Sunday, November 03, 2019

Insulin makes you hungry (10) Processing

I picked up a link to this paper from an image of a table, somewhere on Tinternet. I didn't realise which paper it was. It was really interesting from the metabolic point of view and I kept looking through the results section to find the post-prandial metabolic effect of ultra-processed foods vs unprocessed foods. You know, the effect which might determine where the calories from a given food might end up, either available for metabolism versus lost in to adipocytes.

Ultra-Processed Diets Cause Excess Calorie Intake and Weight Gain: An Inpatient Randomized Controlled Trial of Ad Libitum Food Intake

This is from the introduction

"Ultra-processed foods may facilitate overeating and the development of obesity (Poti et al., 2017) because they are typically high in calories, salt, sugar, and fat (Poti et al., 2015) and have been suggested to be engineered to have supernormal appetitive properties (Kessler, 2009; Moss, 2013; Moubarac, 2015; Schatzker, 2015). Furthermore, ultra-processed foods are theorized to disrupt gut-brain signaling and may influence food reinforcement and overall intake via mechanisms distinct from the palatability or energy density of the food (Small and DiFeliceantonio, 2019)"

What this is saying is that making foods high in calories + "supernormal appetitive properties" makes you eat more, so you become fat. And that they alter gut brain signalling to increase "reinforcement" and so increase intake. You have to put the excess calories somewhere so you get fat.

Supernormal appetitive properties. Energy density. Reinforcement.


But the bottom line is that highly processed foods do produce steady weight gain over two weeks and low processed foods do the opposite.

What we need to know is how a given food affects both the acute and chronic metabolic response, especially insulin levels and signalling. That's not going to come from the psychobabblers.

Luckily there are groups with an interest in the metabolic effects of food, rather than being lost in un-Rewarding theories of reinforcement. Like this group:

Does food insulin index in the context of mixed meals affect postprandial metabolic responses and appetite in obese adolescents with insulin resistance? A randomised cross-over trial

They compared two meals with the same low glycaemic index (GI) but differing insulin secretion indices (Insulin index, II). Both meals had very similar macros and they look suspiciously like processed vs unprocessed. Insulin (and glucose) were higher after the high II meals:

The low II meals generated less hunger in the post prandial period. I'm not sure what hunger has to do with weight gain, I get the impression from people like Hall et al that calorie intake controls weight gain. Hunger is something else, will-power dependent maybe.

The second study has some problems too. The low II food did not taste as good as the high II food. So Rewarders have a lifeline here. And if you are making a marketable commodity to be labelled as "food", anything you can do to increase its palatability is going to improve sales. If palatability should turn out to be intrinsically linked to a food's II then you are set to drive hunger combined with those increased sales. Win-win for the shareholders but not so much for the consumers. No one wants to be fat. Equally, no one can tolerate being hungry...

The second problem is that there was no increase in food intake for the high II group during the end-of-study buffet. An increase in food intake here would have been nice, to corroborate the increased hunger. But that meal was a free choice buffet being offered to people who were already obese, so poor food choices may well have over-ridden the differences in experimental meal induced hunger. Back in the days of better designed studies the post-insulin test meal was a uniform soup-like liquid, consumed via a straw through a screen so there were no visual or food choice cues to influence food intake. A pity, but there you go.

Insulin makes you hungry. Not directly, but by diverting calories in to storage. You lose those calories so your brain gets hungry. Making you fat is how insulin makes you hungry. Pure CICO but the calories-out go in to your adipocytes...



altavista said...

What diets did they use in the 2nd study? It's behind paywall

Peter said...

You have mail


raphi said...

Gabor Erdosi commented:

"Not only insulin, but also GIP correlates well with satiety, in that their postprandial iAUC strongly influences (reduces) food intake during the following meal.
Insulin dynamics alone is totally insufficient to explain hunger. I believe that’s a cup-de-sac.
The role of postprandial releases of insulin and incretin hormones in meal-induced satiety—effect of obesity and weight reduction"

I replied:

"Good point.

Reading the abstract, they mention << In lean subjects ad libitum energy intake was largely predicted by the insulin response to the preceding meal (r2=0.67, P=0.001) >> What do you we observe that in lean but not fat subjects because the fat ones are already diverting a large proportion of calories into their adipocytes? And thus not showing an increase in hunger? (they're 'excessively' hungry by default)

altavista said...

