True or False: Mycotoxins in Coffee Are a Serious Threat to Our Health and the Only Way to Avoid Them is Abstinence

As we are about to see coffee is by far not the worst aflotoxin offender in the human diet. Still, that does not mean that the coffee related exposure to this form of mold that can befall all sorts of grains, nuts and seeds is harmless.

You will probably remember that I casually touched on the possibility of being exposed to aflotoxins and more importantly ochratoxins as a result of the consumption of mold-infected coffee in previous coffee articles. When the issue of the « coffee ➲ aflotoxin / ochratoxin exposure ➲ serious health » triage resurfaced in a brief facebook conversation, recently, I realized that I was not 100% sure if these mycotoxins that are produced by Aspergillus flavus, Aspergillus ochraceus, Aspergillus niger, and Aspergillus carbonarius do or don't pose a serious health risk.

Well, you know how much I hate unanswered questions, so I kept digging until I'd found what I consider to be a half-way satisfying answer to this life-or-death question ;-)

You can learn more about coffee at the SuppVersity

Remember: With Coffee More Won't Help More

Coffee - The Good, Bad & Interesting

Three Cups of Coffee Keep Insulin At Bay

Caffeine's Effect on Testosterone, Estrogen & SHBG

Coffee + Cacao for Breast Cancer Prevention

"Decaf" Won't Help With Weight, ... Ahh, Fat Loss

"The amount of aflotoxin in the average cup of coffee is a serious threat to our health!"

In 90% of the cases the above statement is FALSE! Despite the fact that it is difficult to tell how much mycotoxins you've been flushing down with your morning coffee today, the exact amount of the more common aflotoxins and their similarly kidney-toxic, pro-carcinogenic and coffee-loving cousins, the ochratoxin, in the average cup of (roasted) coffee is probably way too low to be worried about.

Figure 1: Mycotoxin exposure from coffee; calculated based on data from Europe (Vd Stegen. 1997)

Based on the studies I have reviewed for this article, it appears almost certain to say that the relatively low amount of coffee beans per cup (4-8g) reduces your average mycotoxin exposure from 1-4 cups of coffee per day to levels that are almost certainly within one of the various (multi-)national reference ranges (Van Egmond. 2007):

• Europe: 5µg/kg
• Africa: 10µg/kg

• North America: 20µg/kg

• Asia: 15µg/kg
• Latin America: 20µg/kg

Using a selection of commercially available regular and soluble coffee brands, van der Stegen et al. have actually calculated the average daily mycotoxin intake of Europeans with an average coffee consumption of 1-4  to be in the nanogram range - 19ng and 10ng, specifically, for regular and instant coffee drinkers, respectively.

Please remember: We don't know if / what happens or doesn't happen if you stay within or break the arbitrary intake limits. If you take a look at the available evidence from rodent studies, the results Epstein et al. presented in their 1969 paper (see Table 1) later in this article, would suggest that a sensible intake limit would have to be below the 1µg range if we assume a similar toxicity for the average mycotoxin mixture as for the aflotoxin B Epstein et al. used. This assumption is obviously not realistic, but it should remind you of the arbitrariness of the "intake limits".

Just to make sure, we understand each other, here: That's 1000x less than you'd get from only 20g of some of the Brazilian peanuts Freitas and Brigido analyzed in a 1998 study for their mean and maximal mycotoxin content. With 1099µg/kg the worst offenders in this study would easily have you breach the already lax American (North & Latin America) max. tolerable intake limit of 20µg/kg per day - and that despite the fact that this limit is more than 1000x higher than the amount of mycotoxins you'll have in your average cup of coffee.

Green vs. roasted coffee: Do we have to chose between anti-oxidants and mycotoxins?

It goes without saying that the mere fact that the dangers of being exposed to high amounts of mycotoxins from adequately processed and stored coffee appears negligible, does not warrant ignoring the problem completely. The effects of processing and storage are and will thus always be an important issue.

Given the fact that humid and cool (but not cold) is what mold needs to thrive, you will probably already have suspected that the hot and arid environment of a coffee roastery is not exactly the favorite growth environment for the Aspergillus family.

Figure 2: Ochratoxin content (µg/kg) in green, roasted & soluble coffee, left; total antioxidant activity in TROLOX essay of green (=unroasted), lightly, medium and dark roast coffee (Blanc. 1998; del Castillo. 2002)

A lower mycotoxin content is yet not the only beneficial effect of roasting. Contrary to what 99% of the people will tell you, when you ask them, the roasting process increases not decreases the total antioxidant capacity of coffee (TAC).

What does the latest review say about regular coffee consumption and cancer? "The epidemiological evidence consis-tently indicates that coffee protects against liver cancer, and also point toward protective effects for risk of colorectal cancers (with relative risks of 0.50 (95% CI: 0.42–0.59) and 0.83 (95% CI: 0.75–0.92), respectively, in the most recent meta-analyses)" (Bøhn. 2013). The evidence for protective effects against breast and prostate cancer on the other hand is inconclusive - irrespective of the established chemo-preventive effects of coffee phytochemicals Bøhn et al. list in their soon to be published paper in Molecular Nutrition & Food Research early in 2014.

Due to the formation of a whole host of new antioxidant molecules during the roasting process, light or mildly roasted coffee beans have a higher total antioxidant capacity than green ones - irrespective of the reduced chlorogenic acid content, for which the green beans are currently (over-)hyped. If you look at the data in Figure 2 you will see that even the heavily roasted, tar-black coffee beans still have a minimally higher anti-oxidant activity than the "natural" green coffee beans (del Castillo. 2002) - an observation that has been made both in the Petri dish, as well as ex vivo rodent studies (Daglia. 2002).

You've been drinking tons green coffee, lately?

Don't worry! Your past green coffee consumption probably isn't a real problem either. It does after all look as if those beans were yet another example for the infamous "nature kows best" principle. I mean, can it really be "coincidence" that the beans come with "anti-mycotoxin agents" in form of cafestol and kahweol. These coffee-specific diterpenes have been shown to ameliorate the aflotoxin B induced genotoxicity (Cavin. 1998) and the subsequent pro-carcinogenic effects (Cavin. 2001) and can be expected to exert protective effects against ochratoxin toxicity, as well.

In view of the fact that similar evidence exists for chlorogenic acids (CGA), dodecyl chlorogenates (DCGA) and a high(er) coffee consumption, in general (Suárez‐Quiroz. 2013; Ferk. 2013), it is actually not surprising that studies like Shank et al. (1972)  or Bulatoa-Jaym et al. (1982) found links between aflotoxin contaminated corn, grains, potato, peanuts & co., but could not identify an increased risk in liver cancer for coffee aficionados. Consequently, it's (imho) relatively unlikely that your health has already taken a beating - irrespective of the amount of the number of cups of green coffee you've been consuming over the past weeks.

Coffee is not the worst mycotoxin offender in the human diet: In a case-control dietary study of primary liver cancer in humans Bulatoa-Jaym et al. found that 51.2% of their subjects daily aflotoxin exposure came from cassava, 20.3% from corn, 6.8% frompeanuts and 5.8% from sweet potato (Bulatao-Jaim. 1982). On the other hand, many scientists argue that the ochratoxin content of coffee is the real danger, anyway (Bayman. 2006)

I would still like to remind you that even the sum of the previous remarks must not be misunderstood as an incentive to willy nilly forget all previously harbored concerns about "moldy coffee beans"... and I say this in spite of the existing epidemiological evidence that a high coffee consumption decreases the risk of developing and dying from liver cancer (Kurozawa. 2005; El–Serag. 2007). The liver is after all not the only organ that may be affected by the pro-carcinogenic toxins. The kidneys are at least as susceptible to the toxic assault from the mycotoxin filtrate that passes through them.

The liver is not the only organ that's taking a beating

It may thus be hypothetical, but not impossible that a 2x / 2.6x increased risk to develop renal cell carcinoma Mimi et al. report in a 1986 paper on the associations between coffee consumption and kidney cancer may at least be partially related to the higher mycotoxin exposure in those 61 study participants who consumed 1-4 cups of coffee per day (Mimi. 1986).

That mycotoxins can promote the development of kindey cancer had been demonstrated 17 years before the publication of Mimi's paper by Epstein, Bartus & Farber (1969) whose Wistar rats developed renal epithelial neoplasms after being exposed to food-borne aflatoxin B1.

Table 1: Incidence of renal epithelial and malignant hepatic tumors in male Wistar rats ingesting aflatoxin B1 for 147 days; the indces a, b, c provide irrelevant (in this context) extra information (Epstein. 1969)

In that, it's quite remarkable that even the lowest aflotoxin dosage the researchers used in their study (0.25µg/kg chow; HED  ~1.2ng/kg body weight, ; see Table 1) lead to significant rates of cancerous growth in both kidney (28%, if we count both developing and full-blown renal neoplasms) and liver  within the 21 week study period.

There is just one no-go: Storing unroasted beans for years in your humid basement

In view of the large regional difference in aflotoxin infection rates, the different susceptibility of the various coffee cultivars and the influences of weather, storage conditions, blending, processing, and all the other factors that increase or decrease the amount of mold and mycotoxins on coffee (see Figure 3), I would still be hesitant to exclude the possibility that stocking up on highly aflotoxin contaminated unroasted coffee you possibly even stock in a very humid basement of yours to consume the coffee over the course of months if not years could have negative effects on the health of your organs, in general, and the function of your kidney and liver, in particular.

Figure 3: Percent infection of coffee cherries and beans byAspergillusspecies potentially capable of producing ochratoxin A in four Brazilian coffee growing regions from the 1999 and 2000 harvests (Taniwaki. 2003)

I mean, look at the data in Figure 3. It's probably no coincidence that the otherwise virtually uninfected beans of coffee from the 1999 and 2000 harvests in the Cerrado Miniero exhibits a 4% infection rate after being stored intermediately before it is either roasted, shredded or both or simply forwarded "raw" to the mailbox of an "unroasted coffee enthusiast". Similar effects can be expected when the huge coffee manufacturers mix harvests from various regions. If only one is infected, all it takes to have Aspergillus flavus literally "all over the place" is enough time in one of the huge storage silos or the hold of one of the container ships that transport coffee from the "New" back into the "Old World".

Figure 4: The amino acid make up of coffee changes upon roasting (data from Cirilo. 2003).

Life kills, anyway! Let's be honest. In the end, living is a pretty deadly undertaking, anyway. Against that background the uncertainty with respect to the tolerable intake of mycotoxins should not bother you so much to ignore the existing evidence of the beneficial effects of regular coffee consumption (see "Coffee - The Good, the Bad & The Interesting" | read more).

One thing you may keep in mind, though, is that this evidence is based on data from average coffee drinkers, people who drink coffee that's made of roasted beans. Beans that are virtually mycotoxin-free (see Figure 2, left) and have a higher, not lower antioxidant capacity than green coffee beans.

What roasted beans lack, though, are chlorogenic acid and trace amounts of amino acids (see Figure 4), including serotonin. If you are looking for one of these molecules specifically, you are yet probably better of with a hopefully aflotoxin and mycotoxin free green coffee extract and a bottle of pills with the serotonin precursor 5-HTP, anyways.

References:

• Bayman, P., & Baker, J. L. (2006). Ochratoxins: a global perspective. Mycopathologia, 162(3), 215-223. 
• Blanc, M., Pittet, A., Muñoz-Box, R., & Viani, R. (1998). Behavior of ochratoxin A during green coffee roasting and soluble coffee manufacture. Journal of agricultural and food chemistry, 46(2), 673-675.
• Bøhn et al. (2013) Coffee and cancer risk, epidemiological evidence, and molecular mechanisms. Molecular Nutrition & Food Research [early view article]
• Bulatoa-Jaym J, et al. (1982). A Case-Control Dietary Study of Primary Liver Cancer Risk from Aflatoxin Exposure*. International journal of epidemiology, 11(2), 112-119.
• Cavin, C., Holzhäuser, D., Constable, A., Huggett, A. C., & Schilter, B. (1998). The coffee-specific diterpenes cafestol and kahweol protect against aflatoxin B1-induced genotoxicity through a dual mechanism. Carcinogenesis, 19(8), 1369-1375.
• Cavin, C., Mace, K., Offord, E. A., & Schilter, B. (2001). Protective effects of coffee diterpenes against aflatoxin B< sub> 1</sub>-induced genotoxicity: mechanisms in rat and human cells. Food and Chemical toxicology, 39(6), 549-556.
• del Castillo, M. D., Ames, J. M., & Gordon, M. H. (2002). Effect of roasting on the antioxidant activity of coffee brews. Journal of Agricultural and Food Chemistry, 50(13), 3698-3703. 
• Cirilo, M. P., Coelho, A. F. S., Araújo, C. M., Gonçalves, F. R., Nogueira, F. D., & Glória, M. B. A. (2003). Profile and levels of bioactive amines in green and roasted coffee. Food Chemistry, 82(3), 397-402.
• Daglia, M., Papetti, A., Gregotti, C., Bertè, F., & Gazzani, G. (2000). In vitro antioxidant and ex vivo protective activities of green and roasted coffee. Journal of Agricultural and Food Chemistry, 48(5), 1449-1454.
• Epstein, S. M., Bartus, B., & Farber, E. (1969). Renal epithelial neoplasms induced in male Wistar rats by oral aflatoxin B1. Cancer Research, 29(5), 1045-1050.
• El–Serag, H. B., & Rudolph, K. L. (2007). Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology, 132(7), 2557-2576. 
• Ferk, F., Huber, W. W., Grasl‐Kraupp, B., Speer, K., Buchmann, S., Bohacek, R., ... & Knasmüller, S. (2013). Protective effects of coffee against induction of DNA damage and pre‐neoplastic foci by aflatoxin B1. Molecular nutrition & food research. 
• Freitas, V. P., & Brigido, B. M. (1998). Occurrence of aflatoxins B1, B2, G1, and G2 in peanuts and their products marketed in the region of Campinas, Brazil in 1995 and 1996. Food Additives & Contaminants, 15(7), 807-811.
• Kurozawa, Y., Ogimoto, I., Shibata, A., Nose, T., Yoshimura, T., Suzuki, H., ... & Tamakoshi, A. (2005). Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan. British journal of cancer, 93(5), 607-610. 
• Mimi, C. Y., Mack, T. M., Hanisch, R., Cicioni, C., & Henderson, B. E. (1986). Cigarette smoking, obesity, diuretic use, and coffee consumption as risk factors for renal cell carcinoma. Journal of the National Cancer Institute, 77(2), 351-356.
• Shank, R. C., Wogan, G. N., & Gibson, J. B. (1972). Dietary aflatoxins and human liver cancer. I. Toxigenic moulds in foods and foodstuffs of tropical South-East Asia. Food and Cosmetics Toxicology, 10(1), 51-60.
• Taniwaki, M. H., Pitt, J. I., Teixeira, A. A., & Iamanaka, B. T. (2003). The source of ochratoxin A in Brazilian coffee and its formation in relation to processing methods. International Journal of Food Microbiology, 82(2), 173-179. 
• Van Egmond, H. P., Schothorst, R. C., & Jonker, M. A. (2007). Regulations relating to mycotoxins in food. Analytical and bioanalytical chemistry, 389(1), 147-157. 
• Vd Stegen, G., Jörissen, U., Pittet, A., Saccon, M., Steiner, W., Vincenzi, M., ... & Schlatter, C. (1997). Screening of European coffee final products for occurrence of ochratoxin A (OTA). Food Additives & Contaminants, 14(3), 211-216. 
• Yamato, T., Yamasaki, S., Misumi, Y., Kino, M., Obata, T., & Aomine, M. (2002). Modulation of the stress response by coffee: an in vivo microdialysis study of hippocampal serotonin and dopamine levels in rat. Neuroscience letters, 332(2), 87-90.

Warding Off Holiday Weight Gain 2.0: The Anti-Diabesity Effect of Coffee Goes Beyond its Caffeine Content.

Image 1: If they are not laden with pesticides and anti-fungals, the small brown beans from the coffee pant can easily compete with green, black oolong and pu-erh teas, when it comes to countering the unwanted side-effects of the "holiday diet"

Back in the days, both, tea and coffee were luxury goods and people felt privileged if they could have any of them. Today, they have become another of the endless commodities of our convenience society, where coffee, the former drink of the kings (and popes), has gotten a bad rep lately as being the underlying cause of the "adrenal burnout" that has befallen 90% of the visitors of pertinent Internet bulletin boards. I was thusly not surprised that SuppVersity student Fat Free commented yesterday's blogpost on the anti-obesity effects of tea rather sheepishly. As if his wish for "a coffee" on the list of the anti-holiday-weight-gain items was some atrocious act in the sense that "a coffee" could never be as healthy as a hip green tea. I mean wasn't it bad enough that the "holy" green tea was outperformed by its primitive black brother?

Well, guess what, dear green tea connoisseurs, it may well be that (organic) coffee beans are in no way inferior to the unquestionably healthy, yet recently slightly over-hyped unoxidized camellia sinensis leaves. At least this is what a soon to be published study by Yuji Matsuda and his colleagues from the Nagoja University in Japan would suggest (Matsuda. 2011).

Tea or coffee during the holiday season - only a matter taste?

Matsuda et al. put a group of 8-week old mice on a pro-diabetic high-fat diet (this is the type of "high fat diet" that is high both in fat and in carbs and thusly is a perfect image of what 75% of the people are "eating" in the holiday season ;-). In the course of the 17-week study period the mice received either regular drinking water, or 2.5x diluted coffee, or water that was laced with 200mg of caffeine per liter (with a water intake of 13-14g/100g BW this would translate to a daily dose of 2.8mg/100mg and a human equivalent of 2.3mg/kg, or 182mg of caffeine per day for an 80kg human being). The intention was to investigate whether the results of epidemiological studies by van Dam (2002; 2005), Huxley (2009) and Goto (2011), which suggest that regular coffee consumption is associated with a profoundly reduced risk of developing metabolic syndrome or type II diabetes, could be replicated in a laboratory setting.

Figure 1: Body weight at the beginning and end of the study period in the control group and the mice receiving 2.5x dilluted coffee or 200mg/L caffeine in their drinking water; food intake in g per 100g of  body weight (data adapted from Matsuda. 2011).

If you look at the weight changes of the animals in figure 1, it becomes evident that despite a (non significantly) greater food intake esp. in the "real coffee" group, the mice on the coffee or caffeine supplemented high-fat diets gained approx. 8% less body weight than their water guzzling peers.

Figure 2: Fat weight in mice after 17 weeks on high fat diet with either water, 2.5x diluted coffee or water + 200mg caffeine per L (data adapted from Matsuda. 2011).

Now while the intrinsically flawed concept of a "body mass index" that is still propagated by mainstream media would suggest that there is something like an "ideal body weight", the numbers on your scale, alone, have no predictive value in terms of future health risk. The reductions in visceral (epididymal fat) and subcatenous fat accumulation in the mice of the coffee and caffeine arm is thusly a considerably more important finding of this study than the slightly reduced weight gain. After all, the amount of visceral (=inter-organ) fat you are carrying around is one of the few relatively reliable indicators of whether you are going to see your grand-children graduate, or not.

Time and again: Whole foods, or drinks, outperform extracts

If you take a closer look you will notice that despite a general tendency towards lower body fat levels in the coffee and caffeine group, the "whole food", or I should say, "whole beverage" has a much more pronounced effect on the "bad" visceral (epididymal) fat depots. So, just in case you still like your pills, caps and powders: This is only the latest in a long line of foods (this is the stuff that is not sold in caps or powder form) with verified health benefits, where one isolated compound, of which we believe that it is the "active ingredient" turns less potent than the whole food - so, could it possibly be that Nature knows best?

Figure 3: Reductions in inflammatory cytokine (MCP-1, TNF-alpha, IL-6) and adipokine expression in the epididymal fat pads of mice receiving 2.5x diluted coffee or water laced with 200mg/L caffeine in addition to their high fat diet (data calculated based on Matsuda. 2011).

The "whole foods" vs. "extract" difference is also evident in the differential effects coffee and caffeine had the expression of the inflammatory cytokines MCP-1, TNF-Alpha and IL-6 and the adipokines adiponectin and leptin. With a more pronounced expression of the latter (leptin) and an almost identical expression of the former (adiponectin) indicating an improved visceral fat metabolism in the epididymal fat pads of the "coffee-drinking" mice.

Figure 4: Insulin response (area under the curve in mg * min / dl) during glucose tolerance at different time-points during the 17-week study period (data calculated based on Matsuda. 2011).

As the areas under the insulin response curve in the glucose tolerance test go to show. Coffee (=whole food!) consumption does also reduce the transient caffeine induced decrease in insulin sensitivity that has been touted as one of the reasons why coffee would be "bad" for you. As the data from the study goes to show, this effect is only temporary, even for plain caffeine and should not be an issue for the habitual coffee drinker. Moreover, the long term benefits totally outweigh any short term increases in fasting blood glucose (approx. +8% in the first weeks of the study) - or, getting back to the initial research hypothesis: Coffee consumption is a possible way to reduce the risk of developing type II diabetes (at least  for mice ;-)

Coffee or tea? The choice is up to thee!

Since a direct comparison of the data from yesterday's tea study on teas would not be valid, anyways, and because I do not want to disturb the pre-Chrismas harmony and provoke a war between coffee and tea drinkers in the comment area of this blogpost, I would just advice everyone to just decline the soda your relatives may be offering you over the holidays and stick to either tea or coffee... whatever you like better - and by the way, dehydration is neither an issue for the habitual tea nor the habitual coffee drinker (Grandjean. 2000)!

Coffee Rules, Green Tea Sucks!? Study Links Green Tea to Insulin Resistance and Coffee to Insulin Sensitivity. Statist. Outlier, Long- vs. Short Term Effect or Heavy Metal Toxicity?

I can't tell if bathing in coffee is healthier than in tea, but my gut tells me that it is.

Coffee may rob your sleep (see "Sleepness Nights: Are Pre-Workouts and A Huge Cup of Coffee Messing With Your Sleep?" | more), but if you look at the currently available epidemiological data, the average coffee drinker is still a pretty healthy chap. Whether this is due or in spite of the stimulating effects of caffeine is not quite certain, but a closer look at its molecular composition reveals that the average cup of real coffee has at least as many potent antioxidants, as green tea. From a molecular perspective coffee is thus by no means inferior to the catechin-laden purported health-elixir green tea. With its glucose-6-phosphatase inhibitory (van Dam. 2006) and insulin sensitizing effects (Shearer. 2003) of its chlorogenic acid and quinide, coffee has, just like green tea, tons of animal data to support its potent anti-diabetic effect.

What's healthier tea or coffee?

If you asked one hundred people, what they'd choose, coffee or green tea, if personal preferences weren't an issue and their only criteria were "beneficial health effects", I am 100% convinced that the vast majority would go with green tea. That's actually quite natural, the media does after all hype every epidemiological study that supports the notion that green tea drinkers are the healthiest chaps on earth. Studies like the one researchers from the National Center for Global Health and Medicine in Tokyo are about to publish in the venerable scientific journal Metabolism, on the other hand, are rarely present on any of the major science news outlets.

Did you know that... An inverse association between coffee consumption and HOMA-IR has been observed in the US, Sweden, the Netherlands and multi-ethnic Asian populations, the study at hand is yet the first to confirm the existence of health benefits in a Japanese population.

This is where the SuppVersity comes into play. Your place to learn that Pham et al. observed an "unexpected", statistically significant association between green tea consumption and elevated HOMA-IR levels - in other words: The regular consumption of green tea was associated with an impaired glucose metabolism / lower baseline insulin sensitivity.

Figure 1: Relative differences to coffee / green tea "no consumers" in subjects who drink different amounts of coffee and green tea every day; p-values are given in boxes only for significant changes (Pham. 2013).

These results were obtained using data from cross-sectional epidemiological surveys that had been conducted among employees of three workplaces, two municipal offices in Kyushu and one
manufacturing company, in Kanto in 2009 and 2012. Pregnant women and subjects reporting a history of stroke or cardiovascular disease (n = 25), cancer (n = 27), diabetes (n = 52) and chronic kidney disease (n = 9), as well as those who were current usersof anti-diabetic drugs (n = 1) or under medical care for hepatitis (n = 4) were excluded to minimize the influence of confounding factors and be able to make a statement about the associations between coffee and tea consumption and glucose management in the average healthy Japanese worker.

Table 1: Characteristics of the study subjects by coffee consumption; the yellow mark indicates stat. sign. inter-group differences (Pham. 2013)

"Information about dietary intake during the preceding month was obtained using a validated brief self-administered diet history questionnaire (BDHQ). Dietary intakes for 58 food and beverage items including coffee and green tea, energy, and selected nutrients were estimated using an ad hoc computer algorithm for the BDHQ, with reference to the standard tables of food composition in Japan.

The response options for coffee or green tea consumption were never, < 1cup/week (wk), 1 cup/wk, 2-3 cups/wk, 4-6 cups/wk, 1 cup/day (d), 2-3 cups/d, or ≥4 cups/d." (Pham. 2013)

It is probably not surprising that the comparatively detailed dietary analysis revealed significant correlations between the consumptions of coffee and green tea (Spearman’s r= 0.83 and 0.77 for coffee in men and women, respectively; Spearman’s r= 0.68 and 0.64 for green tea in men and women, respectively) - with a high enough subject base you can however subtract the individual influence of the two out.

Is there any reason green tea could compromise our insulin sensitivity

I have to admit that there is little direct experimental evidence that would explain the observations th researchers made, but if you remind yourselves of the first serving of the "Supplements to Improve and Restore Insulin Sensitivity" Series (overview), you will remember that the anti-diabetes effects of green tea / green tea supplements are - if they occur at all - indirect ones.

Don't forget that caps and pills are not worth a penny without you committing to the all the lifestyle changes I outlined in episode one of the "Supplements to Improve and Restore Insulin Sensitivity" series.

Unlike the bioactive substances in coffee, which have a direct beneficial effect on skeletal muscle glucose uptake, those of the often-hailed green tea catechins are primarily side effects of improvements in lipid metabolism and reduced chronic inflammation.

Assuming that the average study participant did not have significantly elevated blood lipids and wasn't chronically inflamed either, this would explain the absence of improvements in insulin sensitivity. What it doesn't explain, though, is the fact that the insulin sensitivity decreased - irrespective of the accumulating evidence which suggests that even diabetics don't benefit from green tea supplementation (latest example from Nov, 8  Wang. 2013)

Usually this is, when you take a look at the discussion in a scientific paper, read, digest and get an idea of what could be a reasonable explanation for unexpected phenomena like this. The conclusion of the paper at hand, does yet only summarize the existing scientific evidence that the vast majority of "previous studies have shown no association between habitual green tea consumption and fasting glucose" (Pham. 2013):

• a Japanese study among 1542 men reportedmarginally-significant higher odds ratios for IR with higher habitual consumption of green tea (T Otake April 2013, personal communication of the authors of the study at hand)
• Rebello et al. reported no association between green tea consumption and HOMA-IR among a multi-ethnic Asian population
• a meta-analysis including 6 clinical trials found no evidence to support an effect of green tea catechins on HOMA-IR

As Pham et al. points out conclusive evidence for or against the benefits of green tea consumption from long-term + large-scale trials is missing. Most clinical trials including those in in the previously cited  meta analyses had relatively short-term intervention (4-24 wks) and modest sample sizes (23-88 subjects). Without further research it is thus more or less impossible if genetic, lifestyle or other confounding variables or a hitherto overlooked negative long-term effect of green tea are responsible for the results. 

Table 2: Levels of toxic trace elements in tea infusion; data compiled by Tanmoy Karak, R.M. Bhagat (2010)

Aside from biological factors, the disappointing results could also be the consequence of the quality of the tea. In Japan, the upper tolerable levels for lead (Pb) are for example 4x higher, than in Europe (20mg/kg vs. 5mg/kg). With the ever-increasing Pb concentrations in tea leaves (Jin. 2005), lead and other toxic elements (see data in Table 2) could be turning the health elixir into an increasingly toxic cocktail.

"Coffee, Tea, Cacao, Caffeinated Sodas & Breast Cancer: 5+ Cups/Day?! Study & Meta-Analysis Show, It May Take More Coffee Than Previously Thought to Ward Off Breast Cancer" | more

Treat with caution: I strongly recommend not to overestimate the results of the study at hand - neither the negative ones about green tea, nor the positive ones about coffee. A BMI-stratified analysis did after all reveal that the inverse association (not causation) between coffee consumption and HOMA-IR was really significant only in the overweight/obese, but not in normal-weight, individuals.

