How Much Carbohydrates Can You Eat Before a High Fat Diet Becomes Unhealthy? Increasing Carbohydrate Intake Turns Physiological Into Pathological Insulin Resistance

High carb + high fat, that's one "high" too much for your health.

As a SuppVersity reader you should be aware that the average "high fat diet" that's fed in rodent (and human) studies to prove how bad dietary fat is for us contains almost as much carbohydrate as it contains fat sources.

Against that background a study like the one a group of scientists from the Gillings School of Global Public Health at The University of North Carolina at Chapel Hill have conducted recently has actually been long overdue: A study to clarify how much carbs are too much carbs when they're consumed on top of a high fat diet.

The conflicting results of previous studies, some of which "have shown that carb-rich diets promote development of insulin resistance and T2DM, while others have shown that high-carb diet is protective against insulin resistance and T2DM compared to HFD" and the fact that there's plent of evidence that shows that "low-carb diet is not necessarily protective against insulin resistance and diabetes" (Mei. 2014), were occasion enough for Shuang Mei and colleagues to readdress the roles of dietary fat and carbs in insulin resistance and T2DM.

You can learn more about high fat / low carb diets at the SuppVersity

False! Adding Fat to Carbs Doesn't Lower Their GI

Minimal Carb Reduction, Max. Results?

2 Days A Week High Protein Low Carb Fast

No Carb Foods Don't Satify Your Cravings

5 Tips to Improve & Maintain Insulin Sensitivity

Carbohydrate Shortage in Paleo Land

The scientist goal was to answer several key questions: (1) First, are dietary carbs necessary for the HFD-induced insulin resistance? (2) Second, how much carb is too much or sufficient to promote the HFD-induced insulin resistance? (3) Third, is fat essential for insulin resistance?

To find the corresponding answers to these questions, the scientists conducted a combined in vitro and in vivo study, in the course of which they kept a group of C57BL/6 mice on chow (ad libitum diet) that contained 0.1, 5%, 10%, and 25.5% carbs on top of 58% fat but dissimilar amounts of protein, i.e. 41%, 37%, 32% and 16.5% of the chow (vs. 23.1%), for 5 weeks. They tracked the calorie consumption, body weight and fat gains, insulin sensitivity, intra-tissue insulin signaling, ectopic fat, and oxidative stress in liver and skeletal muscle of the muscle and determined the role of hepatic gluconeogenesis in the HFD-induced insulin resistance.

Figure 1: White body fat (x10) and energy intake (kcal) relative to body weight (left); body weight at the end of the study, expressed relative to the body weight of the standard chow control group (Mei. 2014)

In addition, Mei et al. examined the effects of fatty acid exposure in cultured cells (not shown) and confirmed that the presence of  fatty acids "is essential for the development of insulin resistance induced by chronic exposure to insulin." (Mei. 2014)

Figure 2: Fasting glucose (left) and fasting insulin (right) values - carbs exacerbate the effects of HFD (Mei. 2014)

Against that background it's not surprising that data in Figure 1 and Figure 2 shows that the rodents became insulin resistant even at 0.1% of carbohydrates in the diet. The degree of insulin resistance, on the other hand, was "dramatically elevated", when the carbohydrate intake was increased to 5% and 10% - with the 10% carb + high fat diet being "sufficient to induce a maximal level of insulin resistance." (Mei. 2014)

Physiological insulin resistance: Insulin resistance is not always bad. When you're low on glucose, as it would be the case when you're dieting (=being in a caloric deficit) and consuming only a relatively low amount of carbs, the downregulation of your bodies insulin sensitivity can stabilize your blood sugar levels by helping to maintain adequate hepatic gluconeogenesis (the production of glucose mostly from amino acids) and avoiding an "uncontrolled" uptake of the scarce glucose from your blood. In the absence of exuberant amounts of carbohydrates, this physiological form of insulin resistance is thus a way to cope with the energy- and macronutrient availability and not generally bad.

A very similar effect was observed for the accumulation of ectopic fat and oxidative stress in liver and skeletal muscle, which was present and significant on the low carbohydrate + high fat diet, but became "dramatically enhanced", only when the amount of carbs in the diet was increased.

In this context it's interesting to mention that the insulin resistance was mediated primarily by an increase of the hepatic expression of key gluconeogenic genes - an increase that was most dramatic by HFD with little carbs. This, as well as the previously cited fact that the occurrence of muscular and hepatic insulin resistance in a cell study depended on the the presence of fatty acid lead Mei et al. to conclude that (a) "dietary carbs are not necessary for HFD to induce insulin resistance but can aggravate insulin resistance in a dose-dependent manner"; and (b) "HFD [in this case really high fat, low carb] alone causes insulin resistance in liver and skeletal muscle with or without dietary carb." (Mei. 2014)

Study says: If you go high carb, you better go really high carb (learn more) - and the study at hand may actually prove why.

Bottom Line: Despite the fact that I have no doubt that the aggravating effects of high(er) carbohydrate intakes on the metabolic damage due to high fat dieting is relevant to human beings, as well, it remains to be seen, if these will occur at the same relatively low amounts of carbohydrate intakes in humans, as they did in the mice in the study at hand (I assume esp. athletes can tolerate more).

If we assume this was the case, many people who are currently jumping aboard the low carb craze, would be ruining their health unless they this form of dieting only while being in a caloric deficit - a state that precludes the accumulation of ectopic (visceral) and liver fat and benefits from an increase in insulin resistance and gluconeogenesis, since both processes contribute to higher and more stable blood sugar levels - and yes, this is what we call physiological insulin resistance!

