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?

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.

Protein

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%.

So – 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.

Further Reading: