Saturday, July 9, 2011

How Does Gastric Bypass Surgery Cause Fat Loss?

Gastric bypass surgery is an operation that causes food to bypass part of the digestive tract.  In the most common surgery, Roux-en-Y bypass, stomach size is reduced and a portion of the upper small intestine is bypassed.  This means that food skips most of the stomach and the duodenum (upper small intestine), passing from the tiny stomach directly into the jejunum (a lower part of the upper small intestine)*.  It looks something like this:


Lovely, isn't it?  Gastric bypass and related surgeries are the most effective medical treatment for obesity by far, typically causing patients to lose most of their excess body fat, and improve quite a bit metabolically.  The mechanism seems pretty straightforward at first glance: shrink the stomach so you can't put much food into it, and you will lose fat.  Bypass part of the intestine that absorbs calories, and you will lose even more fat.

But as is often the case in biology, if you look more closely the situation becomes more complex.  I noted years ago that people who undergo gastric bypass often see their diabetes vanish almost overnight, in a manner that cannot be fully attributed to reduced calorie intake or fat loss (1, 2, 3).  That's probably because of changes in nutrient sensing by the small intestine that occur after bypass.  When it comes in contact with nutrients, the small intestine sends messages to the brain via hormones and nerve signals that communicate the calorie content and macronutrient composition of the food (4), so the brain can respond appropriately. The brain then causes you to feel full, and coordinates activities in various tissues to make sure the nutrients get handled appropriately. 

It turns out that the typical Roux-en-Y surgery does not reduce the proportion of calories absorbed from food much, if at all.  Reduced stomach volume per se also does not explain the effect very well, as procedures that solely restrict stomach volume are not very effective in the long run (4A)**. If obese people who have had gastric bypass are losing weight simply because they can't eat/absorb enough food, then why aren't they hungry?  Why does gastric bypass often improve thyroid status rather than decreasing it as calorie restriction does (5, 6)?  This suggests that the body fat "setpoint" has been reduced, meaning that the body "wants" to be leaner rather than obese.  Another strange thing about gastric bypass surgery is that it doesn't work on everyone.  A case report of a person who lacks a functional melanocortin-4 receptor, a protein critically involved in body fat regulation in the brain, shows that he scarcely lost any weight after gastric bypass surgery (7).  This suggests that the system in the brain that regulates body fatness has to be intact for gastric bypass to be effective. 

One of the important things the small intestine does is communicate information to the brain that is used to determine the reward value of food (8).  The small intestine, especially the duodenum and jejunum, is critical for assigning food reward (8).  One might guess that bypassing the upper small intestine would have a major impact on this process.  Well, apparently a few clever folks have already though of this, because it has been studied and published.  Roux-en-Y bypass changes food reward in obese rats, making them relate to food more like lean rats, and several studies in humans are consistent with that idea as well (9, 10, 11, 12).

Although there are probably other contributing factors, the effectiveness of gastric bypass surgery is likely to be related to its ability to dampen food reward, and thus lower the "defended" level of fat mass, by interfering with the intestinal signals that the brain uses to assign reward to foods.  The two most effective fat loss strategies I've encountered, gastric bypass surgery and drinking bland liquid food through a straw (13, 14), both seem to rely on reducing food reward.


* A less common version of the Roux-en-Y surgery bypasses the jejunum as well.
** Although stomach restriction could have an effect by increasing stomach distention with a smaller amount of food and/or changing ghrelin signaling.  The former is a major satiation/satiety factor, and the latter is both a satiation/satiety factor and probably a body fat homeostasis hormone as well.

74 comments:

Theo said...

Can you explain how the small intestine assesses food reward? From you previous posts I go the idea that food reward was caused by hyperpaletable food (food with added salt, fat, sugar, flavorings, etc) as registered by a person's sense of smell and taste. Given bland food (containing the same nutrients), the body fat set-point is lowered. I'm not really sure what the mechanism is here.

Stan (Heretic) said...

This is very interesting, and counter intuitive. I used to think that it was indeed because of the reduced calories but the fact as you pointed out, of the lack of hunger is very revealing!

What exactly is happening inside the cut-off portions of the stomach and duodenum? Are they completely sealed off? Do they fill up with fluid? Where do the pancreatic enzymes and bile flow in, after a bypass surgery?

Gordon said...

Fascinating analysis again. Would you care to speculate what' signals' are not being sent to the brain from the bypassed organs? Surely confusing for the brain?

praguestepchild said...

Interesting Stephen. I came across a lot of papers about bariatric surgery when I was trying to do a little research about ghrelin. There seems to be a lot of conflicting results there, from what I saw at least.

Any thoughts on the role of ghrelin in gastric bypass?

LisaElizabeth said...

I had a gastric bypass surgery two years ago at age 35. I lost 80 pounds without effort. The last 20 I have to go will require some effort: like normal people, diet and exercise :-)

The exact surgery I had has been highly studied and published scientific papers: www.clos.net

Several things I remember from the education packet: The ghrelin signals would go away. The vagus nerve was cut. Also, Stan, the stomach and duodenum are left alone, with blood supply and the the enzymes are able to flow "normally" and meet up with the food at a later part of the intestine.