• Mei, Shuang, et al. "A Small Amount of Dietary Carbohydrate Can Promote the HFD-Induced Insulin Resistance to a Maximal Level." PloS one 9.7 (2014): e100875.

Anserine + Carnosine Supplementation: A Capped Fountain of Cognitive Youth? Plus: Beta-Alanine + Creatine Could Be A Similarly Brainy Supplement Stack for Young & Old

Carnosine + anserine supps could help her keep up with her grand daughter - physically and mentally!

As a SuppVersity reader you know that  carnosine is the stuff you actually want to increase, when you are taking beta alanine supplements - you want the beta alanine to bind to L-histidine and from β-alanyl-L-histidine aka carnosine. If you are a student who reads and memorizes all article and not just a diligent reader, you will also remember that carnosine acts as a cellular "stress" buffer and that this buffer, as important as it may be during intermittent high intensity exercise, is actually even more important for your neuronal health, or put simply, your brain!

So, even if you haven't heard about anserine before, at least the idea that taking carnosine supplements, or maybe I should say, increasing brain carnosine levels could be a good thing for your cognitive abilities should sound vaguely familiar... and if it does not, this would be another reason to read this article ;-)

You can learn more about brain health at the SuppVersity

Aspartame, a threat to your brain?

Optimal brain-building workout intensity

Bigger Belly Shrinking Brain - Dumb Fatsos?

SVSR: Statins, good or bad for your brain?

Amphetamines in DS Craze & other Supps!

Coffee & Blue Light for Your Brain

You should not be concerned, though, if it doesn't sound familiar, when I tell you that Budzen et al. report in their paper in the Archives of Gerontology and Geriatrics that the provision of both, carnosine and its "bird analogue" anserine, which is the major "buffering" dipeptide in bird muscle, will have astonishingly significant beneficial effects on the cognitive functioning and physical capacity of elderly individuals.

No wonder, considering the fact that carnosine, anserine and related compounds are reported to play an important physiological role in the body.

Carnosine can be transported across the blood-brain-barrier. Beta alanine, too, but as Sale et al. (2013) point out, we don't know if it will "form carnosine or act as a neuromodulator / neuro- transmitter itself, once it's in the brain" (illustration + quote from Sale. 2013). If it does the latter it will, similar to taurine interact with the GABA receptor (Horikoshi. 1988)

• They have antioxidant properties, cytosolic buffering capabilities and maintain an acid-base balance in excitable tissues of animals and humans. 
• Carnosine is an antiglycating agent. That means it protects your cells from the sugary glue that plasters their exhaust pipes until they start malfunctioning (What? No, that's not an accurate analogy, but I guess, you get what it means ;-)
• They have metal ion-chelating properties and can thus prevent toxic damage from "bad" and not so "bad" metals. Eventually even things like zinc and copper, iron, and calcium, metals your body needs for proper function, will harm you, when they cannot be handled by the body appropriately - as amino acid chelates (you don't have to take them in this form, you just have to have the building blocks your body needs to produce them!)
• Carnosine has also been shown to extend the life of cells in cell culture conditions and to regulate the activity of calcium channels in skeletal muscles.

Due to their overall ability to blunt the negative effects of oxidative and carbonyl stress, both agents have long been touted as potential "pharmacological" (in the widest sense) agents.

Studies conducted on rats and mice show that carnosine has a neuroprotective potential against cerebral ischemia, and indirectly reduces the mortality of the animal (Stvolinsky. 2000; Dobrota. 2005; Rajanikant. 2007). Human studies in patients with chronic discirculatory encephalopathy stress, a specific form of what you could call "brainflammation" (=chronic inflammation of the brain) show that carnosine enhances the efficacy of basal therapy of these patients.

Aging ➯ carnosine ↓, physical & cognitive performance ↓ - probably not a coincidence!

Suggested Read: Hydrated or Dumb: Dehydration Affects Brain, Muscle and Other Vital Organs - Plus: 15+ Causes of Dehydration  | read more

Against that background the chronic decline in whole body carnosine levels with age is something scientists have been eyeballing with concerns for quite some time. Studies have shown that the exogenous provision of beta-alanine can bring the carnosine levels in the musculature back up. In view of the fact that "brain biopsies" are not exactly on the list of favorite experimental procedures the average human study participant wants to undergo, it is yet not 100% sure whether similarly significant increases in carnosine, as they have been observed by Favero et al. in skeletal muscle, will occur in the brain and cells of the peripheral nervous system, as well.

So, if we don't know if beta alanine converts, why don't we administer carnosine, directly? That's a good question, but also one that tells me that you are no true "muscle head". Otherwise the information that carnosine is immediately metabolized and won't even make it to your muscle or brain would already have been hardwired into your brain by the marketing machinery of the fitness industry.

If carnosine is metabolized so quickly, isn't the whole study protocol bullocks, then? Yeah...ah I mean, no. It isn't. In fact it's actually quite clever! By administering carnosine in form of a chicken extract ant thus alongside its natural co-factors, of which anserine is probably only one, the scientists made use of the results of a 2011 study by Peters et al. who were able to show that anserine inhibits the previously mentioned degradation of carnosine and could thus solve the "zero bioavailability problem" (Peters. 2011).

Now, I would be curious what other co-factors in the 2g of chicken-protein hydrolysate may have had an impact on the study outcome, as well. Unfortunately, the only thing we know about the supplement that was administered daily for 13 weeks, is that it was standardized for 1g of anserine and carnosine at a 2:1 ratio (i.e. 667mg of  anserine and 333mg of carnosine).

Figure 1: Beneficial effects of the chicken protein extract anserine + carnosine supplement (Budzeń. 2014)

Practically speaking, this means that the effects I have summarized graphically in Figure 1, were brought about by ca. 667mg anserine and ca. 333mg carnosine the fifty-six 65y+ agers consumed on top of a macronutrient-wise astonishingly "anabolic" diet (1.5g/kg body weight protein,  2.5g/kg carbohydrates and 1g/kg fat).

Let's see what else happened in response to this "minimal" intervention

If you take a look at the other differences between the active treatment group, who received 2.5g of the chicken extract that contained 1g of anserine + carnosine at a 2:1 ratio, and the placebo group, you will see that next to the changes, I illustrated in Figure 1,

• 

  If the influx of beta alanine into the brain was not controlled it could have toxic effects | learn more

  the dangerous diastolic blood pressure of the elderly subjects in the placebo arm kept kreeping up, while the one of the anserine + carnosine treated subjects did not budge,
• the resting heart rate of the placebo group measured at the before and after session increased, while it remained unchanged in the active arm of the study, and
• the body mass index of the subjects in the placebo arm of the study remained steady, while the subjects who received the anserine + carnosine supplements lost a significant, but certainly not earth-shattering 0.51kg/m².

It should yet be obvious that the the changes which are shown in Figure 1, namely significant improvements in the "foot up and go", the "back scratch" and the borg scale, a measure of perceived physical exertion during exercise / physical activity, as well as the improvements in the Mini Mental State Examination, a brief 30-point questionnaire test that is used to screen for cognitive impairment, and the Short Test of Mental Status, which is a classic test that's used with dementia patients, are the more important inter-group differences the researchers from the University School of Physical Education in Wroclaw listed in their hitherto only accepted paper for the Archives of Gerontology and Geriatrics.

With exercise and EGCG (green tea), beta alanine has already been shown to increase neuro- genesis - at least in mice: The corresponding paper by Jessica Ossyra from the University of Illinois has not been published yet, but tis wouldn't be the SuppVersity if I didn't tell you that a combination of the green tea extract ingredient EGCG, beta alanine and exercise has obviously recently been shown be a major promotor of neuro- genesis in mice (Ossyra. 2014).

Now, personally, I see no reason why the provision of beta alanine in an endurance training context (medium intensity is still the best brain builder | learn more), alone, i.e. even in the absence of EGCG, would not produce similar effects in human beings. I still have to curb your enthusiasm and add: "This assumption warrants experimental verification."

Bottom line: In conjunction with significant improvements in abstraction, construction and Copying, as well as memory recall the aforementioned changes and improvements in cognitive and physical performance were all supplementation specific and support the notion that the provision of carnosine, when it is administered at a 2:1 ratio with anserine is not in vain.

What you are now probably asking yourselves, though, is whether a similar if not even more pronounced effect couldn't have been achieved by a much cheaper dietary supplement: Beta alanine. The universal carnosine precursor that's no longer "all the rage", but still "the rage" in the fitness industry? Well, why don't we take a look at the archives? ... I don't see anything, sorry. As of now there is no peer-reviewed study we could be used as a comparison, but if you asked me, it seems unlikely that it sustained release beta alanine formulas increase the physical performance of elderly subjects (del Favero. 2012) without having at least minor beneficial effects on the brain -- and if you take a look at the box to the right, you will see: In rodents it does already work :-)

What? If the 3x800mg you would take for 6 weeks to maximize your muscle carnosine levels suffice? Well, I can't tell you that, but that's certainly a good point to start from. And you know what? If you add 1.5g of creatine to each of these servings, this would be a brain-saver stack for both yourself and your grandma. Why? Well, creatine has been shown to compensate for experimentally (following sleep deprivation) or naturally (due to aging) compromised cognitive function, as well (Rawson. 2011).

References:,

• Budzeń, S., et al. "Anserine and carnosine supplementation in the elderly: effects on cognitive functioning and physical capacity." Archives of Gerontology and Geriatrics (2014).
• del Favero, Serena, et al. "Beta-alanine (Carnosyn™) supplementation in elderly subjects (60–80 years): effects on muscle carnosine content and physical capacity." Amino acids 43.1 (2012): 49-56.
• Dobrota, Dusan, et al. "Carnosine protects the brain of rats and Mongolian gerbils against ischemic injury: after-stroke-effect." Neurochemical research 30.10 (2005): 1283-1288. 
• Guiotto, Andrea, et al. "Carnosine and carnosine-related antioxidants: a review." Current medicinal chemistry 12.20 (2005): 2293-2315. 
• Horikoshi, Tetsuro, et al. "Taurine and β-alanine act on both GABA and glycine receptors in Xenopus oocyte injected with mouse brain messenger RNA." Molecular Brain Research 4.2 (1988): 97-105.
• McMorris, Terry, et al. "Creatine supplementation and cognitive performance in elderly individuals." Aging, Neuropsychology, and Cognition 14.5 (2007): 517-528.
• Ossyra, Jessica, et al. "The influence of nutritional supplementation with epigallocatechin gallate and β-alanine in combination with physical exercise on adult hippocampal neurogenesis and contextual fear conditioning in young adult BALB/cJ mice (629.4)." The FASEB Journal 28.1 Supplement (2014): 629-4.
• Peters, Verena, et al. "Anserine inhibits carnosine degradation but in human serum carnosinase (CN1) is not correlated with histidine dipeptide concentration." Clinica Chimica Acta 412.3 (2011): 263-267.
• Rajanikant, G. K., et al. "Carnosine is neuroprotective against permanent focal cerebral ischemia in mice." Stroke 38.11 (2007): 3023-3031.
• Rawson, Eric S., and Andrew C. Venezia. "Use of creatine in the elderly and evidence for effects on cognitive function in young and old." Amino Acids 40.5 (2011): 1349-1362. 
• Sale, Craig, et al. "Carnosine: from exercise performance to health." Amino acids 44.6 (2013): 1477-1491.
• Stvolinsky, Sergey, et al. "Carnosine protects rats under global ischemia." Brain research bulletin 53.4 (2000): 445-448.

