Fasting insulin and weight loss and calories-in vs calories-out

I had this exchange in the comments on a previous post:


Frank said...

Hi Peter.

I'd say that I pretty much agree with your post. Insulin and caloric deficit are not mutually exclusive, ie, low-insulin could enhance fat loss on a caloric deficit or, looked from another perspective, a caloric deficit could enhance fat loss if someone has low insulin level. 

I have only one question for you. For the sake of it lets make thing black and white. 

What do you believe is the most important thing to do, in order to achieve weight/fat loss 

a) be in a caloric deficit (your insulin level does not matter much) 

b) having a low-insulin level (it does not matter much if you're in a caloric deficit or not). 

Again, in real life, I don't believe they exclude each other, but if you could fix only one to have a weight loss, which one would you fix? Calories or insulin? 

The way I see it is that, as you stated, insulin inhibits lipolysis, but more lipolysis does not equal more oxidation. It still has to be matched to energy expenditure. In that case, calories would be the most important factor. That's my point of view and it could be wrong. 

I'm just wondering if you agree to some degree with it, because reading your post, I get the idea that you do. 

Thanks for your time.


Peter said...

Ah Frank, now there is a question.

Without caloric deficit (and I want uncoupling proteins, sleeping metabolic rate, spontaneous movements, etc, etc, etc, everything, accounted for) there will be no weight loss.

But, in real life, if I could only alter just one, it would be insulin.

I would expect no weight loss but I would expect improved health.

What else matters?




There is a flaw in the answer I gave to this question. It's working at the Noddy level of calories-in vs calories-out.

The Noddy approach is perfectly adequate to explain the findings of GnK's paper (PR's weight loss excepted, if she genuinely ate all she was asked to), but embarrassingly stupid in the real world.

Let's look at calories-in vs calories-out in the fixed caloric phase of the Abredeen study.


Calories-in is total calories in to metabolism. There are two sources. Those from the diet, let's assume (incorrectly) these are genuinely all of the 2000kcal/d on offer. Then there is the supply of free fatty acids metered out from adipocytes under the regulation of insulin. Maybe a little glycogen, but I'll ignore that for the discussion.

Under LCHF conditions more FFAs are accessible due to lower insulin levels. More get used and, from Table 1, only 1930kcal of food are needed to supplement those calories-in from adipocytes in order to meet total metabolic needs. Hunger is low. Calories supplied are clearly able to meet voluntary calories out. Demand is within the limits of supply. Some food is refused.

Under MCMF conditions the higher insulin level allows less calories to be supplied from fat in to metabolism (adipose derived calories-in fall), so calories-in accepted from food spontaneously increase to the full 2000kcal/d. Under the study conditions we cannot tell if 2000kcal plus reduced adipose FFA supply is enough for as much metabolic activity as was possible under low insulin conditions. What if it is not? Now the real question is: Does lipolysis automatically increase to supply all needs for calories out? Why should it? Lipolysis is controlled by insulin. Insulin is high, lipolysis restrained.

If there is any shortfall in the calories from fat plus 2000kcal, there are only limited calories available to burn. You can't burn what you don't have. Calories-out would drop because they simply cannot exceed the supply available. I would expect the participants to automatically reduce their calories-out. There is no free lunch. Calories-out = calories-in. All need to be accounted for.

Is it be possible to force lipolysis in the face of hyperinsulinaemia to increase FFAs from fat to a higher level without lowering insulin?

Of course it is. There are other hormones in addition to insulin. You can throw around adrenaline, growth hormone, glucagon and probably a truckload of others I've not thought about. You can add in direct sympathetic nervous system innervation of adipocytes to effect lipolysis if you like. But these mechanisms come with a price. The price is hunger.

I think it's called working up an appetite.




In the Aberdeen study the attempt to maintain caloric intake failed during the LCHF phase because low insulin increased caloric supply from fat. Higher insulin in the MCMF phase limited calories-in derived from adipose tissue and may well have set a cap on total calories available for use during this higher insulin phase.


In Frank's thought experiment it might be easy to fix dietary calories-in, but people might refuse some of them if insulin was low enough for adipose tissue derived FFAs to be available.... If they ate all of their calories but wriggled in their chair a bit more because they had more calories available then the concept of calories-out being fixed is lost....



I'll just finish with a clarification of this phrase from another commenter:

"lipolysis is not beta oxidation"

This is, ultimately, accurate. That doesn't stop it being bollocks.

