June 4, 2009

Leptin, Weight Loss, and Health Improvement

You've probably heard you could reverse your diabetes if you lost weight. And if you have lost a lot of weight and kept it off, you've probably learned this claim is bunk.

Despite the intensity which which this claim is made by doctors, my experience and that of dozens of people who responded to my weight loss poll has been that weight loss, even large amounts of weight loss do little or nothing to change our ability to metabolize glucose.

You might wonder then why there is so much data suggesting that weight loss prevents diabetes. I've given this some thought, and my conclusion is that in the large population studies used to support the "weight loss prevents diabetes" meme what we are really seeing is something else entirely: Fat people who can lose weight easily are most likely those who do not have the fatally disturbed glucose metabolisms characteristic of Type 2 diabetes.

I have never seen a prospective study in which people positive for the genes associated with diabetes were able to prevent diabetes by losing weight. I have seen studies where thin people with diabetic genes already demonstrated defects in energy metabolism and mitochondrial function that made it much easier for them to gain weight.

But even though losing weight will not heal diabetes, weight loss does have some benefits beyond the obvious vanity ones. Everyone knows that weight loss decreases blood pressure--the other major cause of heart disease besides elevated blood sugar.

What they may not know is that weight loss may also decrease systemic inflammation--the inflammation, measured with the CRP (C-Reactive Protein) test that has been strongly associated with heart disease.

One reason that weight loss has these benefits is because of its impact on leptin, a hormone that has a major impact on whether our body stores or releases fat. I'm not going to go into the details of how leptin functions on the body here. It's a fascinating topic I've just started researching. A lot of hooey has been written about it by people selling miracle weight loss cures, so it will take me some time to sort the hype from the truth.

But some fascinating findings about leptin are these: When leptin is high, CRP rises, platelets tend to clot aggressively, and blood pressure rises--all factors contributing to heart disease. Some of the studies documenting this are:

Serum Leptin Level in Hypertensive Middle-Aged Obese Women de Moraes, Camila. The Endocrinologist. July/August 2005 - Volume 15 - Issue 4 - pp 219-221


Effects of Physiological Leptin Administration on Markers of Inflammation, Platelet Activation, and Platelet Aggregation during Caloric Deprivation Bridget Canavan et al. The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 10 5779-5785

There are a couple reliable ways of lowering leptin. One is by losing a lot of weight. All studies show that by the time an overweight person loses 10% of their starting weight their leptin levels have dropped dramatically. Interestingly, further weight loss appears to have no further effect on leptin level.

But significant weight loss is only one way of lowering leptin. As the Canavan study demonstrates, in normal people, at least, you can also lower leptin with a one day complete fast, even if no significant weight loss occurs. The graph on page 5 of the pdf version of the Canavan study shows leptin dropping from about 11 ng/ml to slightly above 3 ng/ml. Over three more days of fasting leptin does not drop much further.

By now my alert, physiologically aware readers are probably seeing where this is going. Because one thing we know about ketogenic diets is that physiologically they mimic starvation, i.e. fasting. Which suggests very strongly that it may be possible to get the leptin lowering effects of a fast from a ketogenic diet--i.e. a diet whose level of carbohydrates is low enough to switch muscles from burning glucose to burning ketones and, eventually, free fatty acids.

The actual carbohydrate intake that corresponds to a ketogenic diet varies with body size and probably with other physiological idiosyncrasies. One size does not fit all despite what you may have read. But you can tell when you've crossed the ketogenic boundary with your own diet when you lose or gain 2-4 lbs of water in a single day. This water fluctuation represents the draining or refilling of your body's glycogen stores. You can learn more about carbohydrate intake, water, and glycogen storage HERE.

For me, the boundary where I start to refill glycogen is at an intake of about 70 grams of carbs a day. I weigh around 142 lbs. A larger person may not hit that boundary until they take in 100 g of carbs.

