Wednesday, May 07, 2008

Weight loss when it's hard 2. Diazoxide

I just thought I'd put this post up as it's fairly topical at the moment.

We all now know that macronutrient ratio is irrelevant, insulin is irrelevant and all that counts is calories. Calories in, calories out, fat people are lazy gluttons. So let's play.

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.

It looks to me as if the diazoxide group had lost 10% of bodyweight and were still loosing. The Slimfast alone group were stalled at about 4.5% bodyweight loss. Note also that the diazoxide group lost 9.3kg of fat vs. 3.6kg in the placebo group.

That is, diazoxide produced an excess fat loss of about 5.8kg in eight weeks. That's 100g per day. Or about 900kcal of fat. Every day.

So what's going on. It's pretty obvious really. This is not a metabolic ward study and the subjects cheated. Must have done. Stands to reason. These are free living people. How can any bloke on a 1570kcal per day diet walk past the gym without slipping in and spending an hour doing bench presses? OK, he promised to keep his exercise unchanged but really, no one will ever own up to having a 900kcal/d gym habit like that.

Or maybe the placebo group cheated. It's pretty obvious that 1570kcal of Slimfast will have you pogged out all day, no room for even a teensie weensie little donut, but hell, if they're half price you might force one down or maybe that will be 10 donuts......

But it's funny that the gym sneaks and the donut moonlighters ended up in separate treatment groups.

Or maybe, just maybe, you could just accept that in the real world, outside a meatball ward, sorry, metabolic ward, the level of insulin in your blood stream influences your rate of weight loss, specifically your rate of fat loss.

BTW The folks in this study are clearly pathological liars too. Any trainer being told that a fatty can maintain a BMI >30 on 1900kcal per day will be snorting in their whey protein shake. You know calories in calories out, yawn.

The placebo group lost 64g of fat per day, which is about 600kcal. This was on 1570kcal/day. So, just by arithmetic, they should previously really have been eating 1570 + 600 = 2170kcal/d to have been weight stable. They claimed to have been eating 1953kcal/d. That's not so far out given the accuracy of food tables. Maybe these were the honest ones.

But the diazoxide group lost 1660kcal/d of fat every day while eating 1570kcal/day of "food" (Slimefast). Does this mean that they had originally been eating 1570 + 1660 = 3230kcal/d to maintain their weight pre study? Now these people claimed 1977kcal/day. Lying porkers. You can't trust anyone. Least of all a fatty. But then everyone lies according to Gibney!

Let's get real. I think both groups ate just 1570kcal/d and skipped the gym. The diazoxide group used all of those calories PLUS 1660kcal/d of their own fatty tissue. The placebo group appeared to use that 1570kcal plus 600kcal of their own fat, but this is an average over time. They lost more than this initially per day, but by the end of the study they didn't look to be loosing any weight at all on those 1570kcal. By week eight they USED 1570kcal/d and that was it. They hadn't lost much weight anyway and now they were weight stable on the same energy consumption that had the diazoxide group loosing consistently. And this was at a much lower energy intake than they had possibly "under reported" at enrollment.

To go back to that apparent idiot Taubes, the problem with fat people is that they do not have access to their fatty tissue. It's only "there" as an energy source when insulin levels are low enough to allow HSL (hormone sensitive lipase) to work. Slimfast drops insulin a bit compared to the SAD, in this study from 204pmol/l to 174pmol/l (neither statistically significant nor biologically significant, after a few weeks anyway). Slimfast plus diazoxide dropped insulin from 168pmol/l to 108pmol/l (statistically p<0.01, biologically weight loss continued).

So where did the energy go to in the diazoxide group, and why did the placebo group stop loosing weight on a marked calorie deficit? Thermodynamics rules. No evaporating calories.

Well, a calorie is a calorie is a calorie. You can't burn what you ain't got. On Slimfast alone (I suspect low fat, low protein, some carbs to keep insulin up almost as much as the SAD) stored adipose tissue is just not available. Lugging around a body with BMI of >30 takes calories. If you don't have the calories, you don't do this. No sneaking to gym for this group, and I bet they were dreaming of donuts by week six, if not before.

In the diazoxide group there were significant periods of time when fatty tissue was available to supply calories because insulin was low. Use it AND loose it, calories that is. Lifting a 150kg body takes calories. If they are available, you can do it, you do do it. You don't need a gym when you weigh this much and have found access to all of that energy in your adipose tissue. Just moving around more makes a difference. I weigh 65kg. Putting on a back pack weighing 85kg would cripple me. I'd burn some calories. Heavy people live with this, shifting about takes energy. A lot. You don't have to change your basal metabolic rate. Just how you move.

So just to summarise this paper. Caloric restriction failed in about 7 weeks. Equal caloric restriction plus lowered insulin levels allowed on going weight loss throughout the study period.