Aluminum More of a Threat Than Thought? German "Feds" Say: Stay Away From Antitranspirants and Beware of the Dozen of Other Aluminum Containing Junk in Your Life

Cancer, Alzheimer's - The X* effect?
*Most deodorants don't contain aluminum.

I have to admit that I missed the original publication of the inconspicious statement of the Bundesintitut für Risikobewertung (BfR. 2014). I am not sure if there is a US or UK equivalent to the BfR, but if there was an US counterpart, those would be the guys that would tell the FDA what they should do, if the industry, the FDA is actually supposed to control had not already taken their job ;-)

All (sadly true) jokes aside, basically the short paper is a re-evaluation of the safety of aluminum - not aluminum in general, but the amount of aluminum in our immediate surrounding. Sources like the particularly nasty Aluminum from antitranspirants

Table 1: Overview of the "worst offenders" among foods and bakery products scientists from the University of Kentucky (Saiyed. 2005)

Processed foods provide the toxic baseline: Antitranspirants are part of the problem, but as usual it's processed food that supplies the baseline of yet another hazardous substance. If you take a look at the list of "worst offenders" Saiyed et al. identified in a 2005 study in a random selection of food from US supermarkets, it's obvious that all of them belong to the processed, convenient or as some of the enlightened people would say "junk" food category.

The BfR assessed the aluminum absorption from antitranspirants based on experimental data on the its dermal obsorption in healthy individuals and found that the systemic absorption for people with intact skin health is 10.5µg. That's ~2µg more than the EFSA says, the contemporary available evidence would suggest to be safe for a healthy 60kg human being.

This means that the uptake of aluminium from antitranspirants is above the maximal tolerable daily exposure levels. For people with skin problems or someone who uses the antitranspirants after damaging the protective layer of the skin while shaving the systemic aluminum uptake is several magnitudes larger. Consequently someone who shaves and applies his antitranspirant afterwards may exceed his total weekly limit (1mg per week) within the first hour of the day!

Figure 1: Tabular overview of the risk profile the BfR released for aluminum containing transpirants; I have translated the relevant parts of the overview, if you want to, you can download the original here.

As the scientists point out, antitranspirants are yet by far not the only potential aluminum sources in our life. Foods like tomatoes, kitchenware and - above all - other cosmetic products like shampoo, lipsticks, cremes (esp. anti-wrinkle and -aging - funny, eh?), toothpaste, and sunscreen all contain significant amounts of aluminum that can make it through our skin or digestive tract right into our blood.

It is thus no wonder that the following tabular overview (I deliberately use the German original) with translated captions) informs us that it is well possible that the aluminum in antitransparent is a health-hazard for the general population. Luckily, "keine unmittelbare Beeinträchtigung" means that you do not have to expect immediate serious adverse health effects - great, ha?

Much ado about nothing and all is good, right?

In view of the fact that the significance of the currently available data is also still insufficient, one could thus assume that you would be overreacting if you threw your aluminum containing antitranspirants away. If you take a closer look at the last row in tabular overview in Figure 1, though, you see the words "kontrollierbar durch Vorsichtsmaßnahmen" = "manageable by safety measures", though. Now what kind of safety measures could you possibly take?

Figure 2: Auluminum has been linked to all sorts of pathologies. The only decently convincing does yet exist for breast cancer (mechanism | left; cf. Darbre. 2013) and Alzheimer's where the negative effect on cognitive abilities has even been confirmed in controlled animal studies (right | exposure to increasing amounts of aluminum leads to corresponding increases in the rates of cognitive decline; cf. Walton. 2013)

Personally I know only two, though: Never apply aluminum-containing antitranspirants to damaged skin parts - A rule that applies for freshly shaved skin, as well! Or, even better stop using aluminum containing antitranspirants altogether.  I know that this is not feasible for some people, but many of us are just so used to it that we do not realize that the stench from puberty is no longer around.

In the end, the message of the statement that provides additional information about the potential involvement of chronic aluminum exposure in the etiology of breast cancer and Alzheimer's, as well as the more recent publication of a similar warning about aluminum containing cometics in general (BfR. 2014) would yet still suggest that you better replace the shampoo, creme, tooth paste, lipstick, sunscreen and antitranspirant of your choice, if they contain aluminum.

