Complete Meals & GI (Non-)Sense, Glutamine & GLP-1, Low Thyroid & High Trigs, N-3 vs. N-6 Interactions, Optimal DHA Dosage in Kids W/ NAFLD, Selenium vs. Aluminum Toxicity

While this is not the exact combination of chicken breast, mashed potatoes and salad in the first one of today's news items, it's more than likely that the predicted GI (and thus probably what you would find if you looked it up in a table) overestimates the postprandial glucose response to this meal by ~50% and says absolutely nothing about the insulin response. It looks like complex meals and over-simplified theories, don't mix well, at all ;-)

78% that's the SuppVersity Figure of the Week and actually part of the additional information I provided on one of today's On Short Notice items. It's the increase in coronary heart disease risk women with subclinical hypothyroidism have compared to their peers with spot on TSH levels of 0.5-1.5mU/L (Asvold. 2012). In conjunction with other more or less recent studies, such as Mitchel's, Hsu's and Sahai's paper confirming the previously often talked about but not well-established 2-fold increase in congenital hypothyroidism from the early 1990s to the first years of the new millennium (Mitchel 2011), the predictive value of high TSH levels in the first trimester (early pregnancy hypothyroidism) for adverse pregnancy outcomes (Schneuer. 2012), the 30% risk increase in all-cause mortality in both women and men with subclinical hypothyroidism Tseng et al. reported in their paper earlier this year or the impairment of spatial working memory (Yin. 2012), Asvold's results only add to the evidence that the potential pitfalls of an increasingly prevalent metabolic dysfunction may have been ignored way too long.

• More GI lovin' - On the menu today: Mashed potaoes with chicken, rapeseed oil or both (Hätönen. 2011) - I thought a mini-follow-up on Friday's post on the GI would be nice, 'cause some of you have not without reason been complaining that not everyone would eat pure white bread, like my students do.
  
  

  

  Figure 1: The real (=measured) GI of a meal does differ significantly from the theoretical prediction. So, even if the concept was worth bothering, the GIs of complete meals simply wrong, if they are not measured (Hötönen. 2011).

  Moreover, the mere fact that the scientists from the Department of Lifestyles and Participation at the National Institute for Health and Welfare in Helsinki, Finland, found that the addition of chicken breast, rapeseed oil and a salad, individually and in combination, had the GI of a meal containing six mashed potatoes (this was the parameter that was held constant) induced more than twofold changes in GI, with the addition of chicken breast having the greatest deviation from the predicted value in this group of 11 (initially 12) healthy subjects, three men and nine women, aged 36.2 (SD 14.1) years with a BMI of 21.3 (SD 1.7) kg/m² and normal glucose tolerance (see figure 1).
  
  Now given the fact that most data on the GI of complete meals has never been measured, but is actually based on the same predictions the scientists used, it stands to reason that...
  

  [...] this highlights the problems encountered when predicting the GI values of mixed meals. The protein com-ponent of the mixed meal evoked the largest insulinaemic responses and markedly increased the II of the mixed meal containing protein. However, introducing fat into the meal decreased the effect of protein on the insulinaemic responses (Hätönen. 2011)

  So, this does not simply bust the idea that you could calculate the GI, it does likewise show you that people who are still overtly scared of insulin (which is hillarious as long as you are insulin sensitive) are doing he exact wrong thing, when they make food-choices based on GI: Whey protein would in that case be in as much a no-go as simply eating a chicken breast with your mashed potatoes would be, because other than what most people believe, it does increase the insulin spike and thus reduce the glycemic index by allowing your body to clear the glucose more efficiently from the circulation.
  
  Suggested reads: The red box in the "Whey is More Insulinogenic than White Bread" post on the partitioning effects of BCAAs and yesterday's Facebook post on the anti-Alzheimer's effects of insulin.

• 

  Suggested read: Amino Acids for Super Humans the purported ergogenic effects of l-glutamine

  30g of oral glutamine have similar effects on GLP-1 as 75g of glucose (Greenfield. 2008) - Still a follow up on the GI discussion, I think you may be interested in. If you are someone who follows the questionable practice of ingesting large boluses of glutamine in the futile believe that this would increase your gains or speed up recovery, you may be pleased to hear that only 30g of oral l-glutamine produced an increase in the "Fat Burning Satiety Hormone GLP-1" (read more on GLP-1) that's on a gram to gram basis more pronounced than in response to insulin (0.41pmol/L per gram glucose vs. 0.75pmol/L per gram of glutamine; in 8 healthy subjects).
  
  Before you go and buy tons of glutamine, you should however consider that GIP, the pro-insulinogenic peptide and glucagon (ramps up gluconeogenesis in the liver) were likewise increased by the ingestion of this bolus of glutamine. It is therefore no wonder that glutamine has never been shown to be a "fat burner". Nonetheless, a 1999 study by Bowtell et al. would suggest that it may come handy to replenish liver and muscle glycogen after a workout (8g alone did increase glucose storage after a workout to a similar degree as a 18.5% glucose polymer solution and additional 25% glucose storage mostly in the liver, when both were coingested; cf. Bowtell. 1999). And if you don't care about that - your gut integrity could also be a reason to consider supplementation in the vicinity of particular strenuous or length workouts (see "Shedding Some Light on the Leaky Gut <> Exercise Connection") 

• Practical relevance? Based on data from a 12-year longitudinal study, even women with subclinical hypothyroidism have 76% risk for coronary heart disease (p = 0.005), than women with spot on TSH levels of 0.5-1.5mU/L (Asvold. 2012). And even women well within in the "normal range" (TSH of 1.5-2.4mU/l) have a 41% higher risk of heart disease, although this is only borderline significant (p = 0.08). For men the TSH level alone had not predictive value. Spec. w/ regards to T3, there are also reports of increased incidence of ventricular disfuntion (Cassetti. 2009), increased cardiac death in CVD patients (Iervasi. 2003) and impaired recovery after a stroke (Alevizaki. 2007). We do yet have to be cautious, here as "low T3" syndrome could as well be the consequence of overall inflammation and the association does not tell us anything about what's the chicken and the egg.
  Low thyroid, high triglyceride (Hashimoto. 2012) -- If you are wondering why on earth your trigs won't come down, it may well be that it's the absence of sufficient amounts of thyroid hormone. I a soon-to-be-published paper in Endocrinology scientists from the Gunma University in Maebashi, Gunma, Japan, report that thyroid hormone regulates the expression of a Stearoyl-CoA desaturase-1 (SCD-1) which controls the production of trigs from carbohydrates.
  
  Surprisingly the 75% increase due to hypothyroidism and the 75% decrease in SCD-1 mRNA expression (both compared to a euthyroid state) the scientists observed in rodents in response to the administration of T3 were not mediated by receptor binding, but simply as a down-stream effect of direct modifications of the SCD-1 gene promoter between -124 and -92 bp by T3.
  
  On a related side note: It is actually the last mentioned mechanism which is the major new finding in the study at hand and not the fact that T3 can reduce the conversion of carbohydrates to triglicerides that is the actual news here. After all, the latter is something scientist should know, but obviously like to forget about ever since the late 1999s (Waters. 1997)

• Omega-6 intake and not low omega-3 intake is the problem (Liou. 2007) -- Another older study, but one I am posting in response to a discussion some of you are having about omega-3 (ALA) intake in the post about safflower oil and DHT, because I simply feel that it's necessary to shed some light  on the erroneous assumption that by simply upping your intake of omega-3s or fish oil intake you could get away without decreasing your omega-6 intake, which in and out of itself will already increase the amount of anti-inflammatory omega-3 fatty acids (supplementation of DHA can still be advisable, specifically if you are a vegetarian).
  
  

  

  Figure 2: Effect of 4 weeks of high (red) vs. 4 weeks of low (green) linoleic acid (n-6) intake on short and long-chain omega-3 plasma phospholipid content in healthy men (Liou. 2007)

  In 2007, already Liu et al. conducted a very interesting experiment in the course of which they fed healthy men diets with identical amounts of omega-3 fatty acids (1% of the total energy intake), but two different amounts of linoleic acid (omega-6) and found that the high omega-6 intake (10.1% vs. 3.8% of the total energy intake) alone decreased the total amount of EPA among the plasma phospholipids (the major long-chain omega-3 fatty acid in fish oil), not just the ratio of omega-3 to omega-6, in the blood of their 29-45 year-old subjects by more than 25% (see figure 2). The paradoxical effect on DHA, on the other hand, would warrant further investigation, and underlines how reliant we are - if anything on the intake of pure DHA, which dropped in consequence to the test diet, which was devoid of fatty fish, while the original diet of the non-vegetarian subjects had fish in it.
  
