Diazoxide, Insulin & Obesity

In his recent post on insulin and obesity, Fat Tissue Insulin Sensitivity and Obesity , Stephan brings up one of those *nagging* studies that have been touted by TWICHOO advocates for quite some time.

Back in May 2008, Peter/Hyperlipid posted Weight loss when it's hard 2. Diazoxide.  This discusses the following study:  Beneficial Effect of Diazoxide in Obese Hyperinsulinemic Adults.

What is diazoxide?  It is a drug that reduces insulin secretion.  As Peter writes:

You can simply reduce insulin secretion using diazoxide. Find enough obese people willing to put up with the hunger generating regime supplied by Slimfast and semi starve them for 8 weeks. Half can have a placebo, half get diazoxide in addition to Slimfast starvation. Figure 1 in the results is where you want to look. The idle porkers starving on Slimfast plus diazoxide lost significantly more weight in 8 weeks than the idle porkers starving on Slimfast alone.

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Is LC Morphing to HAES? Part II: There's Something About Laura

As I stated in Part I of this series, I'm seeing increasing mention of low carbing for health irrespective of weight loss.  The subject of this installment is going to be Laura Dolson of About.com.  Her recent interview with Jimmy Moore is what actually sparked me to blog on this topic.

I wish to put a disclaimer here, and I'll probably C&P this paragraph into each subsequent Part I may add to this series in which I name names.  I have nothing personal against any of these people.  I don't know any of them personally, so I can only go by their interviews, writings and podcasts.  For the most part these folks seem like quality people, although I do find the snarky and often mocking anti-anyone-who-disagrees-with-their-pet-theories attitudes off-putting at times.   In naming names my purpose is not to embarrass anyone or attack them or make them feel badly about themselves.  Lord knows the last thing an obese or overweight person needs is someone else to remind them that they are so.  But in that vein, if these people are going to be out there evangelizing low carbohydrate eating as inherently healthy, especially if they are making part of all of their living doing so, scrutiny is not only warranted, but should be expected.

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Endogenous v. Exongenous Hormones

I'm going to be using insulin as my example in this post.  Endogenous insulin is the insulin produced in your body by your pancreas.  Exogenous insulin would be that derived from outside the body - e.g. insulin injections.  For the most part exogenous hormones are obtained through some "pharmaceutical" route.  In the case of insulin, subcutaneous injections.

Now I’m sure most of my readers are familiar with the picture below:

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Exercise v. Diet for Weight Loss

In recent months, mainly sparked by Mr. Exercise Only Makes You Hungry's appearance on the Dr. Oz show, there seems to have been some renewed interest in the LC community in the role of exercise for weight loss.  Most studies show little effect of exercise only, but, as the authors of this study I'm about to share state,  "these conclusions are drawn from studies in which individual energy intake and expenditure were not rigorously controlled or accurately measured" .  When it has been controlled, the calorie deficits created through exercise alone were not sufficient to produce significant weight loss.

Reduction in Obesity and Related Comorbid Conditions after Diet-Induced Weight Loss or Exercise-Induced Weight Loss in Men

This study was done in weight stable (6+ months prior to study) obese (BMI >27) men with waist circumferences over 100 cm (~39").    The men were sedentary, non-smokers, non-light drinkers, and had normal lipids and glucose tolerance.

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Of Mice & (Wo)Men: When's the last time you saw an 5'4" 130 pound fat woman?

I'm always amused when a rodent study that seemingly counters the calorie-based theories on obesity comes down the pike.  In predictable fashion, someone in the LC webosphere will pick up on it and use it as an example to counter calorie-based theories on weight/obesity.   A recent example of this is brought to us by low carbers' favorite comedian edutainer, Tom Naughton:  Fat Mice & The Laws of Thermodynamics that referenced the following study:  Mild calorie Restriction Induces Fat Accumulation in Female c57BL/6J Mice.  

Now Tom starts out misrepresenting things by picturing a fat mouse, likely an ob/ob.  This study actually involved females of the strain pictured below:

Kind of a cute little critter, no?   The study was also conducted in the context of calorie restriction and it's demonstrated increase in longevity of mice.  They are not a mutant strain genetically predisposed to obesity.

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More on Water Weight & Insulin

There's an interesting related conversation on this topic going on over at Paul Jaminet's site:

Water Weight: Does It Change When Changing Diets? Does It Matter?

For those not familiar with the Perfect Health diet, one component is to get ~400 cal in "safe starches" -- around 100g.  For those transitioning to their diet from a low carb diet, some have experienced a not-unexpected weight gain.  I've added some thoughts to the comments there and -- can't be sure and some is just a hunch -- but I think any weight bounce is probably more carb associated, predominantly glycogen repletion.  It may well be due to replenishing other "carb" molecules with their associated water as well.  My guess is that for the most part these changes show up on the scale more than in dimensions.  That was my experience during the almost 3 years of my "low carb cheating" plan.  I can't know for sure for the first year and a half or so of that, because I never weighed, but I didn't gain size during my cheats (pants still fit fine) and later after I weighed I sometimes saw a few pound gain, but again this didn't effect the fit of the skinny-jeans much if at all.  

However my current interest/focus is building on this recent post of mine:

Insulin, Weight Loss & Water Weight

In that post I referenced two studies that I'll repeat link to here:

Changes in abdominal subcutaneous fat water content with rapid weight loss and long-term weight maintenance in abdominally obese men and women - This one discusses how following rapid weight loss and improvement in insulin sensitivity of the fat tissue, fat mass increases due to increased associated water resulting from improved blood flow.

Disparate Hydration  in Adipose and Lean Tissue Require a New Model for Body Water Distribution in Man.  This one discusses various models of determining total body water content, and the contribution of adipose tissue often ignored for lean populations.  It also discusses the extra and intracellular distribution of water in adipose tissue and lean tissue.

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Exercise to lose weight and reduce lipotoxicity!

Thanks to reader Cody for finding a study I had come across previously regarding IMCL/IMTG.  Actually the study linked to was an update, but there's a secondary lesson, I believe, to be had from the results.  Since this was a study in older folks, there's a sub-message here:  it's never too late!

Study:  Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete’s paradox revisited

We previously reported an “athlete’s paradox” in which endurance-trained athletes, who possess a high oxidative capacity and enhanced insulin sensitivity, also have higher intramyocellular lipid (IMCL) content.

The purpose of this study was to determine whether moderate exercise training would increase IMCL, oxidative capacity of muscle, and insulin sensitivity in previously sedentary overweight to obese, insulin- resistant, older subjects. Twenty-five older (66.4 0.8 yr) obese (BMI 30.3 0.7 kg/m2) men (n 9) and women (n 16) completed a 16-wk moderate but progressive exercise training program.  

Body weight and fat mass modestly but significantly (P 0.01) decreased. Insulin sensitivity, measured using the euglycemic hyperinsulinemic clamp, was increased (21%, P 0.02), with modest improvements (7%, P 0.04) in aerobic fitness (V˙ O2peak). Histochemical analyses of IMCL (Oil Red O staining), oxidative capacity [succinate dehydrogenase activity (SDH)], glycogen content, capillary density, and fiber type were performed on skeletal muscle biopsies.  Exercise training increased IMCL by 21%. In contrast, diacylglycerol and ceramide, measured by mass spectroscopy, were decreased (n 13; 29% and 24%, respectively, P 0.05) with exercise training.   SDH (19%), glycogen content (15%), capillary density (7%), and the percentage of type I slow oxidative fibers (from 50.8 to 55.7%), all P 0.05, were increased after exercise.

In summary, these results extend the athlete’s paradox by demonstrating that chronic exercise in overweight to obese older adults improves insulin sensitivity in conjunction with favorable alterations in lipid partitioning and an enhanced oxidative capacity within muscle. Therefore, several key deleterious effects of aging and/or obesity on the metabolic profile of skeletal muscle can be reversed with only moderate increases in physical activity.

Here's a link to the preliminary work I believe I was looking for (from the references in the above paper):
Skeletal Muscle Lipid Content and Insulin Resistance: Evidence for a Paradox in Endurance-Trained Athletes

So I've blogged a bit about lipid accumulation in non-adipose tissue, lipotoxicity and insulin resistance.  IMCL seems to correlate with IR, but the "athlete's paradox" is that insulin sensitivity accompanies increases in IMCL in athletes.  Therefore IMCL cannot be "toxic" in and of itself.  In this study we see that exercise decreases diacylglycerol and ceramide levels at the same time as IMCL's increase.  The negative effects of IMCL appear to be correlated to the build-up of metabolites rather than the stored triglycerides themselves and/or the turnover of  IMCL -- it's a secondary storage tank in the obese, but perhaps more like a gas tank for the athlete.  Perhaps ceramide is the sole culprit, insulin sensitivity, oxidative capacity and IMTG all increased by around 20%.  Ceramide and DAG both decreased, but only ceramide decreases correlated with insulin sensitivity improvements.

