Sucralose, Hazardous or Innocent? A Review of the Review - Part I: Glucose, Insulin & GLP1 | Sucralose & Diabetes?

Sweet, low and unhealthy? Is sucralose as bad as a recent review would suggest?

I guess I could say "I've written more than enough about artificial sweeteners!" and simply ignore the sensational press release about the "bioactivity" of this increasingly common artificial sweetener you've read on the SuppVersity Facebook News, yesterday (check it out). In view of the fact that most of my previous artificial sweetener articles revolved around a possible impact on body weight / insulin sensitivity, ca. 90% of the claims in the press release are actually "news" - even for SuppVersity readers. Ample reason to take another, closer look at the study outcome and analyze both the "real" results, what the press release made of it and whether or not the panic that's already spreading on the Internet is warranted.

First things first: What are we talking about?

As the press release informs us, an "extensive review published by Taylor & Francis"... stop, so here is our first hint. The authors of the press release are people from Taylor & Francis and have a vested interest in writing it in a way that will have people share the text and their name on the Internet (that worked pretty well, as you can see - even I am talking about it ;-)

This is part I of a multi-part series:

Sucralose, insulin, glucose, GLP-1

Appetite, Obesity & Gut Health

Cancer, Drug & Hormone Interact.

I know that Mark Sisson likes to says this, but this website is not written by a machine, but by a man who has the same "short" 24h days you have... basically, what I am trying to say is that I had to split this review of the review into a "trilogy" - and be honest, you wouldn't want an article thrice as long as this one, would you?

Next on the list is some information about the "extensive review" and the hint that it was authored by Susan S. Schiffman, PhD, "an internationally known sweetener researcher" and Kristina I. Rother, MD, MHSc, "of the National Institutes of Health (NIH)". So, now it stands out of question that what's in this review is the truth and nothing but the truth. I mean, what else would it be if these experts, one working for the almighty and benevolent NIH "summarize[d] the biological properties of sucralose based on hundreds of archival, peer-reviewed scientific journal publications" (my emphasis).

Based on hundreds of [...] publications?

While it is true that the review has 476 references, not all of them deal with sucralose and only few of them provide data that would by any means be relevant to the most important question of all: "Can sucralose consumption harm us". The statement "based on hundreds of [...] publications" is thus misleading, because when it's used in conjunction with the word "review" people will interpret it as the number of relevant papers - or, even worse, of studies the data of which has been used in a systematic review. The paper at hand is yet everything but a systematic review - it's a narrative one.

Next on the list of our "review with your critical thinking cap on the head" list are the following claims about the health / environmental effects of sucralose:

• Please note: I will address all the issues within this trilogy, but for today I will focus on the one with the asterisk (*). As you can see from the headlines in my preliminary outline above, the rest of the issues are going to follow, asap.
  

  The best thing you can do if you want to make sure you're not going to miss a single article is to register for the SuppVersity Newsletter at the bottom of the page or - even better - like the SuppVersity Facebook Page and you'll always be in the know.
  alterations in insulin, blood glucose, and glucagon-like peptide 1 (GLP-1) levels,
• metabolism of sucralose in the gastrointestinal tract to metabolites whose identity and safety profile are unknown,
• induction of cyctochrome P450 and P-glycoprotein in the gastrointestinal tract to levels that may limit the bioavailability of therapeutic drugs,
• reduction in the number and balance of beneficial bacteria in the gastrointestinal tract,
• histopathological findings in gastrointestinal tract including lymphocytic infiltrates into epithelium, epithelial scarring, mild depletion of goblet cells and glandular disorganization in the,
• decomposition and generation of chloropropanols (a potentially toxic class of compounds) during baking, and
• mutagenic alterations using several types of biological assays

What I am going to do now, is to track each and every of them back to the review and take a brief look at the research that's out there to make sure that we are actually dealing with "the truth", here ;-)

Claim I: Sucralose messes w/ blood glucose management

I have to admit I was very curious to see the evidence on which Schiffman & Rother base this claim and was pretty disappointed, when I saw an extensive list of rodent and cell model studies, like those by Jang et al. and Margolskee et al., in which human NCI-H716 cells (Jang. 2007) and mouse enteroendocrine cells (GLUTag; Margolskee. 2007) were used to support the claim that sucralose would lead to an increase in GLP-1 - which is, by the way you usually won't hear as an argument against artificial sweeter use ... anyways, we are going to see why later, for now it should suffice to say that this intrigued me.

