Excess protein turned to glucose?

It seems that part of the more recent trend of defining a "proper" low carb diet as being one that is moderate in protein and high (very) in fat is this notion that excess protein will just be turned to glucose.  Quite often I've seen Dr. Richard Bernstein cautions against eating too much protein because it just gets turned to glucose.  (I did look for a link but was unsuccessful, so if I'm misstating Bernstein here, please do correct me in comments.)   I had looked into this long ago, but never really said much about it, but there are two reasons why this never made sense to me.

First, a little biochemistry.  There are exceedingly few reactions that occur in our bodies without the involvement of an enzyme.   This includes not only anabolic (synthesis, building, energy storing/requiring) reactions, but also catabolic (break down, energy releasing reactions) reactions.  Glucose and fatty acids no more "spontaneously combust" in our bodies than does propane in my grill.  Enzymes are the catalysts of reactions, and reactions that require energy (all of those "genesis" reactions for example) are coupled with energy producing reactions that "drive" them.   Enzyme action is regulated by the amount of the enzyme produced and/or some mechanism of activating/deactivating the enzyme.  While enzyme mediated reactions can be related to substrate (reactant) availability and/or influenced by product availability/build-up, this isn't always the case.  I'd even go so far as to say that unless the reaction occurs in a highly compartmentalized fashion (e.g. within mitochondria), substrate/product concentrations generally have little effect on the reaction rates directly. 


Thus appears to be the case for proteins and the gluconeogenesis reaction.  The mere availability of gluconeogenic substrates does not appear to drive the reaction.  I'll try and dig up the cites I had long ago come across to this effect.  But a pretty well known hormonal response to protein makes for a more common sense based argument against this.  Carbohydrates stimulate insulin to assist in glucose clearance.  Proteins also stimulate insulin, but they also stimulate glucagon.  Why?  Because if you consume protein without any carbohydrate, the insulin secreted doesn't really "know" whether it's supposed to facilitate amino acid transport or glucose transport into cells.  Therefore, protein consumption would result in hypoglycemia without concurrent glucose production in the liver.  Glucagon stimulates glucose output.  If just the protein substrate stimulated glucose production, there would be no need for glucagon, right?  Of course this still leaves us with a potential hypothesis that excessive protein leads to excessive glucagon leads to excessive gluconeogenesis (and glycogenolysis).

Well, continuing on my LoBAG revisit kick, I was actually quite shocked at the protein content of the diets!  Here's the link to the study again.

The mean fasting glucagon concentrations were similar before and after both the control and the LoBAG diets (95 ± 11, 91 ± 8, 91 ± 7, and 94 ± 7 pg/ml, respectively; Fig. 5). After 5 weeks on the LoBAG diet, the glucagon response was similar to the control for the first hour after breakfast. Subsequently, the glucagon concentration was higher at every time point until 0700 the next morning, except for one time point after dinner. Both the net and the total glucagon area responses were significantly increased after the LoBAG diet (P < 0.05).  ...  The glucagon area response increased 2.5-fold after the LoBAG diet.  (Fig. 5 -->)

And let us look back on the glucose profiles.  I'll not clutter this post with the insulin profiles again, but there was no difference in fasting insulin.   In the fasted state is when we expect the gluconeogenesis to be kicked up a notch or two, and if excess amino acids are lying around causing glucose production, we simply would not see the roughly 35-40 point drop in fasting glucose levels.  LC advocates will attribute it to the reduction in carbs, but, again, insulin in the fasted state did not change, and carb intake was just under 150 g/day.   So, well maybe this protein wasn't "excess" in the context of the relatively low carb diet?   For that we can look at a follow-up paper from these researchers.  Now this is for the LoBAG-30 diet, but the protein intake is the same for all LoBAG diets (30% energy) .

At right are the ingested and metabolized amounts of protein.  From the paper:

At the beginning of the study, during the first 24 h while subjects were ingesting the control (15% protein) meals, 105 g of protein were calculated to have been ingested, and 88 g were calculated to have been metabolized (84%; Fig. 3). During the last 24 h at the end of the LoBAG₃₀ diet, 214 g of protein were calculated to have been ingested, and 144 g were calculated to have been metabolized (68%). The difference in percent metabolized approached statistical significance (P = 0.064).

The metabolized protein is determined by nitrogen balance.  It's the nitrogen containing group that makes an amino acid what it is, and unless incorporated into proteins, the amino acids are metabolized with removal of the amine group.  This would include amino acids that serve as substrates for gluconeogenesis.  I'm not  sure what to make for the remainder of the protein -- incorporated into lean mass?  In any case, though clearly more protein is metabolized for energy, if there were a direct effect on gluconeogenesis rates, one would expect that would be part of the increased metabolized protein and be reflected in fasting glucose levels.  It seems far more reasonable to conclude that "excess" protein feeds into the Krebs Cycle at various places as shown in the graphic below.   Note that AA's in green are called gluconeogenic, those in white are ketogenic, and some AA's feed in at multiple possible points.  Also, to date this figure remains for the life of me recall where I took the screenshot from.  If anyone recognizes it, please let me know!

So, I don't see any evidence for claims that too much protein leads to increased glucose and glucose burning.  It might lead to less "fat burning" as protein feeds into Krebs or is directly converted to Acetyl CoA -- the intermediary product of both glycolysis and fatty acid oxidation.  There may be reasons to limit protein, but it does not appear that glucose production is one of them.