible target for the treatment of obese patients with type 2 diabetes."

It means that in high fat environment HIF1 should never be activated. If high fat diet triggers HIF1, always it causes chronic problems. Low insulin resistance of LA diet is one factor that lowers threshold for HIF1 switch via high ROS. But ROS from OXPHOS are not problem, only after triggering HIF1 problem starts (low OXPHOS, high DNL and ACC, NOX2 activation, etc.)

mct4health said...

What surprises me is generality of this pseudohypoxia principle, even for Alzheimer model.

karl said...


From the paper ( )

"high-sucrose HFD (58 kcal% Fat and Sucrose diet number D12331; Research Diets, Inc"

The LFD and HFD didn't even come from the same company - not real science. In real experiments everything possible is done to vary a single variable. You would want the same feed source with only one component altered.

I'm not sold that T2D originates in the pancreas - the damage to the pancreas may well be from the never ending demands on production of insulin.

That being said - there is ONE thing I know for sure - the current state of the research makes it impossible to understand the cause. No end of money to for labs doing bio-weapons work - yet just not seeing funding of the type of work that would nail down the cause of the T2D pandemic which is the leading distal cause of death.

mct4health said...

Hmm, I don't think it does matter, they chose the most harmful diet I think. And even with this horrible diet can HIF1beta KO mice be obese and insulin sensitive at the same time. Isn't it interesting. In our environment are some toxic factors, that cause overactivation of ARNT/HIF1beta. If it would be little bit lower, it would prevent disfunctional beta cells, diabetes. Did you remarked the opposite reaction of insulin secretion to FFA caused by higher glucose, but normalized in KO mice? I see vicious cycle, less insulin, more FFA, less insulin ...

mct4health said...

And it's not pathological insulin sensitivity, see the metabolic flexibility. More fat burns fats, more glucose burns glucose.

Bob Kaplan said...

"I'm spending a lot of time on

Fat metabolism in formerly obese women"

Very interesting paper. "Despite similar plasma glucose concentrations, the FO had lower insulin concentrations throughout the study. This suggests an increased insulin sensitivity of the FO."

In my spare time I've been compiling a list and poking around situatiions of fat gain and seeing if insulin sensitivity shows up. Hypothalamus-damaged mice, hibernation, puberty, obesity, pregnancy, pre- and post-obese, etc.

Pregnancy is quite interesting. It looks like a microcosm of what you've explained with LA and obesity: "During early pregnancy, both glucose tolerance and insulin sensitivity are normal or greater than normal and the insulin responses to oral glucose are also greater than normal ... However, by the third trimester of pregnancy, a progressive insulin resistance develops, and an increase in basal and postprandial insulin concentrations is seen." [Herrera 2016]

karl said...

@Bob Kaplan

My father was an OBGyn - how I first learned about GTT. So insulin is also an anabolic hormone. So in OB - the worry was always large babies that would need forceps or C-section. He was checking for gestational Diabetes way back in the 1960's - probably because his endocrinology prof had been a Dr. Gordon - the guy that published a low carb diet in 1963 that Atkins based his diet on. Gordon had noticed how during the war that a lot of Diabetes got better when sugar was in short supply.

So the question is if part of the change in set point in pregnancy is at a cost to the mother for the benefit of the baby. What happens at the end of pregnancy for the mother is a bit variable - I've wondered if sometimes they are seeing a similar damage to T2D?

Anyway - gestational diabetes is what triggered my long time interest in diabetes - remember experimenting with the Urine test tapes he used back then ( used a color comparison) to test for any sugar in the urine.