Funny that in the context of a 233% more insulinotropic meal, the pancreas does not bother to produce more insulin for 6 hours!! using its reserves instead. That c-peptide chart is scary. Terminator-scary.

Peter said...

Hi raphi and Gabor too,

Interesting paper. I think we have to be very careful as it is a piece of pure observational reporting, certainly for the lean group. As such it can suggest an hypothesis, say that insulin exposure suppresses appetite at the next meal, but we cannot assume that the correlation presented represents what the effect might be of actually manipulating insulin levels on subsequent hunger might be. This was not done.

Happily this hypothesis has already been tested without the confounding variable of meal ingestion/absorption to cloud the issue of what insulin is actually doing. The finding is that insulin, when infused with or without hyperglycaemia, increases spontaneous food intake at the end of the infusion period. The group even checked whether isolated hypoglycaemia, without insulin elevation, increases appetite. It doesn’t. Rodin did the work in 1985. I find is entertaining.

Quite why Prof Astrup found what he did in his lean group is a fascinating area to speculate in but I don’t think we can take an observational study as an indicator of causation of anything. The beauty of Caferoglu’s work is that it was a crossover study, ie the people were metabolically identical at the time of meal presentation so acted as their own controls and the only variable was the duration and size of the insulin effect of the food, which was deliberately manipulated as a specific variable. An intervention study.

I have a lot of respect for Astrup since he came out on the side of butter during the Danish fat tax fiasco but correlation is not causation… Not that he suggests it is.


raphi said...

Gabor's reply:

The reason I disagree with Peter here is the study design. It’s not continuous hypoglycemia/glucopenia and/or hyperghrelinemia that lead to the post-meal hunger feeling, rather the opposing TRAJECTORIES. So the devil is in the dynamics, that’s how the brain integrates nutrient and hormonal signals. Basically, the two graphs above have to be integrated into one where glucose and ghrelin curves steeply cross each other. See below study. It’s basically how the refined carb roller coaster works and can override the direct satiating effect of both GIP and insulin. This is also apparent from the food order studies by Shukla et al. where a carb first meal results in higher glucose, higher insulin, the latter mediating a much quicker drop in glucose. Accompanying ghrelin is attached.
Glucose availability predicts the feeding response to ghrelin in male mice, an effect dependent on AMPK in AgRP neurons

raphi said...

the graphs Gabor is referencing can be seen here (need to join the Nutrita Community FB group)

Alex said...

Hi P.,

saw this and thought of you. Cardiolipins, LA and mitochondria...all the goodies in one bag

best of luck

altavista said...

Insulin makes you hungry, but fat makes you depressed :)

Peter said...

Hi raphi and Gabor too,

Can’t see the graphs yet.

While Shukla et al are interesting the paper contains nothing about satiety or late post meal food intake. Assuming we’re looking at It’s also interesting that Shukla, like everybody else, failed to measure FFA levels under the hyperglycaemia induced hyperinsulinaemia from the carbs-first meal. Insulin will suppress FFAs. Trying to decide what drives hunger when FFAs are not even considered is going to lead to errors.

Sadly I fail to understand the problems with Rodin’s study. If insulin were miraculously a satiety hormone, does that only work when all sorts of other things are happening? Other things which might be the explanation of satiety, rather than the insulin? I also need a clearly laid out explanation for why, when steady state elevated insulin makes you hungry, how exactly it is a satiety hormone. What exactly (apart from the result) is wrong with the study is beyond me I’m afraid. My only problem with Rodin et al is they too did not measure FFAs under steady state hyperinsulinaemia. Hint: FFAs went through the floor. The brain will notice this.

I have absolutely no doubt that AgRP and similar neurons are crucial to appetite. That they sense both glucose and FFA availability and I predict that they will do the sensing absolutely via ROS generation through the metabolism of these substrates. I think it is an open question whether the ROS generation will be facilitated by insulin. I have seen no convincing evidence that insulin is a satiety hormone. I would grudgingly accept it might, maybe, facilitate the ingress of calories to AgRP neurons to generate the ROS signal. One day I’ll get around to checking this but for now peripheral energy availability is clearly monitored by the brain and peripheral energy storage (lost to the brain other than by leptin signalling) is very, very highly driven by insulin.