Now, imagine the insulin drop without the diazoxide and without the hunger generated by Slimfast. Eating 1570kcal of steak, curly kale, bacon, scrambled eggs, double cream etc etc. The rest of your calories can come from that enormous supply of fat in your abdomen first, then on your bum. Forget about hunger.

You might even have the energy to go to the gym. After all, with all those adipose calories available, you can afford the energy to work out.



Sven said...

VERY interesting study. I fear Anthony Colpo won´t invite you for a cup of tea anytime soon. ;-)

Chris said...

But it's funny that the gym sneaks and the donut moonlighters ended up in separate treatment groups.

Excellent! This had me laughing out loud.


mtflight said...

Loved the post and the sarcasm. Write a book! This reminded me of Malcolm Kendrick's style although I think you were funnier, probably because you went further our of your usual style.

So where does one get his/her hands on diazoxide? jk.

Stephan said...

Great post! I'd say that was a pretty good smack-down for the insulin naysayers.

I was surprised the diazoxide didn't affect glucose tolerance; that's hard for me to understand. They say it didn't affect insulin sensitivity, but the glucose tolerance test is about the same as placebo despite secreting a lot less insulin. Is that a contradiction or am I missing something?

Why don't they use this drug more often?

Peter said...

Oh, my blogging software chewed bits of text out! It does that sometimes. Back in place now.


PS Stephan,

There are loads of interesting trends in the result but few reach stat sig.

Chris said...

Blogger has been playing up for me too.....

Anyway, Peter, you might be interested in this post

The guy looks great and on a relatively high fat diet (up to 65% of calories) and his comments on carbs are:

Conversely, eating more carbs drives up insulin, drives carbs towards fat storage, decreases fat-burning by prompting fat cells to hold on to stored fat and makes you hungrier for more carbs. I could burn some or most of all that off again by doing tons of cardio, but that only makes me hungrier for more carbs and perpetuates the cycle. It’s like digging a hole to put the ladder in to wash the basement windows.

Chainey said...

After receiving The Word from Professor McDonald I was just about to ring up some Type-1 diabetic people I know and tell them to drop that NONSENSE of taking insulin and just eat more to put some fat (and meat) on their bones.

Lucky you posted in time.

Peter said...

Hi Stephan,

Just from flicking through Table 3 and speculating...

As you mentioned insulin sensitivity went up from 0.77 to 1.07 in tx group, placebo only from 0.61 to 0.75. Never made statistical significance so...

Also fasting glucose went down very slightly in placebo, up in diazoxide. You could attribute this to lower insulin levels but equally you could attribute it to the higher FFA concentration in the tx group. After all, they're using bodyfat as a significant source of energy. It comes out as FFAs. These increased more in the diazoxide group. Trigs went up very slightly in the placebo group and down in the diazoxide group, what you would expect with a change to FFAs as a calorie source.

Despite fasting glucose going up and fasting insulin going down, the HbA1c went DOWN in the treatment group. This suggests to me a shift towards having FFAs in the blood stream and away from having glucose there, overall. Clearly the same glucose went in to the diet of both groups, so again, I think the diazoxide group were moving about more, shifting glucose it to their muscles due to that non significant increase in insulin sensitivity.

So lots of non significant stuff. Still interesting though!


Sven said...

This study doesn´t show any weight loss advantage of diazoxide:

What now?

Sven said...

Kevin said...

The good doctor might suggest, ever so politely, that the 35 participants lied about their food intake. Also the 35 were hyperinsulinemic. Dunno whether that was a factor.

Peter said...

Hi Sven,

Yes very interesting. I'd love to see the full text if anyone has access, it's beyond my athens account.

Kevin, I'm loathe to disbelieve the reported food intake of obese people, so I'd rather look elsewhere for the explanation, but maybe.

The biggest difference I can see is that the study by Alemzadeh et al used a very fixed calorie intake diet which was identical for all participants in a highly structured if very artificial form.

You can't tell from the abstract how the caloric deficit was achieved in the Danish study and you can't get much of an idea of the metabolic effects either.

It's also interesting that the Alemzadeh group did a similar study, again using fixed calorie meal plans, using metformin in normoglycaemic adolescents with some success.

I wonder what a calculated 2.5MJ deficit would have done in this case?

It's also worth considering this paper and looking at weights and dose rates, comparing between studies, if we had full texts.


Kevin said...

If people can lie to themselves, surely they can lie to investigators. Last night I was mentally adding up the day's calorie count and feeling pretty good about myself (950!) . I couple hours later I realized I'd forgotten about the bowl of ice cream and no longer felt so good about myself. (Add another 800)

Bruce K said...

Peter: "I'm loathe to disbelieve the reported food intake of obese people, so I'd rather look elsewhere for the explanation, but maybe."