I can tell you from experience how amazing it is not to "feel" hungry; that gnawing constant desire for foods (usually "bad"). Foods still taste amazing, but the new element is whether or not my stomach/intestines will tolerate the food. "Bad" foods cause vomiting, diarrhea and/or overall feeling poorly. I spent a year, slowing re-introducing foods back into my diet. This has made a bit of a re-training on what tastes good. The burger and fries still taste good to the tongue, but the body does not always agree! Even better, my stomach is still small enough that I cannot eat a whole burger.

BTW, just after surgery, I discovered tow WAP foundation, and have gone to raw milk and organic foods. My overall diet is about 80/20, some days better than others.

Diabetes was gone in a few weeks. Other health issues have been warded off (provided I don't regain the weight). I figure I am more like a "normal" person now, in that I eat more appropriate portions and I have a more responsive body to exercise and potential weight loss if I want it. (I have decided to have a baby before pursuing the final loss of pounds to goal weight).

I no longer get the "reward" I used to when eating high fat or high sugar foods. I don't get that chemical "high". Is it the dopamine or serotonin stuff that makes us "feel good"? Anyway, those are not triggered from food nearly as much.

I am glad to answer questions, to be a "live subject". Thank you for all the great articles on food reward. I may not understand all of the science, but so much of it makes sense. I am glad to have the surgery as a "tool" in my lifelong struggle with food (emotional eating, years of Pavlovian training to desire certain foods).

Ronald Pottol said...

Any explanation for absorbing enough calories, but not enough micro nutrients? I know that people who have had the surgery need to take supplements, or they will get osteoporosis in just a few years.

Stabby said...

If you know, it would be good if you could do a post with an explanation of exactly how food reward influences insulin sensitivity and thyroid to such a degree that disease would be completely reversed by an alteration in food reward. An evolutionary explanation would be neat too, why would there be such an intimate connection, if indeed that is the mechanism?

Todd Hargrove said...

Stephan,

This has nothing to do with gastric bypass but ... I wonder whether your theory can explain the following common observation. A person eats high reward junk food for years through their youth and is lean. Then, maybe around college, they gain a bunch of weight. No change in diet, but all of a sudden a huge increase in weight. One popular explanation in the paleosphere would be that something in their metabolism "broke" after long term exposure to toxins. Is that plausible? Can you explain this situation in terms of reward? Put another way, are there long term cumulative effects of a high reward diet that don't show immediately?

luckybastard said...

@todd

ahhh the infamous freshman 15. my personal theory, totally circumstantial and nonscientific, is that it may be more of a cortisol issue that is precipitated by external stressors that break the metabolism. when compared to the average student's home life from which they just left to college life there tends to be much less sleep and possibly more stress from studying. combine that with the very real possibility that the quality of food from the dining halls is inferior to that of home and may have higher reward and i think we can build a nice scenario for accelerating metabolic syndrome. just a theory though

Todd Hargrove said...

@luckybastard,

I'm not so much interested in explaining the freshman 15 - that can be done in many ways - cortisol as you say or less sleep or more reward in the from of beer or pizza. I'm interested in the general idea of whether reward can increase fatness in a non-linear way, as toxins might when they eventually "break" something.

john said...

They key factor for weight loss in bypass operations is what happens to the vagus nerve afferents and efferents at surgery, and what happens to the incretin hormones of the small bowel and hypocretin neurons in the hypothalamus. This is why there are so many unusual outcomes from bariatric surgery because the surgeons themselves have zero idea about what they are doing to cranial nerve ten. Its akin to old frontal tractotomies verses modern day deep brain stimulation. Moreover, the epigenetic effects that happened prior to the gastric surgery of the hypocretin neurons are critical for prognosis on the amount of weight loss and the residual fat that will be left. The real interesting part of this story is what happens when you temporarily disrupt the vagus nerve and then turn it back on with direct neural stimulation versus surgical resection. Neurosurgeons routinely do this while bariatric surgeons have zero experience with this. Bariatric surgeons usually permanently damage the vagus nerve afferents and efferents with their Duodenal and Jejunal anastomosis......when we neurosurgeons temporarily turn on and off the vagus nerve some very interesting things occur to the brain gut axis on functional MRI. Dr. K

Andreas said...

Wow, that's a complicated theory. I think there is a much simpler explanation.

Gastric bypass results in an enforced low carb diet through the reduced volume that can be eaten, plus the slower digestion of starch resulting from disconnecting the duodenum (and the amylase from the pancreas).

Going on a strict low carb diet sometimes makes the symptoms of type 2 diabetes vanish overnight. Just like gastric bypass sometimes does. Coincidence? I think not:
http://www.dietdoctor.com/across-the-river-for-water-surgery-for-diabetes

Of course, low carb diets have also been proven to give significantly more weight loss than conventional low calorie advice. At least thirteen high quality trials (RCTs) has shown a significant advantage:
http://www.dietdoctor.com/weight-loss-time-to-stop-denying-the-science

Luckily there is a smarter and more natural solution to the obesity epidemic than cutting away your stomach or giving up food for "bland liquid from a straw".

antispirit said...

"Bland liquid through a straw"

I'm seeing flashbacks to Stephan's first installment of this food reward series. Isn't that what those test subjects ate from that vending machine from Hell?