In view of the absence of a reasonable explanation for the pro-diabetic effects of chronic green tea consumption (it may in fact be heavy metals; see Table 2), I would not suggest you switch from green tea to coffee, if you don't like it. If you are a coffee-boy or -girl, anyway, the study at hand confirms that reductions in diabetes risk are not a good reason to give up on your beloved brown brew ;-)

References:

• Jin CW, He YF, Zhang K, Zhou GD, Shi JL, Zheng SJ. Lead contamination in tea leaves and non-edaphic factors affecting it. Chemosphere. 2005 Nov;61(5):726-32.
• Wang X, Tian J, Jiang J, Li L, Ying X, Tian H, Nie M. Effects of green tea or green tea extract on insulin sensitivity and glycaemic control in populations at risk of type 2 diabetes mellitus: a systematic review and meta-analysis of randomised controlled trials. J Hum Nutr Diet. 2013 Nov 8.
• Karak T, Bhagat RM. Trace elements in tea leaves, made tea and tea infusion: A review. Food Research International. 2010; 43(9):2234–2252.

Sleepless Nights: Are Pre-Workouts and A Huge Cup of Coffee Messing With Your Sleep? Plus: 5h Half-Life & 15h Clearance Time Caffeine Stays

This couple probably didn't have a two huge cups of high-caffeine coffee with 400mg caffeine, each, before bed ;-)

The recent publications of a paper by Drake, Roehrs, Shambroom and Roth in the Journal of Clinical Sleep Medicine woke my interest in the quantitative and qualitative significance of the potential negative effects coffee / caffeine can or will have on sleep (Drake.2013).

In the experiment, Drake et al. describe in their latest paper, the researchers made (much to my surprise) a first attempt "to investigate the relative effects of a given dose of caffeine administered at different times of day on subsequent sleep." (Drake. 2013)

Fixed dose (400mg) + varied times

To do so, Drake and his colleagues from the Sleep Disorders & Research Center at the Henry Ford Hospital and the Department of Psychiatry and Behavioral Neurosciences at the Wayne State College of Medicine, in Detroit, as well as a scientist who worked for Zeo Inc in Newton, compared the potential sleep disruptive effects of a fixed dose of caffeine (400 mg) that was administered at 0, 3, and 6 hours prior to habitual bedtime.

Figure 1: Subjectively determined sleep latency (time it takes to fall asleep in min), total sleep (hrs) and wake time during sleep (min), sleep efficacy (%) and sleep quality (% of placebo) in 12 healthy men and women after the ingestion of a placebo or 400mg caffeine 0h, 3h or 6h before bed (Drake. 2013).

The study was blinded and the sleep duration and quality was assessed by questionnaires and data from the Zeo device all participants had to use (basically the Zeo is a device that measures your brain activity - unfortunately Zeo has gone out of business; cf. Orlin. 2013).

Figure 2: Objectively measured sleep latency (min), total sleep (hrs), wake time (min), sleep efficacy (%), stage 1 & stage 2 sleep (% of total sleep), slow wave and REM sleep times in minutes (Drake. 2013)

Based on this combination of subjective (Figure 1) and objective (Figure 2) data the researchers were able to confirm their hypothesis that 400mg of caffeine will provoke significant (p < 0.05 for all) sleep disturbances, regardless of whether the perfectly healthy subjects (n = 12; 50% women; mean age: 30y, BMI 25kg/m², 94.5% baseline sleep efficacy) consumed it at bedtime, 3 hours prior to bedtime, or 6 hours prior to bedtime. As Drake et al. point out, ...

"[t]he magnitude of reduction in total sleep time suggests that caffeine taken 6 hours before bedtime has important disruptive effects on sleep and provides empirical support for sleep hygiene recommendations to refrain from substantial caffeine use for a minimum of 6 hours prior to bedtime." (Drake. 2013)

For the PM-trainees and pre-workout fanatics among the SuppVersity readers this probably sounds scary. Stimulant-laden preworkout products are yet not the only offenders that could compromise your sleep hygiene.

"1kg Body Fat in 4 Weeks From < 2x Energy Drinks per Day!" | more

Young, sleepless and on caffeine: Recent scientific data appears to confirm that the increasing popularity of sugary, fattening (see link to the left), caffeinated energy drinks, and the high caffeine content of premium coffee are at least partly responsible for the surge in chronic sleep problems among young people (McCusker. 2003; Roberts. 2010; Carskadon. 2011). No wonder if >37% of them drink their first caffeine-containing beverage at 5 pm or later (Bryant Ludden. 2010).

With up to 500mg of caffeine in commercially available 16 oz servings of brewed coffee (McCusker. 2003), even an innocent (large) cup of coffee in the afternoon could have significant negative effects on the quality of the sleep you'll get, when you go to bed relatively early; and you wouldn't be the only one with that problem: Penalazzi et al. found that it is something 90% of the 18-58 year olds enjoy on an almost daily basis (Penalazzi. 2012).

"This must be a mistake. The must be an 'on the other hand' attached!"

You are right, the news are in fact so "bad" that I decided it may be worth digging a little further to see, if I, an outspoken coffee concessionaire, can't find a glitch in this or a conflict to another study that would put a relieving "?" behind the results of the study at hand:

• Statistical significance vs. real-world effects - While it is not a real glitch, it's certainly questionable how great real-world health consequences of the bordeline significant decrease in sleep efficacy and the significant 32% reduction in slow wave sleep actually are.
  With respect to the generic quantity "sleep quality", we could probably say that we give a damn. The loss of 15-22 minutes of slow wave sleep, of which scientists say that it is the time, when we consolidate new memories and our brain recovers from the daily activities, the 32% reduction in slow wave sleep does begin to sound scary. If we also take into account that Tasali et al. observed that ...
  

  "[...] all-night selective suppression of SWS, without any change in total sleep time, results in marked decreases in insulin sensitivity without adequate compensatory increase in insulin release, leading to reduced glucose tolerance and increased diabetes risk" (Tasali. 2013)

  in young, perfectly healthy subjects, I am not quite sure, if the overall beneficial metabolic and cognitive effects still outweigh the potential detriments that arise from the consumption of high amounts of caffeine shortly before going to bed.

• 

  Figure 3: According to Blanchard et al. it can take up to 15h to get rid of 5mg/kg body weight caffeine.

  The "outlier hypothesis" - Unfortunately, the study at hand is not "just an outlier", the sleep disruptive effects of caffeine administration at bedtime are well documented and have even used to model insomnia (Bonnet. 1992).
  Previous dose-response studies, demonstrate that increasing doses of caffeine administered at or near bedtime are associated with significant sleep disturbance (Karacan. 1976; Lasagna. 1977; Yanik. 1987) and the recommendations to avoid caffeine close to bedtime is in every list of sleep hygiene practices. However, evidence is less clear regarding the consumption of caffeine at earlier time. 
• The "Ah, I am used to it hypothesis" - Being "used" as you may have gotten to the sleep disruptive effects of caffeine does not equate being "immune" to them. That's at least what the 36 healthy male and female habitual caffeine consumers in a 1998 study by Jack E. James had to realize, when they skipped on their beloved caffein for just one day and their sleep duration and quality increased significantly ().

Unlike the evidence for the sleep-disrupting effects of late-pm caffeine ingestion, the effects of coffee you drink earlier in the day are less conclusive. The underlying reason for these difference is probably the significant inter-individual difference in elimination half-lives of caffeine in healthy adults.

Coffee only in the AM!?

The time our bodies need to get rid of 50% of the caffeine we've consumed at T = 0 ranges from 2.7-9.9 hours (Blanchard. 1983a,b). According to Blanchard et al. 'the average' 22-year old needs ~15h to get rid of all the caffeine that made it into his / her bloodstream after the consumption of ca. 400mg caffeine. If you wanted to make perfectly sure that your coffee consumption does not compromise your sleep, it would thus appear advisable to drink your 3-4 cups of coffee in the morning.

In the absence of studies that have compared the sleep disruptive effects of caffeine given at different times before bed it does however remain unclear it remains unclear when exactly the 'coffee curfew' should begin.

Learn to abUSE caffeine to modulate your circadian rhythm.

Bottom line: As unbearable as as it may sound for some of you, the currently available scientific evidence appears to suggest that (late) PM coffee consumption is a no-go for anyone for whom optimal sleep quality is more important than the rejuvenating pleasure of a huge cup of strong coffee.

On the other hand, a simple extrapolation from the data of the Blanchard study (see Figure 3)would  suggest that a small cup of coffee with only 100mg of caffeine at 4 o'clock pm is probably not so much of a problem - as long as you keep it 4h+ away from going to bed, your blood should be decaffeinated, when you hit the pillows ;-)

References:

• Bonnet MH, Arand DL. Caffeine use as a model of acute and chronic insomnia. Sleep.
  1992;15:526-36
• Blanchard J, Sawers SJ. Comparative pharmacokinetics of caffeine in young and elderly
  men. J Pharmacokinet Biopharm. 1983a; 11:109-26. 
• Blanchard J, Sawers SJ. The absolute bioavailability of caffeine in man. Eur J Clin
  Pharmacol. 1983b; 24:93-8.
• Bryant Ludden A, Wolfson AR. Understanding adolescent caffeine use: connecting use
  patterns with expectancies, reasons, and sleep. Health Educ Behav. 2010; 37:330-42.
• Carskadon MA Sleep in adolescents: the perfect storm. Pediatr Clin North Am. 2011;58:637-47. 
• Drake C, Roehrs T, Shambroom J, Roth T. Caffeine effects on sleep taken 0, 3, or 6 hours before going to bed. J Clin Sleep Med 2013;9(11):1195-1200.
• James JE. Acute and chronic effects of caffeine on performance, mood, headache, and sleep. Neuropsychobiology. 1998;38(1):32-41.
• Karacan I, Thornby JI, Anch M, Booth GH, Williams RL, Salis PJ. Dose-related sleep
  disturbances induced by coffee and caffeine. Clin Pharmacol Ther. 1976; 20:682-9.
• Lasagna L. Dose-related sleep disturbances induced by coffee and caffeine. Clin
  Pharmacol Ther. 1977; 21:244. 
• McCusker RR, Goldberger BA, Cone EJ. Caffeine content of specialty coffees. J Anal
  Toxicol. 2003; 27:520-2. 
• Orlin, J. Sleep Tracking Startup Zeo Says Goodnight. theCrunch.com. May 22, 2013 < http://techcrunch.com/2013/05/22/sleep-tracking-startup-zeo-says-goodnight/ >
• Penolazzi B, Natale V, Leone L, Russo PM. Individual differences affecting caffeine
  intake. Analysis of consumption behaviours for different times of day and caffeine
  sources. Appetite. 2012; 58:971-7.  
• Roberts RE, Roberts CR, Xing Y. Restricted Sleep Among Adolescents: Prevalence,
  Incidence, Persistence, and Associated Factors. Behavioral Sleep Medicine. 2010; 9:18-30. 
• Tasali E, Leproult R, Ehrmann DA, Van Cauter E. Slow-wave sleep and the risk of type 2 diabetes in humans. Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):1044-9.
• Yanik G, Glaum S, Radulovacki M. The dose-response effects of caffeine on sleep in rats.
  Brain Res. 1987;403:177-80. 