Why would you believe them? Anthony Colpo has pointed out correctly how obese people lie. Dr. Gregory Ellis drove this point home repeatedly in his book, Ultimate Diet Secrets. If you look up "doubly labeled water" studies, you will see a definitive proof that the obese lie about what they eat. They claim to eat <2,000 Calories while eating >3,000. Gary Taubes ignores this evidence, too. There's a tendency in the low-carb church to deny reality. Jimmy Moore is starting to resemble Michael M, based on some pictures Eades posted recently. Could it be the low-carb processed food he eats?

Stephan said...


I just glanced at that paper. Not very convincing. The control and treatment groups started out with very different fasting and OGTT insulin levels. The diazoxide only succeeded in bringing insulin down to where the control group started off to begin with. I'm not sure how much you can take from this finding.

Jimbo Big Toe said...

It's amazing the species has evolved in such a way that we forgot how we got fat.

Sven said...


that could be an explanation. Thx.

Troy said...

fnav0Good post peter! High Quality animal fat, low calories, no hunger, fully nourished, is the way to go...enough energy to live, surf, and lift weights 3 times a week!!!

PJ said...

Well maybe it is just a matter of something in it playing against the slimfast itself. I have personally experimented--with a weight of about 400#, mind you--with using lowcarb slimfast as a primary protein source and at about 600 calories a day I didn't lose a damn bit of weight, nor did I at 1300 calories a day. But when I was eating those calories and NOT using slimfast, weight just poured off me, anywhere from 600 calories to 3000 calories (go figure) -- although eventually on too-low calorie it stalls (I chronically forget to eat, as I'm so focused on whatever I'm doing, a terrible habit). Anyway, it eventually convinced me that mysteriously, maybe even magically, slimfast had actually figured out a way to give me protein and vitamins and low calories and still keep me from losing weight so I needed more of their product LOL. ;-)

PJ said...

I might add, in response to the post/comments about people lying about their intake, that
(a) I imagine there is the same likelihood for anybody on a 'regimented plan' to lie (not just obese people), and
(b) anybody on a low-fat or high-carb plan is almost guaranteed to be miserable and starving half the time, which could potentially even generate some subconscious self-preservation response that relates to "memory" in this regard, and
(c) merely 'having' to do anything with rules often inspires that response in people (across the spectrum) and not just about food, and
(d) anything beyond that is really a ridiculous and insulting prejudice. I have tracked my food intake to the gram, using USDA as measure, and a good digital .5lb scale, and to say that there is obviously more going on than mere calories based on results is the understatement of the century. I've lost enough weight so far to have some idea of what works for me and doesn't, but those things are not (by far) based solely on the "count" of anything -- calories or carbs either -- although the one most primary thing it does seem to relate to is protein and nutrients, but I don't really know detail yet, only that when weight is coming off me is coincidentally running into the times I have both of those acts together (even when the calories vary, as long as the carbs are relatively low, even if not ketogenic).

I cannot tell you how eye-rollingly ridiculous it seems when a person can work 12-18 hours a day, barely have time to pee let alone eat, have NO problem tracking their food because it's the same or less than what their 130lb roommate or workmate is eating, or because it's already pre-measured and counted for dietary planning, and if their weight loss doesn't match the calorie count, people assume that they're lying.

I think many people DO -- it's just that we only critically evaluate the people who are fat, obviously. Thin friends who eat when upset don't feel they have a binging disorder as long as they aren't barfing; if they aren't fat, nobody gives a damn what they eat. Yet I have plenty of friends who do WW who are thin (like, they need to lose 10lbs, maybe) and they lie about their food. I can't figure out why it's assumed that fat people just by-default can't be trusted.

I've read stuff related to research implying that eating foods you are intolerant to can prevent weight loss or even cause gain (or at least water gain); I've read stuff related to research implying that insufficient nutrition (amino acids and micronutrients) can affect weight loss and gain; and I've got enough experience in my own life for my own empirical evidence, to suggest that the "assumption that fat people are all just lying about their food" because the results aren't what is expected is ridiculous.

Sometimes it's obvious people ARE. Not because they are fat, but because of the reasons I noted above, or because a study actually makes clear--based on a group, not an individual--that something else is going on that clearly isn't in the measure. If stuff like that is going to be used as even a consideration related to research, it should be based on measured facts for that study, not social prejudice applied globally.

ItsTheWooo said...


Just popping by to comment so I didn't really read the details but how did they manage to lower insulin levels without inducing diabetes? If the drug worked on hepatic gluconeogenesis that would make sense... or, if it reduced need for insulin via some other means.

