Tuesday, August 30, 2016

Sometimes, you get thumped on the head with a scientific paper...

Now and then, a member of some "low carbing" communities tries to "educate" me. In fact, I am not fundamentally opposed to a lower carb diet, or even no carb periods, but I probably not "faithful" enough to avoid a virtual Sunday morning "Jehova Witness style" call. Here's a paragraph from a scientific paper I have already been sent three times.

A claim so dramatic and peremptory that I should either see the light or crawl back into my hole. This is the type of statement that closes all debates and can easily be summarized for the choir. (it comes from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2129159/#B21

Let's dig a bit into it, in details.
"Contrary to popular belief supported by the leading physiology and biochemistry textbooks, there is sufficient population of glucose transporters in all cell membranes at all times to ensure enough glucose uptake to satisfy the cell's respiration, even in the absence of insulin"

Popular belief, maybe... But textbooks are fully aware of the existence of the different transporters (some of them insulin dependent, some of them gradient dependent, etc...), their respective distribution and roles in different tissues and of the absence of barrier. So, this is basically creating a giant out of a windmill. The "giant" is extraordinary and as such deserves an extraordinary proof. The proof comes from (21), the only article cited multiple times in the paragraph, which you can find here http://joe.endocrinology-journals.org/content/170/1/13.long This is, by the way, an article devoted to doping in sports which summarizes, sometimes without references, some information about insulin. The article hasn't been cited too often as a fundamental work on Insulin metabolism... but I digress..
"Insulin can and does increase the number of these transporters in some cells but glucose uptake is never truly insulin dependent."

What does "truly" actually mean? Is it dependent or not, partially, mostly, not at all, falsely dependent, somewhat falsely dependent? I don't know... "not only dependent" would have been acceptable though.

"Even under conditions of extreme ketoacidosis there is no significant membrane barrier to glucose uptake – the block occurs "lower down" in the metabolic pathway where the excess of ketones competitively blocks the metabolites of glucose entering the citric acid cycle."

This is an almost verbatim quote from (21) - even in ketoacidosis, glucose can enter the cell. But it is blocked "lower down" (which means at the Krebs Cycle level).

So, let's rephrase that: nothing prevents glucose from entering the cell, but it will be under utilized. Fair enough. It is a bit like saying "Falls are never dangerous to humans. The danger occurs "lower down" when the human hits some hard surface.

"Thus, insulin is not needed for glucose uptake and utilization in man"

Aha... Did he just prove that in a flash? Yes, some uptake does occur without insulin. That is the windmill the author had changed into a giant. But utilization? The author just stated that there is some kind of block "lower down" (which happen to be ketones that, in short, insulin would prevent)... I am somewhat confused here.

Anyway, let's go for another verbatim quote of 21, blah blah blah...

In fact, the process appears to be general for all polar (water-soluble) substrates, as transporters are the mechanism by which they are transported across the highly non-polar (lipid) cell membranes. 

and follow that by another interesting statement.

When insulin is administered to people with diabetes who are fasting, blood glucose concentrations falls. It is generally assumed that this is because insulin increases glucose uptake into tissues. However, this is not the case and is just another metabolic legend arising from in vitro rat data.

The claim that insulin lowers BG in diabetics because it increases uptake into tissues is now a "legend". Not bad. We'll get to that...

It has been shown that insulin at concentrations that are within the normal physiological range lowers blood glucose through inhibiting hepatic glucose production [].

Ah, finally, some truth. Yes, insulin does suppress endogenous glucose production. Among many other things. And, indeed, in some ranges, fasting and at rest, uptake does not increase and may even decrease. No demand from the cells. Except when you move your muscles a bit...

Now, let's go back to article 21. An article that deals mostly with doping and ends up on the usual customary note... If it was quoted three times, it must contain additional supporting evidence...

"Both methods need further validation before implementation. Research work carried out as part of the fight against doping in sport has opened up a new and exciting area of endocrinology."

That article also states, the very conventional... (the language is a bit dated, see below)

"The truth is that insulin acts exactly as Schafer had predicted – it acts as both an autacoid and a chalone. Through stimulating the translocation of ‘Glut 4’ glucose transporters from the cytoplasm of muscle and adipose tissue to the cell membrane it increases the rate of glucose uptake to values greater than the uptake that takes place in the basal state without insulin."

Ah, OK, then uptake does increase after all... Why skip that?