Can 5 Cups of Coffee Boost Testosterone to Estrogen Ratio in Overweight Men Transiently by Almost 200%? Plus: SHBG Its Own Receptor and Its Role in Prostate & Breast Cancer

Testosterone booster in men and estrogen amplifier in women? As if there were not already enough good reasons to get your daily dose of the 'kingly' brew ;-)

You would not have to be a diligent student of the SuppVersity to know: Coffee is a truly remarkable brew. Even mainstream media has gotten wind of the multitude of beneficial effects a moderate intake of the former drink of the kings and popes can have on your health and if it was not for the authors and newscasters blind reliance on whatever the press release guys are telling them, it would probably not even have been necessary for me to broach the beneficial effects coffee can have on your metabolic health and overall well-being in posts like "Coffee - 3 Cups a Day Keep Insulin at Bay", "Pre-Workout Caffeine: Fat Liberator, Substrate Modulator, Trans-Fatty Acid Eliminator & Performance Upregulator!" and many more.

So what is it this time? What else can coffee do for you?

I guess something only few people others than SuppVersity readers will be aware of is the fact that caffeine  and therefore coffee makes a nice testosterone booster (Beavon. 2008; study was discussed briefly as part of a longer post on June 20, 2012 an mentioned previous times in other posts) -- at least if you stick to moderate doses of ~300-400 mg before a workout. So, unless you are a newbie or missed the respective news, you should not be surprised that a recent study from the Harvard School of Public Health (Wedick. 2012), which had actually been designed mainly to investigate the effects of 5x 6-ounze cups caffeinated and decaffeinated coffee (both instant coffees; brand: Nestlé’s Taster’s Choice) on serum levels of sex hormone-binding globulin (SHBG), found that the consumption of both 'real' and 'fake' (=decaffeinated) instant coffee did lead to increases in total and free testosterone and profound decreases in estradiol (bound and free).

Figure 1: Levels of SHBG, testosterone, free testosterone, estradiol, free estrogen, the testosterone to estrogen ratio and DHEA in the male participants of the study expressed relative to a caffeine abstinent control group (based on Wedick. 2012)

As the data in figure 1 goes to show these changes were unfortunately transient and the impressive +189% increase in the testosterone to estrogen ratio which occurred during the first month of treatment totally disappeared within the next four weeks. On the other hand, the effects on SHBG the scientists had expected based on the assumption that both SHBG and caffeine intake have been found to be associated with lower risk of type II diabetes in large epidemiological studies, was non-existent in the first and second 4 weeks of the study... at least in the male subjects who were all overweight, nonsmokers and habitually coffee consumers, who had been required to abstain from caffeine intake for at least 2 weeks before the study was conducted.

Figure 2: Levels of SHBG, testosterone, free testosterone, estradiol, free estrogen, the testosterone to estrogen ratio and DHEA in the female participants of the study expressed relative to a caffeine abstinent control group (based on Wedick. 2012)

If you take a look at the data from the female participants (likewise overweight non-smokers, habitual caffeine consumers and, at the beginning of the study, 'dried out'; see figure 2), a different image emerges, in the women we do in fact see a transient rise in SHBG, which goes hand in hand with a decrease in testosterone, de to which the T/E ratio drops by -36% and -54% in the groups drinking caffeinated and noncaffeinated coffee respectively. Just as in their male counterparts, the levels did go back up in the second part of the study so that all values, including the SHBG levels were back in to normal after 8 weeks (please note changes in the 20% range are irrelevant and could be due to having a meal before the test, bad sleep, whatever).

The relative data tells only part of the story

Figure 4: Absolute values of the testosterone to estrogen ratio after 4 and 8 weeks; baseline levels were 16.2, 15.8, 18.2 in the caffeinated coffee, decaffeinated coffee and control group respectively. The data clearly shows: Coffee needs a PCT ;-)

If we do now take a closer look at the actual data and discard the comparison to the control group the scientists the picture becomes even more complex. After all the data in figure 4 clearly indicates that we are dealing with a combined effect here. It is correct that the ingestion of the caffeinated beverage had pronounced effects on the T/E ratio especially in the male participants, what the data in figure 1 does yet not tell you is the fact that this effect was also so pronounced, because simply stopping to drink caffeine reduced the T/E ratio from 18.1 to 8.4, i.e. by 54%(!).

Now this certainly reduces the effect size, but it does not totally negate the effect. After all the 'real' coffee drinkers (w/ caffeine) did still increase their T/E ratio from 16.2 to 24.2 -- a certainly likewise noteworthy increase of +29% that is however still far away from the exorbitant +189% increase compared to the poor guys who did not just lose their coffee, but also their virility.

So what does this tell use?

How cares about SHBG anyways? You should! After all there is relatively conclusive evidence that normal (not exorbitantly high!) SHGB levels have a protective effect against breast cancer in women and mechanistic evidence that they increase the risk of prostate cancer in men. In both cases SHBG acts independently via the largely ignored SHBG receptor that modulates the action of estrogens. Co-activation of SHBG and estrogen receptor in the prostate induces similar effect on prostate specific antigen secretion as DHT (Nakhla. 1997). Since estrogen alone does not have this effect, it is no wonder that stinging nettle root (Urtica dioica), with its SHGB inhibiting effect is a viable tool in the treatment of benign prostatic hyperplasia (Hryb. 1995). In the female breast, on the other hand, SHBG seems to " trigger a 'biologic' anti-estrogenic pathway" (Fortunati. 1999) and does therefore exert anti-instead of pro-carcinogenic effects.

I guess there are more than just the following three lessons to learn from this study, but at the moment these appear to be the most important ones for me:

1. The beneficial effects habitual coffee intake has on type II diabetes risk are, contrary to the scientists hypothesis, not mediated by its effect on SHBG.
2. In overweight men caffeine has a very shortlived beneficial effect on testosterone and the testosterone to estrogen ratio. After 4 weeks the levels do yet return to baseline, so this cannot explain the long-term benefits of habitual caffeine consumption either (maybe you should cycle caffeine instead of testosterone booster < I am just kidding ;-).
3. In overweight women, there is a similar, yet negative effect on testosterone levels, which is likewise transient and lasts less than 8 weeks. 
4. The caffeine ads to the 'pro-testosterone' effects, but even decaffeinated coffee has some effects.
5. Stopping "cold turkey" is not a good idea, when you are "on caffeine"

Now, what is important here is that we are dealing with overweight individuals, in whom the endocrine millieu is usually off. In particular, men tend to have reduced, women tend to have increased androgen levels (think PCOS). The effects we see after short-term withdrawal and the subsequent consumption of a non-negligible amount of 5 cups of coffee everyday could actually have corrective effects on the endocrine milieu, of which both, men and women could benefit, if they would last for more than 4-6 weeks. The detrimental effects of stopping, on the other hand, could be due to the sudden absence of the benefits of caffeine.

Regardless of whether you stop or start drinking coffeine, the endocrine "disturbances" are relatively short-lived and only further testimony to the fact that our bodies will always try to find a new "steady state" in what they consider normal.

Bottom line: There are a myriad of good reasons to drink coffee, getting more manly or more feminine is yet not one of them. Disappointed? Well, on the other hand this means coffee is no endocrine disruptor - and at least in this overweight population it seems to have a marginally beneficial baseline effects (thus the detrimental effects of abstinence).

References:

• Beaven CM, Hopkins WG, Hansen KT, Wood MR, Cronin JB, Lowe TE. Dose effect of caffeine on testosterone and cortisol responses to resistance exercise. Int J Sport Nutr Exerc Metab. 2008 Apr;18(2):131-41. 
• Fortunati N, Becchis M, Catalano MG, Comba A, Ferrera P, Raineri M, Berta L, Frairia R. Sex hormone-binding globulin, its membrane receptor, and breast cancer: a new approach to the modulation of estradiol action in neoplastic cells. J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):473-9.
• Hryb DJ, Khan MS, Romas NA, Rosner W. The effect of extracts of the roots of the stinging nettle (Urtica dioica) on the interaction of SHBG with its receptor on human prostatic membranes. Planta Med. 1995 Feb;61(1):31-2.
• Nakhla AM, Romas NA, Rosner W. Estradiol activates the prostate androgen receptor and prostate-specific antigen secretion through the intermediacy of sex hormone-binding globulin. J Biol Chem. 1997 Mar 14;272(11):6838-41.
• Wedick NM, Mantzoros CS, Ding EL, Brennan AM, Rosner B, Rimm EB, Hu FB, van Dam RM. The effects of caffeinated and decaffeinated coffee on sex hormone-binding globulin and endogenous sex hormone levels: a randomized controlled trial. Nutr J. 2012 Oct 19;11(1):86.

