A Cup of Coffee in the Bluelight District: Synergistic Effects of Caffeine + Blue Light on Psychomotor Effects. Plus: Yerkes-Dodson and U-Shaped Dose-Response Curves

This could be your new wake-up routine: Strong coffee and a bath in blue light.

"The abuse of ADHD drugs in people from all social classes is on the rise..." I guess you will have heard or read news like these several times over the past 12 months and in an article over at Forbes.com that was published on St. Nicholas' Day, Todd Essing even claimed: "Adderall use at work by the healthy to enhance cognitive performance is back in the news." Essing cites, among others, Stephen Petrow whose article over at The Atlantic is what Essing calls "a love letter to his 2-3 times per week Adderall use" - and a scary one for Petrow who is a psychologist by trade and says of himself that he "treats lots of hard-driving career-focussed 20- and 30-somethings". (Essing. 2013)

I guess Essing, whose previous article "When ‘Study Drugs’ Kill" took a reasonably critical stance towards the use of Adderal and similar drugs by healthy individuals, will be delighted by the results C. Martyn Beaven and Johan Ekström present in their latest paper in the peer-reviewed open access journal PLOS|One (Beaven. 2013). The intention of their experiment was ...

"[....] to compare and contrast the physiological responses to blue light and caffeine, administered both separately and conjointly. Measures of cognitive function, reaction time and wakefulness were assessed and it was hypothesized that similarities would be observed with the administration of 240 mg of caffeine and a 1 h dose of ~40 lx blue light." (Beaven. 2013)

Moreover, Beaven and Ekström assumed that combining the caffeine equivalent of two small or one large, strong coffees with the 'enlightening' power of a r  ~40lx  blue light LED light source (Techlight® RGB, 3W,  λmax = 470 nm) would induce alerting and psychomotor effects greater than either intervention in isolation.

What exactly did the scientists test for? The study participants had to complete a computer-based psychomotor vigilance test protocol (PVT) that consisted of 20 trials of a visual and audio Go/No-Go test, an Eriksen Flanker test, and 5 trials of a visual reaction time task (all tasks are available online at www.cognitivefun.net, so just try them out and judge for yourself how significant they are).

In view of the fact that you will probably have read the "Sunlight à la Carte" (read more) article I published as part of my Circadian Rhythm Series, you shouldn't be surprised by either, ...

• the experimental design that involved the ingestion of a gelatine capsule containing either 240 mg of caffeine or a visually indistinguishable sugar placebo with a small glass of water (CAF), the exposure to ~40 lx of blue light from a LED light source (Techlight® RGB, 3W, λmax = 470 nm) or a white light alternative (~100 lx) for 1 h (BLU) or a combination of both, or
• the assumption that caffeine and blue light should exert additive effects on both physical and psychological measures of alertness

... the effects of both caffeine and high frequency (=low wavelength) light have after all been discussed at length, here at the SuppVersity. What struck me (and maybe you, too) as odd, initially, though, was the assumption that "eye colour would influence the degree of the psychomotor and physiological responses to blue light" (Beaven. 2013), as well.

Figure 1: Eye color determines the extent of the melatonin suppressing effects of 2h of bright light exposure during the night. The effect is significantly stronger in "dark-eyed" Asians vs. "light-eyed" Caucasians (Higuchi. 2007)

The assumption that light-eyed participants would show a more pronounced reaction to light exposure is based on observations by Higuchi et al. (2007) who observed a direct link between eye color and the decrease in melatonin secretion in response to light, when they compared the effects of 2h of nightly light exposure in "light-eyed" Caucasians "with blue, green, or light brown irises" to Asians with "dark brown irises" (Higuchi. 2007).

Contrary to what you may have expected, the suppression was increased for the Asians (see Figure 1), not the Caucasians, of whom you'd argue that their ancestors lived at a latitude, where sun is scarce in the winter time, so that you'd have to make the most of it, when it shines.

If we now turn to the results of the study at hand, we'll see that Beaven and Ekström observed a very similar trend in their study, where he increase in visual reactions in the blue light only condition was significantly more pronounced in the blue-eyed, non-shift worker, non-smoking, low to moderate caffeine and alcohol consuming study participants (13 men, 18 women) than in their darker-eyed peers.

Figure 2: Effects of placebo (Pla), blue light (BLU), caffeine (CAF) or blue light + caffeine (BCAF) on psychomotor performance in 24 (13 male, 11 female) healthy subjects with a mean age of 26 ± 4 years; as it is common in science changes that were statistically significant are marked with letters, i.e. "a", "b", "c" (Beaven. 2013)

When they took a closer look at the caffeine (CAF), blue light (BLU) and caffeine + blue light (BCAF) treatment induced performance boosting effects you can see in Figure 1, the researchers from the Mid Sweden University observed a baseline advantage in reaction times in the visual reaction time task in male vs. female study participants (255 vs 274 ms; p = 0.0172). If you scrutinize the data in Figure 2, you will also realize that Beaven & Ekström are generally correct, when they state that their experiment is the first demonstration of distinct effects of caffeine and blue light on aspects of psychomotor function - it's after all hard to deny that (a) both worked and that (b) they did not have identical effects.

Beware of the consequences of the Yerkes-Dodson law

The researchers go on to explain that "[b]oth blue light exposure and caffeine ingestion improved accuracy in the visual Go/No-Go task", but that their combination "did not result in enhancement in the number of correct responses" (see Accuracy in incongruent task in Figure 2). For caffeine alone similar effects have been observed. These observations form the basis of the"Yerkes-Dodson law", in which it is postulated that the relationship between arousal and performance follows an inverted U-shape curve (Fredholm. 1999). Consequently, Beaven & Ekström suspect that

"[...], it is possible to rationalize that the combined treatment of blue light and caffeine dose exceeded the optimal state of arousal and consequently resulted in impaired accuracy." (Beaven. 2013)

At first sight, this hypothesis appears to conflict the improved fast reaction time the researchers observed in the visual Go/No Go task, but when you come to think about it, the stimulating effect of caffeine + blue light that is an advantage, when it comes to relatively simple tasks, may well be too pronounced for an exercise that requires a higher degree of mental focus / contentration.

Learn how to use light to modulate or realign your circadian rhythm.

So what we learn from the results? Actually there are two things you can take away from the study.

• It may well be worth to add a blue light lamp to your list of birthday, not Christmas presents. You do after all you want to have it before Fall 2014.
• You would be well-advised if you remembered "Yerkes-Dodson law" and the futility of a "more helps more" approach to cognitive enhancement.

