Sunday, November 4, 2012

Get Lean & Stay Lean Quickie: Add Cinnamon to Cereals. NPY Detrimental? Melatonin Beneficial! 50,000IU Vitamin D3 Useless. Phtalate DHEP Dangerous! PPAR, AKT & GLUT-4 Agonist From False Black Pepper Surprisingly Potent!

In 1998 the Consumer Union wrote a letter to the FDA complaining about the occurrence of DEHP and other "endocrine disrupting chemicals" in cheese and dairy of which they suspected that they were partially emitted from the plastic wrappings (read more)
Those of you who are following the SuppVersity news on Facebook very closely, will be aware that I announced yesterday, already that there was going to be another installment of On Short Notice, today... another "Quickie", so to say with a couple of selected news on getting and staying lean. Something I know is pretty much a pain in the a** of most of us and if you take a closer look at the news about phtalates it is actually no wonder. I guess on their own those nasty plasticizers would probably not even be a problem, but together will all the other byproducts of our convenient lives, they form a perfect storm.

And you know what's worst, simply wrapping all those plastics that 'infect' even organic foods with the 'P-Virus' around your waist while you're working out will probably make things worse, not better.

Let's get down  to business ;-)

Enough of that! Are you ready for today's quickie -- Note: The next installment of the Athletes' Triad is scheduled for next week. I am honestly sorry for these delays, but I just have "real" work to do on the weekends at the moment and no time to do the respective research that would be necessary to provide you with not just any, but actually useful information. In the mean time I hope you like this post, as well.
  • 6g of cinnamon stretch postprandial glucose response to cereals over more than 2h. That's the result of the latest study from the Ball State University in Muncie (Magistrelli. 2012). Interestingly the effects of 6g of ground Cassia Cinnamon were independent of the body weight and metabolic health of the thirty-seven 18 to 30 year-old normal-weight and obese study participants.

    Figure 1: Postprandial blood glucose with plain cereal containing 50g  carbs and the same cereal with cinnamon in all subjects, normal-weight and obese; by the way if you go by the AUC I doubt there is a benefit, after all the glucose does not drop base to baseline within 120min (Magistrelli. 2012).
    There is however one slight downside to this study: The scientists measured the blood glucose response for only 120min. If you take a look at the graph in figure 1 you will immediately notice that the co-ingestion of 75g of "Cream of Wheat", an instant farina cereal, with 6g of regular cinnamon did lead to a 24% reduction in the area under the glucose curve, but only if you discard what happened after the 120-min period the scientists used to measure. After all, the co-administration of Cassia cinnamon did not do anything that could not be ascribed to a mere reduction in glucose uptake - there is no evidence for an improvement of insulin sensitivity here. On the other hand, the absence of spikes in blood glucose will protective effects against the development of type II diabetes, esp. in the presence of a diet that's overall high in carbohydrates where one blood sugar spike chases the other.
    "To date, no study has documented cinnamon's influence on postprandial blood glucose after a mixed meal. Although preliminary in nature, the available research suggests cinnamon supplementation can significantly reduce short-term glycemic response in healthy adults." (Magistrelli. 2012)
    The last information is actually pretty surprising. Personally I expect the effects to be less pronounced with mixed meals, but since we still don't really know the underlying mechanism it's difficult to predict what exactly is going to happen, when you eat a spoon full of cinnamon right before your steak with rice. This as well as the previously discussed prolonged elevation of blood glucose (see figure 1)  actually raise some doubts about the real-world usefulness of eating tons of cinnamon if you don't actually like it, just as a way to manage blood glucose - specifically if you are not a type II diabetic (or on your way to become one) and avoid "food" like cereals and similar junk, anyways.
  • Neurpeptide Y (NPY) does not protect against obesity -- Based on the results of a recent rodent study from the University of Turku in Finland, it seems that the exact opposite is the case. In that it does not seem as if it would fail to make you satiated and happy. Rather than that it appears to put your metabolism in "high efficacy" mode, so that you gain weight despite the fact that you are not eating more.

    The Finish researchers exposed two strains of mice to a typical Western type diet (high energy, high fat, high carbohydrate) for seven weeks. One strain, the OE-NPY(DBH) mice, had 'naturally' high amounts of NPY in the noradrenergic neurons of the brain, the other were normal wild type mouse. Actually, the scientists had expected that the high NPY expressing mice would gain less weight than their wild-type peers, but much to their surprise, the exact opposite was the case.