A rather more perceptive view is the situation comes from, of all places, the lipophobic cardiologists who published on FFAs and myocardial ischaemia:

"The rate of fatty-acid uptake and oxidation by the heart is controlled by their availability [33]"

Oh, interesting. Availability. A supply led system. Hmmmmmm. I would guess most FFA burning tissue would follow cardiac muscle. Now I can't quite remember what effect insulin has on lipolysis and FFA availability. Silly me.

Peter

Hepatic insulin resistance in KD fed mice

Let's look this abstract. Thanks to Liz for the full text.

The key quote is, of course:

"In conclusion, despite preventing weight gain in mice, KD induces hepatic insulin resistance secondary to increased hepatic diacylglycerol content. Given the key role of nonalcoholic fatty liver disease in the development of type 2 diabetes and the widespread use of KD for the treatment of obesity, these results may have potentially important clinical implications."

I'm not sure what the word for a collection of idjuts is. A moronity?

Despite this the data are very interesting.

Look at those hepatic diglycerides, up 350%!!!!!!

Failure to suppress hepatic glucose output. Not just reduced, but reduced to zero percent suppression. Zero percent!

Wow, are these mice gonna die of diabetes, fatty liver, metabolic syndrome, Spawn of Satan induced inflamasomation.... Okay, I'll calm down now.


These mice are running their metabolism on a combination of free fatty acids and ketone bodies. What would you expect their liver to be full of? Sugar?

Glycogen?

Maybe fatty acids?

Well, in ketosis FFAs come from transport by albumin or release by lipoprotein lipase as exactly that, free fatty acids. They are not stored in this form, they are re-esterified to triglycerides for hepatic storage. The 350% increase in diglycerides is not from being swamped with diglycerides exogenously. They are generated in situ specifically to stop the liver responding to insulin.

These mice have no source of dietary glucose. They are generating and outputting small amounts of glucose from their liver, despite extreme protein restriction, to keep their blood glucose levels compatible with life. Possibly from glycerol.

Then some joker comes along with an insulin infusion. What would happen if their ability to trickle out glucose actually did suppress in response to this malevolent tease? Death would ensue in a few minutes without a rescue glucose infusion as is needed for the mice on CIAB. Hepatic diglycerides are generated to stop the liver responding to insulin when survival makes this an absolute necessity. It's an absolute necessity under extreme ketosis conditions, even without the joker with a bottle of insulin.

To get a breath of KetoSanity we can go back to the paper by Maratos-Flier's group (thanks to John for the heads up on this "non conformist").

These folks didn't look at diglycerides but they did measured the liver triglycerides and found they were nearly twice those of the mice fed crapinabag. Gasp! Fatty liver is where it's at. But these folks did a little histopathology too, using PAS to stain for glycogen. As they say:

"PAS staining showed decreased glycogen deposition in KD animals vs. both HF- and C-fed groups (data not shown)"

If your liver is glycogen depleted what, exactly, should it have as an energy store? Thin air? A small nuclear reactor?

Maratos-Flier et al understand exactly what is going on and see no need to trot out hysteria about ketosis generating a fatty liver which is physiological. It has nothing to do with fatty liver under a carbohydrate based diet.

Now, what would happen if we increased the carbohydrate content of the diet to 15% of calories in the same way as Axen and Axen did in their 2006 blooper?

Ketosis would stop and hepatic insulin sensitivity would return. Probably within three days and certainly within the three weeks A & A allowed. The diglycerides would be gone. Probably so would the bulk of the triglycerides. Under these conditions carbohydrate would clear the fatty liver.

Would the mice be diabetic? You've got to be joking.

So why does carbohydrate restriction improve fatty liver in humans? I would suggest the lack of de novo lipogenesis due to fructose reduction coupled with chronically lowered insulin allowing VLDL output to clear the excess of hepatic triglycerides. The situation is completely different.

I doubt many LC dieters would push themselves to the ultra extreme of the diet enjoyed by these KD consuming mice. If they did, their hepatic lipids, especially diglycerides, would have to increase to produce an utterly essential survival gift of hepatic insulin resistance. Their hepatic triglycerides would rise too.

I think it's an open question about whether placing yourself at the very extremes of physiology is a good or a bad thing. It should certainly assist weight loss, but would it improve health? Interesting question.