Considering the fact that it's Christmas Eve this certainly isn't too bad as far as the total amount of subject matter or its quality is concerned - right? Apropos: Merry Christmas!

References:

• Beaven, C. M., & Ekström, J. (2013). A comparison of blue light and caffeine effects on cognitive function and alertness in humans. PloS one, 8(10), e76707.
• Essing, T. (2013). Managing The Risks Of Taking Adderall To Enhance Work Performance. Forbes.com. Dec. 06 2013 < http://www.forbes.com/sites/toddessig/2013/12/06/managing-the-risks-of-taking-adderall-to-enhance-work-performance/ > retrieved on 12-24-2013.
• Fredholm, B. B., Bättig, K., Holmén, J., Nehlig, A., & Zvartau, E. E. (1999). Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacological reviews, 51(1), 83-133.
• Higuchi, S., Motohashi, Y., Ishibashi, K., & Maeda, T. (2007). Influence of eye colors of Caucasians and Asians on suppression of melatonin secretion by light. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 292(6), R2352-R2356.
• Petrow, S. (2013). The Drugs of Work-Performance Enhancement. The Atlantic. < http://www.theatlantic.com/health/archive/2013/11/the-drugs-of-work-performance-enhancement/281055/ > retrieved on 12-24-2013.

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 ;-)


References:

• 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. <  www.dehp-facts.com/upload/documents/webpage/ECPI%20-%20factsheet%20DEHP%20revised%20-%20140609.pdf > 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.

Melato Cola™ or What? Fructose for Improved Glucose Metabolism and Melatonin to Counter Fructose Overload

There was a time, when Coke still contained "coke"... so why not add some melatonin for health benefits? I am obviously just kidding here, but a combination of fructose + melatonin may actually make sense.

The title of today's SuppVersity article is confusing, I know. Firstly, it contains the almost heretical notion that fructose could actually improve instead of impair your glucose metabolism and secondly it does not appear to make sense that you would have to use melatonin to counter the pro-diabetic effects of fructose, if the latter is in fact so good for you.

Before you are getting totally confused, let me clarify how the improvements in glucose metabolism and the melatonin-powered diabesity protection go together: Both have been observed in a recent study from the Pontificia Universidad Católica Argentina in Buenos Aires, Argentina (Cardinali. 2013), in the course of which the improved glucose metabolism was nothing but a side-finding of a study Cardinali et al. conducted to  examine the effect of melatonin when it is administered to rodents simultaneously with fructose in the drinking water.

This is the Coke + sufficient sleep study ;-)

Obviously this is not as the subheading would suggest the "coke + sufficient sleep study", but in light of the fact melatonin is after all the "sleep" hormone and in view of the results of a recent study by Senador et al. who observed that fructose had a negative effect on glucose management only, when it was available during the light phase (which is the inactive phase for a rodent; cf. Senador. 2012), it comes close; and that despite the fact that fructose timing was yet not an issue in the study at hand. Instead of modifying the timing, Cardinali et al. used different amounts of fructose with half of the rodents in the experimental arm of the study having a 5% and the other half having a 10% fructose solution as their main water supply.

Figure 1: Glycemia (mg/dL) 0-140min after 2g/kg body weight  glucose tolerance test (Cardinali. 2013)

If we trust the nutritiondata.com information about the average fructose content of a "carbonated beverage, cola, with higher caffeine" ...

• the rodents in the 10% fructose group were consuming the total carbohydrate equivalent of coke, but with a 100% instead of ~50% fructose content, while
• the rodents in the 5% fructose group were consuming less total carbohydrates, but roughly the same amount of fructose someone would ingest if he drank nothing but coke.

A direct comparison of either of the groups to the "coke only"-drinking human being is thus not warranted.

It is nevertheless intriguing that the 5% fructose group showed a significantly higher glucose tolerance - not just compared to the 10% fructose group, but also compared to the control group that was fed with water, only (see figure 1).

"Meta-Analysis: Lower Glucose, Insulin and HbA1c Levels From 'Catalytic' Dose of 36g Fructose" | read more

"But isn't fructose the reason you develop diabetes?" Before we get on to the effects of melatonin, I want to emphasize that this is by no means an outlier, in fact, I have written about the catalytic effects of 36g of fructose in a previous post "6x Bananas a Day!? Meta-Analysis: Lower Glucose, Insulin and HbA1c Levels From 'Catalytic' Dose of 36g Fructose" (learn more).

Previous studies have also shown that a 2:1 mixture of glucose + fructose is at least up to the regular glucose only drinks in terms of post-workout glycogen repletion (learn more) - partly because the fructose will keep the liver occupied, while the muscles suck up the glucose.

As previously mentioned the main research interest of the Argentinian scientists was not the effect of fructose on the glucose sensitivity of their rodents, but rather if the administration of 25 μg/mL of melatonin in the tapwater the rodents received would lead to significant changes in the study outcomes.

Figure 2: Effects of melatonin in drinking water with or without 5% [left] and 10% [right] fructose on body weight, systolic blood pressure and glucose response to glucose tolerance test (Cardinali. 2013)

As you can see in figure 1 it did: Melatonin did ameliorate the weight gain, and the increase in blood pressure that was observed even with only 5% fructose in the drinking water. It did not improve the glycemic response of the rats in the 5% fructose group even more, though, but it bulnted the negative effects of the 10% fructose solution had on the glycemic response in the glucose tolerance (figure 2, right).

SuppVersity Suggested Read: "Circadian Rhythmicity - Sunlight, Bluelight, Backlight & Co Mess Learn How THey W/ Your Internal Clock. Plus: Tips & Tricks to Prevent Negative Side-Effects" | read more

Is a melatonin solution the solution? If we also consider the negative effects of 10% fructose feeding on LDL (the rodents on 10% + Mel had even lower LDL than the control), the normalization of triglycerides and the potential therapeutic reduction in uric acid (-30% even vs. control), of which Cardinali et al. point out that it could have therapeutic effects in people with gout and other uric acid related metabolic disorders, it would appear smart that do dissolve the human equivalent dose of 21-35mg melatonin in your drinking water in the morning and keep guzzling it all day long.

Well, as I said, it "would appear to be" smart, but is it really smart? I wouldn't be too sure about that. Despite the fact that that you probably won't die, the chronically increased systemic melatonin levels could have long-term negative consequences on your circadian rhythm that could undo all potential benefits.