Finally, it completes the "lower down" paragraph quoted verbatim in the first paper

"... the block occurs ‘lower down’ in the metabolic pathway where the excess of ketones competitively blocks the metabolites of glucose entering the Krebs cycle. Under these conditions, glucose is freely transported into the cell but the pathway of metabolism is effectively blocked at the entry point to the Krebs cycle by the excess of metabolites arising from fat and protein breakdown. As a result of this competitive block at the entry point to the Krebs cycle, intracellular glucose metabolites increase ‘damming back’ throughout the glycolytic pathway, leading to accumulation of free intracellular glucose and inhibiting initial glucose phosphorylation. As a result, Figure 1 Insulin exhibits both inhibitory (chalonic) and excitatory (autacoid) actions via the same receptor. In these experiments carried out on rat adipose tissue, in vitro insulin simultaneously inhibits lipolysis (the release of glycerol from stored triglyceride) and stimulates lipogenesis (formation of stored triglyceride from glucose). Thus its anabolic action is due to two mechanisms working synergistically. much of the ‘free’ intracellular glucose transported into the cell is transported back out of the cell into the extracellular fluid. Thus under conditions of ketoacidosis, glucose metabolism (but not glucose uptake) is impaired as a direct consequence of the metabolism of fat – the ‘glucose–fatty acid’ cycle (Randle et al. 1965)"

which is a bit old, is widely understood to be generally correct and has been fine tuned since but not drastically. On the whole, when the paragraph is quoted completely, the meaning changes a bit though...

This is followed by a quite longish discussion about other things we also now know to be mostly true and are, in many ways, in complete opposition with the revelations of the original paper...

1. Through facilitating glucose entry into cells in amounts greater than needed for cellular respiration it will stimulate glycogen formation. Thus hyperinsulinaemic clamps will both increase muscle glycogen concentrations prior to events and in the recovery phase after events. Since performance in many events is known to be a function of muscle glycogen stores, Figure 3 The data used in this illustration were obtained from healthy normal subjects using a series of euglycaemic and hyperglycaemic clamps at basal or increased insulin concentrations. Rd1: insulin independent glucose uptake. The data have been fitted to the generic model shown in Fig. 2 (see text for details). Insulin, GH and sport · P H SONKSEN 17 www.endocrinology.org Journal of Endocrinology (2001) 170, 13–25 ‘bulking up’ these stores will most probably enhance performance. There is no documental proof that this technique is being used but informed ‘street talk’ indicates that it is not uncommon. 2. Through use of similar hyperinsulinaemic clamps post-event and during training, it is likely that recovery and stamina will be improved. 3. ‘Street talk’ indicates that insulin is also being used in a more haphazard way, particularly to increase muscle bulk in body builders, weight lifters and power lifters. This use is allegedly by regular injections of shortacting insulin together with high carbohydrate diets. Through this therapeutic regime it is almost certainly possible to increase muscle bulk and performance not only through increasing muscle glycogen stores on a ‘chronic’ basis but also by increasing muscle bulk through inhibition of muscle protein breakdown. Just as insulin has a chalonic action in inhibiting glucose breakdown in muscle glycogen, it also has an equally important chalonic action in inhibiting protein breakdown. Indeed, the evidence now indicates that insulin does NOT stimulate protein synthesis directly (this process is under the control of GH and insulin-like growth factor-I (IGF-I)). It has long been known that insulin-treated patients with diabetes have an increase in lean body mass when compared with matched controls (Sinha et al. 1996). 

in some specific insulin and BG ranges to end up with the conclusion that

Taken together, all these points support the concern shown by the Russian medical officer in Nagano and the immediate response of the IOC to ban the use of insulin in those without diabetes.

To summarize...

The paper I have been mailed several times so I could "educate" myself
  • makes an outstanding sounding claim.
  • that it falsely presents as a revelation that contradicts fundamental textbooks.
  • attempts to justify its claim by cherry picking partial paragraphs
  • out of a single paper that attempts to address a completely different issue
  • and comes from an era where we had concerns that insulin and GH could be used for doping.
  • finally, the original article manages to cram a couple of non sequitur and to contradict itself.
That's a bit light to convince me...

But, of course, the fact that the article is.... hmmmm.... what it is, does not invalidate its premise. In other words, it is not because people e-mail you crap on a semi-regular basis that the pillar of their faith is wrong. It could very well be correct. One could make a completely stupid argument that the Earth is approximately spherical and still be correct.

My goal here is not to attack the idea of low carb in itself, but it would be nice if the people who mail me papers could at least attempt a bit of homework...

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