  In this context, I would also like to point out that DHA is exactly where real fish is far superior to fish oil caps, because it has a way more favorable EPA:DHA ratio than fish oil caps. Salmon fillets for example have - depending on the fatty acid source in the diet 8.5g : 13.8g, 4.4g : 7.8g and 1.5g : 2.9g (all values per 100g) when the feed contains fish oil, fish and rapeseed and fish + rapeseed and rapeseed, only.
  
  And while the ratios are similar regardless of the chow, the data from the Seierstad et al. clearly shows that the fatty acid content of the diets can induce almost 5-fold differences in terms of the total DHA content and the omega-3 to omega 6 ratio (fish oil diet: 6.5, fish oil + rapeseed: 1.7, rapeseed: 0.6) of salmon fillets (Seierstad. 2003). 

• It does not take much: 500mg DHA not more effective than 250mg  (Nobili. 2012) -- At least if it comes to its beneficial effects against liver steatosis in children  (mean age 11 years; BMI 26.6kg/m² and 24.4kg/m², in the low and high dose groups respectively with with NAFLD, the amount of DHA does not appear to be so important. According to the results of their 2-year registered controlled trial, both 250mg and 500mg of Docosahexaenoic acid lead to identical and profound reductions in the odds ratio of developing more severe steatosis during the study period.
  
  

  

  Figure 3: Odds ratio (comparing DHA supplement vs. placebo) of more severe vs. less severe liver steatosis determined every 6 months during the 24-month study period (Nobili. 2012)

  If you take a closer look at the data in figure 3, you will even have to concede that the lower dosage did a better job - while the mean odds ratios were only marginally lower in the 250mg DHA group, the extremely high standard deviations in the 500mg DHA would suggest that the 250mg dose appears to be more reliable. In this regard it may be interesting that the increase in serum DHA did mirror the dosages. With a 0.65% and 1.15% increase in DHA those were about 2x higher in the 20 boys and girls in the high dose group compared to the 20 kids in the control group who received a 290 mg linoleic acid germ oil supplement "placebo" (by the way, a monosaturated fatty acid placebo would have been more of a placebo than 290mg of omega-6)
  
  In view of the fact that the changes in triglycerides, ALT, HOMA-IR and BMI (which was not even different from the placebo group) were likewise identical, it does not appear as if anything that goes beyond the amount you will find in 2x cheap fish oil caps, or 10g even of the cheapest salmon fillet (see last paragraph of previous item) would be necessary to ellicit the anti-steatosis effect of fish oil - since those kids weight on average 55kg, an adult may want to add in another fish oil cap to get up to 360mg DHA per day or simply eat his fatty fish once or twice a week.

• Selenium ameliorates aluminum toxicity (Viezeliene. 2012) -- With the whole upheaval about the potential negative side effects of the aluminum in vaccines, the formerly overlooked yet well-known neurotoxic (Exley. 1992; Gupta. 2005), hepatotoxic (Abubakar. 2003; Perez. 2005) and nephrotoxic metal (Geyikoglu. 2012) has all of a sudden returned to the center of public interest.
  
  Therefore I thought that you will be interested in the results of a study that's going to be published in the next issue of the Journal of Trace Elements in Medicine and Biology - irrespective of whether you believe, like Tomljenovic and Shaw that
  

  "the possibility that vaccine benefits may have been overrated and the risk of potential adverse effects underestimated, has not been rigorously evaluated in the medical and scientific community"(Tomljenovic. 2011)

  After all, vaccines are not the only potential source of aluminum in our environment, so that the ameliorative effects (all values remained normal in the aluminum exposed group, while there were 30%, 55% and 42% increases in GSH in the animals who received only the selenium injection) the co-administration of supplemental selenium had on the GSH reductions in liver, kidney and brain of Balb/c mice weighing 20–25g who were exposed (by i.p. injection)to AlCl3 (25 mg Al(3+)/kg body mass) for 16h could be important, regardless of whether you do or don't intend to get vaccinated.
  
  

  

  There is more about selenium at the SuppVersity, for example on its pro-fertility effects, and its anti-corrosive effects in the brain.