In view of the physiological role of GLP-1 it's by no means clear whether the mentioned increase is actually something to be afraid of (see "Eat More, Burn More and Lose Fat Like on Crack with GLP-1!? Roux-en-y Bypass Study Sheds a Whole New Light on Satiety(Hormone)-Induced Weight Loss" | learn more)

After taking a closer look at the two studies and realizing that I had no way to tell whether it's realistic to assume that our cells are exposed to 1nM or 5nM of sucralose, which is what Jang et al. observed was the dosage they needed to elicit the desired increase in GLP-1 (Jang. 2007). And even if it would - would increases in GLP-1 actually be such a bad thing? I mean, you've read about the use of GLP-1 and its synthetic analogues to treat diabetes I & II (Pettus. 2013; Schwartz. 2013), protect you from NAFLD (Panjwani. 2013), reduce the oxidative damage to the heart during hypoglycemic episodes in type I diabetics (Ceriello. 2013), etc. both right here at www.suppversity.com, as well as over on the SuppVersity Facebook Wall.

The thing we'd have to fear is thus not the release of GLP-1 (for a large majority of the increasingly overweight population this could actually be beneficial), but a "dysregulation" GLP-1, GIP, C-peptide, insulin, glucose, and so on and so forth....

I don't say that it's impossible that this is going to happen, but by no we have no convincing evidence that it will and in view of the fact that a scarcity of glucose is not exactly something to be afraid of in this day and age, an increase in GLP-1 could actually be an advantage for the majority of SAD-dieters. Unfortunately, the real-world (=non-petri dish) evidence from a 2009 study by Ma et al. tells us that this is not going to happen in humans.

Figure 1: GLP 1 (left) + insulin (right) response in healthy individuals to sucrose, saline (control) or 80mg and 800mg sucralose (theoretically this would be as sweet as 48g and 480g of pure sugar; Ma. 2009).

In face of the data in Figure 1, which leaves little doubt that only sugar (sucrose), but neither 80mg, nor 800mg of sucrose will have any effect on the critical hormones / peptides GLP-1, GIP, and insulin, Schiffman & Rother's argumentation breaks down. And if you take into account that the corresponding (theoretical) sweetness equivalents of 80mg and 800mg of sucralose are 48g and 480g of pure sugar, I seriously doubt that we'd have to test higher dosages to make sure that nobody "intoxicates" himself ;-)

Granted: Even the authors cite evidence against the GLP-1 hyothesis

I know, not everyone is willing to briefly type "GLP1 subjects sucralose" into a search engine, wait for the results to pop up and follow the link to the previously cited study by Ma et al. I understand that, but if that was you, you would actually just have to scroll down to the bottom of sensationalist press release, I cited on Facebook and click on the link (or enter the doi) to the (free) full-text, to find the following line on page 402:

"Oral consumption of sucralose without co-administration of glucose (Brown et al.,
2011) produced no significant effect on blood glucose levels. Sucralose delivered by intraduodenal infusion in combination with glucose also exerted no marked effect on blood glucose or plasma GLP-1 (Ma et al., 2010)."

In other words, contrary to the author(s) of the press release, Schiffman and Rother are well aware that their evidence is far from being conclusive. What I am not so certain about, though, is whether they are also aware that their reference to a study by Brown et al. from 2009, where the coningestion of sucralose with acesulfame-K in 240 ml of caffeine-free diet soda (Diet Rite cola) produced an increase in the GLP-1, but not insulin or glucose (see figure 2), could actually be interpreted as a highly beneficial result.

