Protein, Ketogenesis, and Glucose Oxidation

In our last post, we discussed the relationship between protein and blood sugar in ketogenic dieters.

Despite all the evidence we have brought to bear suggesting that increased protein does not increase GNG, there is an important line of argument that does support the idea that increased protein increases GNG. Although the data is indirect, and some of it is poorly documented, it is compelling.

This supporting argument is the relationship between protein and glucose oxidation (the use of glucose as fuel).
As we mentioned in our last post, the rate of GNG is not what we really care about as keto dieters.

What we want to know is whether excess protein leads to using a higher total amount of glucose as fuel.
The amount of glucose oxidation matters, because the benefits we expect to gain from a keto diet are probably a result of using ketones for fuel instead of glucose whenever we can.

In Brief

  • Excess protein probably results in lower ketone levels.
    Although there is a paucity of hard clinical evidence, there are several reasons to believe this is true.
  • There appears to be an inverse relationship between ketone levels and glucose oxidation.
  • Therefore, increasing protein probably increases glucose oxidation.

If so, then

  • Eating more protein would reduce the benefits of a ketogenic diet, by making it less ketogenic, and increasing glucose oxidation.
  • This would need to be reconciled with the combined evidence that I/G appears to be the main determinant of ketogenesis, and yet doesn’t appear to change in keto dieters eating protein.

As always, we’d like to see experimental confirmation of these ideas instead of just relying on the “chains of plausible mechanism” outlined here. Chains of plausible mechanism can be broken by a single weak link, or by other effects that we didn’t take into account.

Protein and Ketogenesis

It is already widely believed and asserted that excess protein reduces ketone production.
For example, this is stated in Peter Attia’s blog, which we highly recommend&nbsp, and in Volek and Phinney’s excellent book, The Art and Science of Low Carbohydrate Living&nbsp¹.
However, as far as we are aware, there aren’t any experiments that measure this directly and without confounders.
The mechanism cited is the rise in insulin that protein induces.
In our previous article, we presented evidence that the insulin-to-glucagon ratio is not significantly changed in response to protein in ketogenic dieters.
That article also cites evidence that the insulin-to-glucagon ratio (I/G) is an accurate predictor (and perhaps even cause) of glucose regulation.
Moreover, there is evidence that ketogenesis is itself regulated by the insulin-to-glucagon ratio&nbsp²,&nbsp³,&nbsp.
So we don’t find that explanation particularly compelling.
Nonetheless, there may be other lines of evidence that we are not yet aware of.

The following indirect argument suggests that protein inhibits ketogenesis.
There appears to be an inverse relationship between ketosis and blood sugar&nbsp.
We have already shown that protein raises blood sugar in ketogenic dieters.
Together, this would seem to indicate that protein decreases ketosis.

If protein inhibits ketogenesis, then the following argument can be made that protein increases glucose oxidation.
It would make intuitive sense that higher blood ketone concentrations would correspond to lower levels of glucose oxidation, since ketones can usually replace glucose for fuel.
In fact, in some studies, an inverse relationship has been shown to hold between glucose oxidation and serum ketone levels in people fasting for short periods&nbsp, and in epileptic children&nbsp.
(See also the the Randle Cycle.)
Therefore, if protein inhibits ketogenesis, it very likely increases glucose oxidation.

Can we determine the effect of protein on glucose oxidation directly?

Scientists do have ways to measure glucose oxidation, for example through indirect calorimetry.
We can measure respiratory quotient (RQ): the proportion of oxygen in exhalation is used to infer the proportion of fat and glucose being used, by taking advantage of the fact that oxidizing fat and oxidizing glucose require different amounts of oxygen.
Then you can combine this with resting energy expenditure (REE), a measure of calories expended,
to determine the total amount of glucose being used for energy.
Observations that would indicate more glucose oxidation include: higher energy expenditure at the same RQ, or higher RQ at the same energy expenditure.

