Thursday, June 29, 2023

Insulin sensitivity makes you fat. Insulin resistance makes you fat. Discuss. (02)

This is just a longevity study but it provides insight following on from my last post.

Let's just recap:

If we start in "control" state and switch to an insulin sensitising diet we have an initial sequestration of fat in to adipocytes and rapid weight gain, red bracket. As adipocytes distend they increase their basal lipolysis, which cannot be suppressed by insulin, and both fasting insulin and post prandial insulin levels must rise. If we fail to observe the initial acute insulin sensitivity phase and limit our observations to the rising insulin resistance phase (blue bracket) we could easily observe that elevated insulin levels are *associated* with future weight gain and assume, incorrectly, that there is causality.

On to the study.

The fat in the control diet is 15% soybean oil, so approx 7% of energy intake as LA. This is not a particularly low LA diet and, as you would expect, fasting insulin levels slowly rise throughout life.

All of the following graphs are extracted from Figure 2 section J, which looks like this

giving this as the control insulin levels:

The high fat (aka insulin sensitising, aka increased LA) diet substituted lard for some of the carbohydrate and was fed ad lib. We don't know how much LA was in the lard, but probably at least 10% of the lard calories were LA. We miss the insulin sensitising hypoinsulinaemic phase as it's long gone by 28 weeks of age:

If we take this graph at face value, at any given age the insulin value is higher in the rats which are fattest, so the logical assumption is that this is causal. QED.

EDIT: I have used my imagination to butcher the above graph back to week eight. Accept or reject at your own discretion!


But my contention is that these insulin levels are only elevated as a consequence of adipocyte size, ie the hyperinsulinaemia is a secondary phenomenon and could be eliminated by suppressing basal lipolysis, usually using good old acipimox. It works.

But acipimox cannot maintain suppressed lipolysis from distended adipocytes for more than a few hours.

Undoubtedly the most effective way of limiting basal lipolysis is to limit absolute adipocyte size. If we could maintain the adipocytes of the rats fed the insulin sensitising diet at the same size as those of the control fed rats there would be no "masking" effect of elevated basal lipolysis to hide the on going life long insulin sensitising effect of the obesogenic diet.

So they pair fed, by calories, exactly the same "calories" to a third group of rats so that they received exactly the same calories of insulin sensitising food as the chow fed mice eating ad lib.

These rats dis not become fat (I know, I know, heavy calories vs light calories, forgive me) and their weights exactly matched those of the control rats. So now we have rats with normal levels of basal lipolysis for age but no excess through eliminating "over eating" (stop sniggering) the amount of food which hunger, driven by excess insulin sensitivity, demanded in the "green-line" rats.

So the red line is the true insulin sensitivity of rats fed the obesogenic diet when not allowed to superimpose the increased basal lipolysis generated by becoming fat per se:

I hope this post complements the previous post and makes it completely clear that an insulin sensitising diet causes rapid sequestration of fat in to adipocytes. This lost fat will a) make you hungry, b) distend your adipocytes, c) increase their basal lipolysis and d) this latter will cause systemic insulin resistance.

This is a very basic and very simple to understand concept.

Aside: d) is core to limiting caloric ingress to cells when FFAs are available in the presence of insulin/glucose, which should not occur. You know, as in

which is a fundamental paper for understanding hyperinsulinaemia. Ignore at your peril. End aside.

What happens to make adipocytes insulin resistant (a late change in the words of Bill Lagakos, and I agree) is much, much trickier and then we're slipping in to Nick Lane territory.


Wednesday, June 28, 2023

Insulin sensitivity makes you fat. Insulin resistance makes you fat. Discuss.

My apologies for disappearing off of the blog, after the trip to Alicante and subsequent half term I got out of the habit of blogging and let the fructose thread go cold. I'll get back to it at some stage but this is what is currently making me think. Here we go.

I have a certain specific outlook on life which suggests that insulin sensitivity facilitates fat storage and insulin resistance limits fat storage.

The two anchor points to this world view are here

I think it is fairly reasonable to suggest that this is not a particularly popular point of view and that it may simply reflect my personal biases and my very selective view of the literature. While there are rodent data to support it, the overwhelming evidence from human studies is that insulin resistance/fasting hyperinsulinaemia are strongly associated with future weight gain. I'll cite the below study (let's call it the Odeleye study after the first author) in particular as it too is derived from the Pima Indians and actually mentions the second of my two anchor studies, link courtesy of Gabor Erdosi via Twitter

Fasting Hyperinsulinemia Is a Predictor of Increased Body Weight Gain and Obesity in Pima Indian Children

This is merely the tip of the iceberg and Gabor has many, many studies which show exactly the same finding. I'll stick a list of them down at the end of this post but we only need one for the purpose of my current discussion, the others give a flavour of how universal the finding is. I've not read all of Gabor's links but the titles alone give you the basic gist of their findings. I chose the Odeleye example as it's a Pima study contradicting my own favourite Pima study. It also leads us on to ventromedial hypothalamic lesions in rats, which I like. And the authors are a bit dodgy, which I also like. But there is a vast literature supporting their findings.