Ingestion of 400mg Caffeine Before a Workout Can Prevent Delayed Onset Muscle Soreness in Resistance Trained Men

Too many side-laterals without coffee?

Still having DOMS despite Alex Leaf's article on "DOMS - Delayed Onset Muscle Soreness: What Is DOMS & How Can It Be Managed? Science, Strategies, Supplements" (read more)?

In that case you are probably not a great fan of pre-workout products, coffee or energy drinks, because if you were, it is not unlikely that you had - instinctively, if you will - done everything right by consuming a hefty dose of the world's #1 OTC drug, caffeine, before each of your workouts.

400mg is plenty, but it does the trick

In case you have no clue what I am talking about, I'd suggest you take a look at the results of a recent paper by Hurley, Hatfield, and Riebe in the Journal of Strength and Conditioning Research (Hurley. 2013). In a series of tests that involved a strenuous biceps workout 4 sets of 10 bicep curls on a preacher bench, followed by a fifth set in which subjects completed as many repetitions as possible. The workout that was performed twice, with a one-week "wash-out" period - once with and once without the ingestion of 5mg/kg of caffeine 1h before the training session.

When the scientists compared the performance, perceived exertion and post-workout muscle soreness parameters they found that the ingestion of 5mg/kg caffeine ...

• had a beneficial effects on the perception of muscle soreness, 
• reduced the levels of perceived exertion, and
• lead to significant increases in performance

As you can see in Figure 1 the equivalent of ~2-3 cups of coffee did nut just ameliorate the pain on day 2 after the workout (that's usually when DOMS hits you hard). It did also speed up the "regeneration", or rather the reduction of pain.

Figure 1: Soreness values expressed relative to baseline testing (left) CK levels after the training session and number of repetitions on the all-out set (right; Hurley. 2013)

I have to admit, I was tempted to write that caffeine sped up the recovery process, but if you read part II of Alex' two-part series on DOMS, you will be aware that it is not warranted to use DOMS as a marker of regeneration ("DOMS - Delayed Onset Muscle Soreness: No Pain, No Gain? Is DOMS Necessary to Build Muscle?" | learn more).

The repeated bout effect is the opposite of the anabolic resistance that can occur after weeks of training | learn more

What about the repeated bout effect? What if it skewed the results? The increase in performance and reduce in muscle damage upon the exposure to a "conditioned" stimulus could in fact have led to lower DOMS values in the second of the two testing session. Hurley et al. do however point out that this effect would be minized by counterbalancing and appropriate randomization as it was conducted in the study at hand.

The non-existent effects on the creatine kinase (CK) levels of the the 12 healthy resistance-trained men (age 18–25 years) supports Alex' assessment that the link between CK and DOMS is a temporary one: While the peak values of DOMS and CK occur at the same time, a high CK level does neither predict a high degree of delayed onset muscle soreness, nor vice versa.

So what's the mechanism here

In view of the fact that the continuous provision of caffeine throughout the recovery phase did not lead to similar / increased reduction in DOMS, it appears certain that the effects of caffeine are acute. This means it works only, if it is ingested 1h before the workout and will thus achieve it's peak value when you are actually working out (depending on the dosage and delivery method, the caffeine levels peak after 40-60 min).

As Hurley et al. point out, the effect could be brought about by a partial blockade of the natural increase in muscular adenosine concentrations that have been observed to increase in the working muscle and blood after high-intensity exercise in previous studies (Tarnopolsky, 2000; Davis. 2003; Motl. 2006). It would also stand in line with the (unsurprising) observation that the subjects’ perceived exertion was significantly lower with caffeine in the final 3 sets of exercise - an effect that has also been attributed to the adenosine-inhibiting effects of caffeine (Davis. 2003):

"This response is attributed to the role of caffeine as a CNS stimulant and inhibiting adenosine receptor activity. Caffeine stimulates the CNS by secreting serotonin into the cerebral cortex, which results in mood improvements, increased mental awareness, and decreased fatigue and tiredness. This is all a result of inhibited adenosine activity thus reducing perception of pain, which could increase ability to perform more repetitions." (Hurley. 2013)

In view of the fact that the adenosine levels have not been accessed, the authors are eventually still stuck for an answer with respect to the exact underlying mechanism of the anti-DOMS effects of caffeine. Adenosine is a likely candidate, though, and before I would do a follow up study on this, I would rather take some money to find out whether 400mg of caffeine taken before a PM workout won't be doing more harm than good by having profound negative effect on your sleep quality.

Sometimes the things we learn from scientific studies have questionable, limited or no practical relevance. For others, like the study at hand or a previous study on the "muscle shaping effects" of certain exercises, this is luckily not the case (read more)

"Who cares about mechanisms, if it works?" I guess in view of the many in-vitro studies we are being bombarded with on a daily basis, most of you will probably agree that not knowing the exact mechanism of the DOMS-reducing effects of 5mg/kg of coffee is less problematic than knowing about the mechanism by which a certain substance works, but being clueless whether and at which doses it will produce the desired effects in humans - right?

Right! Unfortunately, even the results of the study at hand come with a small "*" [asterisk] to indicate that the benefits were observed in subjects who consumed coffee and caffeinated beverages only occasionally. Based on the observation that the performance enhancing effects of caffeine do not differ between habitual / non.habitual caffeine consumers (Tarnopolsky. 2000; Astorino. 2007), it does however appear likely that this is not going to be an issue.

References:

• Astorino TA, Rohmann RL, Firth K, Kelly S. Caffeine-induced changes in cardiovascular function during resistance training. Int J Sport Nutr Exerc Metab. 2007 Oct;17(5):468-77.
• Davis JM, Zhao Z, Stock HS, Mehl KA, Buggy J, Hand GA. Central nervous system effects of caffeine and adenosine on fatigue. Am J Physiol Regul Integr Comp Physiol. 2003 Feb;284(2):R399-404. Epub 2002 Oct 24.
• Hurley CF, Hatfield DL, Riebe DA. The effect of caffeine ingestion on delayed onset muscle soreness. J Strength Cond Res. 2013 Nov;27(11):3101-9.
• Motl RW, O'connor PJ, Tubandt L, Puetz T, Ely MR. Effect of caffeine on leg muscle pain during cycling exercise among females. Med Sci Sports Exerc. 2006 Mar;38(3):598-604.
• Tarnopolsky M, Cupido C. Caffeine potentiates low frequency skeletal muscle force in habitual and nonhabitual caffeine consumers. J Appl Physiol (1985). 2000 Nov;89(5):1719-24.

Lemon Juice, Resistant Starch, Coffee, Blueberries, Chili, Ginseng, Ginger, Mate, Gymnema Sylvestre, Bitter Melon. Supplements to Improve & Restore Insulin Sensitivity #4

Lemon Juice, Resistant Starch, Coffee, Blueberries, Chili, Ginseng, Ginger, Mate, Gymnema Sylvestre, Bitter Melon - they are all in this fourth serving of the insulin sensitizing supplements series and they are all in this collage. Can you identify all of them?

First of all, let me thank you for flooding me with good suggestions for supplements that should be discussed in this last installment of the series. It's Friday now that I start writing this post and it is probably going to be Sunday, before I find the time to finish the last of your suggestions; and that despite the fact that I am going to try to cut the infos short when I can foresee that it is not worth going into more details, anyway.

Not worth going into details? Yep, one of the supps, where this is clearly the case was suggested by Colby who wants me to address sodium-R-lipoic acid, which is nothing else but R-ALA and in my mind a scientifically unsupported spin-off of ALA that may in fact be inferior to the regular racemic form of lipoic acid which contains both the R- as well as the purportedly pro-inflammatory S-form of ALA (more about the benefits of inflammation in the context of hormesis).

Before we start, just a brief reminder: Do not consider spending your money on any of these supplements before you've not made / begun to make the lifestyle changes described in episode one of this series. Otherwise all of these supplements are nothing but a crutch supporting you on your journey along the Royal Road to Diabesity.

Ok, enough of the finger wagging for today; let's get to "your" supplement wishes. Let's see, what have we got?

• Lemon juice (citric acid) - This is another of Colby's suggestions (also asked for by "anonymous" who just missed his chance of becoming semi-famous). Colby says, he read about lemon juice in Tim Ferriss' Four Hour Body (a fascinating book, by the way; the only problem is that people forget that it's an N=1 experiment and few things that worked for Tim will work for you or anyone else, as effectively).
  
  

  

  Not citric acid specific enough, but worth mentioning: In a study where citric acid (the purported active ingr. in lemon juice) was admin. w/ thiamine, arginine and caffeine it lead to FAT GAIN in normal weight individuals (Muroyama. 2003) - this should remind you of the smart rules of supplementation, right?

  Ferris claims that in his experiments only lemon juice, but not vinegar, which happens to work by the same mechanism, i.e. slowing down the absorption of carbs, did actually lower his postprandial blood glucose levels. Unfortunately there is no research to support this claim and thus lemon juice is at best of as limited use as vinegar (see previous post).
  
  Using lemon juice for cooking purposes, on the other hand, has been shown to reduce the formation of pro-diabetic glycation end products during cooking.
  
  Using a marinade with lemon juice for example will reduce the production of AGEs in beef by 10%  (Uribarri. 2010)
  
  Overall, lemon juice is thus another "C" as in "you C-an try it if you are looking for yet another C-rutch", but certainly nothing that is going to solve any of your problems.
• Resistant Starches - Starches that cannot be broken down in the small intestine and will thus not release any glucose are a no-brainer, as far as improvements in insulin sensitivity are concerned. Think of them as fat, because that is what the "really resistant" starches, i.e. those that make it almost unharmed to the long intesine (RS-3 for the natural ones and RS-4 for the artificial ones). Once they have arrived there they are metabolized to short chain fatty by the bacteria in your gut.
  
  

  

  WMHDP pancakes are not good for you, but maybe better than regular ones.

