Biotin Ameliorates Skeletal Muscle Insulin Resistance in Model of Type II Diabetes. Increase in GLUT-4 Expression Yet not Accompanied by Translocation to Cell-Membrane

Image 1: Otsuka Long-Evans Tokushima fatty rats (OLETF, right) have the genetical disposition to become type II diabetics.

Are your nails brittle? Is your hair falling out? No? Then, are you obese or insulin resistant? Yes? ... I guess, by know you are asking yourselves what your hair and nails have to do with your pre-diabetic beer-belly. Well, according to the recently published restults from a study by Yuka Saki and his Japanese colleagues, biotin, the water-soluble nutrient that has been discovered by Bateman in 1916 and is also known as vitamin B7, vitamin H or coenzyme R could well be the missing link. After all, the well-known, but often misunderstood micronutrient plays a central role in both fatty acid, as well as glucose metabolism and is by no means just a "hair & nails" vitamin.

Biotin could help even if "it's in your genes" ;-)

The Japanese researchers used the infamous Otsuka Long-Evans Tokushima fatty rats whose name already implies that their have the unfortunate propensity to gain tons of body fat and develop type II diabetes, even if they are not fed the "high fat" diet (of which at least those of you who are not the first time here at the SuppVersity should know by now that it is high in fat and carbs) to check, whether supplementation could ameliorate the inevitable development of skeletal muscle insulin resistance in these poor critters.

Figure 1: Body weight, fasting glucose and insulin levels at the beginning and end of the 8-week study period (data adapted from Sasaki. 2012)

If you look at the results of the 8 week treatment period in the course of which the 34-week old, already overweight (compared to the non-diabetic LETO group) OLETF rats received either plain water or water with 3.3mg/L biotin (i.e. ~400µg/kg biotin for a rat and 65µg/kg for a human being), the treatment did in fact have the desired effect on glucose and insulin levels (cf. figure 1). The increase in insulin sensitivity, on the other hand, "allowed" the biotin-treated OLETF rats to gain even more weight than their profoundly diabetic peers. This, by the way, is something you will also see in humans, who - just as their omniscient Dr. told them - take their diabetic drugs and / or insulin, but refuse to make the necessary dietary and lifestyle changes.

Figure 2: Glucose uptake, total and membrane GLUT-4 expression in hindlimb muscle of 42-week old OLETF rats with or without biotin treatment (data calculated based on Sasaki. 2012 and expressed relative to non-diabetic LETO control)

What is also interesting is that despite a significant increase in total GLUT-4 (glucose transporter) expression in the skeletal muscle of the OLETF rats, a concomitant increase in receptor translocation to the cell-membrane, of which you have probably read in previous blogposts that it is responsible for the exercise-induced increase in glucose uptake, did not take place (cf. figure 2). Consequently, the glucose uptake in the hindlimb muscle did increase in response to biotin supplementation, but failed to reach the same (100% in figure 2) level as in the non-diabetic control group.

Biotin does not via AMPK... good or bad news?

These observations lead the scientists to conclude that the mechanism that is responsible for the nevertheless beneficial effects of supplemental biotin can not be a direct consequence of AMPK activation, which is at the heart of both exercise, as well as drug (esp. Metformin) induced ameliorations in insulin sensitivity. This is something, I actually find pretty interesting, because a) the elucidation of the exact mechanism by which biotin is able to increase insulin sensitivity and skeletal muscle glucose uptake could lead to novel insights into skeletal muscle glucose metabolism which could also be of relevance for "physical culturists", and b) if biotin, despite being essential for the activation of Acetyl-CoA carboxylase (ACC), a major downstream target of AMPK, does not work by "simply" stimulating the AMPK pathway, it is actually likely that the effects of biotin supplementation and exercise could add up.

DHEA Inhibits Fat Gain More Effectively Than Testosterone. Both Work by Reducing PPAR-γ and Thusly Lipid Storage

Image 1: This is the "Fountain of Youth" in Karlsruhe, Germany. I have never been there, but I guess I should take the next train and check whether water contains 0.4% or 0.8% DHEA ;-)

Outside of the medical practices of some anti-aging docs nobody appears to care about the "good old" dehydroepiandrosterone (DHEA), these days. As a diligent student of the SuppVersity, you are yet well aware of the reviving effects DHEA has on the liver (cf. August, 26, 2011), pancreas & insulin sensitivity (cf. May, 15, 2011) and adipocyte metabolism (cf. April, 8, 2011) in "older" people or everyone with suboptimal DHEA levels. You will also be aware that the adrenal steroid hormone which can be converted to testosterone (and thusly DHT or estrogen) at the target tissue exerted pretty astonishing effects on body composition in a handful of initial (very) high-dose trials. Follow up studies in the late 1990s were yet mostly unable to reproduce these encouraging results and with the increasing concerns about potential side-effects and the lack of funding from the pharmaceutical industry, who did not have an interest in finding out that a non-patentable substance would ameliorate or even cure some of of the ailments they were and still are making a fortune on.

DHEA a Weapon in the War Against Diabesity?

