Pre-Meal Protein Ingestion to Improve Glucose Tolerance: Insulin, GIP, GLP-1 - That's the Whey(!) it Works! Plus: Even Pure Glucose Can "Improve Your Insulin Tolerance"

Can a whey protein appetizer really undo the damage of greasy fast food? Probably not, but it's still interesting to see how it affects the postprandial glycemia.

Insulin resistance is the #1 contributing factor to the obesity epidemic and despite the fact the solution is already out there (read more about the necessary lifestyle modifications), it probably won't hurt to know if something as simple as having a high protein "appetizer" before a junky meal could improve blood glucose management even further, right? "Right, 'cause protein is always, good!" Ah, no... I guess the answer is a little more complex than that... Nevertheless, I still suspect that the results, Tina Akhavan and her colleagues from the University of Toronto present in their soon-to-be-published paper in the Journal of Nutritional Biochemistry will be of interest to you.

The study results are interesting, to say the least...

... and that's not despite but rather because the researchers did not use the usual subjects (rodents, obese individuals or elderly people), but young men (aged 18-29) with a BMI of 18.5-29.4 kg/m². In a randomized cross over design (cross over means that every subject got each treatment - obviously in seperate testing sessions), the subjects drank either...

• 300ml of a 10g or 20g whey protein solution, 
• 300ml of a 10g or 20g glucose solution, or
• 300ml of flavored zero calorie water 

The test drinks were consumed four hours after a standardized (junk = Honey Nut Cheerios + Skim Milk + Orange Juice) "breakfast". 30 min later the subjects were served even more junk in form of a *yummy* frozen Pizza from McCain Foods Ltd.

"Cereals", skim milk, pizza... whey alone won't help to counter that

The Pizza had been prepared "according to manufacturer‘s directions". This means that the reduction in glycemia the scientists observed in response to the protein preload were not because the pizza was still frozen... ok, before I produce even more nonsense, let's take a look at what the whey protein and glucose pre-loads did to the subjects blood glucose responses, right?

Figure 1: Glucose and insulin levels after pre-load and after meal (mean of 30-230min); all values expressed relative to water control, i.e. +85% would mean "85% higher than during control trial" (Akhavan. 2013)

If that's not your first visit to the SuppVersity, I probably won't have to explain the mechanism by which the pre-ingestion of whey (and glucose) reduces the Pizza-induced glycemia - do I? Well, I guess I better repeat it briefly:

1. The ingestion of the whey protein triggers a significant increase in insulin - 127% for the 10g and 191% for the 20g dosage.
2. Contrary to the glucose infusion there is no exogenous glucose that could lead to a rapid elevation of blood glucose (cf. figure 1, left → pre-values); the minimal increase you see is produced by gluconeogenesis in the liver.
3. With the elevated insulin levels, the mean glucose levels in the postprandial phase (30min-230min after the pizza ingestion) is lower with both the glucose and whey preload. The effect is however more pronounced with whey than with glucose. The reason should be obvious: The overall amount of glucose that's got to be stored away is lower.

I know it sounds counter-intuitive, but aside from (2) the mechanism is absolutely identical for the glucose trial - with the insulin already being around low (10g) glucose preload can actually lead to lower postprandial glucose levels than the water control (this is probably only true for healthy individuals).

Insulin? Is that all, or is there more to it?

Now that we have gotten the fundamental mechanism by the means of which "glucose-" and "whey-preloading" before eating pizza can ameliorate the blood glucose surge after the meal, let's take a look at the auxiliary data.

Figure 2: GLP, GIP, PYY, CCK and Ghrelin levels before eating the pizza; all values expressed relative to water control, i.e. +85% would mean "85% higher than during control trial" (Akhavan. 2013)

As the data in figure 2 tells you the increased insulin release was brought about and accompanied by profound increases in the production of the satiety hormones GLP-1 and CCK, as well as the "insulin trigger" GIP (all these changes occured in the pre-meal = pre-pizza phase, only). Ghrelin and PYY, which play an even more important role in the regulatory process that's supposed to control our energy intake, did not show significant treatment dependent differences, though.

What's the practical relevance of these findings? Honestly, I am not sure how relevant the findings from the study at hand actually are. I mean, from a "do this" or "don't do this" point of view - not from a "understanding how things work" perspective.

SuppVersity Suggested Read: "The Satiating Truth About Proteins and Why High Protein and Low Amounts of Low GI Carbs May Not Mix As Well As Most People Think" | read more

For those who would benefit most from reductions in postprandial glycemia, i.e. the obese type II diabetic, it is questionable whether (a) the mean 7% decrease is actually making a difference and whether it would (b) even occur in someone who is having a hard time producing enough insulin to have his / her body react to it.

For the lean individual, on the other hand, the 7% reduction in gylcemia probably doesn't matter at all and the insulin spike before the onslaught of a the "perfect storm" of carbs and fats from a greasy frozen pizza could (worst case scenario) increase the chance of fat storage - I mean the glucose can go to the muscle (learn more), the fat, on the other hand must end up in your adipose organ.