Figure 2: Glucose, insulin and GLP1 response to oral glucose tolerance test conducted 10min after the ingestion of 240 ml of caffeine-free diet soda (Diet Rite cola; boxes) or carbonated water (circles; Brown. 2009)

If glucose is around, an increased GLP-1 response is after all not necessarily a bad thing. In 2002, for example, Zander et al. reported in The Lancet that 6 weeks "on GLP-1" ...

• 

  The WM-HDP ↔ GLP-1 ↔ fatty oxidation connection | reread "Waxy Maize Reloaded" read more

  reduced the fasting and 8h post-meal free fatty acid levels of type II diabetics by -25% and 30%,
• improved the 8h blood glucose levels,
• decreased the HbA1c value from 9.2% to 7.9%,
• normalized the levels of cell-toxic fructosamine, 
• slowed down gastric emptying 
• decreased their ravenous appetite,
• improved insulin sensitivity and β-cell function, and
• induced a -3% reduction in total body fat.

Not much of a surprise, if you are familiar wit the effects of GLP-1 I discussed in the "Waxy Maize Reloaded" article (learn more), right? As far as the physiologically measurable mechanisms for derangements of the blood glucose management go, this leaves us with a potentially centrally mediated dysregulation of glucose sensing for which we do as of yet only have in-vitro "evidence" from a 2009 study by Ren et al. The researchers observed (obviously in the petri dish) that the normal expression of one out of three hypothalamic sweet taste receptors (Tas1R2) in cells from the hypothalamus is reduced in the presence of 0.5mM of sucralose. Up to now we do yet neither know if orally ingested sucrose can actually make it into the brain, whether the corresponding changes in Tas1R2 expression would be physiologically relevant, or what its consequences would be.

"Science Round-Up Seconds: The Pro-Insulinogenic Effect of Artificial Sweeteners + Mechanisms & Consequences" | more

Preliminary bottom line: As far as a potential dysregulation of the glucose metabolism is concerned, I still believe that there is currently not enough evidence to support the claims from the press release or implications of the biased listing of "significant findings" in the conclusion of the full text, where the authors discard all previously cited counter-evidence from human studies and focus on a study by Pepino et al., the questionable implications of which I already discussed in the Science Round-Up on May 21, 2013 (more). In the absence of controlled long term human studies this bottom line must however not be misunderstood as a full acquittal. In other words, the only thing this study demonstrates is how little we actually now.

As far as centrally mediated effects are concerned, the upcoming installments of what began as a comment and became a series of articles on sucralose may provide at least some insights into potential long(er) term effects on blood glucose management. Derangements that occur in response to changes in the gut microbiome, endocrine system or toxic effects of sucralose or its byproducts would after all only become visible after weeks or months of chronic (high dose?) ingestion of this globally approved artificial sweetener.

References:

• Brown, R. J., Walter, M., & Rother, K. I. (2009). Ingestion of diet soda before a glucose load augments glucagon-like peptide-1 secretion. Diabetes Care, 32(12), 2184-2186.
• Ceriello, A., Novials, A., Ortega, E., Canivell, S., La Sala, L., Pujadas, G., ... & Genovese, S. (2013). Vitamin C Further Improves the Protective Effect of Glucagon-Like Peptide-1 on Acute Hypoglycemia-Induced Oxidative Stress, Inflammation, and Endothelial Dysfunction in Type 1 Diabetes. Diabetes care, 36(12), 4104-4108. 
• Fujita, Y., Wideman, R. D., Speck, M., Asadi, A., King, D. S., Webber, T. D., ... & Kieffer, T. J. (2009). Incretin release from gut is acutely enhanced by sugar but not by sweeteners in vivo. American Journal of Physiology-Endocrinology and Metabolism, 296(3), E473-E479.
• Jang, H. J., Kokrashvili, Z., Theodorakis, M. J., Carlson, O. D., Kim, B. J., Zhou, J., ... & Egan, J. M. (2007). Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. Proceedings of the National Academy of Sciences, 104(38), 15069-15074. 
• Ma, J., Bellon, M., Wishart, J. M., Young, R., Blackshaw, L. A., Jones, K. L., ... & Rayner, C. K. (2009). Effect of the artificial sweetener, sucralose, on gastric emptying and incretin hormone release in healthy subjects. American Journal of Physiology-Gastrointestinal and Liver Physiology, 296(4), G735-G739.
• Margolskee, R. F., Dyer, J., Kokrashvili, Z., Salmon, K. S., Ilegems, E., Daly, K., ... & Shirazi-Beechey, S. P. (2007). T1R3 and gustducin in gut sense sugars to regulate expression of Na+-glucose cotransporter 1. Proceedings of the National Academy of Sciences, 104(38), 15075-15080.
• Panjwani, N., Mulvihill, E. E., Longuet, C., Yusta, B., Campbell, J. E., Brown, T. J., ... & Drucker, D. J. (2013). GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE−/− mice. Endocrinology, 154(1), 127-139.
• Pettus, J., Hirsch, I., & Edelman, S. (2013). GLP-1 Agonists in Type 1 Diabetes. Clinical Immunology. 
• Ren, X., Zhou, L., Terwilliger, R., Newton, S. S., & De Araujo, I. E. (2009). Sweet taste signaling functions as a hypothalamic glucose sensor. Frontiers in integrative neuroscience, 3. 
• Schiffman, S. S., & Rother, K. I. (2013). Sucralose, A Synthetic Organochlorine Sweetener: Overview Of Biological Issues. Journal of Toxicology and Environmental Health, Part B, 16(7), 399-451.
• Schwartz, S., & DeFronzo, R. A. (2013). Is Incretin-Based Therapy Ready for the Care of Hospitalized Patients With Type 2 Diabetes? The time has come for GLP-1 receptor agonists!. Diabetes care, 36(7), 2107-2111.

Saturated Fat Kills Gut Bacteria & Modifies Genes in the Distal Small Intestine - Another Reason Why We Get Fat? Plus: Bacteria, Fiber, SCFA, GLP-1 & PYY Revisited

Image 1: Bacteria, there are >100 trillion of them right inside of your digestive track, you can hardly know them all and scientists do neither - the only thing we are beginning to understand, though, is that it may be a good idea to get them to know at least somewhat better ;-)

I guess some of you have already noticed that I was (and probably am now, again) somewhat behind, as far as answering your questions, comments an wise remarks are concerned. Actually it is still more of a coincidence that today's SuppVersity news, which, as you see is not an Adelfo Cerame post (don't forget to keep the fingers crossed for him! This is his weekend!), could actually be interpreted as my somewhat lengthy response to a comment from Vincente on the effects of GLP-1 on chocolate preference in rats and an interesting hypothesis of his, on how this could all relate to my previous post on the fat burning effects of GLP-1 ("Eat More, Burn More and Lose Fat Like on Crack with GLP-1!?"). What, that was Vincente's reasoning, what, if those obese individuals had just messed up their gut bacteria an would lack those beneficial bacteria, which convert the fiber and resistant starch that makes it through your small intestine, right down into your long one to short chain fatty acids?

Does obesity come from within?

I guess by now some of you may already be asking themselves, where all that relates to GLP-1 and eating more, burning more and losing fat like on crack. Well, the missing link if you will is actually not a link, but rather a receptor - the free fatty acid receptor, FFR, which "sniffs" the presence of the short chain fatty acids and triggers the release of GLP-1 and PYY. Those two incretin hormones, of which researchers have found within the past 10 years or so that they are way more than mere "satiety signals. Several research studies in rodents have shown that the anti-obesogenic effects of GLP-1 and PYY are if at all, only partly mediated by reductions in food intake, yet mostly via complex downstream effects on total energy expenditure, glucose and fatty acid oxidation.