I would hypothesize that any disruption in the way a person digests food would do it. Isn't food reward influenced greatly by conditioned experience? Nothing like a novel situation to throw everything out of whack. Not to mention the fact that the entire eating ritual is disrupted. Meal time is a drastically different picture. I would assume, at least.

Jenny said...

Stephen,

The "cure" of diabetes that follows WLS surgery is NO different than what happens to blood sugar a week into an Atkins diet. And it is well known that hunger vanishes on a ketogenic diet too.

When I've looked at the daily food logs people post who have had this surgery it's clear they are eating ketogenic levels of carbohydrate.

In addition, as the stomach stretches back out, allowing more food, and more carbs, to be digested, blood sugars go right back up (a fact you don't hear touted by the WLS community, but I've cited the research on my blog.) This also suggests it is the carbohydrate consumption at work.

There is NO study that compares blood sugars of people with WLS against those of people eating the same number of carbs with normal stomachs. Until there is, I think we have to consider the claims for WLS reversing diabetes to be misleading.

My guess is that the projectile vomiting that occurs when people eat any significant amount of carb has a lot more to do with the effectiveness of WLS than any other factor. Think of it as Antabuse for carbs.

Melchior Meijer said...

Andreas and Jenny,

Gastric bypass immediately restores glucose tolerance in some people. Previously diabetic patients have normal OGGT’s, overnight.

http://care.diabetesjournals.org/content/33/2/375.full.pdf

This effect is not seen after carbohydrate restriction, quite the opposite. I don’t say carb restriction isn’t a smart intervention in diabetes, but it controls the disease, it does not correct it. Something very crucial tot glucose metabolism must be going on (or not going on) in the upper intestine and it should be investigated.

Andreas said...

Melchior,
"Something very crucial tot glucose metabolism must be going on (or not going on) in the upper intestine and it should be investigated."

I don't think this is necessarily rocket science. The most obvious explanation (it seems to me) is the bypassing of duodenum, where the amylase is released, degrading starch to glucose.

By the way: In the case report you link to the bypassed patient still got a blood glucose of over 12, rapidly, after peroral feeding. I'm not sure that really constitutes normal glucose tolerance even if the blood glucose was normal after 2 hours. This 12 mM spike was the result of ingesting just 37 grams of carbs, barely half of a normal glucose load when doing an OGTT. Normal? I think not.

Rob said...

Todd Hargrove,

It think it's primarily a unintentional reduction in activity, in high school and college people are on their feet all day, going to class, working a part time job, etc. Especially in college if you live on campus, you're walking everywhere.

Not saying this is the case with everyone but with me for example, I naturally slimmed down in high school because I was on my feet all day (walking to school, to class and I had a job) but I was eating fast food everyday.

I'm sure there's other factors but I think junk food allows people to passively overeat and combined with a more sedentary lifestyle as they grow older, the pounds start to pack on since their energy imbalance increases.

And since most people aren't genetically lean, their body can't compensate enough (e.g. through NEAT) for the increase in calorie intake relative to their lower energy needs.

Does this make sense Stephan?

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ItsTheWooo2 said...

Thank you Jenny for being the voice of sanity.

It's ridiculous to say that WLS has no effect on nutrient absorption. It is plainly evident that WLS works because it prevents blood glucose surges which then result in low insulin levels. The same thing can be accomplished by a deep ketogenic diet, low carb moderate-low protein diet ala atkins induction. I know because i did it. I went from always hungry to hemorrhaging body fat.

The fact that WLS is relatively temporary and people evnetually learn how to trick their surgery into consuming more glucose is why they regain weight.

WLS does NOT prevent starvation induced hypoleptinemia and attendant thyroid downregulation. This is completely false, WLS is no different than regular dieting when it comes to metabolic slowdown and starvation symptoms. There are trials being done RIGHT NOW for the application of leptin replacement post weight loss surgery.

I work with several people who have had bariatric surgery.

The surgery does nothing that a low carb diet can't do. THe surgery works because people find it impossible to eat and tolerate the shitty food they were eating before, they are FORCED to eat low glucose food and take in few calories. The hunger reduction comes when the insulin levels drop allowing their bodies to access stored fat easily.

The one thing bariatric surgery does that low carb diets can't do is it forces the patient to stay on their diet.

If a person does low carb (with a very poor understanding of why carb restriction is important) nothing is going to stop them from digging into the box of donuts at work or having a huge slice of strawberry shortcake. I am 115 pounds and if I used to weigh 280 and if I feel like having a massive slice of cake at work, nothing prevents me from digesting it and keeping it down and spiking my sugar.

Now my coworker who had gastric surgery, if she tries to do the same thing, she will gag, she will vomit. She HAS NO CHOICE but to stay on the "diet". It's forced bulimia. It's forcing her insulin levels low all the time because it is impossible for her to eat the foods she can not tolerate (high glucose ones).

ItsTheWooo2 said...

Melchior - I don't doubt there are some "perks" to gastric surgery which help improve blood sugar regulation and hunger (independent of the obvious - the fact that gastric surgery makes you vomit everything that spikes sugar).

However what makes you think an "exaggerated GLP-1 release" is a defect that is being corrected?

If a fat person takes a stimulant they will eat less and move more, but no one argues that fat people are deficient of amphetamines.