I would thus strongly advice everyone to stick to my "get 30g of quality protein with every meal" recommendation, instead of turning it into a "get 30g of protein before every meal". Aside from the questionable benefits of having the protein before your meal, having it with / as part of your mwal will also direct you away from pizza and towards healthier food choices. After all, you will be hard pressed to find a pizza with 30g+ of protein in it... and I bet the novel "pizza on a stick" I told you about on Facebook, recently, probably doesn't qualify either ;-)

References:

• Akhavan T et al. Mechanism Of Action Of Pre-Meal Consumption Of Whey Protein On
  Glycemic Control In Young Adults. The Journal of Nutritional Biochemistry. October 2013 [accepted manuscript]

Taste Matters - Bypassing the Taste Receptors Increases the Insulin & CCK Satiety Hormone Response to Food Ingestion - Why is That & What Are the Implications, If There Are Any?

Infusions of nutrient solutions via a tube is often the last resort for doctors to save anorexic patients' lives - it's yet nothing anyone should do voluntarily for the satiety plus Spetter et al. observed.

As a SuppVersity Reader you are no stranger to "incretin hormones" and their release in response to the interaction of food with the taste receptors that are distributed all over your body. Against that background you will probably not be surprised to hear that Martjee S. Spetter and her colleagues from the University Medical Center Utrecht and the Wageningen University found that bypassing oral the stimulation of oral taste receptors decreases the satiety and alters the appetite hormone response to a given meal.

As the Dutch researchers point out, the interaction between oral and gastric signals is an important part of food intake regulation.

Artificial sweeteners have a reputation of making you hungry - find out if they do

Unsatiating Truth About Artif. Sweeteners?

Will Artificial Sweeteners Spike Insulin?

Sweeteners & the Gut Microbiome Each is Diff.

Sweeter Than Your Tongue Allows!

The Latest on the Sweetener Scare.

Sweeteners In- crease Sweet- ness Threshold

In that, Spetter et al. are not the first to obversve that bypassing the oral taste receptors may diminish the suppression of hunger and increases gastric emptying rate. The role of appetite hormones, like cholecystokinin-8 and ghrelin, in this process, however, is still unclear.

The objective of Spetter et al.'s latest study was thus to determine the contributions of gastric and oral stimulation to subsequent appetite and hormone responses and their effect on ad libitum intake.
The scientists recruited fourteen healthy male subjects (age 24.6 ± 3.8y, BMI 22.3 ± 1.6 kg/m²) who participated in their randomized, single-blinded, cross-over experiment with 3 treatmentsessions:

• Stomach distention, only: naso-gastric infusion of 500 mL/0 kJ water, 
• Stomach distention with caloric content: naso-gastric infusion of 500 mL/1770 kJ chocolate milk, and 
• Stomach distention with caloric content and oral exposure: oral administration of 500 mL/1770 kJ chocolate milk.

Due to the specific design of the experiment, the distention of the stomach, of which you've learned previously on the SuppVersity that it is a major contributor to the satiety response (see "True or False: High Volume + Nutrient + Low Energy Foods Keep You Lean." | learn more) was fully controlled in the study at hand.

Hunger & desire to eat increase significantly faster after isocaloric liquid vs. solid meals (Tieken. 2007)

No, the study at hand does not imply that you should tube feed yourself: If we take into account that Jones & Mattes observed only recently that the satiety response to liquid meals is generally impaired, even in lean individuals (obese individuals cannot compensate for energy from beverages or solid foods | Jones. 2014), the results may well be different for a solid meal that would be chewed, not just swallowed like the chocolate milk in the study at hand.

Take a look at the data from Tieken et al. (2007) on the left, for example. They found that a liquid meal providing 25% of the daily energy requirement provides a lower and less sustained suppression of hunger and desire to eat than an isocaloric solid meal.

The stomach distention, only, trial can thus serve as a baseline. If we assume that the taste receptors in the mouth were irrelevant and the satiety response would be controlled solely by the amount of type of nutrients that arrive in the stomach, there should be a difference between the control infusion with water and the infusion of chocolate milk, but there should be no difference between the infusion compared to the ingestion of the chocolate milk.

Figure 1: Fullness rating (top) and desire do eat (bottom) in response to infusion (light and dark grey bars) of water and chocolate milk, respectively vs. the ingestion of chocolate milk (dark bars; Spetter. 2014).

As you can see in Figure 1, the latter was not the case. While there were no differences in the fullness ratings (top) and desire to eat (bottom) between chocolate milk and water, when it was infused through the nose, the subjects felt significantly fuller and had a significantly lower desire to eat, when they drank the chocolate milk the way nature intended it.