There's some suggestion in the research that people on a ketogenic low carb diet do experience the same impact on leptin as do people who fast. To find the data exploring the relationship of leptin to a low carbohydrate diet is not easy, because the majority of studies in high impact journals which discuss "low carbohydate diets" do not describe true, ketogenic, low carb diets. For example, a famous study published in The New England Journal of Medicine which purported to show that the so-called Mediterranean diet was more effective than the Low Carb diet used a "Low Carb" diet where people were eating 120 g of carbs a day after the first few weeks. You can read the details of that diet HERE.

But there is a small amount of research tracking what happens to leptin on a low carb diet and it is quite impressive. You can read about this research in this metastudy published in Nature's journal Obesity Research:

Cardiovascular and Hormonal Aspects of Very-Low-Carbohydrate Ketogenic Diets. Jeff S. Volek and Matthew J. Sharman. Obesity Research (2004) 12, 115S–123S; doi: 10.1038/oby.2004.276

That study found:
There were greater reductions in leptin after the VLCKD [Very Low Carb Diet] (-50%) than the low-fat diet (-17%). The ratio of leptin/total fat mass also decreased more after the VLCKD (-45%) than the low-fat diet (-21%).
This impact on leptin, which occurs very fast during a ketogenic diet because of its physiological similarity to the fasting state may explain the dramatic drop in blood pressure many people experience during the early stages of a low carb diet.

It also suggests that the low carb diet, independent of weight loss, might also have a positive effect on lower CRP and help decrease inflammation and the tendency of blood to clot.

There is one more take away message from this research. One that is lost on many doctors and the health media. Even on the worst weight loss diets--like the famed medically supervised controlled fasts where people are fed mostly on vitamin enriched fluids containing protein, sucrose and omega-6 vegetable oil, which make up an alarming about of mainstream 1990s obesity research--weight loss stops lowering leptin levels once 10% of weight has been lost.

So no matter how fat you are, you should be getting the leptin-related benefits of weight loss, whatever they are, from a weight loss of no more than 10% of your starting weight. And as most low carb weigh loss dieters have learned, while it is difficult and often impossible to get to goal on even a perfect low carb diet, it is easy to lose that 10% of starting weight. Most heavy low carb dieters can easily achieve 20% weight loss, though after that it gets tough-to-impossible, depending on how damaged your metabolism might be.

There's a down side to this, of course. Because when leptin levels drop our metabolisms slow and our brains start hunting for food. Boosting leptin, which many pop diet gurus advocate, may not be the answer, given the negative cardiovascular effects associated with boosting leptin especially the dramatic rise in CRP it causes.

So there's no miracle cure here, folks, but a lot to think about.



Gretchen said...

Some people *can* improve BG control when they lose weight. Look at David Mendosa. He now has an A1c in the 4s, controlling with diet and exercise alone.

A lot can't.

What is crap is when doctors promise everyone that it will happen to them.

ItsTheWooo said...

Interesting, but I highly doubt the claim that lepin levels do not decrease further after 10% of weight loss. This does not make sense with what I have researched, being that leptin is proportional to fat mass, and will be lower at any given fat mass in a weight reduced person.

In myself, I developed hypothalamic amenorrhea (leptin deficiency) at 140-130 pounds. I had menstrual cycles at 280-200 pounds. My starting weight was 280 pounds. So clearly my leptin was decreasing with more and more weight lost and everything I read suggests this is so.

Even though leptin - when high - does a lot of bad things, I think it is just as important to mention that leptin - when too low - does bad things too... and this is a risk ex fatsos like myself will run. When leptin is too low, your thyroid won't work properly, you are chronically hungry/tired, you do not build lean tissue properly anymore (muscles/bone loss giving that post-obese flabby look), if the deficiency is extreme you will become infertile. Diabetes risk increases with low leptin because leptin regulates cortisol and glucagon release (so excessive sugar is made all the time with low leptin).

It is possible to be leptin deficient after weight massive weight loss, it is actually very common, and IMO it is a major cause of recidivism in weight management.

I have been on leptin replacement for a few months and weight maintenance is effortless now. I'm almost scared to be off it because I don't think I have the psychological tools to deal with the chronic hunger/tiredness anymore.

Jenny said...

David Mendosa's situation is unusual for many reasons none of which are appropriately discussed on a blog.

If you don't eat hardly anything at all and exercise four or five hours a day your blood sugar will improve greatly too. But that isn't reversing diabetes, that is controlling blood sugar.