If such an effect is confirmed, knowing its magnitude would be equally important.
I.e., how much extra glucose oxidation would be expected from a certain amount of excess protein?
Is it linear, or is there a large effect at the beginning, and very little effect after, or some other relationship?
All of this is far from clear to us.
We would love to see it addressed experimentally, since even though we are inclined to believe it, there are some potential confounders, including changes in fat and calorie intake, and differential effects of different types of fat and protein.


There is evidence that protein does not increase the rate of GNG.
There is evidence that I/G, which appears to control glucose production and ketogenesis, does not change in keto dieters when they eat protein.
Nonetheless, there are compelling arguments that protein increases glucose oxidation in keto dieters.
Experiments will need to be done to reconcile these seeming contradictions.

In the meantime, limiting protein to levels that are known to be adequate seems prudent.

Further Reading

Lucas Tafur has an interesting and relevant article entitled Safe starches, blood glucose and insulin.


Evidence type: authority

Both insulin and glucose (probably by causing the secretion of insulin) suppress ketones. This is why, for example, consuming more than about 50 gm of carbohydrates per day and/or more than about 120-150 gm of protein per day makes it difficult to be in nutritional ketosis – too much insulin secretion.

¹ Evidence type: authority

Stephen J. Phinney and Jeff S. Volek.
The Art and Science of Low Carbohydrate Living: An Expert Guide to Making the Life-Saving Benefits of Carbohydrate Restriction Sustainable and Enjoyable.
Beyond Obesity LLC (May 19, 2011).
ISBN-10: 0983490708

Another reason to avoid eating too much protein is that it has a modest insulin stimulating effect that reduces ketone production.
While this effect is much less gram-for-gram than carbohydrates, higher protein intakes reduce one’s keto-adaptation and thus the metabolic benefits of the diet.

² Evidence type: review of experiments

Foster DW, McGarry JD.
The regulation of ketogenesis.
Ciba Found Symp. 1982;87:120-31.

(Emphasis ours)


Ketone bodies accumulate in the plasma in conditions of fasting and uncontrolled diabetes. The initiating event is a change in the molar ratio of glucagon:insulin. Insulin deficiency triggers the lipolytic process in adipose tissue with the result that free fatty acids pass into the plasma for uptake by liver and other tissues. Glucagon appears to be the primary hormone involved in the induction of fatty acid oxidation and ketogenesis in the liver. It acts by acutely dropping hepatic malonyl-CoA concentrations as a consequence of inhibitory effects exerted in the glycolytic pathway and on acetyl-CoA carboxylase (EC The fall in malonyl-CoA concentration activates carnitine acyltransferase I (EC such that long-chain fatty acids can be transported through the inner mitochondrial membrane to the enzymes of fatty acid oxidation and ketogenesis. The latter are high-capacity systems assuring that fatty acids entering the mitochondria are rapidly oxidized to ketone bodies. Thus, the rate-controlling step for ketogenesis is carnitine acyltransferase I. Administration of food after a fast, or of insulin to the diabetic subject, reduces plasma free fatty acid concentrations, increases the liver concentration of malonyl-CoA, inhibits carnitine acyltransferase I and reverses the ketogenic process.

³ Evidence type: experiment (non-human animals)

Ubukata E, Mokuda O, Sakamoto Y, Shimizu N.
Effect of various glucagon/insulin molar ratios on blood ketone body levels in rats by use of osmotic minipumps.
Diabetes Res Clin Pract. 1996 Sep;34(1):1-6.


The bihormonal control by insulin and glucagon of blood ketone body level was studied. Mixed solutions with various molar ratios of glucagon and insulin (G/I) were subcutaneously infused continuously for five days by use of the osmotic minipump in the normal rats. The concentrations of insulin and glucagon solution were set at the high G/I molar ratio, the moderate G/I molar ratio and the low G/I molar ratio. In addition, the moderate G/I molar ratio group was divided into three sub-groups: low glucagon and low insulin, moderate glucagon and moderate insulin, and high glucagon and high insulin. After five days, the rats were decapitated to measure plasma ketone body, free fatty acid (FFA), glucose, insulin and glucagon. The FFA level was not significantly different among three groups. The glucose level was not different between the high and moderate G/I molar ratio groups, and decreased in the low G/I molar ratio group. 3-beta-hydroxybutyrate (3-OHBA) and acetoacetate (AcAc) levels in the high G/I molar ratio group were elevated, and 3-OHBA level in the low G/I molar ratio group was lowered compared to those in the moderate G/I molar ratio group. Among three moderate G/I molar ratio sub-groups, there was no difference in 3-OHBA and AcAc levels. These results demonstrate that plasma ketone body levels are controlled by the plasma G/I molar ratio.

Evidence type:

Fukao T, Lopaschuk GD, Mitchell GA.
Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry.
Prostaglandins Leukot Essent Fatty Acids. 2004 Mar;70(3):243-51.

(Emphasis ours)


Ketone bodies become major body fuels during fasting and consumption of a high-fat, low-carbohydrate (ketogenic) diet. Hyperketonemia is associated with potential health benefits. Ketone body synthesis (ketogenesis) is the last recognizable step of lipid energy metabolism, a pathway that links dietary lipids and adipose triglycerides to the Krebs cycle and respiratory chain and has three highly regulated control points: (1) adipocyte lipolysis, (2) mitochondrial fatty acids entry, controlled by the inhibition of carnitine palmityl transferase I by malonyl coenzyme A (CoA) and (3) mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase, which catalyzes the irreversible first step of ketone body synthesis. Each step is suppressed by an elevated circulating insulin level or insulin/glucagon ratio. The utilization of ketone bodies (ketolysis) also determines circulating ketone body levels. Consideration of ketone body metabolism reveals the mechanisms underlying the extreme fragility of dietary ketosis to carbohydrate intake and highlights areas for further study.

(But note that this suggests that there may be a pathway for suppression by elevated insulin alone.)

Evidence type: review of experiments

Amanda E. Greene, Mariana T. Todorova, Richard McGowan, Thomas N. Seyfried.
Caloric Restriction Inhibits Seizure Susceptibility in Epileptic EL Mice by Reducing Blood Glucose.
Epilepsia. Volume 42, Issue 11, pages 1371–1378, November 2001.
DOI: 10.1046/j.1528-1157.2001.17601.x

Our findings in mice together with those in humans indicate that CR, like fasting, lowers blood glucose levels while inducing ketosis (1,41–44). This contrasts with studies of the KD, in which blood glucose levels are not reduced in association with ketosis (5,15). It is interesting to note that the antiseizure effect of the KD was greater when it was administered under restricted than under ad libitum conditions (12), suggesting that reduced blood glucose levels may enhance the efficacy of the KD. Despite evidence for an inverse relation between blood glucose and ketone levels in normal humans and humans with epilepsy under fasting or the KD (45), little attention has been given to the possibility that these dietary therapies prevent seizures through an effect on blood glucose levels. From previous neurochemical studies and from our statistical analyses, we show that blood glucose levels determine both blood ketone levels and seizure susceptibility in EL mice and emphasize the importance of blood glucose as a predictor of epileptogenesis in this epilepsy model.

Evidence type: experiment

J.A. Romijn, M.H. Godfried, M.J.T. Hommes, E. Endert, H.P. Sauerwein.
Decreased glucose oxidation during short-term starvation.
Metabolism, Volume 39, Issue 5, May 1990, Pages 525–530.