Contrary to exogenously administered GLP-1, which is actually being used in the treatment of diabetes an the metabolic syndrome, the in-vivo data from rodent studies, which suggests that high fiber diets protects those little critters from diet induced obesity (Aziz. 2008; Shen. 2008; Zhou. 2008) have, as Robertson et al. pointed out only recently, not yet been confirmed in humans trials (Robertson. 2012). Moreover, the latest results from the Merck Reserach Lab show, contrary to previous evidence from the Cambridge Institute for Medical Research (Tolhorst. 2012), that even our current assumption with respect to the underlying mechanism, could at least be incomplete (Lin. 2012). This does not mean that the short chain fatty acids would not produce the desired increase in GLP-1 nad PYY, but rather that their effects are not solely mediated by  the aforementioned free fatty acid receptor in the gut.

Let's make things even more complicated and bring some long chain fatty acids to the table!

What is yet self-evident though is that the way GLP-1 and PYY modulate energy utilization punches yet another huge hole in the prostrated "calories in vs. calories out hypothesis", one that has little to nothing to o with insulin and one that acquires yet another shade of gray, when we look at the long-chain counterpart of the "bacterial excrements" the dreaded or beloved (depending on the standpoint of the individual) saturated fatty acids (SFA) and a recently published study by scientists from the Wageningen University in the Netherlands (De Wit. 2012), who investigated the long-term effects (8 week, study conducted on mice) of high fat diets with fats from different fat sources

• palm oil - representing the saturated fatty acids,
• olive oil - representing the mono-unsaturated fatty acids, and
• safflower oil - representing the polyunsaturated fatty acids

on body weight gain, liver triglycerides and the whole other standard parameters and their relation changes in the gut microbiome and the amount of fat that "left" the animals undigested.

Figure 1: Fecal fat and energy loss, total energy intake and relative (to control on normal chow) liver triglycerides, oral glucose tolerance and weight gain over the 8 week study period (de Wit. 2012)

A casual look at the data in figure 1 should suffice to see that there is a profound mismatch between almost all classic features of the metabolic syndrome of which we would usually expect that they would be closely associated:

• the rodents in the palm oil group ate the least amount of energy, excreted the greatest amount of fat and total energy in their feces and still gained the greatest amount of body weight and had the highest amount of liver triglycerides (beginning non-alcoholic fatty liver disease)
• the rodents in the olive oil group did not consume significantly more amount of energy or excrete significantly more amount of fat / energy in their feces and still gained ~40% less body weight and did not exhibit similarly high triglyceride storage in the liver as the rodents on the saturate fat (palm oil)
• the rodents in the safflower oil group were comparably ravenous (+20% energy intake), but although they did not excrete more energy and fat than their peers, their bosy weight gain was profoundly reduced and their liver triglycerides were better than in the "non high fat control group" and yet their glucose tolerance was not the best, but the worst of all the three groups

All that does only make sense, when a second parameter, or I should say another 100 trillion bacterial parameters come into play and the SFA induced reduction in microbial diversity and
composition (increased the firmicutes/bacteroidetes ratio) are accounted for, as well. those, this is at least what de Wit et al. believe are namely responsible for the complex changes in genes that regulate the fatty acid metabolism and expression of inflammatory markers, the scientists observed

Chicken or egg, cause of correlation? Or just gut optimization?

Even tde Wit et al. do yet point out that their observations do not provide significant evidence to establish a causal relationship between the bacterial changes, which are a direct result of an overflow of (selectively) antimicrobial saturated fats into the distal part of the intestine, the subsequent disturbances in the bacterial balance and (human!) gene expression in the gut and the  particularly pronounced obesogenic effects of saturated fatty acids.

You could, at least in my humble opinion, even argue that these are simply adaptive effects that ensure that the "host", in this case the rodents, "gets the most" out of his diet - after all, this is exactly what we are seeing here: A modulation of genes related to the conservation and storage of energy, such as the downregulation of the Bcmo 1 gene that predisposes to the development of obesity and non-alcoholic fatty liver disease (Hessel. 2008),  which allows for maximal energy efficiency despite greater fecal energy loss.

Conclusion? Drink safflower oil?

