Gluconeogenesis – The worst name for a rock band ever

gluconeogenesis is not steak to cake says ketogains

At least three times a week I am engaged either in the Facebook group or other places asking questions that generally go like this:  “At what point do I eat too much protein and go into gluconeogenesis ?”  So I wanted to provide a more thought out answer, so here goes.

I should add that my commentary here is largely to be filtered through the lens of T1 diabetes…if you’re T1 diabetic, the regulatory feedback mechanisms are endogenously broken (the pancreas isn’t producing insulin), and must be regulated exogenously (the injection of insulin).

What is gluconeogenesis? 

cory cycle where gluconeogenesis happens

Gluconeogenesis (also known as GNG) is the process by which the body takes “stuff” that isn’t glucose (the more technical term is “non-glucose substrate”) and turns it into glucose.  It is an ongoing process which happens in complete starvation as well as in a modified starvation or even a fully fed state.  Translation – gluconeogenesis happens all the time, in everyone, everywhere.  It seems to happen at a relatively consistent rate.  I will get into some additional details on that rate later, but for now, the message is this – studies which have been conducted on humans are lacking, but those which have been done have shown that the rate of GNG does not materially change when protein content of the diet is manipulated.

Often, GNG is spoken of as “too much protein in my diet causes it to turn into glucose,” or glibly said…“protein turning into chocolate cake.” The biochemical reality is, however, that it is a bit more complex than that.  There are essentially three major contributors to gluconeogenesis which warrant discussion.

Proteingluconeogenesis pathway

Protein is composed of amino acids linked together.  Some amino acids are called “ketogenic” which (for the purposes of our talk) means that they do not or only very seldom can be converted into glucose.  Other amino acids are called “glucogenic” which means that they are capable of being converted by the body into glucose.  What is interesting is that not all glucogenic proteins are all quite as glucogenic as the other.  The two chief amino acids which are the most likely to be converted are Alanine and Glutamine.

Glycerol

For the purposes of this discussion, we can consider glycerol as the backbone that holds triglycerides together.  That is a pretty generic definition but it will suffice.  When the body releases the fatty acids from the triglyceride, the body also releases glycerol into the blood supply where it is taken up principally by the liver, and it can be converted to glucose.

Lactate

Lactate is released by muscle cells under moderate to heavy resistance (muscles cells doing work), and is readily taken up by the liver and reconverted to glucose.

Simply put, Lactate+Glycerol+Alanine+Glutamine = 90%+ of all GNG which goes on in the body.  The remainder is from other glucogenic amino acids.

What regulates gluconeogenesis?

 

Those of you who have seen my responses to discussions on hormones in general will know that I’m fond of saying that context is king, and that insulin is not the enemy, nor is glucagon your friend.  They are simply peptide hormones which keep you alive.  The principle hormonal regulator of gluconeogenesis is glucagon.  At a pretty elementary level, when the body is entering hypoglycemic conditions, the pancreatic α-cells secrete glucagon and one of its chief actions is to downregulate the process of glycolysis (the conversion of glucose to pyruvate) and to upregulate the production of gluconeogenesis.  This point will be important when we get into the rate of GNG later.

So what regulates GNG?  The presence of higher amounts of glucagon seems to be sufficient to globally regulate the rate of GNG.

Can protein consumption change the rate of gluconeogenesis?

 

Not from the data at hand, no.  This is an area that warrants significantly more study than it has been given.  What we can say from the studies we have are the following:

Conn, et al (1936): the rate of glucose production by the body is a very slow and controlled process which requires the “puts and takes” of both substrate availability and enzyme availability.

Jahoor, et al (1990): the rate of GNG does not materially change based upon the infusion of lactate, glycerol, or alanine, even when infused at a rate which caused 5x uptake of the substrate into the liver.

Bisschop, et al (2000):  the rate of GNG increased in individuals who were ketogenic by 14%.

gluconeogenesis wont kick you out of ketosis, protein tub cake imageSo – to translate:

  • The rate of conversion of non-glucose substrate to glucose (GNG) is relatively fixed – it is slow and consistent.
  • The rate of GNG does not seem to be impacted by the protein content of the diet (or at least the amount of amino acids taken up by the liver).
  • The rate of GNG increased by 14% in the Bisschop study for ketogenic individuals.
    • This may actually change once an individual is ketoadapted (see my previous comment about how GNG warrants greater study!)

Why did the rate increase happen…based on the evidence that we have what we believe to know is that GNG works like a hand in a glove.  Substrate (the hand) must be available, but the enzymes responsible for taking the substrate and converting it to glucose must also be available in sufficient quantities (the glove).  One without the other is like a car with no gas and a huge engine or a car with no engine but a full gas tank.  Without both, neither is useful.