(Emphasis ours)


Prolonged fasting (for days or weeks) decreases glucose production and oxidation. The effects of short-term starvation (ie, < 24 hours) on glucose metabolism are not known. To evaluate this issue, glucose oxidation and glucose turnover were measured after 16-hour and subsequently after 22-hour fasting. Glucose oxidation was calculated by indirect calorimetry in 12 healthy men (age 22 to 44 years); glucose turnover was measured by primed, continuous infusion of 3-3H-glucose in eight of these 12 volunteers. After 16-hour fasting net glucose oxidation was 0.59 ± 0.17 mg · kg−1 · min−1 and glucose tissue uptake 2.34 ± 0.12 mg · kg−1 · min−1. No correlation was found between net glucose oxidation and glucose tissue uptake. Prolonging fasting with an addtional 6 hours resulted in decreases of respiratory quotient (0.77 ± 0.01 v 0.72 ± 0.01) (P < .005), plasma glucose concentration (4.7 ± 0.1 v 4.6 ± 0.1 mmol/L) (P < .05), glucose tissue uptake (2.10 ± 0.12 mg · kg−1 · min−1)(P < .05), net glucose oxidation (0.09 ± 0.04 mg · kg−1 · min−1)(P < .005), and plasma insulin concentration (8 ± 1 v 6 ± 1 mU/L) (P < .005). Net glucose oxidation expressed as a percentage of glucose tissue uptake decreased from 22% ± 8% to 2% ± 1% (P < .05). There was no net glucose oxidation in seven of 12 controls after 22-hour fasting. Serum free fatty acid (FFA) concentration (364 ± 34 to 575 ± 48 μmol/L) (P < .005) and plasma ketone body concentration (104 ± 23 to 242 ± 38 μmol/L) (P < .005) increased between 16- and 22-hour fasting. After 16-hour fasting an inverse correlation was found between ketone body concentration and net glucose oxidation (P < .05) and between ketone body concentration and net glucose oxidation expressed as a percentage of glucose tissue uptake (P = .07). No significant correlation could be demonstrated between FFA and ketone body concentration and between FFA and net glucose oxidation. It is concluded that glucose oxidation decreases rapidly even within 1 day of starvation. This may be explained by physiological mechanisms like decreased insulin action and/or inhibition of glucose oxidation by ketone bodies, even in relatively low concentrations.

Evidence type: experiment

M. W. Haymond, C. Howard, E. Ben-Galim, and D. C. DeVivo.
Effects of ketosis on glucose flux in children and adults
AJP – Endo October 1, 1983 vol. 245 no. 4 E373-E378


Sequential glucose flux [rate of appearance – rate of disappearance] studies were carried out in five normal and six epileptic children and ten adult volunteers using [6,6-2H2]glucose to determine the effect of ketosis on carbohydrate homeostasis in children and adults. All subjects were studied after 14 and 30-38 h of fasting while consuming a normal diet and the epileptic children under 14 h of fasting while consuming an isocaloric ketogenic diet (75% fat wt/wt). Glucose flux, when expressed per kilogram body weight, was inversely correlated with the degree of ketosis in children (P less than 0.001) and in adults (P less than 0.01), but not when both children and adults were considered together (r = 0.078). When glucose flux was corrected for estimated brain weight, the relationship between glucose flux and ketonemia was linearly related in children (P less than 0.001), in adults (P less than 0.02), and when all subjects were considered together (P less than 0.001). The inverse relationship between ketonemia and glucose flux corrected for estimated brain mass is consistent with a partial replacement of glucose by ketone bodies for cerebral metabolism and may provide a more rational means of expressing glucose flux data to take into account the higher brain-to-body ratio in children.

An inverse relationship was observed between ketone body concentration and glucose utilization whether expressed on a body weight or estimated brain weight basis. The relationship between glucose utilization (on a brain weight basis) and ketone body concentration may not be completely linear because glucose utilization appears to approach a minimum of 20-30 µmol·min⁻¹ 100 g estimated brain⁻¹ at ketone body concentration of 5 mM or greater. This observation suggests that a basal requirement for glucose utilization may exist that cannot be supplanted by ketone bodies regardless of their plasma concentration and is in keeping with the observation that a basal glucose oxidation rate is required by brain tissue for optimum utilization of ketone bodies (13).