What the wise FDA says: It's funny, that the FDA documents say about thee "GRAS" additives, i.e. substances that are generally recognized as safe, such as the aluminum based food additives that "ingested in excessive amounts, their [sic!] appears to be associated with interference in phosphorus metabolism resulting in rachitic or osteomalacic effects, kidney damage, and interference with glucose metabolism, apparently due to interference with phospho- rylating enzymes." Now, this is obviously no reason to be concerned, because "[t]he high intake of phosphorus in the American diet may provide a protective effects"... hmm, great! So the high amount of phosphor of which scientists long say that it's making people sick "protects" you, my American friend from something the FDA is supposed to protect you from - glorious!

Bottom line: Start with the cosmetics! Unlike the aluminum that leaches into the food from its packaging, the aluminum that makes it from the soil into conventional and organic produce, the aluminum that makes it from the feed into the animals and animal products you eat and the good damn aluminum the f*** up "food" industry adds to their products in form of colorings E 173, stabilizers E 520 (aluminum-sulfate), E 521 (aluminum-sodiumsulfate), E 522 (aluminum-potassiumsulfate), E 523 (aluminum-ammoniumsulfate) and as the leavening agent 541 (acid sodium-aluminumphosphate) in all sorts of baked goods, the "alu lipsticks" are comparatively easy to avoid - to find alternatives that last for a similarly long time and survive kissing and making out, on the other hand, is not going to be easy, I suppose.

If you are no "processed junk junky", ditching antitranspirant & co you cut your intake back to a tolerable 14–35 mg aluminum per week - at least this is what the EFSA estimates a 70kg human being will be exposed to withing 7 days. With a limit of max. 70 mg, you would thus reside in a "green zone" of which no one probably knows how "green" it actually is... in view of an estimated half-life of seven years (Yokel. 1989), I could understand, though, if you say that this is not 100% comforting.

Reference:

• BFR. "Aluminiumhaltige Antitranspirantien tragen zur Aufnahme von Aluminium bei" Position Statement 007/2014 issued by the BFR on February 26, 2014.
• BFR. "Fragen und Antworten zu Aluminium in Lebensmitteln und verbrauchernahen Produkten" FAQ issued by the BFR on February 26, 2014.
• BFR. "Fragen und Antworten zur Risikobewertung von kosmetischen Mitteln" Updated FAQ  issued by the BFR on March 3, 2014.
• Cashman, Allison L., and Erin M. Warshaw. "Parabens: a review of epidemiology, structure, allergenicity, and hormonal properties." Dermatitis 16.2 (2005): 57-66.
• Darbre, Philippa D., Ferdinando Mannello, and Christopher Exley. "Aluminium and breast cancer: Sources of exposure, tissue measurements and mechanisms of toxicological actions on breast biology." Journal of inorganic biochemistry 128 (2013): 257-261.
• FDA. "Aluminum hydroxide." SCOGS-Report 43 (1975). ID Code: 21645-51-2. CFR Section: 184.1139
• Walton, J. R. "Aluminum’s Involvement in the Progression of Alzheimer’s Disease." Journal of Alzheimer’s Disease 35 (2013): 875.
• Yokel, Robert A., and Patrick J. McNamara. "Elevated aluminum persists in serum and tissues of rabbits after a six-hour infusion." Toxicology and applied pharmacology 99.1 (1989): 133-138.

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.

100-200ml Red Wine Per Day Improve HDL and the LDL/HDL Ratio With & Without Mediterranean Diet & Exercise

Good for him, good for her, good for everyone? Is it really possible that red wine can help even those who don't want to the necessary lifestyle changes?

You all know about the limitations of epidemiological studies and the fallacy of the over-generalization of associations between health parameters and red wine consumption in the mainstream media. For me this *bs* is so annoying that I usually don't even take a look at "red wine studies". Luckily, a recent paper by Dirk W. Dorste and his colleagues did still catch my attention: It's about to be published in the December issue of Nutrition Journal and is not based on epidemiological data.

The Luxembourgian scientists gathered their data in the course of a randomized unblinded 2-year trial that involved 108 patients with carotid atherosclerosis and >30% reduced blood flow (65% of the patients were on statin therapy).

122 patients, 4 intervention groups, red wine and/or lifestyle changes

While half of the patients did nothing to improve their health and fitness, the other half of the patients, the lifestyle change group, had to follow a modified Mediterranean diet and perform moderate physical exercise during 30 min/day for 20 weeks. In both of these groups half of the patients were randomized either to no alcohol or red wine groups (100ml/day for women, 200ml/day for men). The end results of this process was a 2 x 2 design that looked like this:

• Med. diet + exercise only
• Med. diet + exercise + red wine

• regular diet + laziness only
• regular diet + laziness + red wine

While the subjects in the groups in the left "regular diet + laziness" column did not receive any dietary advice and were not encouraged to work out, the participants in the "Med. diet + exercise groups" had five 30 min sessions with a registered dietitian "giving advice on healthy eating based on a modified Mediterranean diet and physical exercise" - the cornerstones of this advice were:

• 

  Not into red wine? Learn about "The Ergogenic Effect of Nonalcoholic Beer Front- & Back Loading" | more

  eat 5 portions of fruit/vegetables per day, 
• consume a diet low in absolute fat, 
• prefer vegetable oil (olive or canola oil), 
• eat whole grain products, poultry, low fat dairy products, 
• consume a fat and a lean fish meal per week,
• reduce your consumption of red meat, 
• avoid pork and ready made-meals,
• stay away from sugar and excessive amounts of salt,
• drink 1.5-2 l plain water every day,
• eat the occasional 25g of dark (70%) chocolate,
• include tomatoes and walnuts in your diet,
• get at least 30 min of moderate daily physical activity