Additionally, I don't think it's exactly fair to blame slimfast for their modest reduction in insulin levels in the placebo group. Insulin resistance is a cycle, and much research points to an originating defect in liver glucose production. Basically, they would have been pouring out sugar whether or not they were eating, and that is what is driving their insulin levels so high. Even if they were eating low carb and high fat, it is no gaurentee that this metabolic process reverses itself. I only believe I was able to completely reverse my morbid obesity because I was very young (20) when I started the diet. If I were older, the metabolic abnormalities would probably be more permanent. My hyperinsulinemia was entirely relative to food intake, but this is NOT the case for many obese people, and their hyperinsulinemia is related to more problematic less easily correctable defects in gluconeogenesis and severe insulin resistance.

Basically I don't necessarily believe that low carbing would have been the answer either, especially low carbing with high calorie intakes. I definitely think it would have been better than slimfast, if isocaloric, but I don't necessarily know if it would have been more effective than a drug that targets the problem.

Even low carb isn't the answer, even when it IS the answer. After losing all of my weight, my leptin level is almost non-existent because somehow someway my body seems to remember I used to be 300 pounds. If you know about leptin, you can imagine the effects this has. Ironically the more effective a diet is at keeping off weight and reducing insulin, the more severe the leptin deficiency is. So it's like, damned if you damned if you don't... the better you are at losing weight and getting your insulin down the more you are knocking down your leptin producting and triggering starvation symptoms in your body.

Peter said...

Hi again ItsTheWoo,

Another interesting comment. Diazoxide appears to act directly on the pancreas to suppress insulin production. The only way I can see that this fails to induce diabetes is that Slimfast may well be carbohydrate restricted relative to the previous diet which had established the hyperinsulinaemia needed for study inclusion. Also the hypocaloric effect may well allow more fat burning, lowering intramuscular triglycerides and a reduction in insulin resistance that way. I think most LC people would agree that there is undoubtedly a viscious circle in insulin resistance and that at some point something gets "broken". Whether it is really possible to "unbreak" this I don't know. You think not. Possibly true.

Very interesting re low leptin levels after resolution of a weight problem. Again, maybe it comes back to what is a healthy weight. If carrying some "excess" weight turns out to produce a heathy leptin level, should anyone in this circumstance be aiming for a BMI of 20-22????

So what is a healthy weight? At the moment I can see there could be a trade off between aesthetics and health, where some extra weight may not be a problem. Some sort of compromise between glucose, leptin and insulin. There's a way to go on that one.


ItsTheWooo said...

I suppose that's true, slimfast semistarvation is definitely lower glucose load than a normal diet, but I would expect the diazoxide group to have been running higher blood sugars, though if their pre-medication insulin secretion was just a normal response to either severe insulin resistance or abnormal and disregulated gluconeogenesis. The lower glucose level of the starvation diet shouldn't matter, because we are assuming insulin production is appropriately responsive to need to lower glucose.

Or, alternately, we can assume the non-diazoxide group might have been plagued via chronic hypoglycemia on their restricted diets. If we assume insulin hypersecretion was the primary defect, and not a response to excessive glucose production or insulin resistance.

Personally if I had to imagine my hypothetical response to slimfast starvation as a morbidly obese 20 year old (fortunately I never had this experience) I would definitely expect chronic hypoglycemia. This implies my primary problem was insulin hypersecretion, and my liver gluconeogesis and insulin sensitivity is more "normal".

I guess, if these obese people were like me, and relatively early on on the pathogenesis of diabetes, they are probably suffering primarily from insulin overproduction and hypoglycemia - in which case diazoxide is a good solution since it normalizes insulin production, without risk of diabetes. Of course, if they are like me, an even better solution is low carb, since low carb can completely correct abnormal insulin secretion by preventing blood sugar from markedly rising, or falling. The only time I get hypoglycemia now days is either if I really go overboard on protein (which requires my insulin go up substantially) OR if I overdo exercise, especially weight lifting (which requires my blood sugar go down rapidly).

But, I do think that for at least a certain subset of obese people - especially those teetering on type 2 diabetes - the primary problem is no longer abnormal insulin control and insulin hypersecretion. The problem is excess gluconeogenesis and severe peripheral insulin resistance. These are the kind of people who actually have higher blood sugar & insulin if they eat nothing at all, than if they eat a little bit of food, because the primary defect is in the blood sugar making process, and NOT the blood sugar lowering process. From anecdotal observations on the low carb forums it seems to be that in younger relatively healthy people the problem is entirely blood sugar lowering and so we get great results with low carb... but in older people with more severe insulin resistance and livers that don't work right, low carb is less of a solution because their ability to make energy is screwed up.

ItsTheWooo said...