Restricting your fructose intake to fructose from fruit, only, getting enough sleep and using melatonin timely, i.e. 20min before bed would thus appear to be a more prudent approach to improve / maintain optimal blood glucose levels and insulin sensitivity. And if you are more into hard facts than "erring on the side of caution", you may consider the acute decrease in glucose tolerance, Cagnacci et al. observed in postmenopausal women, when they participated in a blood glucose test after the administration of 1 mg melatonin more convincing (Cagnacci. 2001).

References:

• Cagnacci A, Arangino S, Renzi A, Paoletti AM, Melis GB, Cagnacci P, Volpe A. Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women. Clin Endocrinol (Oxf). 2001 Mar;54(3):339-46. 
• Cardinali DP, Bernasconi PA, Reynoso R, Toso CF, Scacchi P. Melatonin may curtail the metabolic syndrome: studies on initial and fully established fructose-induced metabolic syndrome in rats. Int J Mol Sci. 2013 Jan 25;14(2):2502-14.
• Senador D, Shewale S, Irigoyen MC, Elased KM, Morris M. Effects of restricted fructose access on body weight and blood pressure circadian rhythms. Exp Diabetes Res. 2012;2012:459087.

When Timing Matters - Melatonin: Incorrectly Timed it Ruins Your Glucose Metabolism - Studies Show Acute Increases in Glucose Excursions During OGTT of 186% With 5mg

Melatonin is one of the few supplements where timing is everything.

As of late the nutrient and supplement timing craze has started to abate. People begin to realize that timing doesn't always matter, and that you can still make gains if you don't consume your whey protein shake 2 minutes, but rather 60 minutes after your workout.

For some nutrients and supplements, timing does yet matter and with melatonin I want to introduce you to an example, where the beneficial effects are not just attenuated, but will actually turn against you.

Want to learn more about melatonin? The SuppVersity is the place to be.

Melatonin as potent as Letrozole

Melatonin for Bone & Tooth Health

M. Sleep Aid W/ Anti-Alzheimer's Effect

Melatonin vs. Fructose Overloads

Melatonin as Anabolic On-Switch

M. Anti-Alzheimer + Anti-Body Fat Agent

As a SuppVersity reader, you are well aware of the beneficial metabolic "side effects" of melatonin. Effects that are mostly related to its ability to re-align the circadian rhythm (learn more). As a SuppVersity reader, you will also know that circadian misalignments have been shown to augment markers of insulin resistance and inflammation, independently of sleep loss (Leproult. 2014). And, as a SuppVersity reader, I want you to be aware of the fact that taking melatonin at the wrong time points is going to induce just that: a circadian misalignment with all the negative consequences on your insulin sensitivity that messes with your internal clock is going to have.

Actually, I believe I've mentioned the seminal paper by Angelo Cagnacci et al. which is - at least to my mind - the first one to show that using melatonin the way only a dumbass would do, i.e. taking 1mg early in the morning, is going to ruin the insulin sensitivity of postmenopausal women.

Figure 1: Taken in the AM right before an oral glucose tolerance test, melatonin ruins postmenopausal women's insulin sensitivity. Glucose area under the curve, insulin and the amount of C-peptide that's required are increased (Cagnacci. 2001)

Just a couple of days ago a study from the University of Murcia in Spain confirmed that this problem is not one that occurs only in postmenopausal, but also in 21 young, healthy women (24 ± 6 y; body mass index: 23.0 ± 3.3 kg/m²). In said study, the oral glucose tolerance test (OGTT) was performed on four occasions: In the morning (9 AM), and evening (9 PM); each occurring 15 minutes after melatonin (5 mg) and placebo administration on 4 non-consecutive days.

And what Patricia Rubio-Sastre and her colleagues found clearly confirms the results Cagnacci et al. presented 13 years ago:

"Melatonin administration impaired glucose tolerance. When administered in the morning, melatonin significantly increased the incremental area under the curve (AUC) and maximum concentration (Cmax) of plasma glucose following OGTT by 186% and 21%, respectively, as compared to placebo; while in the evening, melatonin significantly increased glucose AUC and Cmax by 54% and 27%, respectively. The effect of melatonin on the insulin response to the OGTT depended on the time of day (P < 0.05). In the morning, melatonin decreased glucose tolerance primarily by decreasing insulin release, while in the evening, by decreasing insulin sensitivity."

If that's not enough to scare you away from stupid experiments that involve using melatonin as an "anti-oxidant" supplement at other time-points during the day than 1-2h before bed, you probably cannot be helped ;-)

Suggested: Melatonin the anabolic on-switch | learn more

Bottom line: Taking melatonin before a meal and / or anytime but 1-2h before bed is not just going to ruin its beneficial metabolic effects, it's actually going to ruin your insulin sensitivity. So, if you want to use it, make sure you do so at the correct time point.

Melatonin is not the only supplement, where timing appears to matter, by the way. If you want this post to be the first in a series of articles on supplements and other things where timing matters, let me know on Facebook - I may be inclined to write a couple of additional articles ;-)

References:

• Cagnacci, Angelo, et al. "Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women." Clinical endocrinology 54.3 (2001): 339-346.
• Leproult, Rachel, Ulf Holmbäck, and Eve Van Cauter. "Circadian misalignment augments markers of insulin resistance and inflammation, independently of sleep loss." Diabetes 63.6 (2014): 1860-1869.

Cinnamon, Curcumin (Turmeric), Licorice (Glycyrrhizin), Melatonin, Milk Thistle (Silymarin). Supplements to Improve and Restore Insulin Sensitivity - Serving #3

Sleep hygiene was part of the lifestyle tips in the first episode of this series, with this episode you get a tool that can help you get back into the groove: melatonin.

This is Sunday number three with supplements that may help you improve / maintain your glucose sensitivity and I can already tell you it's going to be the last one. In other words, if there are any compounds that have not yet been covered in this series - just a reminder

• Alpha Lipoic Acid, GABA, Taurine, Green Tea, Gooseberry & Fenugreek were addressed in detail as part of supplement list #1
• Berberine, Banaba (Corosolic Acid), Rauwolfia Serpentina, (Apple Cider) Vinegar, Chromium were addressed in detail on supplement list #2 

- this is your last chance to make a wish! So, if you have something special in mind, use the comment section at the end of this article and tell me which agents you want to see in issue #4 on next Sunday.

