Monday, February 17, 2020

Insulin sensitivity makes you fat

TLDR: Excessive insulin sensitivity sets you up to become obese. Becoming obese makes you insulin resistant. Eventually excessive adipocyte size will induce systemic insulin resistance. Further weight gain is still possible given a diet which induces systemic hyperglycaemia combined with a pancreas of steel. Here we go.

I picked this paper up from Pubmed while looking for something else:

Insulin sensitivity is increased and fat oxidation after a high-fat meal is reduced in normal-weight healthy men with strong familial predisposition to overweight

It's very interesting.

Over the years I have collected various models, mostly mouse/rat models, which generate obese, insulin resistant rodents.

These mostly involve damaging the hypothalamus in some way and letting the mice eat ad lib until they reach the desired level of obesity, with the associated insulin resistance. There is the ventromedial hypothalamic injury model

Molecular and metabolic changes in white adipose tissue of the rat during development of ventromedial hypothalamic obesity

The MSG injury model:

Decreased lipolysis and enhanced glycerol and glucose utilization by adipose tissue prior to development of obesity in monosodium glutamate (MSG) treated-rats

Late effects of postnatal administration of monosodium glutamate on insulin action in adult rats

The gold thioglucose injury model:

Adiponectin expression is paradoxically increased in gold-thioglucose-induced obesity

What they all have in common is that the models are always more insulin sensitive in the first weeks after injury compared to the non-injured controls. This excess sensitivity persists until a certain level of obesity is achieved. As obesity increases so does systemic insulin resistance increase (a separate mechanism) until it overwhelms the excess insulin sensitivity and rate of weight gain markedly reduces. The model is now insulin resistant.

Inappropriate insulin sensitivity is what generates the obesity. Insulin resistance limits its progression.

Insulin resistance in adipocytes can, undoubtedly, occur but this is not a feature of the adipocytes in the early stages of obesity. They are insulin sensitive. Insulin acts easily. Adipocytes distend.

Back to the paper. It enrolled young, male, non-obese offspring of obese parents. Let's call them pre-obese. Sadly the paper is from 2004, it's now 2020, I would expect the "pre" prefix might nowadays be redundant. Here are the subject characteristics:

To me it is interesting that the pre-obese chaps were carrying more fat mass than the controls. There is a 1.7kg excess, statistically ns but the trend is there. You have to wonder how close to 0.05 the p value might have been.

Here are the fasting metabolic parameters for both groups:

Notice that the fasting insulin is lower in the group with higher fat mass, provided they have obese parents. It's also interesting that their fasting FFAs are higher than those of the folks with slim parents. This difference is also ns but the numbers after the +/- sign are standard deviations, not standard errors, so my guess these too are close to significance (for what that is worth). I also like the ns elevated trigs, I suspect related to repackaging the elevated fasting FFAs. Which are elevated due to increased adipocyte size allowing increased basal lipolysis. All speculation.

Next we have the insulin response to a quite pleasant sounding, mixed macro, highish fat meal:

The fasting insulin is the one from Table 2, p being 0.007 and for a large percentage of the post-meal eight hour period insulin stays significantly lower in the pre-obese group than in the normal-weight parent group. The pre-obese subjects are consistently more insulin sensitive.

Here is the FFA graph for the same eight hours:

Converting the FFA levels to real money terms it appears that the lean parent group had FFAs of 280micromol/l and the pre-obese people had 390micromol/l. I've already speculated that the elevated FFAs in the pre-obese group are from increased basal lipolysis, not insulin resistance. As soon as insulin is released after the meal FFA levels become identical for eight hours. I've not copied the trigs graph but the trend is for chylomicrons to be the same between groups for 4 hours and then lower in the pre-obese as insulin sequesters fat in adipocytes.