Reversing diabetes would mean eating like a normal person--like my son or my 93 year old mom who can eat a big slice of cake and end up at 83 two hours later.

That's curing/reversing.

But when you only get good blood sugars when you don't eat carbs or when you spend 4 hours on a treadmill to burn them off, that is something different. And many type 2s can do that without dropping a pound if we stop eating carbs.

Mendosa was a devoted low fat fan before he started Byetta and did not limit his carbs until he started it.

Stephan Guyenet said...

Hi Jenny,

Glad you're reading about leptin, I think you're going to get sucked in! I'm starting to think leptin is the linchpin and insulin is downstream, when it comes to metabolic syndrome and maybe even some type II diabetes. Leptin-sensitive neurons in the hypothalamus dictate insulin sensitivity. I may write about that soon.

I think that the apparent halt in leptin decrease after 10% weight loss may be due to a confounding variable: hunger. The leptin level integrates total body energy stores, including fat mass and food intake. If you're calorie-restricted, your leptin level will be much lower than if you were eating normally at the same fat mass level. I suspect that leptin will continue dropping past the 10% weight loss point in people who lose weight without deliberately restricting calories.

Intermittent fasting may be a good way to help restore leptin sensitivity (it works for insulin sensitivity). It upregulates leptin receptors in the hypothalamus if I recall correctly. A ketogenic day once a week might be effective as well. You may not have to go on it chronically to get benefits.

chmeee said...

Hi Jenny

Woould you class a low normal BG two hours after an OGTT as a cure / reversal ? Just curious.... :) BTW, love the blog, keep up the good work.

Jenny said...


My concern with the refeeds is the sudden and dramatic increase in CRP and platelet aggregation in normal women who boosted leptin. People with diabetes already tend to have bad CRP so I wonder if the refeeds could push them towards heart attack or stroke.

Long term, almost all the devoted low carb dieters who post relentlessly online stall out way over goal and even when they drop calories dramatically, they often stay stalled, which is why I believe some of data about weight loss and long term metabolism slowing. What exactly is the connection with leptin isn't clear.

I have another project I'm working on right now that keeps me from being able to do total immersion in this subject, but it is fascinating to me and I am going to keep at it.


The GTT is such an unphysiological test I wouldn't use it as a standard. If you can eat a bagel and end up at 130-140 at 1 hour and 95 at 2 hours, and do it every day for a month and stay normal I'll call you cured.

After long stints of very low carbing or extremely tight control with supplemental insulin I will usually have excellent blood sugar control for a few meals, probably because I've stored insulin. Then I burn through the saved up stuff, or whatever it is, it goes back to my usual highs without insulin.

ItsTheWooo said...

As posted earlier, I am confused about this proposed "halt in leptin decrease after 10% weight loss".
I have never, ever heard about this before, everything I have read suggests that leptin increases and decreases with weight change.
In myself, I have observed signs of leptin deficiency worsen and improve with different weights. As I said, I had no signs of leptin deficiency at 200 pounds, but I did have them at 140 pounds.

My start weight was 280, so hypothetically my leptin level shouldn't have decreased beyond 250. There is no way my natural leptin production at my present weight (123) is as high as it was at 250 pounds. Absolutely no way.

Jenny said...


I may be confusing metabolic slowdown as a whole with leptin here. The slowdown in metabolism at 10% lost which doesn't get worse after 10% is documented in the research at Rockefeller University done by Dr. Hirsch and Liebel.

As I said, I'm really up to my ears right now in a project so I can't check on this for a while.

Gretchen said...

I did not say that losing weight would cure or reverse diabetes. Just that it can allow some people to control with modified diet alone. You still have the defective beta cells and you have to be vigilant.

I give examples in my book "The First Year: Type 2 Diabetes." One guy said that after losing almost 100 pounds, it was difficult for him to get BG over 100.

I used David as an example because a lot of people are familiar with him, and I agree that discussing his particular situation is not appropriate here.

Jenny said...

My poll collected its responses from readers of this blog and of a low carb discussion forum, so the people posting to the blog were people who were likely eating low carb.

The Poll Results are worth a look because while anecdotal, this is a lot more than 2 examples, and very few people reported significant change in their glucose metabolism when eating carbs.

Bernstein wrote back in the original version of Diabetes Solution that he'd seen one case of complete reversal with weight loss, in a case of a young man.

I never said it didn't happen, only that it was rare, and I think we need to eliminate all cases where the "cured" diabetic is eating very little food or very low carbs.

Cured means you can eat 300 g of carbs a day and get normal blood sugar. Lots of people do.

Anonymous said...

insulin resistance-->leptin resistance-->eat a meal and leptin levels go higher but are unable to appropriately signal the hypothalamus that you are "full"-->type two diabetes

Your other claim that "I have never seen a prospective study in which people positive for the genes associated with diabetes were able to prevent diabetes by losing weight." I believe is not supported by the evidence available. In fact there is a study titled: TCF7L2 Polymorphisms and progression to diabetes in the DPP. This study examined the two most strongly associated variants to Type 2 diabetes and whether they were at greater risk for the progression from IGT to T2D. The authors concluded that "we did not detect significant interactions between genotypes at either single nucleotide polymorphisms and the DPP interventions" leading them to believe "that a behavioral intervention can mitigate the risks conferred by genetic background". Weight loss through diet modification needs to be connected with appropriate vigorous exercise (best non pharmacologic intervention to reduce insulin resistance and leptin resistance) which will give patient's pancreas a longer lease on life! There seems to be new pharmacologic data soon to be published with an even stronger effect on these IGT insulin resistant patients...

Jenny said...


You've got the finding of that study backwards. READ IT HERE

From the summary: Results Over an average period of three years, participants with the risk-conferring TT genotype at rs7903146 were more likely to have progression from impaired glucose tolerance to diabetes than were CC homozygotes (hazard ratio, 1.55; 95 percent confidence interval, 1.20 to 2.01; P<0.001). The effect of genotype was stronger in the placebo group (hazard ratio, 1.81; 95 percent confidence interval, 1.21 to 2.70; P=0.004) than in the metformin and lifestyle-intervention groups (hazard ratios, 1.62 and 1.15, respectively; P for the interaction between genotype and intervention not significant). The TT genotype was associated with decreased insulin secretion but not increased insulin resistance at baseline. Similar results were obtained for rs12255372.

Conclusions Common variants in TCF7L2 seem to be associated with an increased risk of diabetes among persons with impaired glucose tolerance. The risk-conferring genotypes in TCF7L2 are associated with impaired beta-cell function but not with insulin resistance.


HOWEVER, you have to remember that the definition of "progressing to diabetes" in this study was to compare blood sugars of people on metformin to blood sugars of people off metformin.

After the washout period when people went off metformin, the advantage seen in the metformin group evaporated as many people's blood sugars rose to diabetic levels.

This was discussed at length in published critiques of DPP.

So what we see here is no difference in the impact of the gene, but a difference in blood sugars between people using metformin and those not.

George said...

I never took the reverse diabetes claim for weight loss literally. My experience is that it helps control your BG which controls your symptoms. You are still a diabetic as eating a piece of cake would immediately show.

Anonymous said...

the effect of genotype was not statistically significant between groups and despite being clinically disadvantaged these people still benefited from intense lifestyle modification or metformin. There was still a reduction in the incidence of diabetes compared to those just getting placebo. The risks conferred by the variants were indeed related to BCF but did not preclude these folks from responding favorably to the treatments (including weight loss + exercise)
The study was a comparison of four groups and metformin was compared to a placebo group as was rezulin (discontinued) and intense lifestyle. No drug continues to work once it is stopped that was never part of the original hypothesis. Even if metformin had a lingering effect, its 31% reduction in progression pales in comparison to the 58% seen in lifestyle. In other words, treating insulin sensitivity in one organ is no physiologic match to treating the entire insulin resistant body with exercise...

Rad Warrier said...

"Reversing diabetes would mean eating like a normal person--like my son or my 93 year old mom who can eat a big slice of cake and end up at 83 two hours later."