  Now, the one thing that renders this starches still interesting is the fact that the fatty acids the gut bacteria produce are "short chain fatty acids" (SCFA) . These are, as the name implies "short" and thus easier digested than their nasty long-chain brethren that make up the lion's share of regular keto diets. Moroever, the SCFA have direct (receptor mediated) effects on the production of the "satiety hormone" GLP-1 that has positive effects on both glucose and lipid metabolism (Yadav. 2013).
  
  It is thus the conversion to SCFA and not the resistant starches which come in the varieties RS1 (=physically inaccessible or digestible resistant starch, such as that found in seeds or legumes and unprocessed whole grains),  RS2 (=resistant starch that occurs in its natural granular form, such as uncooked potato, green banana flour and high amylose corn), RS3 (=resistant starch that is formed when starch-containing foods are cooked and cooled such as in legumes, bread, cornflakes and cooked-and-chilled potatoes, pasta salad or sushi rice) and  RS4 (= starches that have been chemically modified to resist digestion, e.g. WMHDP), due to which RS1-4 get a "B" as in "B-etter than regular starches or sugars, B-ut no quick fix for sure". They are useful only in conjunction with the previously mentioned life-style changes from episode I (no, I will never tire of repeating this ;-).

• 

  From an anti-diabetes perspecitve more coffee appears to help more; in view of its effects on the central nervous system you still better limit your intake to max. 3-4 cups per day (Matusheski. 2012)

  Coffee (caffeine & other stuff) - Is certainly too extensive to be treated in detail, so I will refer you to the numerous previous posts on coffee at the SuppVersity, as well as "Warding Off Holiday Weight Gain 2.0: The Anti-Diabesity Effect of Coffee Goes Beyond its Caffeine Content" | read more.
  
  In addition, I would like to invite you to take a look at the image to the right that shows quite clearly that the anti-diabesity effect, of which you have learned that it could mediated by the benefits of caffeine on the liver (cf. "Diabetes & the Liver - Chicken vs. Egg" | read more) are reversed when you are already obese, diabetic & hyperlipidemic.
  
  While I refuse to officially rank coffee, I can tell you that most of the negative side effects are dose-dependently brought about by its caffeine content, and that I personally have a "never consume more than 500mg caffeine or 2-3 cups per day" rule in place and regret it deeply whenever I defy my rule for more than 2-3 days in a row - not on the diabetic side of things (I am rather a low blood glucose guy), but as far as overall well-being and energy levels are concerned. 

• 

  SuppVersity suggested read: "Want to Relieve Insulin Resistance? Eat your Blueberries!" | read more

  Blueberries (real food) - Let me first tell you that I do not intend to give you an overview of the myriad of proven and purported health benefits of blueberries. If that's what you are looking for, I suggest you take a peak at the latest review by Noerberto et al. 2013 (see references).
  
  What I want to give you instead is a real world example: A 2010 study by Stull et al. who found that the provision of isocaloric smoothies with and without 22.5 g blueberry bioactives to 32 obese, nondiabetic, and insulin-resistant subjects for 6 weeks led to a significant improvement of insulin sensitivity in the absence of changes in adiposity.
  
  According to the scientists the same effects could be achieved with 2 cups of fresh blueberries (or 45g of the powder they used to prepare the study) that makes blueberries an "A" as in "A must, but A bit expensive to have them every day". That does not change that consuming blueberries on a regular basis is going to help you improve or maintain you insulin sensitivity.
  
  Thanks for reminding me of including such a reasonable whole food in the series, Erik - ah and Ian, if you want pterostilbene, just eat your blueberries.

• 

  MCT + Chili a fat loss duo that will reduce your insulin sensitivity. That does not matter while you are dieting or low-to-no-carbing, but is a no go when you are doing neither of that.

  Chili (capsaicin) - Capsaicin is another suggestion from Erik, of which I am not quite sure, where he picked it up. Being mislabeled as "fat burner" capsaicin is just like caffeine a substance that increases the efflux of fat from the fat cells and will thus increase the serum level of free fatty acids. This will promote, not inhibit, insulin resistance. Against that background it is not surprising that Islam et al. report that capsaicin had no hypoglycemic, but insulinotropic (more insulin, but same amount of glucose in the blood = decreases insulin sensitivity) effects in a rodent model of type II diabetes (Islam. 2008).
  Note: If you are wondering why I am so bold to state that MCTs reduce your insulin sensitivity (see caption of the image), here is the study (Marcal. 2013) and this is the explanation: Fast fats = increase in FFA in the blood = insulin resistance. At least in an "average" = non-low carb + non-calorically restricted scenario it's as easy as that. When you replace the "Atkins fats" (= long chain fatty acids) with MCTs, on the other hand, you will obviously see benefits from medium chain triglycerides (cf. De Vogel-van den Bosch. 2011).
  In other words, if it's not used to cut body fat (in conjunction with diet and exercise) it's unlikely that capsaicin will help with insulin sensitivity, which is why it gets a "D" as in "D-on't use". And that would be the case even if capsaicin did not have some dubious effects on the Langerhans cells in the pancreas Gram. 2007). It's weight loss effects are totally overblown (see today's Facebook news) and it has been shown to blunt the beneficial effects of the "satiety hormone" cholecystokinin two decades ago (Ritter. 1985). If you want a "hot" alternative, you should thus go for plain onions (Babu. 1997).
• Ginseng (purported active ingredient ginsenoside Rh2): While there are plenty of rodent studies available, Cho et al. were the first to investigate the effect of Korean red ginseng in human beings and the results of their study which has been published in March this year are not exactly impressive.
  
  

  

  It's easy to see: Ginseng doesn't help healthy people. While the reduction in insulin sensitivity in response to 6g ginseng was not significant, it's obvious that healthy individuals won't benefit (Cho. 2013)

  The Korean researchers administered 6 g of  Korean red ginseng rootlets (n=34) or a placebo to a group of 68 participants (average BMI 26kg/m², average body fat 30.7%) for 12 week period and observed that
  

  "Korean red ginseng had no significant effect on improving the insulin sensitivity over time." (Cho. 2013)

  This is significant, because you can safely assume that its effects on individuals with lower body fat percentages (like you?) are probably bordering zero.
  
  Other studies report a physiologically irrelevant improvement in postprandial glycemia, when ginseng (in this case American) was administered exactly 40min before an oral glucose challenge (Vuskan. 2001). And the (non-significant) reduction in insulin sensitivity in the healthy but chubby subjects of the Cho study (see figure on the top right of this paragraph) is a perfect example of the previously cited imperative of applying the selectivity and specificity principles, when you select and buy your dietary supplements (learn more).
  
  In view of the fact that there is some allegedly inconclusive and "not convincing" (Kim. 2011) scientific support for the usefulness of ginseng in sick people, it still qualify for a "C-" as in "C-ould be useful for those who are already suffering from what we call the "metabolic syndrome". Of these, especially those who suffer from high blood lipids (e.g. Mucalo. 2012) could benefit and in these individuals you will probably also observe downstream improvements in glucose metabolism. These are however secondary to the reduction in blood lipis and will not occur in people like yourself, people who work out regular and lead the lives of someone who has found his / her way to physical culture.

• 

  Suggested read: "Beyond Warding Off Holiday Weight Gain: 250-1000mg of Freeze-Dried Ginger Reduce Visceral Fat In Rodents on High Fat Diet" | read more
  

  Ginger - SuppVersity readers will remember ginger from the list of "20+ Anti-Obesity Agents That Have the Potential to Inhibit Fat Gain Right at the Cellular Level" (read full article). If you do remember this article, you may also remember that the anti-obesity effect is brought about by ginger's ability to inhibit the pro-adipogenic peroxisome proliferator-activated gamma receptors (PPAR-gamma).
  
  Ginger has also been shown to exhibit appetite suppressant effects (Mansou. 2012), to improve the thermic effect of food (ibid.), to hold potential as an anti-NAFLD (non-fatty liver disease) "drug" (Sahebkar. 2011), to ameliorate the negative side effects of diabetes (Li. 2012), and to improve glucose level, HbA1c and insulin sensitivity in type 2 diabetic patients (Mahluji. 2013)
  
  For whole ginger (i.e. not ginger extracts) the dosages are usually in the 2-4g range. And while this is probably not going to hurt anyone, there is simply too little evidence that the beneficial effects of ginger are not "solely" mediated by its potent anti-inflammatory action to award an "A"-level recommendation with respect to its insulin sensitizing effects.
  
  So, assuming that its usefulness is more or less limited to individuals with underlying inflammatory problems ginger gets a "B" as in "there are few B-etter general health foods out there, B-ut its benefits in lean individuals are probably not glucose specific". If you are looking for general anti-obesity effects, on the other hand, I'd suggest you go and grab a couple of ginger roots right now ;-)
• Mate tea (Ilex paraguariensis): The evidence from human studies for or against the usefulness of the last supplement on Erik's wishlist is not exactly what I would call extensive. A study by Klein et al. from 2011 is probably as good as it gets and, as it was to be expected, the results suggest that we are once more dealing with an anti-inflammatory agent that will have the greatest impact on people who already suffer from diabetes / the metabolic syndrome.
  
  

  

  SuppVersity suggested Read: "The Leptin-Ilex!? Does Yerba Mate (Ilex Paraguariensis) Restore Leptin Sensitivity or Does it Just Help You Lose Body Fat by Curbing Your Appetite?" | read more, but don't forget that fat loss and glucose sensitivity are not one and the same. While The former usually entails the latter, it does not always work the other way around.

  Contrary to the diabetic patients in the Klein study, the pre-diabetic mate-tea consumers (3x330ml of tea made from roasted mate tea) in his study, did not register any benefits in glucose metabolism and the improvements in lipid parameters may well be a mere consequence of the concomitant dietary changes Klein et al. observed (Klein. 2011).
  