Which group will be metabolising most fat under hypoinsulinaemic, near-basal lipolytic conditions? Pre-obese have elevated fasting FFAs and they're oxidising more fat, 1150 vs 740mg/kg FFM/d,  ns but you can see the trend:

However, as soon as insulin rises fat oxidation drops because insulin sequesters fat in to adipocytes at levels way below those which translocate GLUT4s. It will also divert intracellular FFAs in to intracellular triglycerides. Lipid oxidation under insulin drops to 90mg/kg FFM x 8h compared to 163mg/kg FFM x 8h in the more normal individuals. Giving p less than 0.007.

BTW FFAs stay high in both groups because the meal was around 50% fat. I would predict that a high carbohydrate, low fat meal would have produced a marked drop in FFAs and a rise in RER, both more pronounced in the people with obese parents. No data on that one.

I do not think these pre-obese people have an injury to their hypothalamus. It is more likely the problem is with their adipocytes causing the excess insulin sensitivity.

I think we can ignore discussion comments about the influence of medium chain acyl CoA dehydrogenase variation as a red herring because the pre-obese folks are oxidising more fat under fasting conditions, ie when more lipid is available. The leptin receptor comment is lovely because we know that in mice with a complete leptin receptor deficiency that providing less than 5% of calories from PUFA is highly protective against obesity while providing 15% PUFA in the diet is grossly obesogenic (first link in the blog post). Clearly dietary fatty acid composition trumps even gross leptin signalling deficiency.

What were the diets like in the pre-obese participants? All we know from this study is that the ratio of PUFA:SFA was higher in the pre-obese people:

"The polyunsaturated to saturated (P/S) ratio was 0.34+/-0.06 in the group with overweight parents and 0.31+/-0.09 in the control group".

However you try to reverse engineer the limited data from the results it's hardly 5% vs 15% PUFA, but these people have taken around 25 years of eating a slightly heart-healthier PUFA rich-er diet to gain an excess of 1.7kg of fat mass. My biases are willing to accept this as real.

Maybe it is, maybe not. I'm not exactly a bias free source of opinion.


BTW leptin is consistently lower in the pre-obese group carrying excess fat mass. My suspicion is that their fat cells "feel" empty, so are refusing to signal their true state of fullness. Once the adipocytes become full enough then leptin will increase to give a more accurate representation of the absolute fat mass. This will be associated with the onset  of the more expected insulin resistance of obesity.


Tony said...

"... the pre-obese chaps were carrying more fat mass than the controls."

Yeah, but the pre-obese chaps were also 3 years older, or am I mistaken?

As a former pre-bese chap, former obese chap, and now slightly-bese chap myself, I can say:
Only 1.7kg weight gain in 3 years?

I misread "Adipocytes distend." as "Adipocytes dissent." :-) Would be a sweet band name!

Tony said...

Completely missed the point why you point out the 1.7kg excess fat!
The age difference does not matter here.

Peter said...

Yes, the authors do discuss the age difference. I very much doubt that the fat mass was ever identical at any given age between the two groups but we can never know that. I certainly would expect the extra seven blocks of butter carried by the pre-obese to have been accumulated over a couple of decades, not a couple of years.

Hmm Adipocyte Dissent...


Tony said...

"The polyunsaturated to saturated (P/S) ratio was 0.34+/-0.06 in the group with overweight parents and 0.31+/-0.09 in the control group"

My gut feeling tells me the PUFA:SFA ratio matters less than the absolute amount of PUFA in the diet. I suspect the pre-obese chaps also eat slightly more total fat? Is there any information on the absolute amount of fat in the diets of the 2 groups? Can you deduct the absolute dietary PUFA of pre-obese chaps vs dietary PUFA of controls?

Peter said...

There is some information but not enough to reverse engineer total PUFA levels and they are only the intakes over a 1 week period as part of the study. In their favour it was a written seven day food diary, not some stupid FFQ. But still impossible and still not a lifelong food choice record...


Abu Dhabi said...

Perhaps the pre-obese have more fat cells, which makes individual cells actually emptier?

Peter said...

Yes, it is possible. Undoubtedly they will end up that way but my feeling is that this early on that hyperytrophy seems more likely than hyperplasia. But we have no data.


Frunobulax said...