Yes, I know, not all of these points are exactly in line with what you (and even I) believe to be cornerstones of a healthy diet, but I do not write about this study, because it was an awesome example for highly beneficial lifestyle changes - quite the contrary: I picked it because the booze worked even without lifestyle changes:

Figure 1: Relative changes (in %) in total cholesterol, LDL, HDL, LDL/HDL and triglycerides after 4 and 20 weeks on one of the four "interventions" (Droste. 2013)

If you compare the red wine only and lifestyle only data from the end of week 20, it is not easy to tell the difference between the two - the greater improvements in HDL cholesterol, and higher reductions in LDL actually give the impression that simply guzzling red wine would be more effective than reinventing your diet and exercise habits

If we take a closer look at the data we do yet (luckily) have to acknowledge that the the subjects who did reinvent their lives were the only ones with lasting beneficial effects on total cholesterol, HDL, the LDL/HDL ratio and the total amount of triglycerides after 20 weeks - and that irrespective of the missing dietary and exercise / training control and despite the disputable dietary advice they received!

"Hard Liquor Increases Post Workout Testosterone by Almost 100% " | more

Bottom Line: This is not the experiment to confirm the hilarious mainstream media hype about the health benefits of red wine, but the results of this prospective study are still intriguing. They do after all support the hypothesis that the literal glass of wine can actually be a crutch that helps you to take a first baby step towards a healthier life. It does not hamper, but improve the beneficial effects of lifestyle interventions on CVD-relevant plasma markers and it's stand-alone effect on the HDL/LDL ratio is - I have to admit that - downright surprising.

Reference:

• Droste, Dirk W., et al. "A daily glass of red wine associated with lifestyle changes independently improves blood lipids in patients with carotid arteriosclerosis: results from a randomized controlled trial." Nutrition journal 12.1 (2013): 147.

Gluten Free, But not Suitable For Celiacs: Milk, Chocolate, Corn, Instant Coffee and 20 Other Foods & Food Ingredients That Could Cross-React With Gluten Anti-Bodies

Unless you got the right, i.e. breast milk as a baby and have rendered your gut "gluten proof" - being breast fed, when you are first exposed (or being exposed later in life) has after all been suggested as a protective factor (Farrell. 2005)

This is not going to be a long post; and still, at least for some of you it is going to be an important post. A post that may have the potential to change your life for the better or for the worse depending on whether you actually suffer from gluten-intolerance or have simply been bamboozeled by the "gluten is the devil" messages that are plastered all over the Internet these days.

Actually, I would hope that you belong to neither of the groups and can thus simply ignore this post. For the unfortunate rest, I have prepared a mini-summary of the results of a recent study from the Immunosciences Lab in Los Angeles (Vojdani. 2013)

Milk and cornflakes - a killer combo

A couple of recent studies, as well as reports from patients all of which clearly suggested that "being gluten free" does not equal "being symptom free" had spiked the researchers interest. Was it possible that the persistent symptoms were brought about by cross-reactions between the anti-bodies that would usually attach to the gluten proteins to trigger an immune reaction and other molecules? Molecules from such innocent foods, as dairy, chocolate, and even coffee!?

Suggested read: "Leaky Gut & Gluten Belly: Bacterial Firebugs Translocate from Your Gut to Your Ever-Growing Visceral Fat Depots" | read more

"[W]hen histological response was assessed in celiac patients after 6 months of following a GFD [gluten free diet], complete normalization and reconstruction of villous architecture was observed only in 8% of individuals, while 65% of these patients were in remission and 27% did not respond to GFD and had no observable change in their clinical symptoms (Lanzini. 2009).

The lack of improvement in histopathology and clinical symptomatology in a subgroup of patients on a GFD may be associated with dietary non-ad-herence or cross-reactive epitopes triggering a state of heightened immunological reactivity in gluten-sensitive individuals (Hadjivassiliou. 1997)." (Vojdani. 2013)

The hypothesis certainly isn't totally odd. Kristjansson et al. were for example able to show that 50% of their celiac patients experienced a significant mucosal inflammatory response similar to that elicited by gluten, when they were exposed to cow’s milk protein. Of the 15 healthy controls in their study, however, not a single one showed the slightest signs of auto-immune related inflammatory processes (Kristjansson. 2007).

So is this "real" celiac disease?

It should be obvious though that the corresponding "cross reactive" agents do not induce celiac disease (which is per definition an auto-immune disease that's triggered by the reaction to gliadin). They are however well able to alter the intestinal barrier integrity - a symptom that is also one of the key feature of the early stages of celiac disease.

Figure 1: Reaction of affinity-purified α-gliadin 33-mer polyclonal antibodies to gliadin and different food antigens; data in large figure relative to control, data in small inset relative to a-gliadin (Vodjdan. 2013)

If full remission of celiac disease cannot be achieved even on gluten-free diet, the underlying reason may thus well be the presence of peptides and antigens that (cross-)react with the same anti-bodies the body of celiac patients produces against the α-gliadin 33-mer peptide aka gliadin. Scientists even speculate that the co-exposition to these agents could eventually lead to the establishment of "new" auto-immune diseases and food allergies and some argue that the ever-increasing spectrum of allergies is partly a result of untreated autoimmune reactions which are then "spreading" to other previously well-tolerated foods and food ingredients.