  Just like many other purported "insulin sensitizers", Mate is thus another food / supplement that has only secondary effects on blood glucose. It's another "C" supplement with "C as in C-an be used by the obese diabetic". Drinking liters of mate, even if you don't like it, just to increase your glucose sensitivity does however seem to be pretty useless for anyone who ain't suffering from abnormal lipid levels and increased whole body inflammation.
• Gymnema Sylvestre - While there are a couple of human studies on gymnema their significance suffers from heavy sponsoring and / or the co-administration of other supplements. If you plod through the research that's out there you will however find some evidence for its usefulness in full-blown type II diabetics (500mg/day; Kumar. 2010) and some interesting effects on the sweet taste receptors (Sigoillot. 2012). The latter are blocked by gymnemic acid and could, at least when we are talking about the glucose receptors in the gut, modify both the absorption kinetics and hormonal response of / to glucose.
  
  In the end, the said effects on the sweet taste receptors may also be involved in the effects Shanmugasundaram et al. describe in a 1990 paper. In their study, the administration of 400mg of an GS extract lead to significant improvements in glucose management in 27 patients with insulin-dependent (=severe) diabetes. Since we do not really know that, and in view of the occasional reports of adverse reactions to gymnema supplements (e.g. a case-report by Shiyovich et al. (2010) that links the consumption of gymnema supplements to toxic hepatitis), I will still rank it as "D" as in "D-o wait until there is more and better research available".
  
  I personally consider the risk of consuming corresponding supplements very low, but the same goes for any potential benefits ... and one thing is certain, it's not "a potential panacea for the management of diabetes" which is what MJ Leach writes to attract attention to his 2007 review of the literature in the Journal of Alternative Complementary Medicine (Leach. 2007)

• 

  Suggested Read: "Purported Health Supplement Bitter Melon Induces Oxidative Damage in Rat Testes and Reduces Testosterone Levels by >50%" | read more

  Bitter melon (Momordica charantia): While the hype has already abated, the marketing guys did a pretty damn good job in pimping bitter melon as the goto panaceum for whatever health problem may have befallen you. With respect to it's insulin sensitizing effects Basch et al. wrote about a decade ago:
  

  "Bitter melon may have hypoglycemic effects, but data are not sufficient to recommend its use in the absence of careful supervision and monitoring." (Basch. 2003)

  Did that change over the course of the past 10 years? Of course not.
  
  So unless Google and sensationalist advertisements that are supposed to look like real journal articles are your main sources of "information" about dietary supplements you will probably have to concede that
  

  "[...] clinical trial data with human subjects are limited and flawed by poor study design and low statistical power [and] the clinical data regarding the anti-diabetic potentials of M. charantia and calls for better-designed clinical trials to further elucidate its possible therapeutic effects" (Leung. 2009)

  and conclude that
  

  "[t]here is insufficient evidence on the effects of momordica charantia for type 2 diabetes mellitus. Further studies are therefore required to address the issues of standardization and the quality control of preparations. For medical nutritional therapy, further observational trials evaluating the effects of momordica charantia are needed before RCTs are established to guide any recommendations in clinical practice." (Ooi. 2013)

  That does not necessarily mean that it does not work, at all, but as a direct comparison with metformin shows, it's not a real alternative for type II diabetics (Fuangchan. 2011), whose HbA1c levels declined by meager 0.24% after being treated with a bitter melon supplement three times a day for three months (undisclosed amount of active ingredients in the caps; cf. Dans. 2007). I hope I do not have to point out that it is unrealistic to expect that you would see better effects in non-diabetics.
  
  I guess, it's probably not necessary to say that, but bitter melon is a bitter pill that gets a "D" as in "D-on't fall for the hype".
  

No block buster supps in this serving: Ok, I have to admit this last installment of the series had a couple of supplemental non-starters in it. Honestly, Ginger is the only one of the items listed above that stands a chance to make it into the insulin sensitizing protocol that's about to conclude this series next Sunday.

Until then, I hope all of you enjoy the rest of this weekend and come back for your daily dose of SuppVersity news tomorrow (all muscle heads listen up, you will like tomorrows news ;-)!

References:

• Babu PS, Srinivasan K. Influence of dietary capsaicin and onion on the metabolic abnormalities associated with streptozotocin induced diabetes mellitus. Mol Cell Biochem. 1997 Oct;175(1-2):49-57. 
• Fuangchan A, Sonthisombat P, Seubnukarn T, Chanouan R, Chotchaisuwat P, Sirigulsatien V, Ingkaninan K, Plianbangchang P, Haines ST. Hypoglycemic effect of bitter melon compared with metformin in newly diagnosed type 2 diabetes patients. J Ethnopharmacol. 2011 Mar 24;134(2):422-8.
• Islam MS, Choi H. Dietary red chilli (Capsicum frutescens L.) is insulinotropic rather than hypoglycemic in type 2 diabetes model of rats. Phytother Res. 2008 Aug;22(8):1025-9.
• Kim S, Shin BC, Lee MS, Lee H, Ernst E. Red ginseng for type 2 diabetes mellitus: a systematic review of randomized controlled trials. Chin J Integr Med. 2011 Dec;17(12):937-44. 
• Kumar SN, Mani UV, Mani I. An open label study on the supplementation of Gymnema sylvestre in type 2 diabetics. J Diet Suppl. 2010 Sep;7(3):273-82.
• Leach MJ. Gymnema sylvestre for diabetes mellitus: a systematic review. J Altern Complement Med. 2007 Nov;13(9):977-83. Review.
• Leung L, Birtwhistle R, Kotecha J, Hannah S, Cuthbertson S. Anti-diabetic and hypoglycaemic effects of Momordica charantia (bitter melon): a mini review. Br J Nutr. 2009 Dec;102(12):1703-8. doi: 10.1017/S0007114509992054. Epub . Review.
• Li Y, Tran VH, Duke CC, Roufogalis BD. Preventive and Protective Properties of Zingiber officinale (Ginger) in Diabetes Mellitus, Diabetic Complications, and Associated Lipid and Other Metabolic Disorders: A Brief Review. Evid Based Complement Alternat Med. 2012;2012:516870.
• Mansour MS, Ni YM, Roberts AL, Kelleman M, Roychoudhury A, St-Onge MP. Ginger consumption enhances the thermic effect of food and promotes feelings of satiety without affecting metabolic and hormonal parameters in overweight men: a pilot study. Metabolism. 2012 Oct;61(10):1347-52.
• Marçal AC, Camporez JP, Lima-Salgado TM, Cintra DE, Akamine EH, Ribeiro LM, Almeida FN, Zanuto RP, Curi R, Boldrini SC, Liberti EA, Fiamoncini J, Hirabara SM, Deschamps FC, Carpinelli AR, Carvalho CR. Changes in food intake, metabolic parameters and insulin resistance are induced by an isoenergetic, medium-chain fatty acid diet and are associated with modifications in insulin signalling in isolated rat pancreatic islets. Br J Nutr. 2013 Jun 28;109(12):2154-65. doi: 10.1017/S0007114512004576.
• Matusheski et al. Coffee and Type 2 Diabetes Risk. In "Coffee: Emerging Health Effects and Disease Prevention" edited by Yi-Fang Chu.John Wiley & Sons, Mar 27, 2012.
• Mucalo I, Rahelić D, Jovanovski E, Bozikov V, Romić Z, Vuksan V. Effect of American ginseng (Panax quinquefolius L.) on glycemic control in type 2 diabetes. Coll Antropol. 2012 Dec;36(4):1435-40. Review.
• Muroyama K, Murosaki S, Yamamoto Y, Ishijima A, Toh Y. Effects of intake of a mixture of thiamin, arginine, caffeine, and citric acid on adiposity in healthy subjects with high percent body fat. Biosci Biotechnol Biochem. 2003 Nov;67(11):2325-3.
• Norberto S, Silva S, Meireles M, Faria A, Pintado M, Calhau C. Blueberry anthocyanins in health promotion: A metabolic overview. Journal of Functional. Foods, Available online 21 September 2013.
• Ritter RC, Ladenheim EE. Capsaicin pretreatment attenuates suppression of food intake by cholecystokinin. Am J Physiol. 1985 Apr;248(4 Pt 2):R501-4. 
• Sahebkar A. Potential efficacy of ginger as a natural supplement for nonalcoholic fatty liver disease. World J Gastroenterol. 2011 Jan 14;17(2):271-2. doi: 10.3748/wjg.v17.i2.271. 
• Shanmugasundaram ER, Rajeswari G, Baskaran K, Rajesh Kumar BR, Radha Shanmugasundaram K, Kizar Ahmath B. Use of Gymnema sylvestre leaf extract in the control of blood glucose in insulin-dependent diabetes mellitus. J Ethnopharmacol. 1990 Oct;30(3):281-94.
• Shiyovich A, Sztarkier I, Nesher L. Toxic hepatitis induced by Gymnema sylvestre, a natural remedy for type 2 diabetes mellitus. Am J Med Sci. 2010 Dec;340(6):514-7.
• Stull AJ, Cash KC, Johnson WD, Champagne CM, Cefalu WT. Bioactives in blueberries improve insulin sensitivity in obese, insulin-resistant men and women. J Nutr. 2010 Oct;140(10):1764-8. doi: 10.3945/jn.110.125336.
• Uribarri J, Woodruff S, Goodman S, Cai W, Chen X, Pyzik R, Yong A, Striker GE, Vlassara H. Advanced glycation end products in foods and a practical guide to their reduction in the diet. J Am Diet Assoc. 2010 Jun;110(6):911-16.e12.
• Yadav H, Lee JH, Lloyd J, Walter P, Rane SG. Beneficial Metabolic Effects of a Probiotic via Butyrate-induced GLP-1 Hormone Secretion. J Biol Chem. 2013 Aug 30;288(35):25088-97.