@Peter I love your blog, but I'm not sure that I agree with this one, which might be a first for me :)

High lipid oxidation in fasted state is an early predictor of weight gain? No, this doesn't sound right at all, in fact it's exactly the reverse of what I would expect to see. I get the point you're making that it could be this way (high insulin sensitivity leading to obesity), but I don't agree that the data fits this, and I also don't think it fits occams razor. I'd expect people with low lipid oxidation to become obese, because they will get hungry if their stored glucose run out.

The thing is, I really don't know if we can make the assumption that the "pre-obese" group will become obese, see below. The authors just assume that, but why should they? These guys beat the trend already, they are not obese even though their parents are. Sure, they might, but I most certainly wouldn't base any conclusions on this assumption.

(8 subjects is an awfully small group btw, but let's assume that we have enough to see the trends. Another issue is that the authors mix obese and overweight, let's assume as well that we're not talking BMIs of 25.5 vs 24.5 here.)

With studies, I always wonder if we are making the right assumption. I think I can formulate an alternative theory that fits the observations but has 100% reversed implications. (So one of them will be wrong, but we don't know which. Or both are wrong.) It goes like this: All observations come from differences in insulin sensitivity alone, which is driven by the diet (carb content, PUFAs and so on). (The "obese parents" people have a HOMA-IR of 1.1 compared to 1,6 in the controls, and low HOMA-IR -- on average -- indicates insulin sensitivity.) That is, my theory here is that we would see exactly the same results if we dropped the condition of parents being overweight or not, just took random lean people and based the selection only on HOMA-IR. Metabolic flexibility (low HOMA-IR) implies that they metabolize more fat in fasted state and more glucose postprandial, they are able to switch from one energy source to the other efficiently. Done, no surprises here.

Now, why would lean people with obese parents have lower HOMA-IR than lean people with lean parents? Let's assume that we have a hereditary predisposition to become obese, which is in line with what the authors assume (I don't care if it's due to genetics, microbiome, epigenetics or whatever your favorite theory is here). The study called for lean people, so they chose people that are predisposed to be obese but aren't. How did they beat the odds? Chances are that they either are more active physically (which tends to preserve insulin sensitivity -- I know that the study ruled out "strong" activity but they may be more active than your usual John Smith) or that they eat less carbs/sugar, or both. So we end up with one group with unusually low HOMA-IR, which reacts one way, and a control group with a more typical HOMA-IR for a western diet which reacts differently. (I remember that typical HOMA-IR averages in studies are often north of 2.0.) The control group did't get fat because of hereditary predisposition even though they ate more carbs, but they have lower insulin sensitivity and higher HOMA-IR due to their diet.

The implication of my theory is that these people are *not* predisposed to becoming obese, because their diet prevents it. In fact, high fat oxidation in fasted state and high carb oxidation after a meal with carbs would be a predictor of staying lean (and not future obesity). And possibly: If your parents are obese, then the only way to stay lean is low-carb diet and physical activity.

Frunobulax said...

(comment split because of length restriction)
To see what is really going on here we're missing two studies. First is the followup: What happened to these people? Did the guys with obese parents become obese in the meantime, or rather more obese than the control group? Second, I would have liked to see two more groups in the original study, one group with non-obese parents and HOMA-IR around 1.1, and another group with obese parents and 1.6 HOMA-IR. (If the latter doesn't exist, this would be another strong clue that my theory is correct.)

As for insulin resistance, my stance here is "I know that I don't know." Jason Fung makes a good point about insulin resistance in a podcast I heard a few days ago (Peter Attia): Why do we assume that muscle cells become insulin resistant, while many other cells (like the ones in the liver producing triglycerides out of glucose, or lipid cells storing fat and not releasing it) remain apparently perfectly insulin sensitive? I don't really agree with his alternative theory that there is no insulin resistance at all (our muscle cells are just crammed with glucose, so the body produces more insulin to get rid of the excess glucose). After all, I know that my fasting insulin was still way higher than normal (HOMA-IR of 1.7) even after several months of keto including a bit of fasting, where should the crammed glucose come from? And we would need to explain what happens in t2d where we have an apparent energy shortage because the glucose doesn't get into the cells. But Fung does have a point: We may have to revise our understanding of insulin resistance, and shouldn't take for granted that everything is as we believe.