Protein, Gluconeogenesis, and Blood Sugar

Recently (for some conception of recent) we asked the question:
If You Eat Excess Protein, Does It Turn Into Excess Glucose?

One of the potentially confusing aspects of this question, is the difference between gluconeogenesis (GNG) — the creation of new glucose that didn’t exist before, and increases in blood sugar.
In response to our post, several people made comments that indicated an implicit assumption that changes in blood sugar can be used as a measurement of GNG, but as we will explain below, this is not the case.
However, it brought to our attention an important distinction.

There are several reasons people might care about excess GNG.
One we have already addressed:
It is not the case that GNG requires excess cortisol.

In terms of the effect of the glucose itself that results from GNG, there are two distinct concerns:

  • How does excess GNG affect blood sugar levels?
    Blood sugar levels are important because too much sugar in the blood at a given time can cause damage to cells&nbsp.
  • Does producing more glucose via GNG ultimately lead to either using more glucose for fuel, or storing it as fat?

So when people worry about protein causing excess GNG, what they are really worrying about is that protein will adversely affect their blood sugar levels, or that they are going to use more glucose for fuel than they intended, or that they will store it as unwanted fat.

While it would be interesting to understand the effect of eating excess protein on GNG, it doesn’t directly address those underlying questions, because there are many other mechanisms in play.
We want to know whether for ketogenic dieters eating excess protein adversely affects blood sugar levels, whether it leads to higher consumption of glucose for fuel, and whether it increases the tendency to store fat.

In this article, we will directly approach the first of these questions.

In Brief:

  • Because the level of sugar in your blood depends on how much is coming in (and there is more than one source), and how much is going out, changes in blood sugar cannot by themselves tell us about the rate of GNG.
  • Nonetheless, when we wrote the original article suggesting that eating excess protein was unlikely to result in an increased rate of GNG, one of the assumptions we made was that eating protein does not raise blood sugar.
    We made this assumption because it is true in non-diabetic, non-ketogenic dieters.
    However, we have recently learned that this is not true in ketogenic dieters.
  • In response to protein, blood sugar rises on a keto diet, even though I/G — the ratio of insulin to glucagon, stays constant, whereas on a glycolytic diet, I/G rises, but blood sugar stays constant.
    There is evidence that I/G is tightly correlated with glucose production, so this is suggestive that in keto dieters glucose production is not affected by eating protein.
    However, we lack direct experimental evidence.
  • Although blood sugar rises in keto dieters eating protein, it stays within safe bounds, at least in our experience, and in the experiment we looked at.

What affects blood sugar?

Fundamentally, the amount of sugar in the blood at any given time depends on two things: how much is coming in, and how much is going out.
On the input side, blood sugar can come from three sources:

  • We can eat carbohydrates, and have sugar enter the blood through digestion.
  • We can make glucose out of glycogen (the limited amount of glucose stored in persistent form in the liver).
    This process is called glycogenolysis.
  • Thirdly, we can produce new glucose by GNG.

Note that because of glycogen storage, it is possible for sugar to enter the blood that has not come directly from GNG.
Even on a keto diet, there is still a substantial proportion of glucose production from glycogenolysis.
Ultimately, of course, the glycogen in keto dieters also comes from GNG that happened previously.

On the outgoing side, the rate of sugar leaving the blood can also change depending on the uptake by cells.
It can be used for fuel, stored as fat, or turned into glycogen for storage (glycogenesis).

This means that changes in blood sugar can happen in either direction, without us being able to conclude anything about the rate of GNG.
Therefore, observations about increases in blood sugar in response to protein are not conclusive evidence about GNG.