Regarding low leptin levels post obesity...
I suppose it is possible that if I gained a little weight, my leptin levels would be somewhat more normal. Right now my leptin level is 1.7. To give you an idea of how low that is, there is one study of leptin in eating disordered women that says a leptin level lower than 1.8 is only found in anorexia nervosa, and largely distinguishes anoretics from people without severe food restriction/emaciation. Right now I am far from starved or emaciated (body fat >21% & calorie intakes 1650 avg no exercise other than walking), but according to my (likely copious) fat cells, I am.

I doubt if the answer is just to "gain a little weight". Likely, I would have to gain a LOT of weight... and that kind of defeats the purpose here (weight maintenance of a normal body fat).

The problem with this line of reasoning (that weight gain is the solution) is that studies show leptin levels do not correlate with adiposity in the post-obese. When obese women reduce their weight even slightly - still at weights well into the obese range - their leptin levels plummet into the ground, resembling levels seen in very thin non-weight reduced women. Something about an "underful" fat cell has a way of shutting off leptin production totally, I guess, so that leptin never correlates with the absolute level of fat mass in weight reduced people like it does for normal undieted people. Though we know it is true, we are not really sure why. There's about zero research into the metabolism and endocrinology of post-obesity so they're not sure either (no money in that, all the money is in the weight loss and diet pills, like weight cycling junkies). I'm just making an assumption here, assuming the fat cell really turns down leptin synthesis if it is shrunken by weight loss.

As a complement to the stereotype that fat people can't lose weight because they are lazy fat gluttons who can't exercise or control their eating, sits the equally hideous stereotype that fat people are out of control emotional eaters who are destined to fall face down into junkfood sooner or later if they even TRY to lose weight.

After doing research on leptin in weight reduction I've come to the conclusion that a lot of the failure to maintain weight, the weaking of control and resolve, is directly related to depression and "emotional eating" instincts triggered by physiologic leptin deficiency. Leptin has powerful effects on the brain especially in regard to "emotional" feelings about food. Leptin is also antidepressant. Depression after weight loss is attributed to psychology, much like rebound food obsession/hunger after weight loss, but I suspect it is more closely related to leptin deficiency.

...which, by the way, occurs at even moderate weight loss.
The only exception to this is in weight reduced people who have hyperinsulinemia - they will continue to have high leptin levels, because of all the insulin acting on the fat cell (but we all know that high insulin levels are redundant with weight gain in psychology and physiology, so it is a moot point of observation).

I'm sure there is a level of weight I can achieve where my - and our - leptin level is restored, but it would be probably in the overweight or obese range, and this is because my fat cells want me to be obese.

I've come to believe obesity can be prevented, but not cured. If I did not have such high insulin levels during childhood, I probably wouldn't have grew so many fat cells, so that my leptin production would be normal with a normal level of fat mass (i.e. a BMI of early 20s). But, because obesity is a chronic disease, caused by insulin excess induced abnormalities in fat tissue (adipocyte hyperplasia, which increases requisite fat mass for normal fat cell function)... my fat cells now require incredible amounts of fat just to function normally.

It's also worth mentioning that leptin, as a hormone, is more physiologically significant in women than in men, even when the different body fat levels in genders are taken into consideration. Tesosterone itself reduces the level of leptin in the body. Men have much lower leptin levels than women, just by default.
This may be one reason for the anecdotal observation that women find it more difficult to lose body fat than men - our physiology is more dependent on leptin. The whole point of nutrition is to grow and live so that you can reproduce, therefore nutrient-indicator hormone leptin is a signal to activate reproductive capacity.
Female fertility has evolved to be closely tied into nutrient availability (from an evolutionary perspective it is a worthless investment for a woman to grow a fetus if it will only kill both her and the baby because of starvation... it is far better for her to become temporarily infertile, and wait for an opportunity of good nutrition to reproduce). For men, there is far less of an incentive since reproducing his genes is such a low investment proposition. I mean even in men there is SOME investment (competition requires strength and health) but it's just a lot less direct in terms of a minimum energy requirement to grow a fetus.

As a complement to the close tie between female fertility and leptin levels, it may also prove true that female physiology is much more sensitive to fluctuating leptin levels than in males. Regarding beneficial changes in growth factors and metbolism, leptin is redundant with tesosterone. And, the presence of tesosterone in men is more constant and less dependent on hormone cycles. So, the presence of tesosterone may negate the importance of leptin. Male fertility and tesosterone is definitely reduced by leptin deficiency, however this is not as marked as in females who can become totally infertile when leptin is too low. This may be another reason to explain the observation that is much easier for men to lose weight and keep it off.

Peter said...

Hi ItsTheWoo,

Thanks for the info

Regarding glucose dumping from the liver:

Perhaps what gets broken is the vagus nerve. Neuropathy is common in type 2 diabetics at the time of diagnosis. Dr Bernstein uses heart rate variability to assess cardiac automomic dysfunction. If the vagal branch to your heart is gone so probably will be the branch to your liver. This would fit in with why young hyperinsulinaemic patients do better, as they have relatively normal sugars, but chronic hyperinsulinaemic/hyperglycaemics who have lost their vagus through glucose toxicity have a much harder time.