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Suggested read: "Beyond Celiac: Study Sheds New Light on Obesogenic Effects of Gluten - Are PPARs & Bacteria Both Involved?" | read more

The problem seems real, if you're really gluten intolerant: With milk, all sorts of dairy products (including whey), instant coffee (but not espresso; see small inset), avenin containing oat products (unfortunately, I cannot tell you how you can recognize the "unproblematic" oats at the super market, but if you google "avenin-free oats" you will see a couple of products and stories pop up; Comino. 2011) and corn having a significant potential for cross-reactivity, it appears almost reasonable that some people come back from their visit with a mostly self-proclaimed expert in all things celiac with an endless list of items they are not supposed to eat and a tiny 5-item list of foods they are supposed to live on for the rest of their lives.

What is not reasonable, however, is that this is the case for more and more people who are basically asymptomatic... well, aside from their "inability to lose weight" that is obviously not related to their "inability to exercise" and their "inability to stop watching TV and browsing the Internet for easy quick-fix solutions to obesity problems", but most obviously be brought about by gluten intolerance ;-(

References:

• Comino I, Real A, de Lorenzo L, Cornell H, López-Casado MÁ, Barro F, Lorite P, Torres MI, Cebolla A, Sousa C. Diversity in oat potential immunogenicity: basis for the selection of oat varieties with no toxicity in coeliac disease. Gut. 2011 Jul;60(7):915-22.
• Hadjivassiliou M, Chattopadhyay AK, Davies-Jones GA, Gibson A, Grünewald RA, Lobo AJ. Neuromuscular disorder as a presenting feature of coeliac disease. J Neurol Neurosurg Psychiatry. 1997 Dec;63(6):770-5.
• Kristjánsson G, Venge P, Hällgren R. Mucosal reactivity to cow's milk protein in coeliac disease. Clin Exp Immunol. 2007 Mar;147(3):449-55.
• Lanzini A, Lanzarotto F, Villanacci V, Mora A, Bertolazzi S, Turini D, Carella G, Malagoli A, Ferrante G, Cesana BM, Ricci C. Complete recovery of intestinal mucosa occurs very rarely in adult coeliac patients despite adherence to gluten-free diet. Aliment Pharmacol Ther. 2009 Jun 15;29(12):1299-308. 
• Vojdani A, Tarash I. Cross-reaction between gliadin and different food and tissue antigens. Food and Nutrition. 2013; 4:20-32.

Liver Enzymes the #1 Marker of Insulin Resistance!? What Do HbA1C & ALT, AST and GPT Tell Us About Diabesity?

Just like type II diabetes, NAFLD is a life-style disease.

While it may not be obvious, today's SuppVersity post is very closely related to Sunday's post about supplements to battle insulin resistance. The recent revelation that the liver enzymes alanine transaminase (ALT aka GPT), aspartate transaminase (AST aka SGOT) and gamma-glutamyl transpeptidase (GGT aka gamma-GT) and not free fatty acid levels are the most reliable predictors of insulin sensitivity in overweight and obese, non-diabetic adults does after all show clearly support the notion that we (scientists, doctors, patiens) should pay much more attention to the liver. It's the liver that controls blood glucose, lipids and even our hormone levels, not the adipose organ. Therefore it is in the liver, our metabolic organ #1, is where the dark diabesity magic happens.

Heal the liver, cure the insulin resistance

Just in: A recent Stanford study shows that the use of VEGF inhibitors that are usually prescribed as cancer drugs can help diabetics manage their blood glucose levels, by increasing the expression of a protein (HIF-2alpha) that's usually expressed in response to hypoxic cell death and will - as a side effect - increase the expression of insulin receptors and thus restore hepatic insulin sensitivity and the optimal function of all the regularory processes that depend on it (Conger. 2013).

Usually you will think of being overweight and undermuscled, of insulin resistant myocytes (muscle cells) and adipocytes (fat cells) and about eating too much simple sugars, whenever someone is talking about the etiology of insulin resistsance. NAFLD, i.e. non-alcoholic fatty liver disease, on the other hand, is still often thought of as one of the long-term side effects of T2DM.

A recent study from the Children's Nutrition Research Centre at the University of Queensland does however suggest that the connection between having a messed up liver and being insulin resistant does not just start much earlier, than previously thought, but is probably also directly involved in the progression from being slightly insulin resistant to being a real diabetic.

Certainly, central adiposity (=high amounts of visceral, inter-organ fat) is and will always be one of the key risk factors for the development of insulin resistance and its progression towards full blown type 2 diabetes. Whether this is mainly a function of the spatial proximity of the constantly inflamed visceral fat depot to the liver is still a matter of current research. What we do know already is however that the presence of NAFLD is an independent risk factor for cancer and heart disease (Guebre-Egziabher. 2013)

Once the liver has taken a beating, the downstream effects are profound

One thing that's for sure, though, is that the downstream effect that occur, whence the liver is beginning to take a hit are profound:

• endocrine imbalances resulting from errors in the cytochrome enzymatic cascade that's responsible (among other things) for the conversion and clearance of all sorts of hormones
• messed up cholesterol levels and lipid profile with increases in LDL and VLDL lipoproteins and decreases in HDL
• chronically elevated  glucose levels due to lowered glycogen storage capabilities and a lack of control of the gluconeogenic processes in the liver that are no longer shut off when insulin is present, 
• increased fatique that's mediated at least in parts by the accumulation and build-up of toxic metabolic byproducts and environmental toxins the liver cannot handle any longer

The list goes on and on and I bet you that all 40 overweight and obese (body mass index≥25.0kg/m²) subjects with elevated ALT and AST values in the study at hand were already suffering from these problems.