But ... in reading the originally referenced article, something else jumped out at me.  They took 25, mainly weight stable, obese, older (avg age ~66), sedentary people and, near as I can tell, did not change their diet.  One can presume most of these were eating a SAD before and after.  The participants were simply put on a moderate exercise regime.  The exercise was 45 min cardio (moderate by heart rate and/or perceived exertion), 4-5X/week -- mostly walking or stationary cycling.  You know ... the type of exercise often poo pooed in the low carb community that can only, according to Taubes, make you hungrier and cause you to eat more.  The subjects actually averaged 3.5X/week for the 16 weeks of the study.  

The result?:   In 4 months an average loss of almost 3-3/4 lbs of fat mass.  If continued for a year, this would translate into an average of 11 pounds in a year.  Not too shabby when compared to the weight losses reported by Shai et.al., but more importantly this counters to oft-repeated claim that you can't lose weight by exercise alone.  

And health-wise?  Insulin sensitivity improved >20%  (even as IMCL increased), as ceramide and diacylglycerol decreased.  IOW, whatever the cause of the IR, exercise alone improved this state.  

So exercise CAN improve health independent of diet. 

Dietary Fat v. Endogenous Fat for energy

It has become increasingly clear to me that regardless of the macronutrient composition of one's diet, dietary fat is only marginally "burnt" for energy on a given day.  The exception to this would be medium and shorter chain fatty acids that are not included in this discussion.

There's a lot of misinformation out there spread by various LC gurus regarding fat burning and storage.  Without carbs, we can still store fat and we do!  The energy substrate for "fat burning" ( is the free fatty acid (NEFA/FFA).  Where do most of these come from?

1.  Lipolysis of "lipid droplets" of stored triglycerides within the cells, often called intramyocellular triglycerides (IMTG) 

2.  Lipolysis of adipose tissue.  

3.  Lipolysis of other circulating triglyceride-carrying lipoproteins  

4.  NEFA/FFA's that "escape" the re-esterification process.

Sources 2-4 are all circulating FFA's and my research all points to the conclusion that circulating NEFA/FFA levels are highly regulated and controlled (or intended to be) by controlling release from adipose tissue (2) constituting the majority of NEFA/FFA in circulation.  The other two sources are relatively minor.  Since trained athletes have higher levels of IMTG, it can also be posited that when the need for fats arises, these stores get tapped first and the cell takes in NEFA/FFA from the blood to replenish the stores.  (This can be envisioned as analogous to using glycogen stores and taking up glucose later to replenish the stores).  In any case, the fatty acids we actually "burn" (beta-oxidation, fatty acid spiral) on any given day are almost invariably derived from stored triglycerides.  

So what happens to dietary fat?  Well ... just as those "idiots" who know nothing about nutrition and science, etc. have been saying all along, it goes into .... drum roll please .............. your fat cells!  Yep!  That's where it goes whether you eat a low fat high carb diet or a high fat low carb diet or whatever other kind of diet.  The  majority of all of your ingested fat goes directly to your fat cells.  Here's how/why.  LCFA's are relatively insoluble in blood, so while ingested carbs and proteins get broken down into glucose and amino acids and mostly go directly into circulation, ingested fats do not.  Most ingested fats are triglycerides that are broken down to FFA + glycerol in the intestine.  The FFA's are taken up by intestinal cells, re-esterified to triglycerides that are then "packaged up" with proteins to form chylomicrons.  Chylomicrons can be "seen" in the blood after a high fat meal -- they are what can lead to the centrifuged serum/plasma being cloudy.   These are released into the lymphatic system and finally enter the blood stream via the thoracic duct.  Chylos are largely cleared from the blood in a matter of an hour or so.   Chylo formation and transport is a necessary component of human nutrition, but chylo-rich blood would be more viscous (not desired).  Therefore clearance from the blood stream is a priority task.  Really ... you actually want the fat you ingest to go into your fat cells!  But I digress ....  Back to the chylos.  It turns out adipocytes have receptors that detect the presence of chylos, and the chylos stimulate the production of (something LC snake oil salesmen wish would go away) acylation stimulating protein -- ASP. ( I'll be putting up a couple of blog posts on this in coming days).  The chylos are broken down, FFA's transported into the cells, and FFA's re-esterified at the direction of ASP pretty much ASaP!  