Does this mean that you are always hungry? This whole area is fascinating to me as I've never been there and a lot of people would like to get there. The other big problem with research here seems to be there are not very many successful weight loss people to study, unless you're talking about using that small window after Weight Watchers before it all piles back on again... Leptin seems powerful stuff. Does LC help in terms of high fat through put, ie there is some fat going in to adipocytes (then coming out again) with each high fat meal, in terms of app control in general or leptin production specifically????


Peter said...

Hi Again ItsTheWoo,

If I ate to Kwasniewski's max allowed weight formula I'd be 84kg at 177cm, BMI around 27. As I've said before, I don't know what an ideal weight should be. Do you feel a BMI classed as overweight but not obese would budge your leptin levels? If so the trade off comes back to aesthetics vs health. And aesthetics are so very culturally determined...


ItsTheWooo said...

Hi again Peter
That is very interesting re: vagus nerve damage. I would assume this would contribute to hyperglycemia but in order for neuropathy to exist there must have been hyperglycemia preceding it, so I imagine that a defect must precede it.

I believed that the official story is liver becomes insulin resistant, so it can not listen to insulin telling it to "shut off" anymore, and this causes constant gluconeogenesis.

I think it is interesting to note that in type 1 diabetics without insulin their gluconeogenesis capacity is moderate - a very high glucose for a type 1 would be 200s or 300s (now were in DKA). It seems that the T1 liver, being normal, is only capable of making a much smaller amount of sugar than a T2 (assuming, without insulin, the T1 liver is working at "full capacity" for sugar making since it is insulin that stops this process). On the other hand, a type 2 can have sugars many times higher than DKA sugars even with some residual insulin making capacity! It seems that there must be something about the pathogenesis of T2 diabetes which involves a liver which abnormally makes sugar in not just context (presence of insulin, due to IR), but more importantly in quantity (the liver simply makes too much sugar in amount).

Good point about the lack of study participants... people who've lost weight and have kept it off are pretty rare. It seems like they just aren't interested in studying us, either. It's foolish, because you would think that identifying hormonal & metabolic abnormalities after weight loss would help them design drugs and surgeries to induce or assist in weight loss. Instead they keep trying the same old approach of targeting chemicals that affect satiety in healthy subjects, or even overweight subjects.

It’s difficult to answer that question (If I am constantly hungry) because I am used to the way I feel and eating to this level of fullness.
For example, I used to weigh 15 pounds less than I do now (although I have no knowledge of my leptin level then, I assume it must have been even lower). Back in those days I was *constantly* starving compared to how I feel today... I would crave eggs, and avocado, and protein. I craved high fat, high protein, energy and calories.

Even though today I can recognize that I was starving, if I was asked the same question back then ( if I was constantly hungry), I would probably say "not really" because I was so used to the way I felt it became normal. Asking a person their perception of hunger really isn’t accurate because you kinda get used to certain levels of hunger or satiety, if they are constant enough. Hunger is defined relatively over a short period of time. A person is hungry if they were relatively more full 3 hours ago. A person who has been slowly starved often can say they don’t feel hungry because they are used to the hunger.

If I had to compare my level of hunger today at 121 pounds to my level of hunger when I was 280 pounds, eating very low carb, I would say I am much, much hungrier now. And, if I compare my hunger 15 pounds ago to my hunger now, I was much, much hungrier back then.

LC/ high fat does help to keep me from feeling less hungry, but it does not reverse the direct effect of low leptin I don't think. It's a type of hunger that has no relationship to meals, it's hard to explain... it's this constant desiring for food. And, you know how normal people get nauseated if they over eat? You kind of lose that too. It’s this hunger that is there all the time no matter how full or hungry you feel. It's a lot better now that I weigh more, but I am sure that if I was not psychologically trained to eat the way I eat, I would probably binge constantly, sadly enough. In rare moments when I let my mind relax, and I just eat, I eat an incredible amount. Prior to weight loss, WITH LC high fat eating, physically it was impossible for me to eat as much as I can eat now because all of the fat made me nauseated. I do not get the nausea as strongly as I used to and it is extremely easy for me to eat an *incredible* amount of fat and protein. In taubes book he talks about how impossible it is to eat stacks of pork chops, and how people in studies have difficulty getting participants to eat that much… I just kinda laughed reading that because the appetite blunting effect of LC only seems to really work when you haven’t lost any significant weight.