  That said, the dosage requirements necessary to maintain healthy GSH levels are probably much lower than the hillarious (for a healthy individual) in the study at hand 1,250µg/kg body weight of sodium selenite (Na2SeO3). Considering the elemental selenium content in Na2SeO3, the latter would equal to ~3,650µg - unquestionably WAY too much (remember this was a one-time dosage that was specifically co-administered w/ the aluminum). Even the 'no observed adverse effect' level for a 70kg man of intake which is ~1000µg/d (Whanger. 1999) appears unnecessarily high, so that the consumption of a handful of brazil nuts once or twice a week and/or other high selenium foods such as tuna, cod, oysters, shrimp, but also eggs, meats, poultry, mushroom and onions on a regular should suffice to get what you need, to fortify yourself against the constant assault of heavy metals.
  
  What would be interesting, though, is a study into the effects of adding selenium to the "safe" aluminum in vaccines. I mean, you cannot seriously tell me that we could not afford doing that and if it reduced any toxicity issues, why not?

That's about it for today, I did not post all too many new facebook news as of yet (I mean, come on, it's Saturday ;-), but if you are into medicinal horror-stories, you will certainly like the story about the flesh eating killer fungus. If you prefer microbes over fungi, you are probably better off with the latest insights into the associations of certain gutbacteria with the incidence of stroke. And if you are more into other aspects of the digestive tract you may be interested in the effects of gastric emptying time on postprandial gylcemia and insulin release.

If none of those news is to your liking, I suggest you either wait for me to post something else (could be happening within the next hours at www.facebook.com/SuppVersity), or simply enjoy the weekend and come back tomorrow when you are rested for another (hopefully) enlightening SuppVersity post.

References:

• Abubakar  MG,  Taylor  A,  Ferns  GA.  Aluminium  administration  is  associated  with enhanced  hepatic  oxidant  stress  that  may  be  offset  by  dietary  vitamin  E  in  the rat. Int J Exp Pathol 2003;84:49–54.
• Asvold BO, Bjøro T, Platou C, Vatten LJ. Thyroid function and the risk of coronary heart disease: 12-year follow-up of the HUNT Study in Norway. Clin Endocrinol (Oxf). 2012 Dec;77(6):911-7.
• Bowtell JL, Gelly K, Jackman ML, Patel A, Simeoni M, Rennie MJ. Effect of oral glutamine on whole body carbohydrate storage during recovery from exhaustive exercise. J Appl Physiol. 1999 Jun;86(6):1770-7.
• Cassetti G, Pinelli M, Bindi M, Bianchi M, Castiglioni M. [Low T3 syndrome and left ventricular diastolic function]. G Ital Cardiol (Rome). 2009 Aug;10(8):553-7. 
• Exley  C,  Birchall  JD.  The  cellular  toxicity  of  aluminium.  J  Theor  Biol 1992;159:83–98.
• Geyikoglu  F,  Turkez  H,  Ozhan  Bakir  T,  Cicek  M.  The  genotoxic,  hepa- totoxic,  nephrotoxic,  haematotoxic  and  histopathological  effects  in  rats after aluminium chronic intoxication. Toxicol Ind Health 2012;15.
• Greenfield JR, Farooqi IS, Keogh JM, Henning E, Habib AM, Blackwood A, Reimann F, Holst JJ, Gribble FM. Oral glutamine increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects. Am J Clin Nutr. 2009 Jan;89(1):106-13.
• Gupta  VB,  Anitha  S,  Hegde  ML,  Zecca  L,  Garruto  RM,  Ravid  R,  et  al.  Alu- minium  in  Alzheimer’s  disease:  are  we  still  at  a  crossroad?  Cell  Mol  Life  Sci 2005;62:143–58.
• Hashimoto K, Ishida E, Miura A, Ozawa A, Shibusawa N, Satoh T, Okada S, Yamada M, Mori M. Human Stearoyl-CoA Desaturase 1 (SCD-1) Gene Expression Is Negatively Regulated by Thyroid Hormone without Direct Binding of Thyroid Hormone Receptor to the Gene Promoter. Endocrinology. 2012 Dec 7.
• Hätönen KA, Virtamo J, Eriksson JG, Sinkko HK, Sundvall JE, Valsta LM. Protein and fat modify the glycaemic and insulinaemic responses to a mashed potato-based meal. Br J Nutr. 2011 Jul;106(2):248-53. 
• Iervasi G, Pingitore A, Landi P, Raciti M, Ripoli A, Scarlattini M, L'Abbate A, Donato L. Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation. 2003 Feb 11;107(5):708-13.
• Liou YA, King DJ, Zibrik D, Innis SM. Decreasing linoleic acid with constant alpha-linolenic acid in dietary fats increases (n-3) eicosapentaenoic acid in plasma phospholipids in healthy men. J Nutr. 2007 Apr;137(4):945-52. 
• Mitchell ML, Hsu HW, Sahai I; Massachusetts Pediatric Endocrine Work Group. The increased incidence of congenital hypothyroidism: fact or fancy? Clin Endocrinol (Oxf). 2011 Dec;75(6):806-10.
• Perez  G,  Pregi  N,  Vittori  D,  Di  Risio  C,  Garbossa  G,  Nesse  A.  Aluminium  expo- sure  affects  transferrin-dependent  and  -independent  iron  uptake  by  K562  cells. Biochim  Biophys  Acta  2005;1745:124–30. 
• Schneuer FJ, Nassar N, Tasevski V, Morris JM, Roberts CL. Association and predictive accuracy of high TSH serum levels in first trimester and adverse pregnancy outcomes. J Clin Endocrinol Metab. 2012 Sep;97(9):3115-22.
• Seierstad SL, Seljeflot I, Johansen O, Hansen R, Haugen M, Rosenlund G, Frøyland L, Arnesen H. Dietary intake of differently fed salmon; the influence on markers of human atherosclerosis. Eur J Clin Invest. 2005 Jan;35(1):52-9.
• Waters KM, Miller CW, Ntambi JM. Localization of a negative thyroid hormone-response region in hepatic stearoyl-CoA desaturase gene 1. Biochem Biophys Res Commun. 1997 Apr 28;233(3):838-43. 
• Whanger P, Vendeland S, Park Y-C & Xia Y. Metabolism of sub-toxic levels of selenium in animals and humans. Annals of Clinical Laboratory Science. 1996;26, 99-113.

