Insulin, Weight Loss & Water Weight

Reader kds posted a link to this Peter of Hyperlipid's blog post about the following study:  .Beneficial Effect of Diazoxide in Obese Hyperinsulinemic Adults

Basically, diazoxide is a compound that has been used to treat hypoglycemia and reduces insulin secretion.   Two groups of 12 obese hyperinsulinemic adults were treated with diazoxide or placebo for 8 weeks while each consuming the same Optifast diet.  Compared with the placebo group, DZ subjects had greater weight loss (9.5 ± 0.69% vs. 4.6 ± 0.61%, P < 0.001), greater decrease in body fat (P < 0.01), greater increase in fat-free mass to body fat ratio (P < 0.01), and greater attenuation of acute insulin response to glucose (P < 0.01).   This is pretty phenomenal and difficult to fathom -- almost twice the weight loss.  It was also reported that there was no significant change in resting energy expenditure (REE, RMR, BMR), and substrate use, as derived from indirect calorimetry, did not reveal any significant change in carbohydrate or fat metabolism in either group.  IOW, there was no stimulation of fatty acid oxidation accompanying the proposed decreased lipogenesis (presumably they're referring to esterification not de novo lipogenesis) and/or increased lipolysis (as evidenced by increases in FFA/NEFA levels).

Now, some may accuse me of rationalizing, but for all the claims I may disagree with, I have yet to see any of the "experts" -- even Taubes and Eades and the MA crowd -- imply that fatty acids can magically be "flushed" from the body without being "burnt" off (beta oxidation).  The only way out is for the LCFA to be broken down ultimately to CO2.  Therefore, there HAS to be an explanation here because insulin is not a magic molecule capable of creating or destroying matter.  If the diazoxide (DZ) didn't lead to increased fatty acid oxidation, and REE was unchanged, then likely futile cycling and uncoupling were not involved either -- these would cause increases in both FA oxidation and REE as they "blow off" or "waste" fatty acids.

So ... where did the fatty acid mass go?
 They HAVE to go somewhere, and if non-oxidized, the FFA's themselves have a constant mass so simply release of the FFA into circulation or storage elsewhere would not alter weight.   What would make a difference, is the water associated with said fatty acids and/or the tissues/cells in which they are contained.  

I came across two papers that are interesting in this regard that I'm not entirely sure constitute a cogent hypothesis, but offer some possibility that this may well be what's going on.  

Changes in abdominal subcutaneous fat water content with rapid weight loss and long-term weight maintenance in abdominally obese men and women

Water content of abdominal subcutaneous adipose tissue increases with weight loss in obese persons with the metabolic syndrome, and may reflect increased subcutaneous fat tissue nutritive blood flow. The increase in water content correlates with the increase in insulin sensitivity, suggesting that weight loss and consequent improved insulin sensitivity could mediate the increase in abdominal subcutaneous fat hydration.
So increased insulin sensitivity -- which increases insulin action on adipose tissue --  can cause greater hydration of fat tissue - e.g. increase fat mass.  If the work of Sims cited in GCBC is correct, and carbs increase insulin sensitivity in adipocytes this could perhaps explain why in the short term (the time frame of the above study was 9 weeks weight loss followed by 1 year maintenance) we often see differences in weight loss  exceeding the glycogen depletion differential.  I've posted before how low carb in effect mimics adipocyte IR (excessive NEFA release) so maybe this is also at play.

In the DZ study the authors discuss that DZ can directly impact adipocytes as well as to reduce insulin levels which would mimic decreased insulin sensitivity if sensitivity of the adipocytes is not improved.  If this is the case, the placebo group conceivably had increased water content in the fat = greater "fat mass" while the DZ group had the same or even further decreased water content in the fat = lesser "fat mass".  Interestingly several of the DZ group experienced edema.  That might seem to counter this hypothesis except that perhaps some of the water liberated from the fat tissue in the DZ group collected in other tissues, but still some may well have been excreted.  As I said, this kind of thinking off the top of my head, but it is a plausible explanation for that which MUST be explained!

Adipose tissue contribution to total body water has been generally disregarded be cause its water content per unit weight is less than one-fifth that of the traditional "lean body mass." Indeed Pace's formula defines the "lean body" as containing all body water (16). Such a formulation was useful when adipose tissue formed a minor percentage of body weight, and when body composition measurements in vivo were limited to indirect estimates, such as skin fold thickness and body density. The advent of fatter populations, and of more varied and to some extent more direct measurement techniques have disclosed significant water, primarily extracellular, as sociated with adipose tissue. Widespread interest in obesity as a disease state, and in body composition measurements in obese patients, as well as a gradually fatter "normal" population, have motivated a new experimental look at the water phase of adipose tissue, and based on these measurements, a new model for adipose tissue in man.
Some acronyms used:  TBW = total body water, AFM = adipose free mass, AT = adipose tissue, ECW = extracellular (between cells) water, ICW = intracellular (inside cell) water.  The water content of AT is ~14% of which ECW is ~11% and ICW is ~3% for an ECW:ICW ratio of ~3.5:1 .  The water content of AFM is ~79% in on average for all,  but the distribution of ECW:ICW differs considerably in obese v. lean:  ECW ~33% vs. ~24% in obese v. lean for a ratio of 0.76 for obese v. 0.42 for lean.  The ratios and distribution varied widely with ECW related to degree of obesity and ICW varying inversely.