    In 1990 Kaye et al. conducted post-mortem analyses on the brains of patients with anorexia nervosa and found highly elevated levels of NPY. These results do actually stand in line with those of the study at hand, after all anorexic patients don't feel any exuberant hunger (in the later stages of the disease) and their bodies are running in a mode that is meant to conserve even the smallest amount of energy they consume.
    And as if that was not already strange enough, the scientists also found that female OE-NPY(DBH) were much more prone to gain significantly more weight and larger white and brown fat depots with no difference in UCP-1 levels, hyperphagia (=overeating) or decreased activity. And the weight gain was not without consequence, as these mice
    "...also displayed impaired glucose tolerance and decreased insulin sensitivity. OE-NPY (DBH) and WT males gained weight robustly, but no difference in the degree of adiposity was observed." (Ruohonen. 2012)
    Now what's interesting is that similar effects were only observed in 40% of their male counterparts and in exactly none of the wild type males on the Western type diets. These observations lead Ruhonen et al. to the conclusion that ...
    "[...] increased NPY release may predispose females to a greater risk of weight gain under high caloric conditions." (Ruhonen. 2012)
    And if you asked me this must be mediated by whatever gender-specific direct effect on feed efficacy and the changes in brown adipose tissue morphology the researchers observed in the NPY overexpressing mice. This would be good news, since brown fat figure much less in human beings than in rodents. Unfortunately, with identical body temperatures and UCP-1 expression in all animals that is at best one of the causative factors. It can hardly explain all the profound weight and fat gains in the non-hyperphagic (not overeating) OE-NPY mice.

    Now, at least for me this raises the question if this is not yet another instance, where the artificially increased NPY levels in the absence of the natural confounding factors, such as increased GLP-1 levels, for example (click here to learn more about GLP-1), couldn't be the actual reason and any conclusions with respect to pro- or anti-obesogenic effect of NPY based on the results at hand would be as unwarranted as the usage of drugs that target this and other neuropeptides in isolation.
  • Just in case you have missed the Circadian Rhythm Series, this would be the right time to read about how to boost / not hamper melatonin, live by your internal clock and get healthy and lean (and stay the same) - light and foods timing are key, here (learn more).
    Thiazolidinediones + melatonin, a dynamic duo vs. insulin resistance -- A group of researchers from the Indira College of Pharmacy in Tathawade, India, have just published a study on the combined effects of PPAR agonists and melatonin as a means to ameliorate dexmethasone (artificial cortisol) induced insulin resistance in rodents (Ghaisas. 2012).

    The data of the study casts a particularly good light on melatonin which does, contrary to the potentially fattening PPAR agonists pioglitazone and rosiglitazone, not entail a simple increase in glucose storage within the adipose tissue. The combination treatment did also normalize the levels of superoxide dismutase, catalase, glutathione reductase and lipid peroxidation in liver homogenates, an effect the scientists partly ascribe to the antioxidant effects of melatonin , as well (the reduced blood glucose is obviously another factor) 
  • 50,000 IU of vitamin D per week improve 25OHD in previously vitamin D deficient subjects but don't produce the expected improvements in insulin sensitivity. Contrary to one of the most underrated dietary supplement, namely melatonin (see previous news item), the most overrated, namely vitamin D3, does not do anything for insulin sensitivity -- even when the subjects are deficient to begin with and their 25OHD levels do actually respond to supplementation (Simha. 2012).