If messing with your GI tract can trick your body into producing a lot of GLP-1 so that glucagon levels are suppressed, and diabetes/insulin levels decrease, that doesn't mean a lack of GLP-1 caused the diabetes in teh first place.

They make diabetic drugs that dupe or augment GLP-1. Januvia, byetta. Januvia and byetta is much safer than gastric bypass and does the same thing.


One lesser known complication of gastric surgery is excessive beta cell growth and resulting hypoglycemia.
GLP-1 makes beta cells differentiate.

Perhaps this side effect is a direct result of chronic abnormal GLP-1 levels from the gastric surgery?


http://meltingmama.typepad.com/Patti20handout20120-2009.17.07.pdf

Occasionally this side effect is so severe a pancrectomy:

"In very severe cases, pancreatectomy has
been required for control of insulin secretion; pancreatic
pathology demonstrated diffuse islet hyperplasia and
expansion of beta-cell mass, with no insulinomas."


If the "treatment" results in the pancreas growing beta cells like it's a cancer, it's safe to say that the high levels of GLP-1 produced after bypass surgery is not a cure but yet another bandaid treatment.

ItsTheWooo2 said...

Oh and by the way, GLP-1 levels are dependent on nutrient composition of your diet. I've known this since I was in my early 20s when I was just learning about why high fat low carb diets work, and why I ALWAYS feel full if I eat something high in fat but not something low in fat regardless of carb or protein level.

Dietary fat is much better at augmenting GLP-1 levels than carbohydrate. This may be yet another reason fat people are biologically predisposed to grow obese when the diet is rich in carbohydrate.

http://jap.physiology.org/content/106/1/122.full

"In summary, these data suggest that removing fat from the diet expedited exogenous glucose delivery into the systemic circulation and reduced the concentration of key gastrointestinal peptides, yet maintained plasma glucose concentration at control levels. "


It has been suggested that in some fat people, dietary carbohydrate blunts glp-1 release whereas fat produces it normally.

http://www.ncbi.nlm.nih.gov/pubmed/8984033

"There was pronounced attenuation of plasma GLP-1 secretion to oral carbohydrate in the obese compared with lean subjects but no such difference in response to oral fat load. There were no differences in the plasma GIP responses to carbohydrate or fat feeding. There was an apparent fall in plasma GLP-1 values in all subjects after administration of heparin.
CONCLUSION:

Postprandial GLP-1 secretion in response to oral carbohydrate is considerably attenuated in obese subjects. The cause of this attenuation of GLP-1 secretion is not known although we suggest that both this fall and the overall reduction in GLP-1 values in obese subjects may be related to an increase in plasma non-esterified fatty acids."



The take home message:

WHAT you eat affects GLP-1 a lot.

There is evidence fat people do not produce GLP-1 normally.

There is evidence that if certain fat people eat a low carb high fat diet, their GLP-1 release will be much more normal.


A fat person with a MCR4 receptor mutation will not be helped by a low carb diet - or gastric bypass - as their obesity is not a result of "glucose intolerance" (a broad label for anyone who does not metabolize glucose and insulin normally). The person with the MCR4 mutation has a central defect in appetite regulation, sort of like praeder willis. In most cases of "glucose intolerant" obesity the appetite regulation is fine, the problem is the metabolism is broken and so appetite is increased as a result of that metabolic derangement.

Steve said...

ItsTheWooo2,

For someone who appears to have a great deal of respect for science, I find it somewhat puzzling how many of your posts contain the following sentiment:

"I know this is a fact because it happened to me!"

Stephan Guyenet said...

Hi Theo,

The small intestine detects the calorie content of food, and the brain uses that information to assign reward to the cues associated with what you just ate (e.g., smells).

Hi Stan,

I don't know.

Hi Gordon,

There are probably a lot of signals that are not being sent, which is why reward is altered. The stomach also alters ghrelin secretion in many cases, which could be part of the effect.

Hi Praguestepchild,

Yes, it is confusing. Some studies are consistent with the idea that ghrelin could be a major contributor, others directly contradict it. I have a hard time believing that a reduction in ghrelin is necessary for the surgery to be effective, given conflicting results like that, but it could very well contribute in some cases.

Hi LizaElizabeth,

Thank you very much for sharing your experience.

Hi Todd,

Age certainly increases susceptibility to weight gain, but there's another factor associated with college that could also contribute: beer. I doubt many people in college are metabolically "broken" unless they're diabetic, but I'm willing to have my mind changed.

Hi Jenny,

Carbohydrate restriction cannot explain the extreme improvement in glucose tolerance that occurs with gastric bypass. If you give diabetic bypass recipients a glucose tolerance test within days of surgery, most of them will no longer react in a diabetic manner to a normal glucose load. Carb restriction can't explain that.

Also, when they have obese controls who lose an equivalent amount of fat by eating a low-calorie diet (with a similar amount of carbohydrate as the bypass recipients), they don't end up with nearly as impressive improvements in glucose control as bypass recipients.

There is clearly something going on with gastric bypass that is independent of carb restriction, and is also independent of calorie restriction. My colleague David Cummings wrote this article that reviews the evidence I just discussed:

http://www.ncbi.nlm.nih.gov/pubmed/19363506

Hi Melchior,

Yes, exactly.