What all this says to me is that, especially short term, a lot of body composition analyses are really to be taken with somewhat of a grain of salt.  Any general "diuretic effect" that would impact extracellular water content would disproportionately influence both fat mass (FM) and fat free mass (FFM/LBM).  Given the differences in the ratios, greater losses of ECW would skew FM losses more, especially when FM is considerable.  

Again, I've not done an awful lot of mental math gymnastics here, but I think water weight has been both under and over estimated.  On the one hand, to some extent, weight is weight and volume is volume.  If I can shrink my fat by decreasing ECW, I'm all for it!!!  If moving FA's from fat cells to, say, muscle cells influences my water distribution in an aesthetically pleasing manner, I'm all for it with a few reservations on the whole lipotoxicity thing.  But, especially in the obese when we're talking tens of if not hundreds of pounds of excess weight, water sure does make up enough of the equation to explain just about any anomaly we see in any short term study or even longer term one where relatively minimal losses are involved.   Water is ~14% of fat tissue and ~79% of fat free tissue.  When the former is relatively low, that's one thing, when it's high, it can be a different story.  I'm sure in addition to gains and losses, there are shifts that are included in the measurements of fat tissue and lean mass.  


LynMarie Daye said…
Take a look at this:

Diazoxide didn't appear to have any effect on weight loss in the above study. No free full text though to compare and contrast :`(
Nigel Kinbrum said…
Is it possible that the treatment group felt better than the placebo group and increased kcals out via increased Exercise Activity Thermogenesis & NEAT?
CarbSane said…
@Nige: I'm thinking not because this should have shown up with increased carb or FA oxidation to "fuel" that activity.

@LMD: Good catch ... I'm gonna make a "hard copy" run soon and will add that one to my list. I have some other issues with the study in this post, but wanted to focus on water weight possibilities. In that study the deficit was constant, in this one the caloric intake was constant for all. Does that make a difference?
fredd said…
What is your take on water weight lost during diets (more specifically, the start of them)? People often see rapid weight loss of up to 10lb (~4.5kg). Would you say this is water weight lost from both muscle, liver and fat?

Doing the numbers, we have:

400g muscles
100g liver

Assuming a maximum of 4g water stored per gram of glycogen, we have a maximum of 500x4 + 500 = 2500 grams of weight lost from glycogen/water loss. Note that this is maximum, and a lot of people would not completely deplete their muscle and liver glycogen, so I am a bit skeptical about this.

So we have 2.5kg of the 4.5kg we see. So now we have water in fat tissue... would we be losing 2kg (~5lb) of water just from fat tissue???
CarbSane said…
I think these very large losses tend to be experienced in those with a lot of extra weight to lose, and -- this is anecdotal -- generally in those with excessive trunk fat. But when folks re-start induction to "break a plateau" and such, they often don't see the same thing. Also, I've seen many many reports of "only" 2 pound losses in a week of Atkins induction. I think this is due to the diuretic nature of the diet, and perhaps more of the water comes from that between the fat cells leading to rapid changes in dimension as well. Seems the poorer/carbier the diet before hand, the greater the effect. I don't think anyone disputes that overcarbing and the inflammatory nature of obesity leads to a "bloated" state that is often rapidly reversed on low carb.
fredd said…
But for the overweight experiencing such large losses, given that the body only stores a certain amount of that "overcarbing" and oxidises the rest, it is still hard for me to understand the large losses! My only thought is must be a combination of water weight from glycogen (small amount, as mentioned, not many of these people experiencing large losses would be depleting glycogen stores), fat and reduction of water absorbed by the actual foods/carbs in their old diet vs new diet?

p.s. Thank you for the reply, it is nice when bloggers answer comments ;) I really enjoy your blog and wish there were more like it!
Rosie Brag said…
This comment has been removed by the author.
CarbSane said…
@fredd: I try to answer all comments, but as this blog has gotten busier I'm beginning to marvel at those with MUCH higher traffic who still seem to manage so many responses. I really don't know about large weight swings, but water balances can be shifted considerably so it doesn't confound me too much.

@Rosie: Welcome to the asylum! It is not normal for glucose to be excreted in the urine, so diabetics who do so have uncontrolled BG and hyperglycemia leading to "spillage". In this regard they are excreting some calories and this may contribute to body weight if/when they appropriately metabolize or store virtually all ingested carbs. I'm not sure if the number of calories are significant either, it's not for ketones, and I don't know how much glucose we're talking about.

As I've blogged about here many times, glucose is not generally stored as fat except in large dietary excesses. It is misleading to look to the effects of artificially altered insulin injections to that of naturally produced insulin. Nobody challenges that insulin has a role in fat metabolism, just its ability to basically take over the process and turn a fat cell rogue.

I'll have a look at your link when I get a chance. If I forget to get back to you, please do drop a friendly reminder. Thx.