At this point, the main thing LC gives me is stable blood sugar, it certainly doesn’t prevent me from being too hungry to eat. Another unfortunate effect of low leptin appears to be less glucose tolerance. When I was thinner I was chronically hypoglycemic and my tolerance for carb or protein was non-existent. My glucose tolerance appears much better and I am very rarely hypoglycemic, but LC keeps me even more stable.

I am actually participating now in a study of leptin replacement for hypothalamic amenorrhea (interesting to note I am the only participant with low leptin via massive weight loss; all of the other women have low leptin from being athletes). I have a 50% chance of being given leptin (I won’t know till 8 months are up). I have good reason to believe I’m in the experimental group, and as a result of taking this medication my hunger, appetite, blood sugar control, mood, energy, and even muscle growth have all changed to be much more favorable. Before taking leptin I always felt like a starving person, not a healthy normal weight person. I felt like I was delaying the inevitable, like it was pointless. Though I recognize much of what I am feeling and noticing may simply be placebo effect I honestly believe leptin replacement has made a tremendous difference in my well being. All post obese people should be on it as standard treatment, IMO.

ItsTheWooo said...

Whew... sorry for all these long posts but this is a very interesting topic and discussion :)

Well, regarding my leptin level, I think a BMI >25 would *probably* restore my leptin to a somewhat adequate thresshold. I say this because a BMI of 24.9 (weight 145 pounds) is the last time I had a period (that was, about 4 or 3 years ago). If we assume the begining of my amenorrhea is the beginning of a more severe leptin deficiency, then it stands to reason that less severe leptin deficiency is at a BMI greater than 24.9.

But, this is like the difference between extremely severe (so as to cause infertility) and mildly deficient (so as to have some fertility, albeit marginal). Even at 25, my leptin is probably still quite low.
For me, a level of body fat where doctors recommend you lose weight is the level of body fat where my body just barely works.

ItsTheWooo said...

Regarding leptin synthesis and LC eating...

In studies "leptin" seems to be kind of a place holder for "insulin"...that is to say, leptinemia correlates well with the level of insulinemia. So, in studies of fat sick people, the trend of leptin predicts the trend in health (lowering leptin correlating with improving health and weight loss, as lowering leptin is a marker for lowering insulin).

I think one reason my leptin is SO LOW is actually a direct result of LC eating, in fact. I think the odds that LC could increase leptin are pretty slim (no pun intended). I've read the insightful entry on ASP; ASP appears to work by increasing glucose-stimulated insulin release. It's still insulin doing the fat storing (moving fat into cells) right? Either way, I think we can both agree that the ability for fat to move in cells is really reduced on LC as compared to a carb-replete diet. The fat cell tends to be in deficit most of the time, and the net effect is that leptin production is markedly reduced.

I'm pretty sure if I ate more carbs my leptin level would come up a bit, because leptin follows insulin / fat storage. But then again, so would my body fat, so it is a moot point. If I have to increase insulin and gain fat, I would prefer to eat more calories from sugar free cheesecake and ribs to accomplish the same thing, that would at least be enjoyable, LOL (eating more fat, which reduces glucose tolerance, would raise insulin without raising carbs).

Douglas Porter said...


you said,

My hyperinsulinemia was entirely relative to food intake, but this is NOT the case for many obese people, and their hyperinsulinemia is related to more problematic less easily correctable defects in gluconeogenesis and severe insulin resistance...


I do think that for at least a certain subset of obese people - especially those teetering on type 2 diabetes - the primary problem is no longer abnormal insulin control and insulin hypersecretion. The problem is excess gluconeogenesis and severe peripheral insulin resistance. These are the kind of people who actually have higher blood sugar & insulin if they eat nothing at all, than if they eat a little bit of food, because the primary defect is in the blood sugar making process, and NOT the blood sugar lowering process.


... but in older people with more severe insulin resistance and livers that don't work right, low carb is less of a solution because their ability to make energy is screwed up.


I've come to believe obesity can be prevented, but not cured.

You might be interested in this site

They talk about various types of insulin resistance, but most interestingly they discuss how the alpha & beta cells of the islets of the pancreas function as pairs and the blood glucose sensing device is located in the beta cells with communication between the alpha and beta cells. Chronic high blood glucose levels can cause an amyloid plaque to form breaking the connection between the alpha and beta cells much as in Alzheimer's disease in the brain. The default state of the alpha cells making glucagon is to make glucagon. This signal is suppressed by the beta cells which make insulin when sugar levels are high. When the connection is broken, then the beta cells make glucagon continuously and often inappropriately raising blood glucose levels, which in turn raise insulin levels. It would appear to me to be an accelerated form of aging. I do not know what you would do about it, but this may be an explanation of the problem.


ItsTheWooo said...

Hi Porter,
That is a very interesting explanation of one reason why the liver makes glucose inappropriately. It seems, additionally, these amyloid plaques also may prevent blood glucose from being turned off.