Things never are as you would expect them to be

Now, everyone would expect that the decrease in desire to eat and the increased fullness in response to the regular (=oral) ingestion of chocolate milk would significantly reduce the energy intake on a subsequent meal, right?

Figure 2: In contrast to what the data in Figure 1 would suggest there was no significant difference between the effects the intra-nasally infused chocolate milk (CM) and the regularly consumed CM had on the ad-lib. intake on a subsequent meal  (Spetter.2014) - How can that be? Maybe the higher satiety hormones in the infusion trial (see Figure 3)

Well, as you can see in Figure 2 this is not the case. There is a reduction in energy intake, but in contrast to the comparison to the water infusion (right), the difference between the oral chocolate milk vs. the intra-nasally infused chocolate milk was not significant.

Figure 3: The increase in the satiety hormones insulin (top) and CCK-8 (bottom) is more pronounced, when the taste receptors in the oral cavity are bypassed (Spetter. 2014)

But why is the intra-nasally administered chocolate milk eventually more "satiating"? Well, if you take a closer look at the previously mentioned CCK-8 and insulin response (see Figure 3), you will see that the increase in these satiety hormones (yes, insulin increases satiety; cf. Anika. 1980; Vanderweele. 1994) is more pronounced, when the taste receptors in the oral cavity are bypassed and the chocolate milk is infused intra-nasally. For the ad-libitum meal that was served 45 minutes later, this increase was more important than the increased feeling of "fullness", let alone the highly subjective desire to eat" (Figure 2).

As Spetter et al. point out, this initially counter-intuitive result provides evidence for the "common but relatively poorly underpinned idea that learned associations between sensory signals and ensuing metabolic consequences serve to adapt hormone responses based on nutrient content" as it was previously observed by Zafra et al. (2006) and Power et al. (2008).

In view of the obesity problem, the results support the idea that a relative lack of oral stimulation, due to e.g. caloric beverage or other fast food consumption can result in overeating by weakening satiety (de Graaf. 2010), an effect of which Jones & Mattes have shown that it is impaired in obese individuals and reduced in lean and obese individuals, when the energy they consume comes from liquid foods, like shakes (Jones. 2014) | Comment on Facebook!

Reference:

• Anika, S. M., T. R. Houpt, and K. A. Houpt. "Insulin as a satiety hormone." Physiology & behavior 25.1 (1980): 21-23.
• de Graaf, Cees, and Frans J. Kok. "Slow food, fast food and the control of food intake." Nature Reviews Endocrinology 6.5 (2010): 290-293.
• Jones J.B., Mattes R.D. "Effects of learning and food form on energy intake and appetitive responses. Physiol Behav. 21 (2014):1-8.
• Power, Michael L., and Jay Schulkin. "Anticipatory physiological regulation in feeding biology: cephalic phase responses." Appetite 50.2 (2008): 194-206. 
• Tieken, S. M., et al. "Effects of solid versus liquid meal-replacement products of similar energy content on hunger, satiety, and appetite-regulating hormones in older adults." Hormone and metabolic research= Hormon-und Stoffwechselforschung= Hormones et metabolisme 39.5 (2007): 389.
• Vanderweele, Dennis A. "Insulin is a prandial satiety hormone." Physiology & behavior 56.3 (1994): 619-622.
• Zafra, María A., Filomena Molina, and Amadeo Puerto. "The neural/cephalic phase reflexes in the physiology of nutrition." Neuroscience & Biobehavioral Reviews 30.7 (2006): 1032-1044.

The Satiating Secret of Arginine, Lysine and Glutamic Acid. Plus: Things You May Not Know About These Aminos

No, no and no. No amino acids = no satiety = no weight loss.

Personally, I have never been interested in products that would increase satiety. Being a born masochist, at least, when it comes to cutting body fat, I always liked being hungry... well, at least until I had to learn that there is an intricate hormonal connection between "being hungry" and the diet-induced reduction in metabolic rate, hormonal production etc. That changed my whole perspective on agents that increase satiety completely, and I started to read read papers like the one Jordi et al. are about to publish in one of the upcoming issues of the Journal of Physiology (Jordi. 2013).

The satiety shoot-out

According to the researchers from the University of Zurich, the top-dogs, or rather the most satiating among the so-called proteogenic amino acids, which are ...

• L-Leucine (Leu / L)
• L-Lysine (Lys / K)
• L-Methionine (Met / M)
• L-Phenylalanine (Phe / F)
• L-Proline (Pro / P)
• L-Serine (Ser / S)
• L-Threonine (Thr / T)
• L-Tryptophan (Trp / W)
• L-Tyrosine (Tyr / Y)
• L-Valine (Val / V)

• L-Alanine (Ala / A)
• L-Arginine (Arg / R)
• L-Asparagine (Asn / N)
• L-Aspartic acid (Asp / D)
• L-Cysteine (Cys / C)
• L-Glutamic acid (Glu / E)
• L-Glutamine (Gln / Q)
• Glycine (Gly / G)
• L-Histidine (His / H)
• L-Isoleucine (Ile / I)

... are L-arginine (Arg), L-lysine (Lys) and L-glutamic acid (Glu). The Swiss scientists were able to demonstrate that these three amino acids induced neuronal activity in the area postrema and the nucleus of the solitary tract. That sounds funky, but non-significant, right? Well, it wouldn't be, as long as you did not take into consideration that we know from previous studies that these brain regions are responsible for the regulation of energy intake - specifically our appetite for more.