Peter said...

Hi Frunobulax. Excellent. There is never one single correct interpretation, especially with small groups and no follow on. I'll need a little while to digest your comment but it's absolutely in line to look at alternative explanations. Especially if they are correct...


Gretchen said...

Then there's that study in grizzly bears that showed that they get very insulin sensitive in late summer and pack on the pounds. It's only during hibernation that they become insulin resistant.

That makes intuitive sense to me and explains why some very obese people are insulin sensitive. They're obese *because* they are insulin sensitive. Then the question is why not everyone who is obese is also insulin sensitive?

What needs to be worked out is which tissues are resistant or sensitive. You could have insulin sensitive fat cells and insulin resistant muscles, a bad situation unless you wanted to get fatter, or vice versa.

Maybe people are studying this, but I usually see papers in which they just measured overal sensitivity/resistance.

karl said...

I think we are close to 'knowing' that inappropriate insulin sensitivity is what causes obesity. I also think that PUFA's can cause inappropriate sensitivity. But, I wonder if there are other factors that mess with the ROS signaling system? ( I figure insulin is the short term feedback - not the level setting bit of the loop - ( read about PID loops - could be the P(proportional) and I(integral feedback) is via sensitivity and the D (differential) is insulin?).

I've been looking at photo effects - light penetrates - there is even work showing effects of light on the brain (at 810nm redder than red):

So I've been wondering if photo exposure can change insulin sensitivity.. Does the light create ROS? (Inside the cell)..

Further OT:

Looks like there is a NO effect :

I am rather amazed that most of the photo research is on UV and vit-D - I can't find any narrow spectrum studies - surveys looking for possible effects - the microwave work was mostly about radio safety - a big gap as we move up to redder than red light..

Might not be via NO :

cavenewt said...

karl, re photo effects—

Isn't that Jack Kruse's bailiwick? I've never quite known what to make of his comments.

Frunobulax said...

Another post that is too long for one comment, shoot. Sorry, sorry, SORRY!

@Gretchen I'm pretty sure we can come up with some alternative theories for obesity, no problem :)

It seems that insulin is only one factor and we're missing parts of the puzzle. I always wanted to look up the mice that Gary Taubes mentions that will starve to death while staying fat, because their body won't release the fat for some reason. I really wonder if this is related to their lab diet. Would that happen in their natural habitat, or is it only because they are fed chow that contains something that throws their metabolism off?

On a very high level, it seems clear that some food (like n-6 PUFAs, possibly in combination with something else) causes us to convert more glucose to fat and store it in our fat cells, and at the same time prevents us from using that glucose for energy. Bottom line, people have to eat more (getting even fatter) or use less (lower base metabolism). So our fat cells appear to be perfectly insulin sensitive, if insulin is the key component here. But is the reason why the glucose is "rejected" in our muscles and diverted to the liver (-> triglycerides) really insulin resistance?

Let's assume for a moment the answer is "no" and go with Fungs idea that we're not insulin resistant. So all that comes now is a wild conjecture. But let's think it through. The idea is not that we get NOT insulin resistant (which would imply that the action of insulin is impaired for many cell types using insulin), but that only one specific pathway is impaired that is activated by insulin: Glycogenesis, the conversion of glucose to glycogen.

Now, again very high level (as I started to learn about all this stuff just a very short time ago, and still have a LOT to learn). I don't agree with Fung that insulin stops working because the glycogen stores are full, because this happens to people who eat undercaloric (but high carb). But another possible explaination is that the conversion from glucose to glycogen is blocked. Only so much glucose goes into the Krebs cycle at a time. A carby meal can give us energy for a day, but the blood glucose is down to something like 4 grams total after a few hours, when we have digested the meal. This works because we convert the (harmful) glucose to (harmless) glycogen, and back to glucose as needed.