Ah, ... it should be obvious that none of the following agents qualifies: Cinnamon, Curcumin (Turmeric), Licorice (Glycyrrhizin), Melatonin, Silymarin - why? Well those are the ones you can read about in the paragraphs below :-)

• Dosages for cinnamon supplements range from 1-6g+ of pure real cinnamon (cinnamomum vera) to 150-500mg of extracts (depending on their quality). You should be aware though that "fake" cinnamon (cinnamomum cassia, which is sold in the US simply as "cinnamon") contains (highly variable amounts) of coumarin a liver toxic and carcinogenic substance w/ an upper intake limit of 0.07mg/kg body weight that may easily be exceeded by eating common foodstuffs like oatmeal with cinnamon in small children (Fotland. 2012).
  

  According to Fotland et al. this can lead to toxicity reactions within weeks. So don't be cheap and better make sure not to buy "fake cinnamon" (=cassia) for you or your kids and loved ones.
  Cinnamon (Cimmomium verum!) [B]: Cinnamon is unquestionably one of the best known supplements for diabetics. "High blood sugar? Have some cinnamon in your sugar-laden Starbucks coffee!"... and this is exactly where the problem is. Everyone knows that cinnamon works - acutely(!), because he or she can measure his blood glucose after the ingestion of the said Starbucks coffee with and without cinnammon, but...
  1. according to the latest meta-analysis the long-term benefits of using cinnamon to manage blood glucose levels in type II diabetics are zero - the most important measure of their overall glycemic status, i.e. HbA1c, does not change significantly; or I should say: it reacts formidable in studies lik Lu et al. (2012; 120 or 360mg/day treated alongside standard diabetes drug) and deteriorates in others (Mang. 2006; Wainstein. 2011; etc.)
  2. studies in healthy individuals suggest that the blood glucose lowering effects are a mere results of an inhibition of the digestion and absorption of high GI carbs (6g regular cinammon w/ rice or pudding; Hlebowicz. 2007)
  There is however recent evidence that some of the secondary plant material, i.e. the proanthocyanidins you will find in cinnamon water extracts exert a direct protective effect on stressed pancreatic beta cells.
  Just a note for those who feel I am a "supplement hater": I am not the only one displaying a healthy degree of skepticism towards the hoopla that surrounds the use of cinnamon as an anti-diabetic. The "gold standard" review from the Cochraine Foundation says: "There is insufficient evidence to support the use of cinnamon for type 1 or type 2 diabetes mellitus. Further trials, which address the issues of allocation concealment and blinding, are now required. The inclusion of other important endpoints, such as health-related quality of life, diabetes complications and costs, is also needed" (Leach. 2013)
  Overall, cinnamon is thus a "B" as in "one of the B-est agents to protect yourself from developing insulin resistance and diabetes": It can also be interesting for type II diabetic looking to improve his blood lipids, but this is a different topic (cf. Khan. 2003). So, if you can't keep away from the sweet stuff of which you know ever since episode 1 of this series that you are not supposed to eat it, some cinnamon won't hurt - if you hate the taste, though, don't force it down. It's not really worth gagging.

• 

  In healthy human beings the administration of 6g of curcuma longa before a 75g glucose tolerance test does just one thing: It spikes insulin without improving the glucose uptake. Technically this is a decrease - not an increase in insulin sensitivity, which would have to be observed if curcumin was an insulin-sensitizer.

  Curcumin (Turmeric; curcuma longa) [C] - Curcumin is probably among the hottest supplements out there. Everybody appears to know exactly what it does and obviously everything is ueber-potent and super-healthy. It does therefore appear almost unquestionable that curcumin is going to help with insulin resistance, as well... right? Well, unquestionable as it may apper, the mere assumption that it would do so is not just unwarranted, but downright misleading.
  
  While there is evidence that its anti-inflammatory effects can help restore normal insulin sensitivity in diabetic individuals and animals, such as the streptocitozin-induced diabetic rodents in a 2011 study by Na et al., the important evidence from human studies is not there. In fact, in a 2010 study from the Skåne University Hospital in Sweden, Wickenberg, Ingemasson and Hlebowicz were able to show that curcumin worsens the insulin sensitivity of fourteen healthy subjects.
  
  Being first and foremost and anti-inflammatory agent, it is at imho not surprising that curcumin is not the ideal insulin sensitizer. In view of the fact that the obese and inflamed may need a little help to get their baseline inflammation back in check, before any "anti-diabesity" agent may even start working curcumin does however still qualify as a "C" as in "take in C-ombination" with other agents, but only if you're actually dealing with inflammatory problems (e.g. high CRP-1 value in serum; type 1 diabetes and problems with heme oxygenation, cf. Aziz. 2013). After all, the emerging role of reactive oxygen specimen in muscule- and thus tissue- and anti-obesity-specific glucose uptake clearly suggest that the suffocation of all inflammatory signals is not going to help, but hinder glucose uptake (Merry. 2012).
• Licorice (glycyrrhizin) [D] - While it has a bad rep as a "cortisol increasing" agent that puts you at risk of developing high blood pressure glycyrrhizin does actually have the ability to reverse diet-induced insulin resistance and get the GLUT-4 glucose transporters back out on the cell surfaces. Sil et al., for example report that they observed corresponding improvements of insulin sensitivity in a rodent model of high frutcose feeding (which is actually not much different from the average victim of the American diet; dosage was 50mg/kg or 600-750mg/day for a human being; Sil. 2013)

  

  Table 1: Analysis and comparison of active ingredients in Radix Glycyrrhizae (licorice) from Europe and China by capillary-zone electrophoresis (Rauchensteiner. 2005)

  As you can see in the table above the glycyrrhizin content of different forms of licorice is somewhere between 2-3mg/100mg (Rauchensteiner. 2005). In other words, to hit the 600-750mg you will necessarily need an extract - unless you want to consume kilograms of licorice.
  
  

  

  What about testosterone? A larger scale 4-week trial with 100g/day of licorice containing 0.15% glycyrrhizic acid could not find any significant changes in sex steroid hormones (Sigurjonsdottir. 2005)

  Whether that's a smart thing to do is however questionable, as licorice does not just have the potential to increase blood pressure, but is also a relatively unpredictable agent. Most of the glycyrrhizin will never even make it through the gut and into your blood, but rather be converted to other metabolites by your gut microbiome. Injections on the other hand appear to be possible, but the example of a 72-year old subject of a case report from the year 2000 goes to show you that in some cases the anti-diabetic effects may be a tad bit to potent. The subject did after all end up being profoundly hypoglycemic after the injection of 80mg of glycyrrhizin (Motoo. 2000).
  