That these results should not be taken as an incentive to guzzle safflower oil (or drop your coconut oil for the latter) should be obvious. Just as obvious, by the way, as the realization that despite all the hoopla and my own excitement about the newly discovered importance of the gut microbiome as one of the possible contributers to the global obesity epidemic. We are understanding way too little about its interactions with its host, i.e. us, to exclude that we are not - yet again - confusing cause and effect, causation and correlation and take our gut microbiome, which is eventually nothing else than a mirror of our healthy or unhealthy lifestyle for the real deal, and try to modulate and fix the mirror image with anti-, pro- or prebiotics without working on what stands right before the mirror: The sedentary, convenience food consumer, who works to jobs and rather watches TV till late at night instead of getting his 7-8h of sleep....

References:

1. Aziz AA, Kenney LS, Goulet B, Abdel-Aal el-S. Dietary starch type affects body weight and glycemic control in freely fed but not energy-restricted obese rats. J Nutr. 2009 Oct;139(10):1881-9. Epub 2009 Aug 19. 
2. Hessel S, Eichinger A, Isken A, Amengual J, Hunzelmann S, Hoeller U, Elste V,  Hunziker W, Goralczyk R, Oberhauser V, von Lintig J, Wyss A. CMO1 deficiency abolishes vitamin A production from beta-carotene and alters lipid metabolism in mice. J Biol Chem. 2007 Nov 16;282(46):33553-61.
3. Lin HV, Frassetto A, Kowalik EJ Jr, Nawrocki AR, Lu MM, Kosinski JR, Hubert JA, Szeto D, Yao X, Forrest G, Marsh DJ. Butyrate and propionate protect against  diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One. 2012;7(4):e35240.
4. Robertson MD. Dietary-resistant starch and glucose metabolism. Curr Opin Clin Nutr Metab Care. 2012 Jul;15(4):362-7. 
5. Shen L, Keenan MJ, Martin RJ, Tulley RT, Raggio AM, McCutcheon KL, Zhou J. Dietary resistant starch increases hypothalamic POMC expression in rats. Obesity  (Silver Spring). 2009 Jan;17(1):40-5. Epub 2008 Oct 23.
6. Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, Cameron J, Grosse J, Reimann F, Gribble FM. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes. 2012 Feb;61(2):364-71.
7. Zhou J, Martin RJ, Tulley RT, Raggio AM, McCutcheon KL, Shen L, Danna SC, Tripathy S, Hegsted M, Keenan MJ. Dietary resistant starch upregulates total GLP-1 and PYY in a sustained day-long manner through fermentation in rodents. Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1160-6.
8. de Wit NJ, Derrien M, Bosch-Vermeulen H, Oosterink E, Keshtkar S, Duval C, de Vogel-van den Bosch J, Kleerebezem M, Müller M, van der Meer R. Saturated fat stimulates obesity and hepatic steatosis and affects gut microbiota composition by an enhanced overflow of dietary fat to the distal intestine. Am J Physiol Gastrointest Liver Physiol. 2012 Jun 14.
9. Zhou J, Martin RJ, Tulley RT, Raggio AM, McCutcheon KL, Shen L, Danna SC, Tripathy S, Hegsted M, Keenan MJ. Dietary resistant starch upregulates total GLP-1 and PYY in a sustained day-long manner through fermentation in rodents. Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1160-6. 

Eat More, Burn More and Lose Fat Like on Crack with GLP-1!? Roux-en-y Bypass Study Sheds a Whole New Light on Satiety(Hormone)-Induced Weight Loss

Image 1: A gastric bypass should always be the last option; with all the possible complications it is nothing to treat lightly (img medcenterone.com)

Everyone who has read the Intermittent Thoughts on "Goal Setting and Programming Success" with the three somatypes, SuperSize Homer, Peter Griffin and Anorexic Stan, will be aware that I do acknowledge the oftentimes life-saving benefits of surgical anti-obesity interventions, when everything else fails. Until recently, I did however assume that"cutting off" a part of your stomach or using a sling or other devices to reduce its size would simply reduce a patients ability to overeat, thusly reduce hi caloric intake and help him to cut his weight back into a region that is no longer life-threatening. The recent publication of a study by scientists from the Harvard Medical School (Nestoridi. 2012) does yet suggest that the effects of roux-en-y gastric bypasses are in fact way more far reaching than, at least I, had previously thought.