Steve said...

I would think that reduced ghrelin is a part of the gastric bypass success, but I agree it's not all of it. VSG surgery, which only shrinks the stomach, does seem to be successful, although long-term results aren't available yet.

Andreas Eenfeldt said...

Stephen,
Regarding OGTT sometimes normalizing after GBP: After disconnecting the stomach and duodenum glucose in fluid taken per os is reasonably absorbed much quicker as it basically ends up in the small intestine right away.

When doing an OGTT the blood sugar is tested after 2 hours. After GBP that is a long time after the very rapid spike in the blood sugar. Improving the OGTT number by missing the blood sugar spike hardly makes anybody healthier, it just makes a number on paper improve.

A strict low carb diet can often normalize the blood sugar for a type 2-diabetic right away. Then there is no need to remove a healthy organ.

Melchior Meijer said...

Andreas,

Thanks. A 12 mMol/l peak is hardly normal, I agree. But this guy's glucose tolerance was still significantly better if the load was given perorally, compared to gastroduoduodenally. Unfortunately, they did these GTT's with Nutridrink, not with a pure glucose solution. Nutridrink contains hardly any pure glucose but more complex sugars, which might strengthen your amylase argument.

But still, the overall evidence that gastric bypass improves glucose tolerance independent of macronutrient composition, calories and body fat mass, seems quite compelling to me. By the way, I am very aware that gastric bypass can have horrible consequences, like debilitating and almost unmanagable hypoglycaemic attacks. It offers unexpected insights though.

I like this reflection from a recent meta analysis:

"The ensuing body of literature has generated two leading theories attempting to explain this weight-independent anti-diabetic effect after RYGB. The 'hindgut' proposes that rapid delivery of partially digested nutrients to the distal bowel up-regulates the secretion of incretins such as glucagon-like peptide-1 (GLP-1). The result of the increased incretin secretion is an enhanced glucose-dependent insulin secretion, as well as a number of other changes causing improved glucose tolerance (4). In the second theory, 'the foregut hypothesis', the exclusion of the duodenum results in the inhibition of a 'putative' signal that is responsible for insulin resistance (IR) and/or abnormal glycaemic control. In a non-obese diabetic rat model, surgical diversion of the proximal bowel caused rapid improvement of diabetes without reduction of food intake or change in weight (5). Many aspects regarding surgical treatment of T2DM are still questionable and unexplained. Emerging data are starting to clarify the mechanisms participating in the anti-diabetic effect, and also challenging long-held theories."

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gunther gatherer said...

Hi Stephan, you said: "It turns out that the typical Roux-en-Y surgery does not reduce the proportion of calories absorbed from food much, if at all."

So given this apparent paradox, that the obese surgery subjects don't eat less but all their diabetic markers immediately go down and they lose weight, can you please, pretty please, answer my question(s) regarding why calories ingested would have anything to do with weight loss or gain?

If eating behavior isn't changed after surgery, but almost every subject reverses their diabetes, then would you agree that body composition is primarily a brain-regulated process?

There are just too many skinny, relatively healthy people eating the same amount of calories as fat pre-diabetics to chalk this all up to caloric intake.

Stephan Guyenet said...

Hi Andreas,

That cannot explain the increase in glucose tolerance either, because you see the same effect in IP glucose tolerance tests where the glucose is delivered directly into the bloodstream. The increase in glucose tolerance is due to a metabolic effect of the bypass on insulin secretion and insulin sensitivity.

Hi Gunther,

What I meant in that sentence is that they don't have malabsorption. They do reduce their calorie intake by quite a lot.

Calories consumed are a very important factor in body fatness, although they aren't the only factor. Obese people do eat more than lean people-- that is always the case (after matching for gender, height and physical activity) when it's measured in an accurate manner. The problem is that self-reporting is not accurate.

Stephan Guyenet said...

Sorry, I meant "IV glucose tolerance tests", not "IP"

gunther gatherer said...

Thanks Stephan. This is all coming together to form a general pattern of "abundance" and "subsistence". What I mean is that the body (mostly the brain) senses its surroundings based on input from food odor, quality, taste, etc. I believe Seth talks about this too in his Shangri La writings.

Bland, unrewarding food ("subsistence" times) seems to signal that it's time to use fat stores. Hunger goes down, markers of health go up and the body strengthens in different ways (trigs and other markers). Rich, high calorie and tasty food signals that there is plenty around the body, and so you should "stock up" in order to prepare for the next drought or lack of game or whatever.

This makes sense from an evolutionary perspective. You can counter by saying the Kitavans never go hungry, but they do have rotations of available foods from season to season; maybe lots of fruit for a couple of months ("abundance") and then back to the sweet potato or other pretty bland and monotonous root starches ("subsistence").

Neolithic lifestyle has our brains thinking it's abundant all the time, hence the obesity, morbidity and possibly even overpopulation. What do you make of this?

gunther gatherer said...

BTW, Cynthia Kenyon's experiments with C.Elegans seems to confirm this too. Knock out their olefactory sense, and they live much longer.

Nutrient sensing causes downstream effects which prepare the body for good times and bad times. This seems to be the case for every species.

Andreas Eenfeldt said...