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.

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]

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.

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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.

Fast Absorbed High Molecular Weight Resistant Starches Make a Comeback in Diabetic Formula: Are RS-4 (WM-HDP) Based Products An Ideal Meal Replacement for Diabetics?

Pick your metaphor: Clutching to a straw, or hobbling around on a crutch

If type II diabetics were into quasi tube-feeding (=living of meal replacements) or adhering to any diet of some sort, the study Cruz Erika Garcia-Rodriguez and colleagues have recently published in the European Journal of Nutrition could actually be help us solve the to diabesity problem. For me it is  however more of a good reason to take another look at what became of RS-4 (resistant start type 4 = synthetic resistant starches made from waxy maize or tapioca; learn more).

I mean, do we have good reason to mourn, now that Myotropics ThermiCarb(TM) is gone and no legitimate and reasonably prized follow-up product is available?

The stuff still works, but does it also help?

Aside from the fact that I personally consider the idea to feed diabetics liquid foods ludicrous and counter-productive (you do not heal a cripple if you hand him a crouch), the latest results Garcia-Rodriguez et al. present in their paper confirm what we already knew: RS-4 is a non-insulinogenic carbohydrate source that produces

• higher levels of the incretin hormones ghrelin, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), and
• lower levels of insulin and C-peptide compared to iso-energetic "regular carbs" 

at least in the 24 healthy individuals (BMI 23.2kg/m²) who participated in the study at hand. For their type II diabetic counterparts (BMI 35.5kg/m²; HnA1C 8.3%), on the other hand, a significant reduction in postprandial glycemia was the only advantage the researchers could detect.

Diabetic diet formula wars

The actual product the scientists evaluated for their sponsors from Vegenat S.A was albeit not a simple WM-HDP (=waxy maize Hydroxypropyl-Distarch Phosphate) powder.