  Despite potential anti-diabetic effects (read more) and the potent anti-obesity effects (3g of licorice per day = 2% body fat reduction in normal weight volunteers w/out dietin → learn more) you have read about here at the SuppVersity licorice does therefore get a "D" as in "D-on't take", because it seems as if the margin between 'enough to elicit beneficial effects' and 'so much that you are risking side effects' is pretty narrow.

• 

  Melatonin has also been shown to have beneficial effects on glucose uptake and glycogen synthesis after exercise and scientists speculate that it could play a major (facilitative) role in skeletal muscle adaptation to exercise (learn more)

  Melatonin [C]- I know, I know, it's a "dangerous hormone" ... well, nobody will propose that, when we talk about prescribing verifiably more dangerous oral contraception to women. I wonder how that is!? After all, this "dangerous hormone" could, mitigate the negative side effects many of the oral contraceptive appear to exert on the glucose metabolism of young, previously healthy women (for an in-depth discussion see Lopez. 2012). Ah, I am digressing, once again. So let's get back to melatonin.
  
  Assuming you follow all the recommendations from installment 1 of this series you should not be in dire need of melatonin supplementation. Sometimes, however, life comes in the way - for me that happened in the course of the last weeks. Oftentimes it's not even necessarily the "bad things" in life that keep you from getting enough sleep and producing a truckload of endogenous melatonin. It is in these situation, where some supplemental help in pill- or capsule-form may in fact come extraordinarily handy as an acute treatment that will work by its beneficial effects on skeletal muscle glucose uptake (Ha. 2006), leptin expression in response to insulin (Alonso-Vale. 2005) and 24h glucose homeostasis (la Fleur. 2001)
  
  In view of its many-fold effects on the mammalian metabolism and the age-related decline in melatonin production, it is actually not surprising that the provision of melatonin to aging rodents (0.4μg/ml in drinking water) was able to restore plasma insulin and leptin levels to youthful levels and continued treatment until old age maintained suppression of visceral (retroperitoneal + epididymal) fat levels without any effects on plasma corticosterone and total thyroxine (T4),  testosterone, insulin-like growth factor I (IGF-I) and total triiodothyrone (T3) compared to placeo (Rasmussen. 2002)
  
  That being said, for young(er) individuals, it may be sufficient to restore a normal circadian rhythm by strategically supplementing at the right times. In conjunction with a consequent "lights out strategy" (learn more), this should get you back on track and your insulin resistance up. Melatonin is thus a classic "C" as in "C-an be used by everyone"; a "C" that does however need some basic information about when you want to take the 1-10mg of melatonin to derive the greatest benefits (learn more about phase shifting your circadian rhythm) .
• Silymarin (Milk thistle) - Not exactly one of the agents you would expect on a list like this, but contrary to many better known anti-diabetic agents milk thistle can - just like cinnnamon, by the way - inhibit the accumulation of human islet amyloid polypeptide in the pancreas and the subsequent development of the end stages of diabetes (=the inability to produce insulin). In a 2006 study from Iran the provision of milk thistle to type II diabetics (200mg silimarin, 3x daily) lead to significant reduction in acute (blood glucose) and long-term measures of (HbA1c) of glucose management, as well as improvements in insulin levels (see figure below).

  

  Changes in fasting blood sugar (FBS), long-term marker of FBS (HbA1c) and insulin levels in randomized controlled trial w/ 51 type II diabetics; data expressed relative to median values across all groups (Huseini. 2006)

  In view of the results from the randomized controlled human study depicted in the figure above and based on the fact that silybin / silymarin / milk thistle helps controlling NAFLD, of which you learned earlier this week that it may as well be the cause not the consequence of insulin resistance (learn more). Milk thistle deserves a "B" as in "B-etter than many more specific agents". Dosages range from 500-1,500mg per day and you should make sure you get a standardized product and not an extract with non-disclosed amounts of active ingredients in it.

I know there are more agents, but I do also know that I cannot address each and every herb that may have the potential to reduce your blood glucose levels by 1pt. So unless you want me to make the last five picks, take your chance and let me know which agents you are still missing in the comments.

References:

• Allen RW, Schwartzman E, Baker WL, Coleman CI, Phung OJ. Cinnamon use in type 2 diabetes: an updated systematic review and meta-analysis. Ann Fam Med. 2013 Sep-Oct;11(5):452-9.
• Alonso-Vale MI, Andreotti S, Peres SB, Anhê GF, das Neves Borges-Silva C, Neto JC, Lima FB. Melatonin enhances leptin expression by rat adipocytes in the presence of insulin. Am J Physiol Endocrinol Metab. 2005 Apr;288(4):E805-12.
• Aziz MT, El Ibrashy IN, Mikhailidis DP, Rezq AM, Wassef MA, Fouad HH, Ahmed HH, Sabry DA, Shawky HM, Hussein RE. Signaling mechanisms of a water soluble curcumin derivative in experimental type 1 diabetes with cardiomyopathy. Diabetol Metab Syndr. 2013 Mar 12;5(1):13.
• Fotland TØ, Paulsen JE, Sanner T, Alexander J, Husøy T. Risk assessment of coumarin using the bench mark dose (BMD) approach: children in Norway which regularly eat oatmeal porridge with cinnamon may exceed the TDI for coumarin with several folds. Food Chem Toxicol. 2012 Mar;50(3-4):903-12. 
• Ha E, Yim SV, Chung JH, Yoon KS, Kang I, Cho YH, Baik HH. Melatonin stimulates glucose transport via insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway in C2C12 murine skeletal muscle cells. J Pineal Res. 2006 Aug;41(1):67-72.
• Hlebowicz J, Darwiche G, Björgell O, Almér LO. Effect of cinnamon on postprandial blood glucose, gastric emptying, and satiety in healthy subjects. Am J Clin Nutr. 2007 Jun;85(6):1552-6. 
• Huseini HF, Larijani B, Heshmat R, Fakhrzadeh H, Radjabipour B, Toliat T, Raza M. The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: a randomized, double-blind, placebo-controlled, clinical trial. Phytother Res. 2006 Dec;20(12):1036-9.
• Khan A, Safdar M, Ali Khan MM, Khattak KN, Anderson RA. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care. 2003 Dec;26(12):3215-8.  
• la Fleur SE, Kalsbeek A, Wortel J, van der Vliet J, Buijs RM. Role for the pineal and melatonin in glucose homeostasis: pinealectomy increases night-time glucose concentrations. J Neuroendocrinol. 2001 Dec;13(12):1025-32.
• Lopez LM, Grimes DA, Schulz KF. Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus. Cochrane Database Syst Rev. 2012 Apr 18;4:CD006133.
• Lu T, Sheng H, Wu J, Cheng Y, Zhu J, Chen Y. Cinnamon extract improves fasting blood glucose and glycosylated hemoglobin level in Chinese patients with type 2 diabetes. Nutr Res. 2012;32(6):408-412.
• Mang B, Wolters M, Schmitt B, Kelb K, Lichtinghagen R, Stichtenoth DO, Hahn A. Effects of a cinnamon extract on plasma glucose, HbA, and serum lipids in diabetes mellitus type 2. Eur J Clin Invest. 2006 May;36(5):340-4. 
• Merry TL, McConell GK. Do reactive oxygen species regulate skeletal muscle glucose uptake during contraction? Exerc Sport Sci Rev. 2012 Apr;40(2):102-5. 
• Motoo K et al. Non-insulin-dependent Diabetes Mellitus in an Elderly Patient with Hypoglycemic Attacks Induced By Glycyrrhizin Administration. Journal of the Japan Diabetic Society. 2000; 42(8).
• Na LX, Zhang YL, Li Y, Liu LY, Li R, Kong T, Sun CH. Curcumin improves insulin resistance in skeletal muscle of rats. Nutr Metab Cardiovasc Dis. 2011 Jul;21(7):526-33. doi: 10.1016/j.numecd.2009.11.009. 
• Rasmussen DD, Boldt BM, Wilkinson CW, Yellon SM, Matsumoto AM. Daily melatonin administration at middle age suppresses male rat visceral fat, plasma leptin, and plasma insulin to youthful levels. Endocrinology. 1999 Feb;140(2):1009-12. Erratum in: Endocrinology 2002 Apr;143(4):1269.
• Rauchensteiner F, Matsumura Y, Yamamoto Y, Yamaji S, Tani T. Analysis and comparison of Radix Glycyrrhizae (licorice) from Europe and China by capillary-zone electrophoresis (CZE). J Pharm Biomed Anal. 2005 Jul 15;38(4):594-600.
• Sigurjonsdottir HA, Axelson M, Johannsson G, Manhem K, Nystrom E, Wallerstedt S. Liquorice in moderate doses does not affect sex steroid hormones of biological importance although the effect differs between the genders. Horm Res. 2006;65(2):106-10.
• Sil R, Ray D, Chakraborti AS. Glycyrrhizin ameliorates insulin resistance, hyperglycemia, dyslipidemia and oxidative stress in fructose-induced metabolic syndrome-X in rat model. Indian J Exp Biol. 2013 Feb;51(2):129-38.
• Wainstein J, Stern N, Heller S, Boaz M. Dietary cinnamon supplementation and changes in systolic blood pressure in subjects with type 2 diabetes. J Med Food. 2011;14(12):1505-1510.
• Wickenberg J, Ingemansson SL, Hlebowicz J. Effects of Curcuma longa (turmeric) on postprandial plasma glucose and insulin in healthy subjects. Nutr J. 2010 Oct 12;9:43.

Circadian Rhythmicity - Sunlight, Bluelight, Backlight: How Street Lamps, iPads & Co Mess W/ Our Internal Clock. Plus: Tweaks, Tools & Apps to Prevent Negative Side-Effects

Image 1 (uci.edu): There are billions of clocks in our world, but the most important one of all, our biological clock has gained scientific attention only over the past couple of years - a momentous mistake, as scientists are starting to realize.

This is the first installment of the long promised yet often postponed SuppVersity series on Circadian Rhythmicity and how it impacts your physiology and psychology. Despite the fact that I eventually decided to spare you all the funky acronyms, clock genes and hardly legible names of at best incompletely understood feedback mechanism and complex switches I cannot forbear discussing a couple of fundamental principles to set the scene and ensure you understand what I am talking about, when I say "blue light" or "melantopic part of the spectrum". Don't be scared, I am trying to make it as easy as possible and if you still don't understand a word, I would hope that you do at least enjoy my sense of humor ;-)

Before we get lost in all the complicated details, yet again, let's start out right away by shedding some light (pun intended) at the most obvious, easiest to understand and to a great degree tweakable control parameter of our circadian rhythm: Light!

Sunlight! What do you know about it? And how does it control your circadian rhythm?

Image 2: Sir Isaac Newton used a prism to make the frequency spectrum (for us, the frequency determines the color of the light) visible

Let's start with a question that sounds so stupidly simple that you will probably rarely ever hear it voiced publicly: What exactly is sunlight? There are about as many answers to this question as there are photons, which are emitted from the photosphere of our sun in every second. Fortunately, we do - as it is common in science - not have to provide the one and only correct answer to this question but can rather pick the contextually appropriate one from a set, which does, among other answers, also comprise the Bethe-Weizsäcker cycle, the wave- and particle model of light and many other intricate theories. For our current purposes, it will yet suffice to keep in mind that light is an entity which has two physiologically important qualities:

• intensity, which would be the number of the photons per time unit that's hitting a certain area of retina and 
• frequency, which denotes the energetic load each of this photons is carrying (frequency = speed of light / wavelength)

Since the number of photons we are exposed to at every given moment we are not surrounded by total darkness is incomprehensibly large, we do not notice that each of them has a distinct frequency. To us, the light of the sun appears to be yellowish white and that despite the fact that Sir Isaac Newton already knew (and artfully demonstrated, as you can see in image 2) that our "white light" is in fact blue, green, yellow, turquoise, red, violet, ...

Figure 1: Each light source has its characteristic spectrum, i.e. it emits light with different frequencies (in case you forgot, you get the frequency of light by dividing the speed of light by the wavelength), or physically speaking photons with a characteristic energy distribution - relative to the total amount of photons sunlight, for example, contains much more highly energetic "blueish" photons, while the light of one of the classic Edison-esque light bulps contains a higher amount of low energy (high wavelength = low frequency) "reddish" photons.

Now the actual "spectrum", as scientists call the set of distinct frequencies in a certain signal, of our sunlight, is - contrary to what figure 1 may suggest - not continuous, but discrete. Moreover, for any given light source (our sun included) the occurrence or non-occurence of certain frequencies is highly dependent on the particles by which the light is emitted. Astronomers use this fact to their advantage and determine the material composition of stars by analyzing their characteristic light spectrum, which, in the case of our sun, covers a visible and non-visible part (in this case "visible" designates visible to our eyes). The reason I am emphasizing this here, is simple: Just as or sun has its characteristic spectrum, the light bulb in the lamb on your desk, the backlight of your computer screen, the tube of your old television screen, the lamps on the street, and so on and so forth... they all have their individual spectral foot- or maybe I should rather say frequency-print.