Peter

Fasting insulin and weight loss on a water fast

I think we have to be very careful with the term fasting insulin.

If we read, in a clinical paper, that fasting insulin level was X iu/ml it is perfectly reasonable to assume that this level simply reflects the carbohydrate content of the diet over the two or three days in the lead up to the blood draw. You only have to look at Grey and Kipnis' paper to see that, independent of weight change, fasting insulin can be simply dialed by adjusting the macronutrient ratio. It can be dropped from 40 microIU/ml to 10microIU/ml and cranked back up to just over 50microIU/ml, each shift occurring over a few days:



If we go to a rather better conducted study we can look at the effect of starvation on fasting insulin levels. What happens if you live on water for 5-6 weeks? Well, I guess it's obvious that body weight drops. Here are the clinical data for the eleven volunteers:



I worked out the average weights at the start and end of the study. The drop was from 135.8kg to 115.6kg, something in the region of 20kg of body weight. Obviously some of this would be glycogen, glycogen-water and muscle, but a big chunk must be fat.

What happens to fasting insulin?



Well, there are three different "fasting" insulins on this graph. The first is 45microIU/ml. This is the fasting insulin on the normal diet of an obese person. Second is about 38microIU/ml, after restriction of carbohydrate to 300g/d with caloric intake at 2500kcal/d. The third is between 20 and 14microIU/ml, achieved after three days total fasting and this level basically doesn't budge over the following 6 weeks, even though bodyweight drops by 20kg.

This later value is a great deal higher than a non obese person would have under prolonged fasting conditions and remember that the people in this study are preselected as having failed on every diet they have ever tried and they are willing to undergo the risks of a prolonged water fast. They do not appear to be hyperinsulinaemic as a consequence of their excess weight if a 20kg acute weight loss has no effect on blood insulin levels.

The blood glucose normalises within three days of the start of fasting. At this point physiology's role is to control hepatic glucose output. All tissues which use glucose via insulin should have stopped accepting glucose to spare it for the brain.

In these people the level of insulin required to do this in the region of 10 times that of a spontaneously slim person.

Obviously, if you perform a cross sectional observational study of fasting insulin vs bodyweight there will be a positive correlation between the two variables. It is a perfectly valid hypothesis to propose that obesity CAUSES hyperinsulinaemia. Equally, if you are as stuck in the rut of fasting insulin inhibiting inter-meal lipolysis as I am, it would be perfectly reasonable to hypothesise that people with the highest fasting insulin are the fattest because hyperinsulinaemia CAUSES obesity. Both are potentially valid explanations of the observation.

Who would lose weight fastest on a water fast?

Calories in, calories out... Obviously calories-in during starvation is solely supplied by lipolysis and protein breakdown, once glycogen is depleted. With a BMI of 50kg/m2 "calories-in" from fat breakdown are essentially unlimited, if they happen to be metabolically available. So weight loss should be determined by basal metabolic rate plus exercise/spontaneous movement. A fat person should have a slightly higher basal metabolic rate just to run the support tissue for moving their fat around, even if the fat itself has a relatively low metabolic rate. You must also remember that an overweight person is like me doing a squat with 60kg on my back every time they sit down and get back up again from a chair. So on both of these counts you would expect the fattest people to have highest "calories-out" and so lose weight more rapidly than less obese people.

They don't.

I data trawled and carefully selected choice points from table 1, discarding the half which don't fit the line. I used the blokes only. All is forgiven Dr Keys. Plotting weight loss against starting weight gives a crude (negative) correlation for men. Let me be the first to admit that the relationship does not hold if you include the female subjects. Life would have been easier if we had been given individual starvation insulin levels, rather than having to take bodyweight as a rather crude surrogate. The three women outliers who ruin the plot are, interestingly, short stature.

Here's the plot for the men:




On a water fast the higher your starting weight (surrogate for "fed" fasting insulin, remote surrogate for "starvation" fasting insulin), the less weight you lose over 5-6 weeks.

Elevated insulin is associated with obesity BECAUSE it inhibits lipolysis.

Maybe there are other explanations. I just can't see them. None as blind as...

Peter



Of course addressing what causes elevated fasting insulin and why it doesn't normalise on prolonged fasting is a whole new ball game. People should look in to it. Carbohydrate restriction obviously gets you part way to sorting the problem. It side steps it rather than curing it. I have said this before.