The effect of protein on blood sugar

It is well established that under typical test conditions protein ingestion does not significantly effect blood sugar levels, either alone&nbsp¹ or in combination with other foods&nbsp².
This graph shows the typical response to glucose (solid line) and protein (dashed line) ingestion in two non-diabetics after an overnight fast&nbsp³:

Of course, the “typical conditions” in those experiments did not include keto dieters.

However, there was an experiment in 1971 that did test the blood glucose response to protein in people who had restricted carbohydrates to ketogenic levels for one week, and compared it to the values after reintroducing carbohydrates for a week&nbsp.
The group size was small, and the keto-adaptation time was short, but nonetheless, the results showed that blood glucose did in fact rise in the keto dieters ingesting protein.
The experimenters also measured the blood levels of the blood sugar regulating hormones insulin and glucagon and their ratio, I/G.

There is evidence that it is I/G, and not the absolute levels of either hormone, that ultimately regulates glucose production&nbsp,,,.

Interestingly, in the keto dieters, although the levels of these hormones significantly changed, their ratio did not.

Here is a summary of the results:

Diet type Fasting After Protein
glucose insulin glucagon I/G molar ratio glucose insulin glucagon I/G molar ratio
Ketogenic 78 +/- 3 8 +/- 2 128 +/- 17 1.7 +/- 0.3 90 +/- 3 15 +/- 4 218 +/- 10 1.83 +/- 0.4
Glycolytic 94 +/- 5 17 +/- 4 87 +/- 15 4.35 +/- 1.38 “baseline or lower” 28 +/- 14 167 +/- 13 8.2 +/- 4.66

In response to protein, blood sugar rises on a keto diet, even though I/G stays constant, whereas on a glycolytic diet, I/G rises, but blood sugar stays constant.

Because the number of subjects was small, the authors emphasize that this study cannot give us precise estimates of the numerical values of blood sugar (or hormones) in response to protein.
It can only tell us that this rise in blood sugar happens qualitatively.
In other words, they’ve shown that a rise in blood sugar happens, but we can’t be sure that the average rise is going to be 10 mg/dL if we tested a lot more people.

It is important to understand that this is not a very complete picture.
For example, it doesn’t show whether there is a relationship between how much protein is eaten and blood sugar.
It could be, for example, that any amount of protein results in the same increase in blood sugar.
It could be that protein ingestion results in a small rise in blood sugar with a duration that depends on the amount of protein.
It could be that eating protein on a keto diet causes your blood sugar to rise steadily according to the amount of protein eaten until it reaches some maximum value, such as a 20 point rise, after which no further amount of protein has an effect.
What is very unlikely is that the amount of protein has an unlimited effect: we would not expect, for example that if eating 50g of protein caused a 10 point rise, then eating 300g of protein would cause a 60 point rise.
There is still a lot to learn here.

Note: Incidentally, these experiments would be easy for any of us to do at home. For example, you could get up after an overnight fast and measure your blood sugar.
Then ingest 25g of protein, and measure your blood sugar every half hour until it returns to baseline to see how your blood sugar changes and for how long.
Do that for three days, and then try it with 50g for three days.
Then try 100g and then 200g.
Use the same kind of protein in each case, like lean beef or egg whites (save the yolks for later!).
Tell us what you find out.

One important conclusion from all of this, though, is that, at least at these protein levels, blood sugar stays in a safe range&nbsp.
There is good reason to be concerned about the level of sugar in your blood over the long term.
We will write more about that in subsequent posts.
For now we can simply note that the fasting level of blood sugar in this experiment was at the low end of the range considered optimal, and the rise in response to protein was well below the amount considered dangerous.


This article was most spurred by a comment on the original article by Anna K. Thank you, Anna.

Once again, we are indebted to friendly correspondents for access to relevant scientific papers.
This article was supported by friends in Windy City, Orlando, and Edinburgh.
We couldn’t have written it without you!