Stephen,
Normalization of IV glucose tolerance tests? Before significant weight loss? That's odd as the bypass should not affect that too much.

Do you have any good reference on that for me to check out?

Stephan Guyenet said...

Hi Gunther,

That makes sense.

Hi Andreas,

I looked into it and it looks like what I said about IVGTT wasn't totally accurate. Insulin sensitivity as assessed by IVGTT increases dramatically within 6 days of Roux-en-Y surgery in diabetics, while IV glucose tolerance itself tended to improve a bit but it wasn't significant at 6 days post surgery.

http://www.ncbi.nlm.nih.gov/pubmed/15946424

The point is that there are things happening with gastric bypass that cannot be attributed to changes in how glucose is digested/absorbed in the intestine, although that doesn't mean changes in digestion/absorption aren't involved as well.

CarbSane said...

Stephan I am curious how the prevalence of regain - significant in many cases, complete in others - fits in with the reward theory here. Every one of the, admittedly few, folks I know who've undergone GBP have done so. Essentially they learn to "deliberately eat around" their smaller stomachs and such.

To Andreas, Jenny and others, I recently blogged on a comparison of a VLC diet vs. that "crash diet" that was in the news lately.
http://carbsanity.blogspot.com/2011/07/diabetes-crash-cures-vlcal-vs-vlcarb.html
Although not directly comparable, six months on a ketogenic diet did not come close to reversing beta cell dysfunction. Anecdotal evidence abounds that LC can help folks manage their hyperglycemia, but they do not tend to regain proper glucose tolerance -- often it seems they become less and less tolerant of even a few grams of carbs the longer they eat VLC/HF in maintenance (or regaining). I suspect those that do actually reverse their diabetes are the ones who spontaneously reduce intake significantly, eat lower fat and ultimately add back carbs once weight loss has been achieved. In the case of GBP, I suspect the dramatic caloric restriction is accompanied by increased GLP-1 enhancing insulin secretion while also enhancing glucose tranport into peripheral tissues.

This is not to say GBP is a preferred cure, just that we can learn a lot from the results we see. The dramatic improvements demonstrate far greater potential for reversal of the disease.

Stephan Guyenet said...

Hi Carbsane,

I can't speak for all forms of bariatric surgery, but my understanding is that Roux-en-Y has a high rate of long-term (10+ year) efficacy. Surgeries that only restrict stomach size without bypassing the upper small intestine have a poor rate of long-term efficacy.

I've been thinking about the diabetes crash diet thing. I wonder if an extended water-only fast would be an easier and equally (or perhaps more) effective way of having the same outcome. I'm thinking two weeks. There is some literature on fasting as a treatment for diabetes-- apparently it was common in the first half of the 20th C.

Melchior Meijer said...

Stephan, do you know more about the innervation of the upper intestine and its function? I recently read somewhere that there are taste receptors in the duodenum and jejenum. Not directly related, but fascinating, was the finding that type 1 diabetic mice are cured basically overnight when the nerves in their pancreases are paralized with an injection of capsaicin (the stuff in red pepper). As soon as their pancreatic nerves stop firing, their supposedly dead beta cells start regenerating. I have a hunch that the crux in this gastric bypass effect might be neurological. Would love to hear your view on that.

gunther gatherer said...

Hi Melchior, can you give more info on how they paralysed the nerves of the pancreas with capsaicin? Did they just take it orally in a capsule or did they do something else?

Melchior Meijer said...

Hi Gunther,

One moment please, I'm not working on my own computer, but I'll try to find the reference. I'm sure the capsaicin was injected. It was a Canadian team.

Melchior Meijer said...

Hi Gunther,

Hans Michael Dosch et al in 'Cell'.

http://www.ncbi.nlm.nih.gov/pubmed?term=dosch%20capsaicin

gunther gatherer said...

Many thanks, Melchior. Also several Type II diabetics are blogging about using capsaicin to control their blood glucose.

My guess is that if capsaicin's job as a plant toxin is to stun nerves, then it would also stun the nerves of the duodenum and jejunum after eating it. If these two organs do most of the calculating of a food's reward value to send the info to the brain and decide a host of other health effects, then eating some capsaicin say an hour before a meal could be an effective way to at least lower the reward value of one's meal.

This sounds like something that would have already popped up in indigenous populations by now. Also, maybe capsaicin is not the only plant toxin that can numb the nerves. I suppose there would be a bunch that could be put to good use...

gunther gatherer said...
This comment has been removed by the author.
gunther gatherer said...

Here are some mumblings on Duh Innernets on capsaicin to control diabetes and blood glucose:

http://diabeticlifediet.com/my_diabetic_diet_foods/find_diabetic_diet_foods/capsaicin_diabetes_control/

Melchior Meijer said...

Thanks Gunther. I had similar thoughts. Very exciting.

Stephan, based on your writings and some comments, I make a bold prediction. An oral glucose tolerance test performed with an absolutely tasteless glucose solution will produce a smaller rise in blood glucose and a smaller area under the curve than an ogtt performed with the flavored glucose solution that is commonly used. Wild hypothesis: impaired glucose tolerance is partly a result of chronically over exited nerve cells and taste receptors in the upper intestine. The chronic use of unnaturally strong tasting foods (regardless of macro nutrient composition and energy content) contributes to glucose intolerance and diabetes (this explains also why drinking diet soda is associated with diabetes). Eating relatively bland foods (which is more in line with our evolutionary past) will correct glucose tolerance and – as you propose – weight loss.