The problem with that hypothesis is that it can't be the originating defect either, because it fails to explain why hyperglycemia exists in the first place. Amyloid plaque accumulation is a problem secondary to pre-existing hyperinsulinemia and hyperglycemia. Amyloid is removed by insulin-degrading enzyme; whenever there is hyperinsulinemia, amyloid builds up inappropriately. Thus, the reason every sad sad elderly diabetic I see in the hospital eventually becomes demented.

Since amyloid build up is secondary to an already preexisting hyperinsulinemia, it seems that yet again there must be an even more primary defect causing the hyperinsulinemia.

Personally I think some people's livers might make more sugar than others, and this predisposes them to become very vulnerable to diabetes and carbohydrate overload.

Diabetes is a polygenic disorder so I'm sure there are multiple vulnerabilities, but I tend to believe most if not all have livers that overproduce sugar just by genetics. Hyperglycemia doesn't become apparent until late in life when insulin resistance & beta cell death starts setting in.

If the problem were as simple as the liver making excess sugar in context (i.e. in the presence of insulin) this fails to explain why type 2 diabetics can have sugars in the thousands, but type 1 diabetics (who have normal livers) do not. If a type 2 liver was just making sugar normally they would not run sugars any higher than a type 1 with no insulin.

Amyloid plaque accumulation is, like neuropathy (the vagus

Bruce K said...

Woo: "In taubes book he talks about how impossible it is to eat stacks of pork chops, and how people in studies have difficulty getting participants to eat that much."

It would be impossible for most to eat a lot of calories from a total meat diet. Esp if the meat was raw or lightly cooked. Cooked meat has more appetite stimulating effects. Have you tried eating more raw and lightly cooked meat?

"I just kinda laughed reading that because the appetite blunting effect of LC only seems to really work when you haven’t lost any significant weight."

Have you tried a no-carb diet? The Bear would say eating any carbs or fiber will make you hungry. On the zero-carb diet (meat, eggs, butter, oils, limited cheese), hunger goes away forever. It's possible you've messed up your metabolism severely, and the only way your leptin would ever be normal is to eat raw meats or zero-carb (or both).

I ate all-raw for 18 months, but I developed problems due to drinking raw milk and vegetable juice. It's better to eat butter or ghee, than milk and cheese, IMO. I would also be wary of raw egg whites, because of enzyme blockers, anti-nutrients, and allergenic protein (ovomucoid). Prior to raw diet, I was eating an extremely low-carb, and struggling to lose more weight. I lost 10 lbs after switching to raw food, while eating MORE carbs, fat and protein than I had been on low-carb. Those carbs were from unheated honey and fresh juices (no fiber).

eclypz - owner - said...

Woo, have you tried metformin?

Also there are supplements and nutrients out there that can help correct a leptin problem without excess carbs.

Do a search for the Leptigen product from Avant Labs. It's no longer made but you can read about the ingredients and possibly make your own carb-free leptin cocktail!!

Low Carber said...

hehe loved the post. I agree with mtflight...write a book :)

Peter said...

Ah well, I was a little ticked off at the time... The book, yeah, one day. Probably when my wife completes hers!


Malahidael said...

Re: zero carb and The Bear, I did it for four months. Hunger does NOT go away forever. In fact, I was hungry all the time with all meat. I gained ten pounds and was constantly exhausted. It was very hard for me to regulate my energy. The Bear does say that zc is very difficult (perhaps impossible) for females. My husband went zc, lost 18 pounds, and is only hungry once a day--eats a pound of raw beef and a pint of cream, and is good to go for 24 hours. He is also stronger than he has ever been. I've gone OD, and am feeling better, but ask me in 4 months how my weight/energy are.

Peter said...

Hi Malahidael,

Yes, we're all a bit different. I've said to a number of people that my main interest is normoglycaemia without excess insulin. Weight is not necessarily the best indicator of this... Of course what we want on a practical basis may well be more than an HbA1c in the 4% zone. Ask my wife!


Ace said...

Since low insulin is the goal for weight loss, I wonder if supplements that increase insulin sensitivity, such as alpha lipoic acid, carnitine or vanadyl sulfate, might also increase weight loss, particularly once you've already minimized insulin production by going VLC.

What do you think?

Peter said...

Hi Ace,

Possibly so. Certainly metformin is mentioned by Jenny Ruhl as helping weight control...


crankybastard said...

Your gloating over the idiocy of the insulin-naysayers may be a tad premature, seeing as diazoxide appears to have a directly lipogenesis-inhibiting effect independent of its insulin-lowering action; thus, this study doesn`t necessarily tell us much about the (allegedly fat-blasting) effects of lower insulin, which the authors even admit somewhere in the full text.