So on to speculation as to why we saw the 14% increase.  In a ketogenic individual, the relative amounts of insulin and glucagon are shifted – the body secretes less insulin (because of fewer blood glucose spikes) and essentially the same amount of glucagon is secreted to regulate GNG and keep the blood sugar within the tolerances to keep you from dying.  So long as this occurs, the body will (at least in theory) continue to actively upregulate the production of glucose from substrate.  This will happen until there is sufficient blood glucose to initiate the β-cells of the pancreas to secrete insulin and slow the process down.  The two hormones work in concert with each other to regulate the process of gluconeogenesis.  Glucagon has the side effect of mobilizing stored fat, which will also create the increase in available glycerol for substrate, so it is likely that the additional substrate available (all things equal calorically speaking) would cause maximal rates of gluconeogenesis in a ketogenic individual because:

  • Limited insulin levels and consistent glucagon levels (shifting of the I/G ratio)
  • Greater substrate availability.
  • Potential (needs study) increase in enzymatic production which would allow for greater use of the GNG substrate created from greater fat oxidation.

At this point, you’re probably asking yourself, “What is the takeaway from the science?” The best that the scientific studies can tell us is this: The rate of gluconeogenesis is essentially fixed, and there’s not much that we can do to change it. Certainly, what you eat can manipulate insulin and slow down GNG, but there is no evidence that we can speed up GNG by consuming more protein (or lactate, or glycerol, or anything else).

The evidence seems to indicate that without more cellular enzymes, the rate will stay the same as it always does. Furthermore, the risk of under-consuming protein is vastly more problematic than is the risk of over-consuming protein. Translation – eat an appropriate amount of protein for your lean mass, as we’ve said all along.

 

About Author

Tyler Cartwright
Former fat guy (well, I'm still fat...but less so and getting thinner and stronger). I've lost 282 lbs - while on a ketogenic diet. I love to lift, to learn, and to live...anything else...just ask.

8 Comments

  1. Nick

    Would taking exogenous ketones like McT powder help keep you in ketosis while consuming a lot of protein? 1.5 g per lb lbm?

    Reply
    1. Tyler Cartwright (Post author)

      There’s no evidence to indicate that this level of protein would cause you to leave a ketogenic state, so I’m confused by the question.

      Reply
  2. Ed Stewart

    In the GNG process if there is adequate substrate available, both glycerol and amino acids, is it known if the body prefers one substrate over another? If more amino acids are available than are required for GNG and cell maintenance what happens to the excess? Can GNG generate more glucose than is required for metabolism and therefore the excess is converted into body fat?

    Reply
  3. Christian

    Hey, a correction if I may:
    You mention that during hypoglycemic conditions glucagon is released (correct) and that causes the conversion of glycogen (polymers of glucose) stores in the liver to be cleaved into glucose. At this point free glucose can be metabolized via glycolysis (this is where you, I believe, strayed). Glycolysis is the catbolization of glucose to pyruvate (you seem to imply glycolysis is the conversion of glycogen to glucose). Otherwise, great article, it’s nice to see scientific knowledge used instead of anecdotal evidence!

    Reply
    1. Tyler Cartwright (Post author)

      Corrected, good catch, and thanks!

      Reply
  4. AJ

    What about whey protein in and of itself? I have heard that whey (or even BCAA) is insulinogenic, thus altering the I/G profile.

    My personal experience has shown that if I do a protein sparing modified fast including whey (Lyle Mcdonald) which keeps high protein (1g per body weight) but drops other macros, I cannot enter ketosis.

    However, if I drop whey and keep protein low and limited to real food, (0.6 per g lbm) easy ketosis.

    Is it the lower protein or is it the lack of whey?

    Your post would imply the latter.

    Reply
    1. Tyler Cartwright (Post author)

      First, let’s discuss WHY whey is insulogenic. It’s insulogenic because it is VERY fast digesting and absorbing as a form of protein. That’s why it’s ideal for peri-workout nutrition. It ensures that amino acid substrate is available at the time that it is most needed by the body. That it is insulogenic means it has raised BG. However, a rise in BG, as well as a rise in insulin does not necessarily prevent ketosis. It may lower it somewhat, as there is some evidence that the presence of insulin requires a substantial glucagon response to remain ketogenic…to that point, the Bisschop study indicates that for a ketogenic individual, the glucagon increase is commiserate with the insulin spike (something that wasn’t observed in the non-ketogenic dieter) meaning the I/G ratio is preserved when protein consumption happens.

      As I stated, MUCH more research is warranted on the topic, however the evidence does not indicate that protein consumption (or even infusion of the most gluconeogenic substrates we know of) has any impact on the rate of GNG. So we can almost certainly say that:

      1. The evidence does not indicate that GNG can be substantially manipulated through diet, and that NEWLY formed glucose vs BG spikes from diet are two very different pathways that should not be confused. This is why I’ve said for quite some time that BG is a poor proxy for GNG.
      2. Though BG DOES rise in ketogenic dieters consuming protein, it generally remains safely within reason for non-diabetics.

      To your question about the dropping of protein low, my gut says that you’re probably replacing it with fat, and fat will be oxidized into ketone in the liver, and can be absorbed directly by cells for energy…so there is likely more ketone being manufactured by the body because of your changing dietary ratios, and as such, you test with higher ketones. Just a spidey sense answer, however.

      Reply
      1. Eric

        It seems that whey, and perhaps dairy in general will create an insulin spike without increasing blood glucose. //high-fat-nutrition.blogspot.com/2011/08/i-have-read-good-calories-bad-calories.html
        Hints of this effect can be seen in studies like this: //ajcn.nutrition.org/content/82/1/69.full

        Reply

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