Table 1: Nutrient composition of formulas used in the study (Garcia-Rodriguez. 2013)

"The tested DSF (T-Diet Plus Diabet NP, Vegenat S.A., Spain) [...] provided 402 kcal/845 kJ (400 ml serving) with 32 g as CHO (40 % of energy), 20.1 g as fat (45 % of energy) and 22 g as protein (15 % of energy) and contained a mixture of vegetable and fish oils (20 mg/dl of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA)). It also included 7.2 g (20 % on total CHO) of fibre content (inulin and cellulose 20/80 wt/wt). The CHO in this new DSF was low dextrose equivalent (DE) purified and atomized maltodextrins (5–8 DE) (31.7 %) obtained by the hydrolysis of starch, and RS type IV (53.7 %) obtained from partially hydrolysed maize starch by heating in the presence of food grade acid. [...]

The CP [control] was a normoproteic and normocaloric diet which differed to T-Diet Plus Diabet NP in its CHO composition, containing 18–20 DE purified and atomized maltodextrins (99.4 %) obtained by the hydrolysis of starch, and in its fibre content, that is, inulin- and cellulosefree." (Garcia-Rodriguez. 2013)

In contrast to the healthy subjects, on whom the scientists tested only the carbohydrate fraction of this new product the 10 diabetics consumed different commercially available nutritionally complete liquid diet supplements, i.e. T-Diet Plus Diabet NP (Vegenat S.A., Spain), Glucerna SR (Abbott Laboratories, Chicago, IL, USA) and Novasource Diabet (Nestlé Healthcare Nutrition, Switzerland) in 400ml servings after an overnight fast.

Figure 1: Area under the curve (AUC) for biochemical parameters and gastrointestinal hormones in diabetic (left) and healthy volunteers (Garcia-Rodriguez. 2013)

As the data in figure 1 (left) goes to show you, the real-world differences between the products were yet by far less earth-shattering, than you may have expected; and that despite significant differences in their carbohydrate make-up:

• Glucerna SR contains a complex carbohydrate mixture consisting of fructose (22.9 %) and slowly digestible maltodextrins (49.9 %). It also includes shortchain fructo-oligosaccharides and fibre (6.9 % on total CHO). 
• Novasource, on the other hand is, based on starch (84 %) and fructose (24 %) as well as fibre (11.7 % on total CHO).

Compared with Glucerna SR and Novasource the product of the study sponsor was also the only one with significant amounts of n-3 fatty acids from plant (linoleic and linolenic acid) and marine sources (EPA+DHA). And still,  as a comparison of the response of the healthy subjects to the same product vs. a regular maltodextrin based formula shows. Neither the lower insulin, c-peptide, triglyceride and GIP levels (all beneficial for weight loss) nor the non-significantly increased GLP-1 levels the scientist observed in the lean individuals were present in the overweight diabetics.

It should be mentioned, though that the control supplement for the healthy individuals was not identical to any of the two formulas that were compared to T-Diet Plus in the experiment with the diabetics. Whether the differences between T-Diet Plus and a "regular" meal replacement would be more pronounced would thus still have to be tested in diabetics.

---

Certainly no food for diabetics, but as workout fuel for lean athletes RS-4 pancakes could still be useful (more)?

Bottom line: Questionable weight benefit and non-existent anti-diabetic effects - that certainly sounds like any of the commercially available mainstream weight loss products and or meal replacements for diabetics. The significant decrease in blood glucose AUC after the ingestion of the RS4-powered formula, however, could still make a significant health benefit. Just like the crutch that helps you to walk from A to B without straining an already injured ankle even further, RS4 based products could help type II diabetics control their blood glucose levels more than the fructose + regular starch based competition and that would directly reduce the risk of complications!

However, other than real food and lifestyle changes esp. exercise / general physical activity, by the means of which more than half (∼54%) of the patients in the often-quoted Malmö study improved their oral glucose tolerance to an extend that their blood glucose levels were no longer in the critical range (Eriksson. 1999), consuming resistant starches does not have the potential to eradicate diabetes.

References:

• Eriksson KF, Lindgärde F. Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise. The 6-year Malmö feasibility study. Diabetologia. 1991 Dec;34(12):891-8.
• García-Rodríguez CE, Mesa MD, Olza J, Buccianti G, Pérez M, Moreno-Torres R, Pérez de la Cruz A, Gil A. Postprandial glucose, insulin and gastrointestinal hormones in healthy and diabetic subjects fed a fructose-free and resistant starch type IV-enriched enteral formula. Eur J Nutr. 2013 Sep;52(6):1569-78.