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CarbSane said...

I now know three people "in real life" who underwent the full GBP, not talking lap band, lost a lot of weight. Two have gained it all back (one added more) and the third is on the way. So I guess perhaps just more evidence to consider how reward may be *a* dominant factor, but not necessarily *the* dominant factor.

Melchior Meijer said...

And imagine if it also works the other around… If only agreable tastes – signalling energy is on its way – excite the upper intestinal nervous system in the above suggested dentrimental way, then it would be possible that unagreable tastes, like bitter, would have the opposite effect. In that case regularly ingesting bitter substances would improve glucose tolerance and result in loss of excess body fat.

gunther gatherer said...

Melchior, I was thinking that too. Perhaps using bitter flavors as a "fake out" to the sensory apparatus before eating would lower food reward even more. Worth considering.

Melchior Meijer said...

Yes Gunther, sounds plausible.

But then... along comes CarbSane. What to make of her observation? ...the slaying of beautiful hypothesis by an ugly fact ? Thanks CarbSane ;-). See if can come up with some smooth ad hoc explanations.

gunther gatherer said...

I would say there are many nerves involved for food reward sensing. Not just in the small intestine but also in the mouth, then olefactory sensing and then finally your sheer memory of the food itself. GBP only removes a few of these factors, so I can see why weight could come back after the initial weight loss.

Also, nerves are known to grow back. Maybe the nerves formally residing in the duodenum and jejunum either grow back lower down the GI or there are other sensing nerves lower down that "learn" to pick up the slack. Or maybe the brain compensates by supersensitizing taste and smell.

Nutrient sensing was so important during our evolution, I wouldn't be suprised if our bodies could find a workaround after certain nerves are cut out.

Melchior Meijer said...

Hi Gunther,

We are thinking exactly along the same lines. Over time other sensoric systems compensate for the lost upper intestinal sensing, I just thought, and almost steered my bicycle under a van ;-). Most of what we suggest here, could very easily be tested.

gunther gatherer said...

Melchior's point about interspersed bitterness made me recall this:

When I taught English in Asia 20 years ago, I noticed Japanese and Chinese people did not eat their white rice mixed up with their meal. It was mostly as a kind of palate cleanser between bites, or even between plates of food. You eat a bit of meat or veg, then eat rice, meat, then rice, etc. They were all extremely slim by Western standards (very good glucose tolerance) though they clearly ate at least as much as we do.

Fried rice (mixed up with pork, eggs, flavorings) could be found on the street but people told me not to eat too much of it because it "made you fat". Chinese people thought it was pretty funny how westerners would come to Asia and mix the rice and meat all together in one bowl. It didn't mean much to me then, but now I recall they were a hellova lot fatter than the Asians around them eating the same thing separately.

Could the difference between good glucose tolerance and pre-diabetes be as simple as how and when you eat your white rice?

David Pier said...

I think this pertains to Gunther's line of reasoning:
http://www.ncbi.nlm.nih.gov/pubmed/20637192
"Fasting hypometabolism and refeeding hyperphagia in rats: Effects of capsaicin desensitization of the abdominal vagus"

Melchior Meijer said...

Gunther, fascinating observation. But if they were eating these different food stuffs seperately but in the same meal, the different signals would still hit the duodenum at approximately the same time, wouldn’t they? Or do you mean the oral and olfactorial sensing? How was their meal frequency? I imagine that long periods between meals (no snacking, no soda’s, no chewing gum, etc) give the sensoric systems enough time to chill out (and keep the organism glucose tolerant if the connection is real).

gunther gatherer said...

Hi David, many thanks for that. I'm having trouble understanding the authors' point. Due to its effect on the vagus nerve, is capsaicin going to be better when you eat or when you fast?

CarbSane said...

@Melchior: You know I exist to increase your cognitive dissonance ;)

I've been fascinated by the whole GBP/diabetes thing ever since I came across it. For those who view it as just another way for bariatric surgeons to make money by pushing these procedures, it should be pointed out that this was discovered essentially by accident b/c of hypoglycemic episodes in those taking medications.

Melchior, that paper is equally fascinating. Here's the full text:
http://tinyurl.com/6z8xegb

Stephan Guyenet said...

Interesting discussion. CarbSane, Roux-en-Y surgery statistically has a high rate of long-term success. There of course are exceptions, and I don't know why. It could have to do with the fact that every surgeon does it a bit differently-- some cut the vagal nerve afferents to the small intestine and others don't.

That being said, I know you could call this "moving the goalpost", but I agree with others that there is the possibility of neural adaptation over time here. The jejunum is also involved in reward sensing, and perhaps other more distal parts of the small intestine as well (they release gastric peptides in response to food and they're innervated so it's plausible). These may gradually take over from the duodenum in some people. Just an idea.

Melchior, I don't know that much about small intestine innervation, but I know that it involves two-way flow of information that both controls GI function (e.g., motility) and receives information (e.g., calories, macronutrients).