So if we can't store the glucose as glycogen then we're in trouble. Just assume that glycogenesis is (partially) blocked for some reason, what would happen? Blood glucose rises, insulin rises. Eventually the high insulin levels would activate glycogenesis anyway, but until then the liver has converted a lot of the glucose to triglycerides already (because that pathway is not blocked). Sounds familiar? Most glucose goes to fat and is not available as energy. Insulin is still high, glycogen stores are empty, muscles need glucose (insulin blocks ketone production), we go hypo and need to eat again. Neoglucogenesis is probably running overtime but can't satisfy the demand, because our body is not designed to run on glucose manufactured from protein with no ketones to help out. (That would explain why neoglucogenesis runs in overdrive for many diabetics.) This all fits. Glucose and triglycerides do their damage in the pancreas, and eventually we'll have diabetes. For diabetics, insulin shots jumpstart glycogenesis and relieve the symptoms temporarily.

Frunobulax said...

If n-6 PUFAs are the culprit we don't need insulin resistance at all, because the PUFAs will accumulate in our bodies with time (in our fat tissue as per, plus Fettke says it gets used as building blocks for cell membranes, but I don't have a reference for that). So our body becomes a big PUFA store with time, boom! glucose metabolism is kaputt. Note that there could be other independent mechanisms blocking glycogenesis. Wheat contains WGA, a lectin that blocks insulin receptors ( and increases fat storage ( It could have the same effect as n-6 PUFAs, which would explain why the ancient egyptians, who ate bread, bread and more bread (yet no sugar) had a lot of diabetes (as per Mike Eades).

@Peter I admit that I have yet to read a lot of your posts. (Something that is very much on my todo list.) Could a low F/N ratio block glycolysis?

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

One excess "not" in that one sentence. Should be "The idea is that we get NOT insulin resistant"... Ah well, I'm fairly tired and can't edit that comment. Time for bed :)

But there is one thing I forgot. Calcium (cAMP) blocks glycogenesis, and both linoleic acid and arachidonic acid mess with calcium in our body ( Could this be the reason why n-6 PUFAs block glycolysis?

@karl I'm don't know anything about feedback loops, but I think we have two feedback loops here, conversion to glycogen and conversion to triglycerides. Glucose and insulin affects both, but they have different endpoints. I think it's more like a bathtub: Usually most water goes through the sink (to muscles) and only excess via the overflow drains (to lipid cells). But if the sink is blocked for some reason, most water is cleared via the overflow drains.

Peter said...

Hi again Frunobulax,

My own feeling as I re-ead the study is that these people are already on the way to obesity. While 1.7kg excess in a group size of eight may be ns, it might not be ns in group sizes of 30. That’s my take. I also consider that people learn their obesity at the family table, so avoiding long term obesity is hard if that is your background, but I accept that these are a pre-selected group of “potentially” obese people.


Some of the studies on the obesogenic effects of omega 6 PUFA clearly show that adipocytes (in that particular model) remain insulin sensitive when the whole mouse/rat becomes insulin resistant. I have blogged on this but nowadays the blog is so unwieldy that even I can’t find stuff half the time! It’s interesting to speculate that adipocytes might only become pathologically insulin resistant when exposed to high insulin concentrations. Adipocyte insulin resistance is absolutely not related to adipocyte size, though basal lipolysis is.


Over the years I’ve not looked in to NO very much. My impression is that it is more of a “downstream” signalling molecule from the ETC (complexes III and IV?), aimed more at maximising oxygen delivery rather than at fuel partitioning. Having said that I doubt anyone is as happy as me out in the sunshine once the UV come back. Getting close, here in the northern hemisphere!


I always struggled with Jack’s comments somewhat. He clearly has a very personal world view but I could never quite follow his thought processes right through. I have to say that nowadays I’m not really an omega 3 fan. A few mg per day, max the saturates and avoid the bulk of omega 6s seems good enough at the moment…