Does a roux-en-y bypass "actively" burn fat!?

In their experiment Erini Nestoridi and her colleagues had observed that the overweight mice in the active arm of their study, i.e. those mice who were not just cut open (sham group), but had also received the roux-en-y gastric bypass (RYGB), did not only lose body fat like crazy, they did also consume significantly more calories, expended significantly more oxygen (a marker of fatty acid oxidation), had a significantly lower respiratory quotient (=burned more fat than glucose for fuel) and wasted almost twice as much energy in the form of body heat than their sham-operated peers, so that their overall energy balance looks like they were on DNP or any other "true" thermogenic fat burner (cf. figure 1)

Figure 1: Energy intake, respiratory quotient (higher levels = more glucose, less fatty acid oxidation), heat production, fat free mass and fat mass during and at the end of the 8-week intervention trial subsequent to either sham or roux-en-y gastric bypass operations on obese mice (data calculated based on Nestoridi. 2012)

In combination with the to-be-expected increase in fecal energy loss (44kcal/day vs. 13kcal/day), which occurred as a consequence of the decreased transit time and ability to absorb nutrients from the chow, these changes explain very well, why, at the end of the 8-week intervention period, the RYGB mice had lost all their unhealthy fat depots, while their sham operated had gained another 6g of body weight.

Gastric bypasses increase the GLP-1 response and thusly restore metabolic health

All that reminded me of some research with regard to the metabolic role of the so-called satiety hormones, CKK, PYY and above all GLP-1 I have been doing as of late. Glucagon-like-peptide 1 (GLP-1), in particular, exerts profound and far reaching metabolic effects, which have little to do with the satiety function its label "satiety hormone" does imply. Interestingly, the restoration of normal fasting blood glucose levels, the  normalization of the glucose response to an oral glucose tolerance test, the increased fatty acid oxidation and even the RYBG mice' profoundly reduced preference of the hypercaloric high fat chow (after the surgery the rodents had free access to normal and the highly palatable "high fat" chow, on which they had accumulated a 50% body fat percentage before the surgery) have all been associated with increases in GLP-1 levels in previous studies. In their 2005 review of the literature, Burcellini et al. even mention the involvement of cerebral GLP-1 in cognition and memory (Burcelin. 2005).

A 2012 case-report in which Myint et al. (Myint. 2012) describe a RYBG patient who suffered from recurrent episodes of hypo(=low)glycemia due to increased GLP-1 levels would support my hypothesis that GLP-1, or rather its increased expression subsequent to gastric bypass operations could be the root cause of all the beneficial metabolic effects in the rodent study at hand and the thousands of human beings whose lives have been saved by this surgical intervention, as of yet. That this is not just a transient or outlier effect, but something we see across the board in all RYGB patients and which remains, even at a10-year follow-up has been confirmed by Mohamad S. Dar and his colleagues from the East Carolina University, who examined the GLP-1 response to oral meal consumption in 5 RYGB patients 10 years after the operation and found that the "exaggerated GLP-1 response [is] maintained [...] despite statistically significant
weight loss".

The fat burning effect of eating to satiety

Image 2: Adelfo's progress during his contest prep are an excellent example for the highly desirable "side effects" of eating to satiety.

Now, it would not only be plain out stupid to get a gastric bypass done, when that is not medicinally necessary, it would also compromise the value of "my" hypothesis that GLP-1 could in fact be the main working mechanism behing RYGB induced weight loss, if it was not (a) increased / higher in the billions of people who do not get obese in the first place and if there were not (b) other most prominently dietary means to increase GLP-1 which trigger similar beneficial metabolic effects. As you may imagine, I would not have proposed this hypothesis, if I had not already come across pertinent research, such as a 2006 study by Nicola Pannacciulli et al. in which the NIH researchers found a statistically significant association between GLP-1 levels and resting energy expenditure in 46 glucose tolerant male and female subjects with BMIs ranging from 18.6-50m²/kg (Pannacciulli. 2006).