8g+ (HED) of Arginine Boost Glucose Clearance & Triples GLP-1 Release in Lean and Obese Mice. Plus: 14+ Studies On Things Arginine Can Do For Diabetics & Athletes

Type II diabetes and insulin resistance has long become an issue for lean individuals as well. But can you really abuse your "pump supplement" as a means to stash away your post-workout carbs at a significantly increased pace?

Statements like "XY boosts" and figures like "+30%" are real attention-grabbers. I mean 200mg/dl glucose vs. 300mg/dl glucose after a 2g/kg glucose load that must certainly be significant, right? Well, as always, there are exceptions to the rule, but I can reassure you: it's not the case with the latest study from the College of Medicine at the University of Cincinnati (Clemmensen. 2013). How I know that? Well the I wrote about the real world significance of the increased glucose clearance, as well as the brown-adipose-tissue building and white adipose tissue burning effects of arginine, previously (see "Arginine: BAT Builder and WAT Killer" & "Arginine Enriched Biscuits for Diabetics"). Thus, the most recent revelation that the conditionally essential amino acid that's notorious for its non-existent effects on the pump is able to increase the GLP-1 response to a sugary meal and thus double the glucose clearance in lean mice only adds to what SuppVersity readers knew all along:

There is way more to arginine than "the pump"

Being aware that everybody believes to know exactly that the big bad insulin is the reason for the current obesity epidemic, I guess it's better to remind you that this is not just an unwarranted over-generalization, but completely beside the point. So I suggest you (re-)read "The "Pro-Insulinogenic" Effects of Non-Nutritive Sweeteners + Mechanisms & Consequences" (just do it!), if you feel like running away, when you take a closer look at the right hand side of figure 1:

Figure 1: AUC under the glucose curve (left), actual glucose response after oral glucose tolerance test 15min after the ingestion of arginine in lean and obese mice (middle) and insulin response to arginine and subsequent ingestion of dextrose during the OGGT (right; Clemmensen. 2013)

What you are seeing here is an insulin SPIKE that deserves to be written in capital letters, but the way it ameliorates the surge in blood glucose in the diet-induced obese (~type II diabetic) mice could actually protect the rodents from developing many of the neurological and endocrine side effects of high blood glucose levels and not insulin, which has only recently been demonstrated to ameliorate the cognitive decline in dementia and Alzheimer's (Craft. 2012).

I know you are not dietary obese

Figure 2: GLP-1 response in the lean mice in the study at hand (foreground, top-right; Clemmensen. 2013) and selected effects of GLP-1 (background; from byettahcp.com)

Now, while the data on the right hand side of figure 1 may be relevant for your obese neighbor,  we are actually more interested in the data on the left, which does, by the way, make it quite clear that the problem with being obese is not an increase in insulin release, but the mere fact that even that is not going to help you clear the sugar out of the blood stream.

Compared to the obese mice, where we see a slight, but at 60min significant improvement in glucose clearance, the lean mice did not even give the 2g/kg body weight of glucose they received a chance to accumulate in their blood. Rather than that, they cleared it almost instantly.

The researchers hypothesis that this effect was mediated by the concomitant up to 3x increase in GLP-1 production was supported by a follow up experiment using a genetically modified strain of mice that lacks the GLP-1 receptor, in whom the corresponding improvements in blood glucose management were absent. In the discussion of their results, the researchers add:

Suggested read: "Glycemic Load, the GI's Complex Brother, Turns Out to Be A Good Predictor of Postprandial GLP-1 and GIP Response" | read more

"The GLP-1 incretin effect has traditionally been ascribed to effects on intestinal L cells elicited by ingested carbohydrate, but the findings reported here support the involvement of gut hormones to link protein ingestion with insulin secretion.

This has also been recently suggested in studies of humans consuming meals of specific macronutrient composition (Carrel. 2011).

Also, we have recently reported that long-term dietary supplementation with L-arginine improves glucose metabolism in mice exposed to a low-protein diet (Clemmensen. 2012)." (Clemmensen. 2013)

Despite the fact that GLP-1 analogues have been used with quite some success in the treatment of type II diabetes in the recent years, our understanding of the far-reaching effects of this "satiety hormone" is still far from being comprehensive (suggested read: "Eat More, Burn More and Lose Fat Like on Crack w/ GLP-1"). What we do know is that it occupies a central position in the control of our energy intake, though. And I am pretty sure is not the SuppVersity post about glucagon-like peptide 1 (GLP-1), you are about to read.