When you think about lipid transport, why do we have different types of particles?  Why doesn't the liver scavenge up chylomicron remnants and repackage them into new chylomicrons instead of other lipoproteins?  Because our bodies do distinguish between dietary fat and endogenous fats, and I propose this is critical to regulating circulating lipids.

So ... am I trying to say that eating fat makes you fat?  Nope!  Because at any given point in time, lipolysis is going on elsewhere in the fat cell releasing some of the stored fat.  Yes, insulin regulates the release of FFA's from fat cells in a suppressive capacity.  More insulin = suppressed lipolysis, less insulin = increased lipolysis.  Ah ha!  Not so fast.  This is nothing more than insulin playing traffic cop for the heirarchy of macronutrient utilization to meet immediate energy needs.  Because carb storage is inefficient (low energy density) and limited (the average adult has the capacity for like 750g or a little more than 1.5 lbs), when dietary carbs are available, they are utilized first to meet energy needs.  But this does not last forever, and once the carbs are gone, lipoysis is ramped up.  

Does high fat vs. low fat matter?  Not really if one reads the literature and in depth studies without an agenda or books to sell.  Let's say a person's total energy expenditure is 2500 cal/day;  Person A goes on a 2000 calorie 20%protein/20% fat/60%carb diet containing about 45g fat and 300g carb; Person B goes on a 2000 calorie 20%protein/70% fat/10%carb diet containing about 155g fat and 50g carb.   Both A & B are in 500 cal/day energy deficit.  Person A will likely directly burn most of the 300g carb, perhaps converting a small amount to fat via de novo lipogenesis.  They will deposit 45g dietary fat into their stores, but in varying rates as the day goes on, they will draw about 100g of  fat out.   Person B also uses their 50g carbs first and deposits 155g fat.  They will, however draw about 210g out of the stores.

The preceding paragraphs are obviously an over-simplification.  In reality, nobody is ever utilizing just one substrate for energy, but we are "wired" to utilize that which is least efficiently stored (carbs) preferentially to that which is efficiently stored (fats).  Furthermore, the metabolic processes enhanced during fasting (or carb restriction) are glucose sparing and override this heirarchy to some extent to preserve the glucose for where it's needed most (e.g. brain).  Lastly, the amount of fat released from the stores is significantly more than is needed (in either nutritional state) with about half of mobilized fat returned to the fat cell.   

Fat and/or carbs make us fat when either or both are consumed in excess of energy needs.  Fat accumulates if we're chronically depositing more fat than we are utilizing to meet energy needs.  Fat stores diminish when we're chronically utilizing more than we deposit.  

Interval Training and Fat Loss

The effects of high-intensity intermittent exercise training on fat loss and fasting insulin levels of young women.

OBJECTIVE: To determine the effects of a 15-week high-intensity intermittent exercise (HIIE) program on subcutaneous and trunk fat and insulin resistance of young women. 

DESIGN AND PROCEDURES: Subjects were randomly assigned to one of the three groups: HIIE (n=15), steady-state exercise (SSE; n=15) or control (CONT; n=15). HIIE and SSE groups underwent a 15-week exercise intervention. 

SUBJECTS: Forty-five women with a mean BMI of 23.2+/-2.0 kg m(-2) and age of 20.2+/-2.0 years. 

RESULTS: Both exercise groups demonstrated a significant improvement (P<0.05) in cardiovascular fitness. However, only the HIIE group had a significant reduction in total body mass (TBM), fat mass (FM), trunk fat and fasting plasma insulin levels. There was significant fat loss (P<0.05) in legs compared to arms in the HIIE group only. Lean compared to overweight women lost less fat after HIIE. Decreases in leptin concentrations were negatively correlated with increases in VO(2peak) (r=-0.57, P<0.05) and positively correlated with decreases in TBM (r=0.47; P<0.0001). There was no significant change in adiponectin levels after training. 

CONCLUSIONS: HIIE three times per week for 15 weeks compared to the same frequency of SSE exercise was associated with significant reductions in total body fat, subcutaneous leg and trunk fat, and insulin resistance in young women.

I do not have access to the full text on this one.  It would be interesting to see the caloric expenditure for the two exercise groups.  I think this is the study often referred to regarding superiority of interval training.  The energy expenditure remained elevated for a considerable time after the exercise.