Additional info: Just to complete the list, I want to add a non-proteogenic amino acid (an amino acid that is not used by the body to "build" proteins) with profound satiety effects. One you actually have heard about several times in the past weeks: Taurine! In 2012 Solon et al. published a study that shows quite conclusively that taurine, once it crosses the blood brain barrier, will reduces food intake, but also locomotor activity in rodents (Solon. 2012). As the scientists point out, These effects are accompanied by the modulation of expression of the "satiety hormone" NPY.

L-arginine has research to support its use as anti-diabetic weight-loss adjuvants (learn more); and the results of the study at hand suggest that its benefits may be mediated by its effects on the brain & gut.

From a "what are the downstream effects on my metabolism"-perspective, however, it may in fact be even more important that the amino acids also provoked an increase in gastric distension by differentially altering gastric secretion and/or emptying. After all, ...

"[...] these peripheral mechanical vagal stimuli were dissociated from the amino acids' effect on food intake. [So that it is prudent to assume that] Arg, Lys and Glu had a selective impact on food processing and intake suggesting them as direct sensory input to assess dietary protein content and quality in vivo. " (Jordi. 2013; my emphasis)

In other words: L-arginine, L-lysine and L-glutamic acid are not simply going to reduce your cravings they will also tell your body: Hey there's some good quality protein coming in.

---

Hold on! Where are the proven benefits? I have to admit all that sounds as if it would be of questionable relevance but any SuppVersity reader for whom this is not the first visit to this webpage will probably have read about the surprisingly profound weight loss benefits of L-arginine, which have only recently been tracked down to its interactions with the GLP-1 one of the so-called satiety proteins with far-reaching downstream effects on glucose and fatty acid metabolism (learn more about the fat burning prowess of L-arginine).

As far as glutamic acid is concerned, it may be worth mentioning that Freiberg et al. reported more than 20 years ago that certain glutamic acid derivates can act directly on the cholecystokinin receptor, which is - along the the PYY receptor one of the major "You are full! Now stop eating"-switches of the mammalian body (Freiberg. 1990).

Figure 1: AUC in response to ingestion of 25g of glucose or water w/ or w/out 150mg/kg lysine (Kalogeropoulou. 2009)

Similarly unknown as the involvement of glutamic acid in the concert of satiety hormones is the effect lysine (150mg/kg) had on the glucose, insulin and glucagon resonse of healthy volunteers, when Kalogeropoulou et al. administered it either alone or in conjunction with 25g of glucose to thirteen healthy volunteers, where it triggered an increase in glucagon and insulin, when it was administered alone and significant reduction in the blood sugar response, when it was administered in conjunction with the 25g of glucose (Kalogeropoulou. 2009). Interestingly the increased glucsose disposal did not depend on an increase in insulin, so that it must be related to downstream improvements in insulin sensitivity and the efficacy of glucose uptake.


References:

• Freidinger RM, Whitter WL, Gould NP, Holloway MK, Chang RS, Lotti VJ. Novel glutamic acid derived cholecystokinin receptor ligands. J Med Chem. 1990 Feb;33(2):591-5.
• Kalogeropoulou D, LaFave L, Schweim K, Gannon MC, Nuttall FQ. Lysine ingestion
  markedly attenuates the glucose response to ingested glucose without a change in
  insulin response. Am J Clin Nutr. 2009 Aug;90(2):314-20.
• Jordi J, Herzog B, Camargo SM, Boyle CN, Lutz TA, Verrey F. Specific Amino Acids Inhibit Food Intake via the Area Postrema or Vagal Afferents. J Physiol. 2013 Jul 29. [Epub ahead of print] 
• Solon CS, Franci D, Ignacio-Souza LM, Romanatto T, Roman EA, Arruda AP, Morari J, Torsoni AS, Carneiro EM, Velloso LA. Taurine enhances the anorexigenic effects of insulin in the hypothalamus of rats. Amino Acids. 2012 Jun;42(6):2403-10.

On Short Notice: Oxytocin to Boost Testosterone & Block Cortisol? Exercise for Life-Extension? Which Tea for Metal-Chelation? Which Fat to Reduce Calorie Intake by ~30%?