So here is the paradox:

Protons says:

Excessive insulin sensitivity facilitates excessive fat storage

and conventional wisdom says:

Insulin resistance makes you hyperinsulinaemic and this hyperinsulinaemia overcomes insulin resistance to facilitate excessive fat storage.

If we set this up as a simple dichotomy and assess evidence by the kilogram (once upon a time studies were published in *paper* journals. Getting a copy involved going to a library and paying 10p a page to photocopy them. You could assess likelihood of Truth by the weight of the paper used to publish. The "weight" of the evidence... Showing my age here) then clearly insulin resistance precedes weight gain. All one needs is insulin hypersecretion to overcome insulin resistance and you have obesity.

How does one tease out the explanation, especially when both directly contradictory concepts have the potential to be correct?

Let's go to the Odeleye Pima study and see what we can find. Here is this line in their discussion:

"However, our results are in contradiction to those obtained in adult Pima Indians in whom insulin resistance and high insulin secretion were associated with a lower weight gain (7,8). Reasons for the discrepant results among studies in children and adults remain to be clarified."

which is as true today as it was in 1997.

In rodent derived support of their findings in Pima children they mention

"These results [in Pima children] are consistent with those in animal studies in which hyperinsulinemia precedes an increase in body weight. In rats, lesions of the ventromedial hypothalamus result in hyperinsulinemia before excess weight accumulation (26)."

giving us, as ref 26, this study:

Unfortunately this study says nothing of the sort. From the abstract 

"One week after the lesions, total glucose metabolism was more sensitive and responsive to insulin than in age-matched controls."

and from the discussion

"Thus, for a similar increase in plasma insulin levels (i.e., +100μU/ml over basal insulinemia) VMH-lesioned rats actually showed a 92% reduction on hepatic glucose production, while such percentage inhibition was only 46% in control rats (Fig. 1)."

Aside: Also, by six weeks this enhanced ability to suppress hepatic glucose output of week one was severely compromised in the VHM rats. Secondary to adipocyte distension and increased FFA release in my opinion. It is essential to distinguish primary from secondary effects. End aside.

and from Table 1 we have

This is the best rodent study that Odeleye's group could find. I'm afraid their contention that hyperinsulinaemia precedes weight gain is simply not supported by the study they provide. Fasting insulin of 111μU/ml is neither biologically nor statistically different from 94μU/ml.

which was available at the time and is even less supportive of their statement

but they didn't. I said they were a bit dodgy! Made me giggle anyway.

There are a number of other fascinating snippets in the rodent studies but I'm wandering and so will try to get back on topic.

Just before I move on to what is actually happening I'd like to throw in the insulin section of Figure 1 from my first anchor study. Pre-obese people are particularly insulin sensitive. I've always cited Table 2 which has HOMA-IR scores to show this. It is quite possible to argue that these fasting data do not represent the dynamic effect on insulin levels in the period after a meal and that post prandial hyperinsulinaemia could easily negate the effect of the fasting values. Luckily for my position the study also fed a mixed meal and tracked insulin levels for six hours following the meal. Like this:

The pre-obese, excessively insulin sensitive people are consistently and significantly hypoinsulinaemic cf controls for at least six hours after a mixed meal. Nice.


People at significant risk of obesity are consistently hypoinsulinaemic cf controls, in both fasting and post prandial states.

You can model this by inducing an hypothalamic lesion in rats.

You can model it by high level neonatal MSG exposure in rats

You can model it by the feeding of linoleic acid in rats.

What's happening?

This is my summary:

The time scale might be in weeks for a rodent model changed from chow to a high linoleic acid diet or years for an human neonate given his first bottle of soybean oil based infant formula soon after birth. The intervention might be even further back if his mother has been heeding a cardiologist's advice to limit saturated fats and substitute with polyunsaturates.

Okay, that's really the end of the post but here are those human observational studies. My assumption is that they are *all* observing the blue bracketed section of the graph labelled "Slowing weight gain".

I have absolutely no doubt that their data are accurately reported. I have serious doubts that any of the authors could explain the left hand end of my graphic. Which is also correctly describing reality. Any hypothesis must explain all the data. Both aspects are correct.

All links via Gabor, much appreciated.

Insulin resistance as a modifier of the relationship between dietary fat intake and weight gain _ International Journal of Obesity

Long-Term Change in both Dietary Insulinemic and Inflammatory Potential Is Associated with Weight Gain in Adult Women and Men

A longitudinal study of serum insulin and insulin resistance as predictors of weight and body fat gain in African American and Caucasian children

Ten-year weight gain is associated with elevated fasting insulin levels and precedes glucose elevation

Pre-teen insulin resistance predicts weight gain, impaired fasting glucose, and type 2 diabetes at age 18–19 y: a 10-y prospective study of black and white girls

Acute Postchallenge Hyperinsulinemia Predicts Weight Gain: A Prospective Study

Long-Term Change in both Dietary Insulinemic and Inflammatory Potential Is Associated with Weight Gain in Adult Women and Men

Insulin resistance as a modifier of the relationship between dietary fat intake and weight gain