Figure 1: Correltion coefficients for blood glucose, blood insulin and HbA1C (Gray. 2013)

No wonder that the data in Figure 1 confirms that there is no other parameter - including BMI, adiponectin, blood lipids, i.e. LDL, HDL, etc., I-CAM or ghrelin (the latter are not shown in the figure) that come remotely close as far as their reliability as markers of insulin resistance and the corresponding elevations of the long-term glucose marker HbA1C are concerned.

This does also mean that the study at hand would refute the results of previous experiments which suggest that the mobilization of FFA in the circulation promotes insulin resistance, however

Please remember: AST, ALT & CK will be elevated after workouts so take a couple of days off before you get blood work done.

"this [particular] study found no direct correlations between FFA and markers of insulin sensitivity. Furthermore, there were no clear correlations between markers of insulin sensitivity (glucose, insulin, HbA1C, or HOMA scores) and physical activity or self-reported fatigue. Fatigue scores were correlated with C-reactive protein, suggesting that inflammation may play a role, although there was no significant correlation with ICAM-1"(Gray. 2013)

Overall the currently data from the Gray study does therefore clearly support the notion that there is a  direct "link between liver function, adiposity, and the development of IR [insulin resistance]" (Gray. 2013) that goes well beyond the common understanding of 'adiposity begets insulin resistance, insulin resistance triggers NAFLD'.

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Figure 2: Liver tissue in rodents fed a hypercaloric high sucrose diet with (B) and w/out (A) taurine.  Taurine inhibited the development of hepatic steatosis (Gentile. 2011)

Bottom line: While the results of the study at hand certainly shift the focus away from the fat cells and towards the liver, they do not change the fact that "insulin resistance and the subsequent development of T2DM remain primarily lifestyle disorders" (Gray. 2013). In other words, if you followed all the "non-quick fix" tips from part I of the "Restore & Keep Insulin Sensitivity" series, in the first place - you would not have to worry about insulin resistance or non-alcoholic fatty liver disease (NAFLD).

Still, with a new emphasis on the involvement of the liver, the way we approach insulin resistance with supplements may in fact change... Although, when you come to think about it two of the top-supplements from the first and second serving of insulin sensitizing supplements, you will realize that many of them (e.g. alpha lipoic acid, taurine, berberine, etc.) are also known "liver protectors" (Gentile. 2011; Valdecantos. 2012).

Similar data on both improvements in liver health and insulin sensitivity is available for NAC (Haber. 2003) and milk thistle (Maghrani. 2004), as well. It is thus not too far off to assume that whatever you do to protect your liver is also going to have beneficial effects on your glucose metabolism; and what's even better it will improve your blood lipids, make your that your endocrine system works optimally, protect you against the constant assault of environmental toxins and reduce your chance of being carried off by diabetes, cancer and heart disease... still not convinced? Well, then think about something my good friend Carl Lanore likes to say "liver has the words 'to live' or 'life'" in it ;-)

References:

• Gentile CL, Nivala AM, Gonzales JC, Pfaffenbach KT, Wang D, Wei Y, Jiang H, Orlicky DJ, Petersen DR, Pagliassotti MJ, Maclean KN. Experimental evidence for therapeutic potential of taurine in the treatment of nonalcoholic fatty liver disease. Am J Physiol Regul Integr Comp Physiol. 2011 Dec;301(6):R1710-22.
• Gray B, et al., Liver enzymes but not free fatty acid levels predict markers of insulin sensitivity in overweight and obese, nondiabetic adults, Nutr Res. 2013 [published ahead of print]
• Guebre-Egziabher F, Alix PM, Koppe L, Pelletier CC, Kalbacher E, Fouque D, Soulage CO. Ectopic lipid accumulation: A potential cause for metabolic disturbances and a contributor to the alteration of kidney function. Biochimie. 2013 Jul 27.
• Haber CA, Lam TK, Yu Z, Gupta N, Goh T, Bogdanovic E, Giacca A, Fantus IG. N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress. Am J Physiol Endocrinol Metab. 2003 Oct;285(4):E744-53. Epub 2003 Jun 10.
• Maghrani M, Zeggwagh NA, Lemhadri A, El Amraoui M, Michel JB, Eddouks M. Study of the hypoglycaemic activity of Fraxinus excelsior and Silybum marianum in an animal model of type 1 diabetes mellitus. J Ethnopharmacol. 2004 Apr;91(2-3):309-16.
• Conger K. Approved cancer drug potentially could help treat diabetes, researchers find. <http://med.stanford.edu/ism/2013/september/diabetes.html> retrieved September 16, 2013.
• Valdecantos MP, Pérez-Matute P, González-Muniesa P, Prieto-Hontoria PL, Moreno-Aliaga MJ, Martínez JA. Lipoic acid improves mitochondrial function in nonalcoholic steatosis through the stimulation of sirtuin 1 and sirtuin 3. Obesity (Silver Spring). 2012 Oct;20(10):1974-83.