Image 1: This is still my preferred way to boost oxytocin - regardless of possible ergolytic effects ;-)

Due to the sudden heat-wave over here in good old Germany I thought, I'd use these early morning hours to get another installment of "On Short Notice" on it's way before my brain dries out (or I drown in the public swimming pool ;-). I hope you enjoy the four items on the recent interest in intranasal the hormone modulating effects of oxytocin, it's effect on cortisol and progesterone, estradiol and (I know you were waiting for that ;-) testosterone, my early morning / late evening (depending on whether you see this from my or Wyatt's perspective) 'intellectual' exchange on the potential longevity effects of exercise and why it probably is not life-extending in the literal sense, the different antioxidant potency of green, black and white tea and their ability to chelate metals (=help to remove all not just "bad" metals from the body) and the best fat, DHA or MUFA to blunt appetite and help you stick to your diet.

Don't forget to come back later today (or maybe early tomorrow for some of you ;-), for a third installment of "On Short Notice", which will hopefully suffice to "get rid" of the stock I have... ah, I did not forget about the Circadian Rhythm Series, by the way, it's just that the SuppVersity rhythm got slightly out of sync ;-)

• 

  Figure 1: Effects of 26IU of intranasal oxytocin at rest on progesterone, estradiol and testosterone in healthy men (large; based on Gossen. 2012); effects of 24IU or 48IU of intranasal oxytocin administered before a steady state cardio session on cortisol levels in healthy young men (small; from Cardoso. 2012)

  Intranasal oxytocin to block cortisol & boost testosterone A whole series of studies has been published recently; all of them have one thing in common, they investigate the various physiological and psychological effects of oxytocin. Of these, the two studies by Gossen et al. and Cardoso et al. are yet probably of greatest interest for the average physical culturist. After all, the researchers from the Centre for Research in Human Development at the Concordia University in Quebec (Canada) were able to show that the administration of 24IU (not the higher dose of 48IU, though;see figure 1) effectively reduced the increase in cortisol in a 70% HRmax steady-state cardio session in 17 healthy young men (aged 18–3; mean ± SD; 23.1 ± 3.5), in the experiment they describe in their Aug 2012 paper in Psychoneuroendocrinology (Cardoso. 2012).
  And even though the German scientists from the University of Aachen report minimal, but statistically significant increases in testosterone in 8 young men (mean age 26.4 ± 2.6 years) at rest, 210min after the (likewise) intranasal administration of a minimally higher dose (26IU) of oxytocin (Gossen. 2012). Both of these observations are not just very similar to what your average natty test booster is supposed to do, their real-world effects are probably also as insignificant. Also, did you ever try to tear down the gym and rep out a couple of PRs a couple of minutes after having sexual intercourse? If so, you should actually be aware why oxytocin probably ain't the ideal pre-workout supplement - in this regard it is also somewhat unfortunate that Cardoso et al. did not do a real performance test (suggested read: "Will Sex Before A Competition Hamper Your Performance"; note: this is not about sex minutes before the competition ;-).
  And when it comes to building muscle, previous research from Phillips lab at McMasters University appears to suggest that blocking cortisol is a hilarious idea, anyway. After tall, cortisol was the only endocrine hormone the elevation of which in the vicinity of resistance training sessions showed a positive correlation (r=0.29, P=0.03 cf. West. 2011) with increases in lean muscle mass in the large-scale by West et a.
• Exercise gets rid of the junk in your body, but will it help increase your lifespan? Basically this could be the headline to an interesting exchange of thoughts, I just had with Wyatt Brown on the SuppVersity facebook wall - one I believe is well worth being "recorded" as a short news item. The discussion came about in response to me posting the link to a study by He et al. who found that the way exercise induces autophagy (=natural, healthy cell death) contributes to its beneficial effects in the prevention of all sort of ailments, above all cancer and neurological problems such as Alzeimer's & co, because it allows your body to get rid of the debris and junk that's accumulating from just living your life (no matter how healthy or unhealthy that may be). Since exercise is not the only thing that can ramp up autophagy, and caloric restriction (as in starving yourself to live longer) can do the same, Wyatt mused about whether or not you could achieve the same (more or less; for animals vs. humans) proven benefits of life-long caloric restriction by exercise.

  

  Image 2: Twin studies are one of the ways to identify whether genes or lifestyle are the fundamental determinants of how old we get. One of the consistent findings of the numerous pertinent studies is that lifestyle factors (diet, exercise, but also our outlook on life, friends and family!) determine how well we are able to use the time that our genes (or whoever you want) has granted us on earth. Not more, but not less, either: If 100 years are what we got, all exercise and healthy eating will allow us to make it to that age with great ease, not more... and let's be honest, if that was the biblical age of 100y, wouldn't it be ungrateful to ask for more?