What does blue light say? It says: "Get up, it's a new day!"

Image 3: Melatonin (blue) is produced in the pineal gland (purple) in the absence of light stimuli (Soc for End. 2011)

This is important, because sunlight and a couple of million year later the light of fire, evolution has had little time to catch up with all those "strange" light sources it is facing today. And despite the fact that the ingenious invention, we know as "eyes", has undergone numerous evolutionary revisions, ever since nature invented the prototype (probably) during the so-called Cambrian Explosion a couple of million years ago, the specific composition of the light it was made to detect never changed, until homo (sometimes not exactly) sapiens entered the scene and had the ingenious idea to use artificial light source to finally put an end to the annoying rhythmicity of light and dark  and boring spectral homogeneity of the light, we are now no longer exposed to on daily basis only, but - more often than it would be conducive for our health - on a nightly basis, as well.

Only over the course of the past two to three decades, however, are we finally beginning to understand that the handy 24/7 availability of "light" at any desired intensity, along with the oftentimes unnoticeable otherness of this light with respect to its spectral composition (see figure 1) may constitute one of the most underrated health risks we are facing in our 24/7 convenience society: Light pollution.

What does artificial light say: "Stay up it's not yet night... but wait, it's not really day, either!?"

The sentence "most polluting are the lamps with a strong blue emission, like Metal Halide and white LEDs" from one of the most recent reviews of the literature on "light pollution" does already tell you something about where we are heading, here. With the impeding disappearance Thomas Edison's good old light bulbs, the 'fire from the ancestral cave', as I would like to phrase it for all paleo lovers out there, is about to be extinguished ... isn't it interesting, by the way, that the discontinuation of the production of classic light bulbs is vindicated by environmental concerns ... but before I am losing sight of the topic at hand, let's rather take a look on how much worse those "modern" lighting systems actually are and what alternatives we have, if we don't want to return into our fire-lit or pitch dark (man-)caves certain people nobody would even know if it were not for the 100% non-paleolithic 24/7 "enlightening" invention of the Internet as yet another one cave... ah, pardon "one size", of course, fits it all solutions the lights from our computer screens are transmitting right into our brains.

Figure 2: At least for city lights and the like, the energy efficient yellowish sodium vapor lamps could provide some relieve of the nightly "light stress" we are exposed to (data based on Falchi. 2011)

If we take a closer look at the data in figure 2 we will certainly have to concede that the fire in the cave which does by the way have the greatest resemblance to the good old 65W incandescent light bulb from figure 2 was still relatively benign as far as its ability to suppress our natural melatonin production is concerned - 26% and even 54% less suppressive than energy efficient metal halide and LED based light sources as they are used in the funky xenon lights of your shiny new Porsche, or the bright display of your iPad, to be precise. And still, according to Falchi et al. who published a paper with suggestions on how to reduce the overwhelming (nocturnal) exposition to bright and more-importantly "bluish" (in this context this refers to light sources which emit signifcant amounts of light from the higher frequencies / lower wavelengths of the visible spectrum, cf. figure 1, blue) light sources, there would be a better solution to illuminate our streets at night than large campfires or energy-inefficient incandescent light bubs: The yellowish low pressure sodium lamps, at least those of you who live in Germany may remember from their childhood, when they were still used to illuminate crosswalks along otherwise unlit roads, constitute the least "light polluting" an,d at least from physiological point of view, most "sustainable" nocturnal lighting solution (Falchi. 2011).

A call for action: Reduction, revision, regulation?

Figure 3: Superposition of the spectra of sunlight.classic light bulbs and the meltopic = melatonin suppressive frequency band (latter from Hallan. 2004). It is obvious that the relative contribution of melatonin suppressing high frequency (=low wavelength ~380-550nm) light is significantly lower for light bulbs than for sunlight. With an almost monochromatic light emission in at 589.0 and 589.6 nm low pressure sodium lamps (not shown in this figure) are yet unrivaled, among the low(er) meltopic light.

In their paper with the title "Limiting the impact of light pollution on human health, environment and stellar visibility" Falchi et al. also suggest that need for policy makers and scientists to collaborate to come up with prescriptions and technologies that would

• take account of existing nighttime lighting habits in order to minimize the impact on human activities
• allow easy identification of non-compliant light sources and
• allow easy measurement in the field, when needed

In addition, Falchi et al. formulate the following very concrete recommendations, which are (surprise!) even supported by the American Medical Association (cf. AMA. 2009):

1. establish a "protected range" within the 440-540nm range of the spectrum that corresponds to the maximum sensitivity of the scotopic vision and will thus have the greatest effect on the natural nocturnal melatonin production
2. limit direct light exposure of the eyes by no not allowing luminaries to send any light directly at and above the horizontal
3. avoid over lighting, shut off lights when the area is not in use and restrict growth of the total installed flux

I will leave it up to you in how far you feel these measures are (a) effective and (b) how realistic it is to assume that they will put into practice anytime in the near future.

In case you agree with my personal assessment, though, and believe that relying on governmental regulation usually produces more problems than it solves, you will be happy to hear that the use of the previously mentioned blindfolds, dark curtains and even the use of blue blocking glasses, as suggested by Dom Leste in response to my recent post on the "1lbs Fat Loss Bonus of 40 Minutes of Additional Sleep", can provide the much needed relief from the melatonin suppressing effect of constant "blue-light" exposure (Sasseville. 2006). 

Technologically advanced approaches to nutural circadian rythmicity

Image 3: F.Lux is probably the most popular program to adapt your screen brightness and hue to the time of the day, but there are alternatives and mobile solutions of which Lux, for example, looks pretty neat.

And just in case you did not get your daily dose of SuppVersity news before it's actually high time to shut off your computer and mobile devices, there are meanwhile a couple of programs that will adjust the screen brightness and hue according to the time of the day. Based on my cursory review of the available software solutions (note: the angle at which the sunlight enters the atmosphere is the reason that it changes its "color" in the course of the day), the F.Lux software by Stereopsis is apparently the most popular among a whole host of programs which are available for almost every operation system from A as in Android to Z as in ... well, Z as is "WindowZ" *rofl* (see caption of image 3 for links).

So do those programs work? Or do they at least make sense?