That finding about capsaicin injection reversing T1DM is fascinating. There is emerging research that innervation influences cell survival/death, proliferation and inflammation in metabolic tissues. Roux-en-Y surgery seems to cause beta cells to proliferate, and some researchers attribute part of the improved glycemic control to increased insulin production. Perhaps that has something to do with altered nerve signals to the pancreas-- the pancreas clearly reacts to what's happening in the intestine in a manner that can't be completely explained by circulating glucose. Circulating peptides like GLP-1 are probably part of the story, but I bet there is indirect intestine-pancreas communication via the vagus nerve.

CarbSane said...

WRT that study reversing T1DM, I quick scanned and it seems it prevented the total demise of the prediabetic mice.

-saIN- said...

Can you talk about the Lap-Band surgery a little too?

gunther gatherer said...

Here's some studies relating to nutrient-sensing adaptations that occur when mice are bred without taste receptors:

http://www.cell.com/neuron/retrieve/pii/S0896627308001190

http://scitizen.com/neuroscience/food-reward-in-the-absence-of-taste-receptor-signaling_a-23-1929.html

gunther gatherer said...

Here is the take-home quote from the above:

"Araujo reasoned, the sense of taste did not evolve to provide us with pleasant moments to be remembered, but rather to help us finding calories in nature in an efficient way. The actual reward that matters, that is the one that will help survival, is calories not taste."

So taste (and I guess, smell) only directs us to the high-caloric foods. The actual calculating of how rewarding the food is takes place down below. Though how the mice were able to distinguish the sucrose-laden sippers I don't know.

Melchior Meijer said...

Gunther, thanks fort that. Are you aware of that experiment where athletes were given a glucose solution versus a similar tasting solution containing a non caloric artificial sweetener? They had to cycle until exhaustion. When they became tired, they were given a zip of the drink, but… they had to spit it out. The result: the guys who tasted the glucose solution increased their time to exhaustion, the guys who tasted the fake solution did not. Ergo: 1. we are able to detect if a sweet taste represents energy and 2. the taste of an energy containg drink/food is enough to temporarily lift fatigue and improve performance.

Which when you think about it makes sense, because it takes a relatively long time before a small glucose fix has been converted into glycogen for use in the muscles. We do not run on blood sugar. The small amount of extra energy in a sportsdrink or gel cannot explain the acutely improved performance.

Sorry, no link right now. Edward Chamber, University of Birmingham.

Melchior Meijer said...

Sorry, that should be Edward Chambers. Here's the full text:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2683964/?tool=pubmed

CarbSane, Many thanks for that whole paper by Dosch et al! Very fascinating stuff.

Melchior Meijer said...

Chris from Conditioning Research found this about exercise and amylin (very relevant if you ask me):

http://conditioningresearch.blogspot.com/2011/07/exercises-impact-on-gut-hormones.html

Stephan, thanks a lot for your reflection.

Laura said...

http://www.sciencedaily.com/releases/2011/07/110712094048.htm

Same research, slightly longer article.

Tutor Sheets said...

I found this site helpful... It talks alot about Hoodia. http://me-slim.blogspot.com

I don't think that Gastric Bypass causes any fat loss by itself. The fat loss comes from the extreme diet that the person must endure during recovery.

Razwell said...

Brilliant post, Stephan. We know enough now to declare the Caloric Hypothesis dead.

Although, here still is much to learn. The unknowns being far greater than the knowns. Namely, the full biochemical explanation of fat cell regulation, and also the chemical behavior of fat cell receptors.

Solzy said...

Hyperlipid posts here on how one can have a high fasting blood glucose level on LCHF, but it doesn’t reflect the underlying reality and he ventures why):

http://high-fat-nutrition.blogspot.com/2007/10/physiological-insulin-resistance.html

His FBG levels (in American medical terms) range from 100-120. Yet his HbA1c is 4.4. My FBG levels are the same as his, and my HbA1c is OK also (5.8).

Laura said...

Great read, espeically for a dietitian! Thanks!

vortexbanding said...

I had gastric bypass in 2008 and I am hungry all the time (and gain weight rapidly) when I let "carb creep" back into my life.

The only way I lose weight with High Protein and Low Carb. Period.

By the way, I had a vagotomy last month (due to post-RNY induced ulcer) and I am even more hungry now (and eating way too much junk).

DH said...

Stephan,
What about those that binge and purge (eating disorders)? Would you expect a higher setpoint or food reward to play any role here?

Kate Witz said...

Yes.. Gastric Bypass Surgery is really helpful to lose fats. There are many benefits of such type of surgery.

Mitchell Sexner said...

I think this bypass procedure should only be done on patients who have a chronic case of obesity which has caused them to suffer from many weight-related illnesses like diabetes, heart ailments, joint problems and others. If it was just a simple case of excessive weight issue, then the patient should try natural means of shedding those extra pounds first before trying this bypass procedure which should be the last option. I am personally afraid of surgeries and I would like to avoid any surgical errors as much as possible.

Anne Davenport said...

My sister also had a gastric bypass surgery last month. She suffered from nausea and vomiting and even difficulty in eating. We tried natural food, fruits and leafy vegetables, but we were in vain. We tried the operation of mini gastric bypass surgery in India. Luckily, she's Ok now. Just a tip, after the surgery, just eat low-carb veggies