  A very good question, indeed and one I do not have a definite answer to. In view of recent reviews of the role of exercise in the longevity of centenarians (the oldest of the old; cf. Venturelli. 2012), it does however seem more likely that exercise does not have direct effects on the life-span, but, as Huffman states, "[e]pidemiologic evidence in humans supports exercise as a strategy to reduce the risk of morbidity and mortality" (Hufmann. 2010). Unfortunately, a low mortality won't help you to make it past the 100 ± X years your genes have in stock for you. The insights into the genetic determinants from pertinent studies into single-nucleotide polymorphisms (SNPs ~ single gene variations) does support this notion (Sorensen. 2012): The oldest of the old don't stick out, because their genes protect them from premature death, but simply because their genes allow for more cell cycles to occur before the 'natural reserve'. We already know that telomere length is a fundamental determinant of this 'reserve', so that it is not really surprising that telomere length at birth is one of the most reliable predictors of longevity (Heidinger. 2012)!
  Now, if we just use a totally random number to use basic math to make us understand, what this means, we could say that your telemore length at birth may be sufficient to make it to age 100, assuming that it is not prematurely shortened or you are dying from whatever other "natural" (not accidents etc.) cause, such as cancer, metabolic syndrome, CVD etc., exercise will of course help you to make it to those 100 years, but when the say 100,000 total turn overs that your telomeres allow for are done, you are done as well - no matter how "healthy" you eat and how much you exercise in the 99.99 years before. If you complement this "preventive" (=mortality reducing) effect by literally living on the slow lane, i.e. downregulating all your metabolic processes by starving yourself, you will obviously slow down the turn-over rate, as well. For simplicity of the calculation we assume that all these processes are linear (which I can guarantee they are not) and you are eating so little that you achieve a 50% slow down. That would mean that your turn-over rate would be reduced from 1,000 / year to 500 / year. Your reserves would last 2x longer and, assuming you eat and exercise and thus decrease your mortality risk, will allow you to make it to the ueber-biblical age of 200years! Great? Well you decide...

• 

  Image 3: If you want to get rid of metals, white tea should be your tea of choice, if you are already low on iron, copper, zinc & co. you should at least drink it away from your meals, though.

  Different tea preparations different effects antioxidant activity and metal chelation ability  It is nothing new that green and black tea will have differential effects on your physiology. What is yet a novelty is a comparison of the antioxidant and metal chelating activity the exact same hand plucked leaves of a specific cultivar (in this case PC108, bred in Malawi, typically used for black CTC tea production) will have when it is used for the production of either white, two black (Orthodox and CTC; both methods produce leaves of fannings or dust grades that are commonly used in tea bags, CTC = crush + tear + curl is processed by machines, while orthodox usually involves a mixture of mashine and manual processing) or two green (w/ and w/out caffeine) teas - a comparison like the one Patricia Carloni and her colleagues present in their latest paper in Food Research International (Carloni. 2012).
  As you will probably have expected the least processed green tea exhibited the greatest, while the most processed CTC black tea the least antioxidant activity (green ≥ low-caffeine green > white ≥ black Orthodox > black CTC), what may come as a surprise though is the superiority of white tea in the metal chelation essay the scientists performed. Closely followed by the orthodox black tea, the CTC tea (<50% of the white tea metal chelating activity) and the two green teas (<25% of the white tea metal chelating activity).

• 

  Figure 2: Reduction in calorie intake on standardized breakfast 20min after the ingestion of 6ml of a lemon flavored oil emulsion and in the course of the day compared to no oil control (based on Harden. 2012)

  Fat satiety effects: DHA > Olive Oil (MUFA) > regular diet That would be the ranking according to the satiety effects of the different fatty acids, as elucidated in a recently published study in the British Journal of Nutrition (Harden. 2012). For their study, the researchers had recruited 18 healthy normal-weight men. In a single-blind, three-way crossover study design the subjects received a single 6ml dose of either DHA or oleic acid (olive oil is 60-80% oleic acid, alternatives would macadamia ~60% and high-oleic acid sunflower oil >82%) with lemon flavor. The day before, the subjects had consumed standardized diets. 20min after the ingestion of the emulsion, they had a standardized breakfast, went home and went about their regular daily business for the rest of the day.
  The telephone interviews the researchers conducted on the next day showed that the ingestion of the DHA emulsion had exerted an, as the researchers argue cholecystokinin (CCK) dependent, decrease in energy intake of -20% and -29% for the breakfast and the total daily energy intake, respectively. That would make DHA a pretty effective tool to stick to my often-suggested -20% caloric deficit when you're dieting - at least for healthy individuals. Whether this will work for the obese, let alone morbidly obese with their deranged satiety signaling remains to be seen, though.