Despite the lack of peer-reviewed research on the general, let alone individual effectiveness of these programs, the results of numerous recent publications on the negative effects of non-adaptive screenlight and even regular (undimmed) household illumination, on the natural circadian rhythm would suggest that the use of respective software programs, or simple electronic dimmers could limit well-established detrimental short term effects such as the...

• 

  Figure 5: Emission band of the iPad (white screen), blue LEDs and the transmission band of orange-tinted glasses (Wood. 2012) + the melatonin suppressive frequency band (red, dashed line, my addition) - it should be obvious that the iPad hits a homerun with his brilliant display and you can bet that the "Retina Display" of the iPad2 emits even more natural light ;-)

  ... -8% and -23% reduction in melatonin production from the use of an iPad at 00:00 or 01:00 a clock, respectively, Britanny Wood and her colleagues from the Lighting Research Center at the Rensselaer Polytechnic Institute in New York observed in 11 healthy subjects with a mean age of 18.9 years
• ... postponement (~2h) and shortening (-90min!) of the nocturnal melatonin expression which occurred in 99% of 112 young healthy subjects who were, just like about everyone who would be sitting in his office in the afternoon and on the couch in front of the telly in the evening, exposed to regular electric room light (constant spectral composition and intensity <200 Lux) for 8h before they went bed (Gooley. 2011)
• ...50%-90% suppression of melatonin, 80% of the people suffer from, when they accidentally or deliberately try to switch from one to another sleeping rhythm by simply not switching the light out and staying up late (Gooley. 2011)
• ... significantly more pronounced suppression of melatonin production of computer, laptop, mobile devices and TVs with LED displays as compared to the old-fashioned CCFL backlit displays (Bues. 2012)
• [...]

...I guess it's about time I stop listing all those negative effects, after all, even the above list, which is by no means comprehensive and could easily extended by two dozens of additional citations from the last 3 years, only, could convey the impression that it would in fact be the best for us to return into our man- and woman-caves, shut the electricity off and lead the idyllic life of our paleolithic ancestors... and if you want to do that and find a place where this is possible, I won't put a spoke into your... ah, wait wheels are neolithic witches' brew, but I guess you get the notion anyway ;-)

Don't worry, you don't have to reside in paleolithic darkness - thanks to neolithic science!

For the rest of you, I have already outlined a couple of easily implementable strategies to avoid the negative aspects of artificial light exposure, where the light (artificial or not) is not a necessary or desirable part of your life (blindfolds, curtains, special light sources, computer software, orange blue-blocking glasses, keeping the lights low, dimmers, etc.; check out my previous blogpost "1lbs Fat Loss Bonus of 40 Minutes of Additional Sleep", as well).

Figure 5: You can take this sketch of mine as a sneak peak of what to expect in the future installments of the Circadian Rythmicity Series and the smiley as a clear-cut evidence that we are not doomed to live in darkness for the rest of our miserable neolithic existance (parts of background image from Froy. 2012)

Apropos desirable, not all neolithic technology is bad and I am honestly darn happy I am no paleolithic hunter, let alone gatherer! Used appropriately, even the funky over-sized LED screen I recently got at the office has its advantages. Compared to a regular LCD screen, for example, it will significantly improve my working memory/attention, when I am working overtime (cf. Cajochen. 2011). Since I don't intend to make use of this advantage today, however, you will have to wait another week for the next installment of this series to be written if you want to learn about behavioral, psychological and technological tweaks and gimmicks by the means of which you can use light(s) to your advantage to realign a compromised circadian rhythm, increase cognitive and physical performance, minimize the negative effects of after hours or shift work and much more.

I for my part am now enjoying the sunlight for maximal melatonin suppression, cognitive and physical performance and a powerful signal to my circadian clock that she is still accurate and would suggest you do the same - unless you want to leave me some feedback on this first installment of the Circadian Rhythmicity Series and where you want it to be heading, of course!

References:

• American Medical Association (AMA), House of Delegates. Resolution 516 e Advocating and Support for Light Pollution Control Efforts and Glare Reduction for Both Public Safety and Energy Savings. 2009. 
• Bues M, Pross A, Stefani O, Frey S, Anders D, Späti J, Wirz-Justice A, Mager R, Cajochen C. LED-backlit computer screens influence our biological clock and keep us more awake. Journal of the Society for Information Display. 2012; 20: 266–272.
• Bukalev AV, Vinogradova IA, Zabezhinskiĭ MA, Semenchenko AV, Anisimov VN. Light pollution increases morbidity and mortality rate from different causes in male rats. Adv Gerontol. 2012; 25(1):49-56.
• Cajochen C, Frey S, Anders D, Späti J, Bues M, Pross A, Mager R, Wirz-Justice A, Stefani O. Evening exposure to a light-emitting diodes (LED)-backlit computer screen affects circadian physiology and cognitive performance. J Appl Physiol. 2011 May;110(5):1432-8. Epub 2011 Mar 17.
• Falchi F, Cinzano P, Elvidge CD, Keith DM, Haim A. Limiting the impact of light pollution on human health, environment and stellar visibility. J Environ Manage. 2011 Oct;92(10):2714-22.  
• Froy O. Metabolism and circadian rhythms--implications for obesity. Endocr Rev. 2010 Feb;31(1):1-24. 
• Gooley JJ, Chamberlain K, Smith KA, Khalsa SB, Rajaratnam SM, Van Reen E, Zeitzer JM, Czeisler CA, Lockley SW. Exposure to room light before bedtime suppresses melatonin onset and shortens melatonin duration in humans. J Clin Endocrinol Metab. 2011 Mar;96(3):E463-72.
• Hollan J. Metabolism-influencing light: measurement by digital cameras, Poster at Cancer and Rhythm Oct 14-16, 2004, Graz, Austria. 
• Sasseville A, Paquet N, Sévigny J, Hébert M. Blue blocker glasses impede the capacity of bright light to suppress melatonin production. J Pineal Res. 2006 Aug;41(1):73-8.
• Soc for End. "Melatonin" in Glosarry. 2011 March < http://www.yourhormones.info/hormones/melatonin.aspx > visited 2012 Aug 05.
• UCI.edu. Illustration to article "The Clock Watcher". < http://www.uci.edu/features/2009/05/feature_circadian_090528.html > visited 2012 Aug 05.
• Wood B, Rea MS, Plitnick B, Figueiro MG. Light level and duration of exposure determine the impact of self-luminous tablets on melatonin suppression. Appl Ergon. 2012 Jul 29.