    Despite a weekly dose of 50,000 IU of vitamin D3 and a + 42% increase in 25-OHD levels (to be fair it must be said that the levels were still relatively low and nowhere near where some experts want to see it), the researchers from the Department of Internal Medicine at the Texas Tech University Health Sciences Center at Permian Basin did not observe any improvements in glucose uptake after 8 weeks of supplementation in their 12 healthy subjects with baseline plasma 25-hydroxy vitamin D (25OH-D) levels of less than 20 ng/mL.
  • More about DEHP and its occurrence in your environment: Prepackaged foods are among your best sources to get your detrimental dose of DEHP every day. Belgian children have been shown to get up to 80% of their DEHP and other phtalates from school lunch. And bread was the worst offender (Sioen. 2012) - probably because it's packed 'sandwich style' in plastic containers of which Cirillo et al. were able to demonstrate that these and other plastic packagings leech the phtalates right into the food (Cirillo. 2011). It is therefore no wonder that the packaged hopsital foods are full of it (Teresa. 2012).
    Apropos, having a venyl flooring in either schools or hospitals will only increase the DEHP load due to the emission of the plasticizer into the air (Yu. 2012) and the DEHP content of the bags with blood transfusions are so high that the anti-doping agencies use it as a marker of illegal blood transfusions (Monfort. 2012). Moreover, phtalates leech into milk and dietary products fat-enriched food such as cheese and cream during processing and storage (Kappenstein. 2012); vegetable oils in plastic containers are likewise full of it (Wu. 2012).
    Cooking seems to remove some of the phatalates, but that does not work for vegetables for example (Fierens. 2012). No wonder foods are still the #1 source, followed by bottled water and indoor air of phatalate exposure in Westerners (Martine. 2012).
    Unfortunately, the negative effects of DEHP and its metabolites are not restricted to obesity or the prenatal period, they also induce insulin resistance and metabolic syndrome later in life (Rajesh. 2012) - effects which can be ameliorated by increased vitamin C + E intakes. DEHP has also been shown to reduce progesterone and lead to apoptosis of the ovarian granulosa cells and subsequent infertility (Li. 2012a). Similar detrimental effects have been seen in male rodents (Li. 2012b).
    Natural metabolite of ubiquitous plasticizer DEHP sets you and your unborn kids up for obesity DEHP is used in a wide range of soft PVC products ranging from lifesaving medical devices such as medical tubing and blood bags, to footwear, electrical cables, packaging, tarpaulins for lorries, flooring, stationery and roofing. According to a recent study that's been published in Bioscience Reports its natural metabolite MEHP [mono-(2-ethylhexyl) phthalate] has the potential of turning you into a fat, sick slob:
    "In the present study, we show the dose-dependent effects of MEHP on adipocyte differentiation and GPDH (glycerol-3-phosphate dehydrogenase) activity in the murine 3T3-L1 cell model. MEHP induced the expression of PPARγ as well as its target genes required for adipogenesis in vitro. Moreover, MEHP perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to a low dose of MEHP significantly increased b.w. (body weight) and fat pad weight in male offspring at PND (postnatal day) 60. In addition, serum cholesterol, TAG (triacylglycerol) and glucose levels were also significantly elevated. These results suggest that perinatal exposure to MEHP may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders." (Hao. 2012)
    In the latest risk assessment of the EU and the DEHP Information Center it is of course 100% save... which bags the question, whether the guys working there simply consider being obese normal, so that anything that makes you even fatter is "save" and does not pose any more of a health threat than life in general, or if they just deliberately ignore that molecules rarely go in and out of our bodies unmetabolized and thus settled for a set of totally meaningless petri dish experiments, before they concluded:
    "The use of DEHP has been carefully considered by EU scientists and it is already well regulated by European legislation relating to toys and childcare articles, cosmetics, food contact materials and medical devices." (DEHP Information Center. 2009)
    Hallelujah! Unfortunately it's metabolite MEHP [mono-(2-ethylhexyl) phthalate] obviously is not such a nice guy :-/  
  • Figure 2: Serum markers and adiposity, as well as mRNA expression in adipose tissue of male and female mice after 14 weeks on "high fat" diets (based on Estrany. 2012)
    High fat diets (Western style) for women only? I know, this is once again a rodent study, but it is still intriguing that scientists from the Universitat de les Illes Balears in Palma de Mallorca and the Instituto de Salud Carlos III in Madrid, Spain, found that male rodents become insulin resistant and obese, when they are fed a high fat diet (30% fat, in other words high fat + high carb), the female rodents, on the other hand, switch to a 'fat burning mode' or as the scientists state they ...
    "[...] counteract excessive fat intake by improving their ability to use lipid fuels, which limits adiposity and maintains insulin sensitivity." (Estrany. 2012)
    Just as in a previous study neither the male nor the female rats showed the usual symptoms of hyperphagia (overeating), and the body weight gains in all groups were normal.