As I mentioned in the introduction, already. This was not the last "On Short Notice" item for this weekend. So, digest this, have some sex to calm down (unless you are about to work out, obviously), and drink a cup of tea to increase your chance to make sure that your end is not arriving before it's time and you can come back for more ;-)

References

• Cardoso C, Ellenbogen MA, Orlando MA, Bacon SL, Joober R. Intranasal oxytocin attenuates the cortisol response to physical stress: A dose-response study. Psychoneuroendocrinology. 2012 Aug 10. 
• Carloni P, Tianob L, Padellab L, Bacchettic T, Customud C, Kayd A, Damian E. Antioxidant activity of white, green and black tea obtained from the same tea cultivar. Food Research International. 2012.
• Gossen A, Hahn A, Westphal L, Prinz S, Schultz RT, Gründer G, Spreckelmeyer KN. Oxytocin plasma concentrations after single intranasal oxytocin administration - A study in healthy men. Neuropeptides. 2012 Aug 9. 
• Harden CJ, Jones AN, Maya­Jimenez T, Barker ME, Hepburn NJ, Garaiova I, Plummer SF, Corfe BM. Effect of different long­chain fatty acids on cholecystokinin release in vitro and energy intake in free­living healthy males. British Journal of Nutrition. 2012; 108:755­-758
• He C, Sumpter R Jr, Levine B. Exercise induces autophagy in peripheral tissues and in the brain. Autophagy. 2012 Oct 1;8(10).
• Heidinger BJ, Blount JD, Boner W, Griffiths K, Metcalfe NB, Monaghan P. Telomere length in early life predicts lifespan. Proc Natl Acad Sci U S A. 2012 Jan 31;109(5):1743-8. Epub 2012 Jan 9.
• Huffman DM. Exercise as a calorie restriction mimetic: implications for improving healthy aging and longevity. Interdiscip Top Gerontol. 2010;37:157-74. Epub 2010 Aug 10. 
• Soerensen M. Genetic variation and human longevity. Dan Med J. 2012 May;59(5):B4454.
• Venturelli M, Schena F, Richardson RS. The role of exercise capacity in the health and longevity of centenarians. Maturitas. 2012 Aug 7.
• West DW, Phillips SM. Associations of exercise-induced hormone profiles and gains in strength and hypertrophy in a large cohort after weight training. Eur J Appl Physiol. 2012 Jul;112(7):2693-702. Epub 2011 Nov 22.

True or False: High Volume + Nutrient + Low Energy Foods Keep You Lean. Bonus-Question: Will a High Volume Make Your Stomach Go Baggy & Mess Up Your Satiety Response?

There are millions of ways to con- sume 100kcal and volume isn't the only difference (img greatist.com)

I have repeatedly pointed out that filling yourself up on vegetables and other high volume, high nutrient (vitamins, minerals, polyphenols, etc.), low energy foods is one of the fundamental principles of weight management. The question that remains, though, is whether this principle is so effective because of the food we eat (tons of veggies), or rather due to the fact that there is no room for the foods we thusly don't eat (the typical processed junk)?

I guess, it's not debatable that replacing trashy foods with healthy ones is the most important factor. We have all heard about the beneficial effects "high volume foods" and the downsides of the average high energy + low nutrient 100kcal junk-food snack. But how important is the volume, actually? Isn't food "quality" (whatever that may be) all that counts?

You can find more True or False articles at the SuppVersity

Pasta "Al Dente" = Anti-Diabetic

Vinegar & Gums for Weight Loss

Teflon Pans Will Kill You!

Yohimbine Burns Stubborn Fat

You Can Wash Pesticides Away

Milk = Poisonous Hormone Cocktail

It's surprisingly difficult to answer this question and after reviewing the most important studies, I have to say that I still can't tell for sure how important the volume is.

Figure 1: Effects of pylorectomy (removal of the part of the stomach that contains the vagal nerves) and vagal deafferetation on the ability of CCK to affect liquid food intake in rats (Moran. 1988)

What I can tell you, though, is that it appears to be certain that the mechanical stretch will be detected by vagal affarent endings in the stomach (Phillips. 2000; Berthoud. 2001). These "stretch detectors" are hard-wired to your brain, where they are processed in the so-called "nucleus tractus solitarius" (Näslund. 2007). Unfortunately, the exact role of the "nucleus tractus solitarius" in the satiety response is not even partly understood.

What we do know is that electrophysiological recording studies as well as behavioral studies have found that the effect of a given dose of cholecystokinin (CCK) is increased in the presence of stomach stretch (Schwartz. 1993 & 1995) and disrupted, when the vagus nerve is damaged or the NTS lesioned (Edwards. 1986; Moran. 1988; Smith. 1985).

With CCK being a major satiety hormone (and on top one that actually does what it's name implies, i.e. signal satiety) it appears to be quite certain that the multiplying effect the mechanical stretch exerts on the satiety effect of CCK is one of the secondary mechanisms by which eating high volume foods keep you lean.

Do you remember? You've read about a couple of things that will increase the release of CCK and would thus synergize with the effects of what I would like to call "high volume eating": (1) The pre-ingestion of protein before a meal | learn more, (2) Arginine, lysine and glutamic acid | learn more, and lastly and unsurprisingly a gastric bypass operation | learn more. Another well-known trigger of CCK release is the ingestion of fatty acids (low amounts suffice; long chain polyunsaturated fatty acids are particularly effective; Gribble. 2012) - is not satiating.