A preliminary GLP-1 cheat sheet for the obese and non-obese dieter

The following list of dietary GLP-1 "agonists" is yet still "work in progress" and more of a preview on a future, comprehensive blogposts of the role of the metabolic function of the incretin hormones, I am currently working on (whenever I have 1s of time to spare ;-):

• short chain fatty acids (Tulhurst. 2012) 
• fermentable fiber (Greenway. 2007)
• fermentable resistant starches (Zhou. 2008)
• bile acid (Katsuma. 2005; Parker. 2012)
• egg and meat hydrosolates (Cordier-Bussat. 1998)
• milk proteins (Hall. 2003; Juvonen. 2011)
• fish oil (only if administered interperitoneal; Motoshita. 2008)
• fats, when added to starchy carbs (e.g. Frost. 2003)

Unfortunately, things can become quite confusing, because despite all those "starches" and "fibers" in the list, there are studies, which report the exact opposite effects for some of the classic dietary fibers, like psyllium, for example (Karhunen. 2010). Conflicting results by Wang et al. who report 2x increased GLP-1 levels in response to psyllium or sugarcane fiber enriched high fat diets (Wang. 2007), do thusly raise the question if the GLP-1 response is either (a) species-specific (the Wang study was done on mice), (b) depends on the accompanying nutrients (both studies used rather high fat foods / chow, though), or whether (c) the difference is a simple consequence of the study design, i.e. acute (Karhunen) vs. chronic (Wang) ingestion of fiber-(en)rich(ed) food / chow.

Could it not be about insulin, but about GLP-1?

And although we certainly cannot rule out (a) completely and must acknowledge that (b), i.e. man vs. mouse, will always make a difference, I personally believe that overall (c), i.e. the differences between the acute, the longer term and the chronic effects are, are most likely responsible for the differences in GLP-1 response and the ensuing metabolic effects. After all, fermentable fiber, fermentable resistant starches and psyllium all increase the production of short chain fatty acids in the colon. The beneficial effects the latter have on the amount of GLP-1 that is released will however arise at a very late stage of the digestion process. the decrease in GLP-1 Karhunen et al. report in their study, on the other hand, was measured right after the ingestion of the meal.

Don't forget: In non-insulin resistant individuals, glucose, or rather its transportation via the GLUT-2 receptors is a stimulator of GLP-1 release, as well. It is thusly not really surprising that Lee et al. have recently been able to show that its release is impaired in diabetic rats (Lee. 2012). With an intact GIP response (cf. WMHDP article for more on how GIP is making you fat) diabetics and most likely also "just insulin resistant" individuals are thusly getting all the negative without any of the beneficial effects of carbohydrate ingestion, so that GLP-1 is yet another piece in the "why low-to-no-carb works / may even be necessary for obese diabetics, but is unnecessary for healthy individuals" puzzle, I've been putting together with a whole host of posts over the past couple of weeks.

Given GLP-1's role as a mediator of glucose disposal and fatty acid metabolism, it is thus likely that the long-term health benefits I have hinted at in the context of the gastric bypass study, arise only when we have a steady "elevation" or rather steadily high-normal levels of GLP-1, instead of some punctuated spikes, as Karhunen observed them for "non-fibrous" foodstuff or Juvonen for low viscosity foods (Juvonen. 2009).

If we also take into account that Cheong et al. report that large fluctuations in blood glucose levels exert greater ER stress on rat insolinoma cells than chronic hyperglycemia and that the former, i.e.the large blood sugar fluctuations, yet not chronic hyperglycemia downregulate the GLP-1 receptor expression (which would induce a metablic state we would have to label "GLP-1 resistance") on these cells (Cheong. 2011). We could go as far as to speculate that the ups and downs of the glucagon-like-polypeptide 1 and the subsequent down-regulation of its receptors at the cellular level and not our contemporary scapegoat, insulin, could be at the heart of the diabesity epidemic... but I will get deeper into that in the upcoming incretin hormone special, so stay tuned!