Friday, May 17, 2013

Science Round-Up Seconds: Breast Cancer, GH Induced Insulin Resistance, Stretch + Contraction Increase Molecular Hypertrophy Signals and Probiotics & the Obesity Pandemic

When we are talking about the extinction of endangered species such as the Siberian tiger, we are adopting a perspective that will also help us to understand such things as the pitfalls of probiotic supplementations as a "solution" to the diabesity epidemic
It's Friday the day after the SuppVersity Science Round-Up (download the podcast) and you all know what that means: Right! Time to summarize the stuff that did not make it into the show and provide you with a couple of thoughts, as well as additional information on the topics, Carl Lanore and I did already cover (this does also imply that you have to listen to the show if you want the info on the genetic and non-genetic underpinnings of breast cancer).

If I had to come up with a motto, something that connects the topics in the show and thus obviously also the ones that will be discussed in this article, I guess it would be "ecosystems". I have repeatedly pointed out in the past that I am not a believer in the "back in the good old days everything was better" interpretation of "Paleo". What I do believe in, however, is the notion that exposition entails adaptation.

You can't control the adaptation, but you can control the exposition

Now, these adaptation processes whether they be negative such as the growth of cancerous tissue in the breast or ovaries of a woman like Angelina Jolie are beyond our reach: The environment that triggers them, on the other hand, can be manipulated - whether that's by getting your breasts and ovaries removed to rid yourself of the 50-80% (you heard me right! the "real" chance carriers of a defect BRCA1/2 gene to develop cancer ranges from 50% to 80%, by the age of 70) or - and this is obviously a pretty drastic change of subjects, by emphasizing peak contractions in a semi-stretched position to benefit from the upregulation of the proteins p-Akt, p70S6K, p38 MAPK and ERK 1/2, i.e. the driving forces of protein synthesis, it's always your manipulation of the environment that will bring about "adaptation" (used in the broadest sense).
Figure 1: Graphical summary of the main results, i.e. the stretch initiated activation (+, ++, +++) of the signaling molecules on different conditions with either short, long (at maximal peak contraction) or slightly longer (+25%, but still way from lockout) positions and the corresponding tension on the soleus muscle of the rodents (Van Dyke. 2013)
If I was successful, the above introduction should have set the scene and thus provided an environment for your perspective on things to change / align with mine. I've manipulated the "cognitive environment" that determines or at least influences the way you are about to understand what follows, i.e. the missing side-kick on the recently observed negative effects of growth hormone on insulin sensitivity and glucose uptake in healthy men and the comprehensive discussion of the (imho) misunderstood role of the gut microbiome as both, a trigger and solution to the obesity epidemic.

Can exogenous growth hormone trigger insulin resistance?

Within our new cognitive framework you will probably have transformed the above question as follows, by now: "How does the exogenous administration of growth hormone change the the endocrine environment and why does this entail an adaptive response of which most people would say that it's highly detrimental?" From this "mini-evolutionary perspective", as you may call it, it's surprisingly easy to understand what exactly has happened in a recent study from the University of Aarhus in Denmark (Vestergaard. 2013).

In their effort to probe the hypothesis that there was a connection between ghrelin, growth hormone and the increases in retinol-binding hormone (RBP4, to be specific) that are observed in patients with developing and/or full-blown metabolic syndrome, Vestergaard et al. conducted two studies of which only the second one, which involved nine totally healthy young men in their twenties (23y; BMI 23kg/m²), will - without major qualifications - transfer to you me or other healthy physical culturists.

The men received a course of daily 2mg GH injections while consuming a previously standardized diet containing 50–60 % carbohydrates, <30 % fat, and roughly 10–15 % of protein (in % of total energy intake). Before and after the intervention period, the participants had to report to the lab at fasted and thus optimally prepared for the hyperinsulinemic euglycemic clamp test.
Figure 2: Basal fasting glucose and insulin concentrations, as well as M-value (=marker of insulin resistance) in healthy young men after eight days of placebo and GH administration, respectively (left; p-values over bars); glucose infusion rates (GIR) indicated by during hyperinsulinemia after placebo / GH administration (right, Vestergaard. 2013)
The selected results I plotted in figure 2 are quite unambiguous. As expected there was a huge increase in the IGF-I concentrations in response to the 8-day course of 2mg GH per day.

The 8% increase in fasting plasma glucose and even more so, the doubling of the insulin levels that were required to keep these elevated glucose levels stable, certainly come as a surprise, if you're thinking about it from an broscientifically influenced mechanistic point of view. I mean, doesn't broscience tell us that GH is the good guy that's going to make you lean and ripped?

How come we are seeing a -34% reduction in glucose sensitivity (this is actually what's measured as the so-called "M value" in the euglycemic clamp studies).

Within our previously established cognitive framework, the answer to this question is actually quite straight forward. To get to the bottom of the counter-intuitive effects of GH we just have to think about the "natural" environment that will trigger the release of GH from the somatotropic cells within the lateral wings of the anterior pituitary gland.

Did you know that the normal GH response to hypoglycemia is blunted in the obese and the reduced obese (Ball. 1972)? Without GH to get their blood sugar back up, overweight individuals and formerly obese will thus have to resort exclusively to corticosteroids (cortisol) to regulate their blood sugar levels.
In this context, it's also worth mentioning that insulin induced hypoglycemia is still considered a valid - yet maybe not optimal - in children who are suffering from retarded growth. With the injection of exogenous insulin and the kids becoming hypoglycemic the body should compensate for that by secreting growth hormone. If that's not the case, this is a good indicator of a general malfunction of the pituitary gland.
Hah? Right! Hypoglycemia or borderline hypoglycemia is among the primary triggers of somatotropin aka GH release. Now, think about it - would it make sense that a hormone that's supposed to increase fatty acid oxidation to supply your body with glucose would at the same time increase insulin sensitivity and thus have your muscles suck up all the precious glucose your brain is longing for?

On the contrary, it is only logical that GH - just like it's falsely vilified potent cousin cortisol (yeah, you heard me right, you won't see both at the scene on the same time, because they serve a similar purpose at least wrt to glucose metabolism) - will decrease the insulin sensitivity of your muscles in order not to "waste" the precious glucose which should be scarce once GH goes up.

In the study at hand, the environment in which the high growth hormone levels occur are totally different: Once you plug people to a euglycemic clamp, there is a mismatch between the actual environment, which is normal / high glucose, and the natural (if you will "evolutionary) expected environment for elevated GH levels - and what you see in figure 2 is the inevitable consequence of this mismatch: a significantly lowered glucose sensitivity... quite cool, how a small change in the way we are looking at things allows us to understand phenomena that do initially appear totally inexplicable, right?

Lifestlye changes, not probiotic supplements are the solution to the diabesity epidemic

Now that we have first-hand evidence for the explanatory power of our new perspective let's stick to it and apply it to the false expectations studies such as the recently released investigation into the "anti-obesity" effects of the common gut bug Akkermansia muciniphila in a rodent model of diet-induced obesity (Everard. 2013).
Figure 3: The AM count is reduced in response to the dietary enviroment, the environment - not the lack of bacteria - is the root cause of the negative effects on fasting glucose, fat mass gain and thickness of the intestinal mucus lining all of which can be partly (the latter even fully) restored to normal with supplementation (Everard. 2013)
If we take a look at the data in figure 3 it is undebatable that the provision of exogenous live (this does not work at all with dead bacteria) Akkermansia muciniphila (AM) can significantly reduce the weight and fat gain in the rodents receiving a species inappropriate high fat diet. As the data on the AM content of the gut microbiome of the obese mice on the right hand side of figure 3 reveals this effect is yet a simple result of the restoration of the "original" microbial composition in the intestinal tract of the rodents.

Siberian tigers on corn fields!? Does this really make sense?

Since the term "original" refers only to the amount of the bacteria Dr Antoon Akkermans identified as one of the many bacteria the count of which is decreased / changed in obese rodents (and humans), it is yet not surprising that we are seeing nothing but ameliorative effects.

Glutamine may offer another way to accelerate gut healing and improve amino acid absorption or rather avoid the "abuse" of BCAAs, arginine etc. for other metabolic purposes (learn more)
Within our cognitive framework of "ecosystems" and "adaptations", the chronic administration of living bacteria to counter a specific aspect of the diet induced detrimental effects on the gut microbiome has may be compared to the laughable efforts of biologists to save certain animals from extinction by breeding them in a Zoo and releasing them into an environment, where deforestation, pollution and all the other nasty things, we, the crown of evolution, enjoy about as much as the average Westerner likes to wash down his super-sized fast food menu with a "refreshing" *rofl* 2L XXL pot of coke (drinking plenty is healthy for you, ain't it? ;-), will have them die before their time unable to reproduce in time to contribute to the species' natural survival.

Once you understand that, you will have to realize that you are wasting your time and money on false promises if you don't change the environment, i.e. the way you live and the foods you eat first before you even think of using probiotic supplements as an adjunct to accelerate the normalization process, which should - just like the detoriation - take place irrespective of the supplementation as a mere results of the dietary modulation of your gut microbiome, anyways.

With these insights, I am going to release you into the weekend... and who knows, maybe you'll notice the effects the environment you expose yourselves to in the coming days has all sorts of beneficial or detrimental influences on your physical and mental health. Listening to even more non-science-based Angelina Jolie news on the television and radio, for example, is probably not going to have beneficial effects on your psyche ;-)

  • Ball MF, el-Khodary AZ, Canary JJ. Growth hormone response in the thinned obese. J Clin Endocrinol Metab. 1972 Mar;34(3):498-511.
  • Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM, de Vos WM, Cani PD. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013 May 13.
  • Van Dyke JM, Bain JL, Riley DA. Stretch activated signaling is modulated by stretch magnitude and contraction. Muscle Nerve. 2013 Apr 26.
  • Vestergaard ET, Krag MB, Poulsen MM, Pedersen SB, Moller N, Jørgensen JOL, Jessen N. Ghrelin and growth hormone induced insulin resistance: no association with retinol-binding protein-4 Endocr Connect EC-13-0019; published ahead of print May 7, 2013, doi:10.1530/EC-13-0019