    "Normal" body weight gain and insulin resistance? That should actually ring a bell. Correct! "Normal-weigh obesity" or being skinny fat! And in fact, the underlying reason for Estrany et al.'s observations seems to be that the diet increased the inflammation in the male rats, while it did not do so in the female rodents. What exactly it was that made the difference here, will yet still have to be elucidated, but my best bet is estrogen, which is by no means just the bad guy as which it is portrayed within the fitness community.
  • Molecule in false black pepper aka Embelia ribes turns out to be natural GLUT-4 + PI3K/AKT activator, PPAR-gamma agonist and anti-diabetic. What's particularly exciting about the embelin the active ingredient in Embelia ribes Burm, a member of the species Myrsinaceae, which is widely distributed in India and and has a documented history of being used as a diabetes 'medication' in the Ayurvedian traditional medicine system, is that it increases insulin sensitivity without predisposing to further weight gain and adiposity, as the standard Thiazolidinediones (TZDs) such as rosiglitazone and pioglitazone do.

    Using the same streptozotocin (STZ) induced rodent model of type II diabetes you have encountered in numerous other studies that have been covered here at the SuppVersity a group of researchers from the Loyola College in Chennai and the University of Madras (Gandhi. 2012), have found that 50mg/kg body weight of embelin that had been extracted from fresh E. ribes fruits by drying and eluting the raw material in benzene...
    • Figure 3: Effects of embelin vs. rosiglitazone on insulin levels and rel. expression of antioxidant enzyme activity (Gandhi. 2012)
      reduced body weight gain, blood glucose and plasma insulin in treated diabetic rats,
    • modulated the altered lipid profiles and antioxidant enzymes,
    • exerted cytoprotective effects on the β-cells of the pancreas,
    • increased the PPARγ expression in epididymal adipose tissue,
    • inhibited adipogenic activity (=fat gain),
    • mildly activated PPARγ levels in the liver and skeletal muscle, and
    • regulated insulin mediated glucose uptake in epididymal adipose tissue through translocation and activation of GLUT4 in PI3K/p-Akt signaling cascade.
    And best of all, contrary to most natural anti-diabetes, these effects were no mere downstream effects of the antioxidant effects of Embelin, but can be ascribed to direct receptor binding: The active ingredient from false black pepper does not only show a high binding affinity for PPARγ, in the experiments Gandhi et al. condcted, it also had stable binding affinities for the active sites of PI3K, p-Akt and GLUT.

    Embelia ribes in Ayurveda The false black pepper is no newcomer to the scene of natural medicine / health supplements. Embelia ribes has been used in Ayruveda for centuries as an appetiser, laxative, carminative, anti tape-worm cure, to ameliorate / protect from snake bites, against skin deseases, bronchitis and urinary discharges, versus dyspepsia, liver ailments, jaundice, and glatulence.
    The results certainly are exciting, specifically in view of the fact that emeblin could be interesting not just for type II diabetics and individuals with insulin resistance, but also for lean mean women who are looking for a tool that would optimize their insulin sensitivity without the pro-obesogenic effects that render most other "insulin sensitizer" at best useless. And if we assume that similar effects on PI3K and p-AKT do occur in skeletal muscle, as well (this was unfortunately not measured in the study at hand), embelin could even help you build some muscle. Just as its general efficacy in human beings the last hypothesis does of course still require experimental verification... but don't worry, you know that I will keep you posted on any future studies!
That's it! What? You want more? But that's what a quickie is supposed to be it's the frequency that makes it worthwile not the length... ah, I guess I better wish everyone a happy Sunday before I am starting to go into further details here ;-)