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But does that even work for you? For (pre-)diabetics we can rely on data from Piatti et al. (2001) who found a 34% increase in insulin clearance after one months on 3g/day l-arginine and data from Lucotti (2006) who observed that the addition of 8.3g of l-arginine to a hypocaloric diet + exercise regimen boosted the loss of fat mass and and waist circumference while increasing the lean mass retention and improving daily glucose and fructosamine profiles, significantly. For the sick / obese we do also have human (H) and rodent studies (R) supporting

• 

  Whenever the word "vascularity" appears on one of the boards, this image pops up. Now we know that arginine alone won't make your veins pop, but could it be that we have hitherto overlooked that it could help you meet another more important criteria to look like that - namely to drop body fat? Learn more in a previous SuppVersity article on arginine's BAT building and WAT killing effects and it's use as a repartitioning Agent (read more)

  an anti-platelet effect of 8.4g arginine per day in hypercholesterolemic humans (Wolf. 1997; H)
• indirect anti-oxidant effects of 2x3g arginine per day in in diabetic patients with atherosclerotic peripheral arterial disease of lower extremities (Jablecka. 2012; H)
• an ameliorative effect on diabetes induced gastrointestinal malfunction (Míguez. 2004; R)
• improved wound healing when administered alone (Witte. 2002; R) or with proline (Raynaud-Simon. 2012; R)
• significantly reduced body fat mass in rodent model of diet induced diabesity (Fu. 2005; R)
• beneficial effects on the hypertensive offspring of diabetic dams (Cavanal. 2007; R) 
• direct mechanistic effects that inhibit the storage of fat in white adipose tissue (Tan. 2012; R + H + PIG)
• reductions in diabetes induced bone loss (Pennisi. 2009; R)
• amelioration of the negative effects on insulin sensitivity in response to a low (no typo!) salt diet (Ruivo. 2006; R)

The benefits for lean individuals are not that clear, studies like Gater et al. (1992), for example, tested the effect of the purportedly GH boosting combination of arginine + lysine and saw no effects in their healthy young participants. Other studies did however find ...

• 

  Suggested read: "Post-Workout Glycogen Repletion - The Role of Protein, Leucine, Phenylalanine and Insulin." | read more

  a reduced oxidation of glucose when well-trained cyclists used a mixture of 1 g carbohydrate/kg body mass and 0.08 g arginine-hydrochloride/kg body weight to refuel their muscle glycogen after a workout (Yaspelkis. 1999)
• significantly lowered blood pressure and improved renal function and carbohydrate metabolism in healthy volunteers (Siani. 2000)
• significantly increased rates of glucose disposal during exercise in trained cyclists (McConell. 2006; Linden. 2011)
• direct beneficial effects on glucose and fatty acid metabolism in muscle cells (de Castro Barbosa. 2013)
• reduced blood lactate accumulation & oxygen consumption during submax. exercise after prolonged intake of L-arginine-L-aspartate (Burtscher. 2005)

So, if it there was not the likely possibility that many of these benefits occur only with a low(ish) protein intake,  I would say: Arginine can do a lot of interesting things for you. With a possible beneficial effect on post-workout glycogen repletion being what I consider most significant for the lean physical culturist. There is yet one thing arginine cannot do and that's worth remembering, because it tells you something about the supplement business: It won't increase the pump.


References:

• Burtscher M, Brunner F, Faulhaber M, Hotter B, Likar R. The prolonged intake of L-arginine-L-aspartate reduces blood lactate accumulation and oxygen consumption during submaximal exercise. J Sports Sci Med. 2005; 4(3), 314-322.
• Carrel G, Egli L, Tran C, et al.Contributions of fat and protein to the incretin effect of a mixed meal. Am J Clin Nutr. 2011;94(4):997–1003. 
• Cavanal Mde F, Gomes GN, Forti AL, Rocha SO, Franco Mdo C, Fortes ZB, Gil FZ. The influence of L-arginine on blood pressure, vascular nitric oxide and renal morphometry in the offspring from diabetic mothers. Pediatr Res. 2007 Aug;62(2):145-50.
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