In view of the fact that the NTR, ie. the nucleus tractus solitarius, integrates (adds up and processes) a whole host of signals from the gastro-intestinal tract, it's also hardly surprising that a gastric bypass surgery and the corresponding increase in stretch per volume unit of food that has just recently been shown to change not just the satiety response to food but also the way foods taste and smell for patients who have undergone Roux-en-Y gastric bypass surgery (learn more in the SuppVersity Facebook News).

Figure 2: Model depicting signals that influence food intake. Not all elements are relevant in the context of this article - focus on the way the satiety signals that are generated in the gastrointestinal (GI) tract during meals provide information about mechanical (e.g., stomach stretch, volume) and chemical properties of the food to the brain (Woods. 2004)

Other mechanisms by which the gastric stretch may contribute to an increase in satiety / reduction in food intake and, via the release of GLP-1 and other glucose regulating satiety hormones (learn more about GLP-1) are the reduction of gastric emptying (Read. 1994), and other interactions between the vagus nerve and the brain, which include aside from directly satiety related mechanisms also the activation of serotonergic neurons (remember: serotonin is the happy hormone) in the brain (Mazda. 2004).

Bonus question: Is high volume eating setting you up for obesity? You could argue that the constant gastric distension and consequently increased postprandial gastric accommodation will reduce the satiety response to small calorie dense meals. Now aside from the fact that you will get fat, no matter what if you eat those on a daily basis, a study from the Gastroenterology Research Unit in Rochester and the Mayo Clinic did not find a sign of increased postprandial gastric accommodation or reduced satiety in any of of their 13 obese subjects (Kim. 2012).

So, yes! There is more to eating tons of veggies than not eating tons of other food. Moreover, although we don't yet know exactly what this "more" is, we can already say that all the existing evidence appears to support that it the high food volume, the stretch of the stomach and the vagally mediated downstream effects on the release and effect of our satiety hormones (incretins) is one of the factors that contribute to the ability of high volume, high nutrient, low energy foods to keep you lean.

On it's own, the multi-layered stretch-response is probably significantly less important than the reduction in junk-food intake. In conjunction with the synergistic effects of a high protein diet, and a reasonable amount of long-chain fatty acids in the diet, it could yet be what distinguishes people who have to resort to a gastric bypass as a last resort to save their lives from those individuals, who manage to flip the switch, turn their life around and lose their life-threatening overweight without the help of a surgeon.

References:

• Berthoud, Hans-Rudolf, Penny A. Lynn, and L. Ashley Blackshaw. "Vagal and spinal mechanosensors in the rat stomach and colon have multiple receptive fields." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 280.5 (2001): R1371-R1381.
• Edwards, et al. "Dorsomedial hindbrain participation in cholecystokinin-induced satiety." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 251.5 (1986): R971-R977. 
• Gribble, Fiona M. "The gut endocrine system as a coordinator of postprandial nutrient homoeostasis." Proceedings of the Nutrition Society 71.4 (2012): 456. 
• Kim, Doe‐Young, et al. "Is there a role for gastric accommodation and satiety in asymptomatic obese people?." Obesity research 9.11 (2001): 655-661.
• Mazda, Takayuki, et al. "Gastric distension-induced release of 5-HT stimulates c-fos expression in specific brain nuclei via 5-HT3 receptors in conscious rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 287.1 (2004): G228-G235.
• Moran, Timothy H., et al. "Pylorectomy reduces the satiety action of cholecystokinin." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 255.6 (1988): R1059-R1063.
• Näslund, Erik, and Per M. Hellström. "Appetite signaling: from gut peptides and enteric nerves to brain." Physiology & behavior 92.1 (2007): 256-262.
• Phillips, Robert J., and Terry L. Powley. "Tension and stretch receptors in gastrointestinal smooth muscle: re-evaluating vagal mechanoreceptor electrophysiology." Brain research reviews 34.1 (2000): 1-26.
• Read, Nicholas, Stephen French, and Karen Cunningham. "The role of the gut in regulating food intake in man." Nutrition reviews 52.1 (1994): 1-10.
• Schwartz, Gary J., et al. "Gastric loads and cholecystokinin synergistically stimulate rat gastric vagal afferents." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 265.4 (1993): R872-R876.
• Schwartz, Gary J., Gervais Tougas, and Timothy H. Moran. "Integration of vagal afferent responses to duodenal loads and exogenous CCK in rats." Peptides 16.4 (1995): 707-711.
• Smith, Gerard P, et al. "Afferent axons in abdominal vagus mediate satiety effect of cholecystokinin in rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 249.5 (1985): R638-R641.
• Woods, Stephen C. "Gastrointestinal satiety signals I. An overview of gastrointestinal signals that influence food intake." American Journal of Physiology-Gastrointestinal and Liver Physiology 286.1 (2004): G7-G13.

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!