I do end up normally around 4.5 mmol/L (81 mg/dL) 2 hours after eating a big slice of cake, apple or blueberry pie, a cup of ice cream or very sweet Indian sweets like Laddoo, Gulab Jamun or Rasgulla. To ensure that it is not a reactive low, a couple of times I have checked blood glucose levels at half hour intervals and many times at 1 hour intervals. No, there is no spike anytime. But if I take a normal lunch of rice and curries or similar medium carb food, my 2 hour reading can be anywhere between 6 to 7.5 (108 to 135.) Looks like sweet things stimulate my pancreas to produce more insulin!

Might add that I could bring down my blood glucose levels from diabetic to more-or-less non-diabetic levels through eating less than before, exercising and taking Metformin.


Boz said...

My A1C has dropped to 5.3 and my blood pressure from 150/86 to 120/76 on the last 2 months. I've been eating a lower carb, more organic diet and lost 26 lbs. My insulin usage has been cut nearly in half.

Quilt fanatic said...

If find this fascinating and will further research it myself. Thank you for your work.

I have a question. Although I am already a low car eater, I would like to know what is considered to be a safe 'low carb' diet intake per day? How low can we go?

Jenny said...

You can go to Zero on the carbs, as long as you consume enough additional protein to allow the liver to create glucose via gluconeogenesis to fill the needs of your brain. I put together a calculator that helps with this. It's pretty rough but might be helpful.

Metabolic Calculator.

The assumptions are listed on the screen that gives you your results.

If you eat no grains at all you should supplement with B vitamins. Because a very low carb diet can be diuretic at first, you might need to supplement with potassium and magnesium.

The biggest problem with no carbs or very low carbs is the tendency to get bad breath. This may be from ketones or from consuming too much protein which creates ammonia as it is broken down.

I've tried very low carb (10g a day or less) but it feels too weird for me to stick to for more than a week.

Quilt fanatic said...

Your calculating tool is excellent I hope everybody checks it out. It was actually quite helpful and I printed out a copy of my instructions to follow. You have answered many questions. Thank you so much.

caring dietitian said...

Nice post! I really dislike those people who spread false health claims. They do nothing but confuse individuals who are trying or even struggling to be healthy. Diabetes is not easy to deal with. The changes it entails cause not only physical but emotional changes as well. And to give false hopes to these patients is just unacceptable. Thanks for shedding some light into this "weight loss reverses Diabetes" issue.
Also, thanks for the information you share about Leptin. This is quite new and not a lot of people are familiar with it. Once again, thank you.

Trinkwasser said...

My readings on leptin and leptin resistance have so far been somewhat contradictory, presumably since it has only recently been discovered and is still being researched.

Does anyone have a "Leptin 101" type source? (Preferably one updated regularly)

Our familial genes seem to show a disconnect between leptin and insulin resistance in that it's us skinnies who have worse symptoms of metabolic syndrome/diabetes and some of the people who gain weight have much better numbers. I put on weight on a high carb diet but didn't start ballooning until fats were severely restricted: doing the opposite reversed the process just as rapidly. In my case the BG preceded the weight gain and the BG control reversed it, which does not tie in at all to *some* claims for leptin, but which does tie in with others.

Jenny said...


I haven't found all that much about leptin. Partially that is because researching obesity and weight loss is a miserable draining process where you encounter 150 idiotically designed or venal studies for every one that might point to useful information.

There is just too much money in selling bogus weight loss products--surgical, pharmaceutical, and supplements, and too much emotional investment in pre-existing beliefs among researchers.

I can only do so much of it before I burn out reading the crap, so I can't promise to give it the rigor I've given the blood sugar-related research.

Trinkwasser said...

You too huh?

Then what's worse is when the conclusions of the crap papers are trumpeted by "experts" like these

"It just doesn't make scientific sense," says Lowden. "These faddy diets irritate me because they make it difficult to help people realise that in the long term, there is only one way to lose weight and stay slim, and that's through eating a healthy, balanced diet and doing more exercise."

IF it was that simple we could all pack in and go home. Maybe in only s few more decades they'll start to notice the disconnect between their beliefs and the Real World.


if I find time I'll dig through some of these, a generally reputable source