  • Cirillo T, Fasano E, Castaldi E, Montuori P, Amodio Cocchieri R. Children's exposure to Di(2-ethylhexyl)phthalate and dibutylphthalate plasticizers from school meals. J Agric Food Chem. 2011 Oct 12;59(19):10532-8.
  • DEHP Information Center. DEHP Fact Sheet (revised). June 14, 2012. < > retrieved on Nov. 03, 2012.
  • Estrany ME, Proenza AM, Gianotti M, Lladó I. High-fat diet feeding induces sex-dependent changes in inflammatory and insulin sensitivity profiles of rat adipose tissue. Cell Biochem Funct. 2012 Oct 30.
  • Fierens T, Vanermen G, Van Holderbeke M, De Henauw S, Sioen I. Effect of cooking at home on the levels of eight phthalates in foods. Food Chem Toxicol. 2012 Sep 14;50(12):4428-4435.
  • Ghaisas MM, Ahire YS, Dandawate PR, Gandhi SP, Mule M. Effects of Combination of Thiazolidinediones with Melatonin in Dexamethasone-induced Insulin Resistance in Mice. Indian J Pharm Sci. 2011 Nov;73(6):601-7.
  • Gandhi GR, Stalin A, Balakrishna K, Ignacimuthu S, Paulraj MG, Vishal R. Insulin sensitization via partial agonism of PPARγ and glucose uptake through translocation and activation of GLUT4 in PI3K/p-Akt signaling pathway by embelin in type 2 diabetic rats. Biochim Biophys Acta. 2012 Oct 24. doi:pii: S0304-4165(12)00302-9.
  • Hao C, Cheng X, Xia H, Ma X. The endocrine disruptor mono-(2-ethylhexyl) phthalate promotes adipocyte differentiation and induces obesity in mice. Bioscience Reports. 2012; 32:619–629.
  • Kaye WH, Berrettini W, Gwirtsman H, George DT. Altered cerebrospinal fluid neuropeptide Y and peptide YY immunoreactivity in anorexia and bulimia nervosa. Arch Gen Psychiatry. 1990 Jun;47(6):548-56.
  • Li N, Liu T, Zhou L, He J, Ye L. Di-(2-ethylhcxyl) phthalate reduces progesterone levels and induces apoptosis of ovarian granulosa cell in adult female ICR mice. Environ Toxicol Pharmacol. 2012 Sep 1
  • Li XW, Liang Y, Su Y, Deng H, Li XH, Guo J, Lian QQ, Ge RS. Adverse effects of di-(2-ethylhexyl) phthalate on Leydig cell regeneration in the adult rat testis. Toxicol Lett. 2012 Oct 11. 
  • Martine B, Marie-Jeanne T, Cendrine D, Fabrice A, Marc C. Assessment of Adult Human Exposure to Phthalate Esters in the Urban Centre of Paris (France). Bull Environ Contam Toxicol. 2012 Oct 23.
  • Magistrelli A, Chezem JC. Effect of ground cinnamon on postprandial blood glucose concentration in normal-weight and obese adults. J Acad Nutr Diet. 2012 Nov;112(11):1806-9. 
  • Monfort N, Ventura R, Balcells G, Segura J. Determination of five di-(2-ethylhexyl)phthalate metabolites in urine by UPLC-MS/MS, markers of blood transfusion misuse in sports. J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Sep 21. doi:pii: S1570-0232(12)00560-0.
  • Rajesh P, Sathish S, Srinivasan C, Selvaraj J, Balasubramanian K. Exposure to diethyl hexyl phthalate (DEHP) to adult male rat is associated with insulin resistance in adipose tisssue: Protective role of antioxidant vitamins (C & E). J Cell Biochem. 2012 Sep 18.
  • Ruohonen ST, Vähätalo LH, Savontaus E. Diet-induced obesity in mice overexpressing neuropeptide y in noradrenergic neurons. Int J Pept. 2012;2012:452524. doi: 10.1155/2012/452524. Epub 2012 Oct 18. 
  • Simha V, Mahmood M, Ansari M, Spellman CW, Shah P. Effect of Vitamin D Replacement on Insulin Sensitivity in Subjects With Vitamin D Deficiency. J Investig Med. 2012 Oct 29.
  • Wu P, Yang D, Zhang L, Shen X, Pan X, Wang L, Zhang J, Tan Y, Feng L, Ying Y. Simultaneous determination of 17 phthalate esters in edible vegetable oils by GC-MS with silica/PSA-mixed solid-phase extraction. J Sep Sci. 2012 Nov;35(21):2932-9.
  • Xu Y, Liu Z, Park J, Clausen PA, Benning JL, Little JC. Measuring and Predicting the Emission Rate of Phthalate Plasticizer from Vinyl Flooring in a Specially-Designed Chamber. Environ Sci Technol. 2012 Oct 23.