Peter said...


That is a study which is going to hurt a lot of people! I wonder if they got pay dirt because lard is relatively high in omega 6 PUFA? I also wonder if they adulterate their pork fat with cotton oil to make lard, the way some countries do?


Peter said...

Alex, just took a peek, looks good!


Peter said...

Alta, re C-peptide. Yes, I looked at that and thought thoughts about hepatic insulin resistance and elevated insulin due to poor hepatic insulin extraction. Or they have a duff assay!


karl said...

Sometimes it might pay to actually ask people why they eat so much. Talk to someone that is carrying an extra 50kg[110lb] - they really don't like being fat, they have been told they have a moral failing - but if you actually ask - they feel incredibly hungry - seek out carbohydrates. They feel cold and lethargic if they stop eating - even with 50kg of available fuel.

If you get out of the blame-the-patient-mode and can look at this as an over-storage problem, everything makes sense.

I think we have to look at what I would call the storage product insulin-sensitivity*insulin. While we can measure insulin(not perfect - changes rapidly) measuring the insulin-sensitivity of adipose tissue appears out of grasp.

The only bit that seems to explain this is the protons - If some epidemiologist would only dig up the import numbers of seed oil vs T2D in various countries -(there should be some time lag).

I suppose looking at a further point - when did they start feeding pigs and chickens imported corn would be needed as well.

OT: IMO the prevailing narratives about why humans have no fur are just hand-waving crap so I've been digging up things about this - I'm thinking about photo-chemicals products in the skin - no one has done the basics here - the loss of fur appears to have happened when our brains kicked in to overdrive. Our brains make us unique in needing a huge amount of energy. Skin produced photo-chemicals we know about - Vit-D - melanin - I suspect there are several other photo-products waiting to be discovered...

Why do the drugs melanotan(Afamelanotide), melanotan-II, Bremelanotide all analogues of the peptide hormone α-melanocyte-stimulating hormone (α-MSH)) effect our brains?

But I don't think it is a big jump to think it likely there are other important photo-chemicals. The correlative Vit-D studies are used with faulty logic to give causation to just Vit-d - what if the Vit-D level is also an indicator of solar exposure which produces other bits?

One of the receptors MC4R appears to be connected with obesity "Defects in MC4R are a cause of autosomal dominant obesity" and insulin sensitivity.

melatonin modulates of the synthesis of melanin - why so many brain connections with a photo-product?

Peter said...


Yes, people get fat because they are continuously hungry. Their food choices make them hungry. Dietary advice promotes wrong choices. Core blame clearly goes to the cardiologists nowadays but anyone promoting sugar and starch plus PUFA substitution of saturated fats must carry the blame too. I see hunger as central.


altavista said...

Don't blame the lard and admit you were wrong all along. It's hard enough to find any satfat studies as is :)
Also admit evolution is not that stupid to hand your life to a 1-cell endothelial layer.
Or the second decimal from 0.47 to 0.49 :)

Alex said...


@ "...adulterate their pork fat with cotton oil..."

The content of omega6/PUFAs in lard depends on the animal's fodder. Maybe on the breed as well? I should think the fodder changed significantly in the last 60-70 years. More grains, more LA.

I rather think they just don't know the content of LA or don't care. Ppl are in general more ignorant than treacherous. Just bad science.

altavista said...

Alex, that test is bs IMO. There is a comment in an old post somewhere, that actually mice cognitive function improved, that's why they stayed calm. So you can spin it either way :)

cavenewt said...

Alex re "...adulterate their pork fat with cotton oil..."

it's not just animal feed, at least historically. Starting in the 1800s, lard was adulterated with cottonseed oil to make it less expensive. See Tucker's blog about this; scroll down to the section "Timeline of introduction of seed oils".

annlee said... Dr Cywes offers an interesting look at the interplay of glucagon and insulin in this. For those not familiar with him, he is originally South African (Prof Tim Noakes was one of his teachers!), and practices pediatric bariatric surgery these days in Florida, USA. He works hard to avoid cutting - but will if it helps the patient and nothing else will.

His first session with them is here -