The most widespread of these ailments certainly is diabetes; a pathology the management of which (not it's treatment!) has generated a $42 billion dollar market (data from 2010) that is estimated to grow to $114.3 billion dollar by 2016 (inverstorplace.com). It is thusly no wonder that the recently published study by Kei Fujioka and his colleagues from the Departments of General Internal Medicine and Parasitology at the Gifu University Graduate School of Medicine in Gifu, Japan, was not funded by a Japanese (let alone US ;-) pharmaceutical company, but by a research grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Fujioka. 2012).

Figure 1: Simplified illustration of the adrenal hormone production cascade

Based on the scattered conglomerate of previous results the researchers speculated that feeding Otsuka Long-Evans Tokushima fatty rats chow with 0.4% dehydroepiandrosterone (DHEA) in it would ameliorate if not totally prevent the development of type II diabetes and / or related pathologies to which this rodent strain, which is also one of the standard models for type II diabetes, is particularly prone.

Figure 2: Relative differences in epdidymal fat pad weights, serum glucose, triglyceride, total cholesterol and free fatty acid levels in LETO and OLETF rats after 52weeks on chow with 0.4% DHEA (=100mg/day; human equivalent: 16mg/day); data expressed relative to rats on control diet (data adapted from Fujioka. 2012)

As you can see in figure 1 rodents don't have to be genetically disposed to get type II diabetes to benefit from a human equivalent of ~16mg/day. The ever-hungry (=polyphagic) LETO rats, the scientists put on the same 0.4% DHEA diet for 52 weeks has similarly reduced visceral fat depots (epididymal fat - LETO: -50%; OLETF: -33% vs. control), triglycerides and free fatty acids. The improved glucose levels were yet only statistically significant in the otherwise diabetic OLETF rats and the increase in total cholesterol in the LETO group is difficult to judge without at least some additional data on the ratio of "good" HDL to "bad" LDL.

DHEA vs. Testostosterone - Who is the "King" of Metabolic Hormones

Luckily, the Fujioka et al. were not satisfied with these results and conducted another experiment. This time with normal rats (Wistar strain) and with a second group which received 0.4% testosterone in their chow.

Figure 3: Fat weight, triglyceride content of liver and gastrocnemius muscle, body temperature and adipocyte diameter in male wistar rats after 4 weeks on DHEA (0.4%) or testosterone (0.4%) containing chow; data expressed relative to control on standard chow (data adapted from Fujioka. 2012)

Compared to the poor critters in the control group, who had to content themselves with the "non-anabolic" standard chow, both the rats in the DHEA and the testosterone groups had reduced body fat levels (remember the control rats were "normal", not fat!), reduced triglyceride deposition in both liver and muscle tissue, an increased body temperature and a statistically highly significantly decreased adipocyte size (cf. figure 3) - and believe it or not, all these beneficial effects were more pronounced in the DHEA group.

Figure 4: DHEA-S (µg/dL), testosterone (ng/dL) and PPAR-γ expression in control, DHEA and testosterone group at the end of the study period (data adapted from Fujioka. 2012)

In view of the initially mentioned role of dehydroepiandrosterone as a precursor to testosterone (cf. figure 1) and its own yet negligible ability to interact with the androgen receptor (Tan. 1997), it should not surprise you that the purported mechanism behind their beneficial effects on "all things fatty" is identical: a reduced expression of the "triglyceride storage receptor" PPAR-γ, the same receptor the smart business men from the pharmaceutical industry target with their lipid and blood glucose lowering drugs to treat high blood glucose and/or lipid levels for increased obesity, and subsequently another increase in glucose and lipid levels which will "unfortunately" require either more of the old or even better less of the more expensive "next generation" drugs... *clever, right?*

Similar Effects in Healthy, Young Human Beings are Highly Questionable

Image 2: Neither Drogba (l) nor Ronaldo (r) are candidates for DHEA supplementation (img VanityFair WC special edition).

Assuming that you are not already on your way to your local supp store to make sure you get the last bottles of DHEA before the FDA comes up with another horror story based on which this "dangerous supplement" has to be added to the banlist, I want to caution you that a 2010 study from the PA University of Novi Sad (Ostojic. 2010), in Serbia did not find any beneficial effects on body composition in 20 young soccer players who received an oral DHEA supplement (100mg/day) for 4 weeks - and that, despite +40% increases in total testosterone (free testosterone unchanged), +27% increases in estrogen and 197% increases in DHEA. As an active non-sedentary, non-obese, non-metabolically deranged individual, like the 19-22 year old soccer players in the Ostojic study, it is unlikely that your six-pack will show overnight, just by popping grams of DHEA per day.

Before we do not know why in some trials (rodents and humans) oral DHEA supplements yield phenomenal results (in the study at hand, both the lower dosage, as well as the "chronic" administration in very low doses spread across the day could be decisive factors), while they totally suck in others, the "specificity rule" from the Three Simple Rules of Sensible Supplementation would preclude anyone under the age of 35+ (DHEA levels begin to decline ~30y) from supplementing with DHEA, unless this someone knows (not just guesses!) from bloodwork that his/her DHEA levels are at least borderline low. And don't forget, even then DHEA or rather its downstream metabolites (estrogen in particular) can be similar suppressive on your own natural hormone production as "real gear" or the reputed OTC "pro-hormones" 90% of which are active steroids, anyway.