Evidence type: summary of experiments

Campos C.
Chronic hyperglycemia and glucose toxicity: pathology and clinical sequelae.
Postgrad Med. 2012 Nov;124(6):90-7. doi: 10.3810/pgm.2012.11.2615.

(Emphasis ours)


Type 2 diabetes mellitus (DM) is a progressive disease characterized by elevated plasma glucose levels. Type 2 DM results from a combination of factors affecting both peripheral tissue insulin sensitivity and β-cell function. A survey of the scientific literature on DM, glucose toxicity, hyperglycemia, nephropathy, neuropathy, reactive oxygen species, and retinopathy cited on PubMed/Medline from January 1975 to May 2011 was conducted. The relevant publications, chosen at the author’s discretion, were used to synthesize this narrative review article. Chronic hyperglycemia imposes damage (glucose toxicity) on a number of cell types and is strongly correlated with the myriad of DM-related complications. Tissues most vulnerable to the effects of prolonged elevated plasma glucose levels include pancreatic β cells and vascular endothelial cells. The ensuing β-cell dysfunction promotes decreased insulin synthesis and secretion, further perpetuating the associated hyperglycemia. As for the vascular endothelium, chronic hyperglycemia is strongly correlated with many DM-related microvascular complications, including retinopathy, nephropathy, and neuropathy. The role of hyperglycemia in macrovascular complications is not well defined. Pathophysiologic modifications that arise in response to chronic hyperglycemia persist and may promote DM-related complications that manifest years later, even if plasma glucose levels have been brought under control. Increasing awareness of the mechanisms by which even modest hyperglycemia promotes long-lasting tissue damage highlights the need to achieve early tight glycemic control in patients with DM before substantial disease progression.

¹ Evidence type: review of experiments

Franz MJ.
Protein: metabolism and effect on blood glucose levels.
Diabetes Educ. 1997 Nov-Dec;23(6):643-6, 648, 650-1.

“Protein has a minimal effect on blood glucose levels with adequate insulin. However, with insulin deficiency, gluconeogenesis proceeds rapidly and contributes to an elevated blood glucose level. With adequate insulin, the blood glucose response in persons with diabetes would be expected to be similar to the blood glucose response in persons without diabetes. The reason why protein does not increase blood glucose levels is unclear. Several possibilities might explain the response: a slow conversion of protein to glucose, less protein being converted to glucose and released than previously thought, glucose from protein being incorporated into hepatic glycogen stores but not increasing the rate of hepatic glucose release, or because the process of gluconeogenesis from protein occurs over a period of hours and glucose can be disposed of if presented for utilization slowly and evenly over a long time period.”

² Evidence type: experiment

José Galgani, Carolina Aguirre and Erik Díaz.
Acute effect of meal glycemic index and glycemic load on blood glucose and insulin responses in humans
Nutrition Journal 2006, 5:22 doi:10.1186/1475-2891-5-22

“When mixed meals are consumed, other food and macronutrients will be present. In this study, the results were similar to those observed in studies using isolated carbohydrates [6] and imply that other macronutrients had a negligible effect on the differential serum glucose and insulin responses. It has, in fact, been reported elsewhere that the amount and type of carbohydrate account for about 90% of the total variability in blood glucose response, whereas protein and fat in mixed meals scarcely contribute to the variance in blood glucose and insulin responses [1,2].”

³ Evidence type: experiment

Jerome W. Conn and L. H. Newburgh
J Clin Invest. 1936;15(6):665–671. doi:10.1172/JCI100818.

Evidence type: experiment

Walter A. Muller, M.D., Gerald R. Faloona, Ph.D., and Roger H. Unger, M.D.
The Influence of the Antecedent Diet upon Glucagon and Insulin Secretion.
N Engl J Med 1971; 285:1450-1454December 23, 1971DOI: 10.1056/NEJM197112232852603

Evidence type: experiment (non-human animal)

H.J. Seitz,
M.J. Müller,
W. Krone,
W. Tarnowski
Coordinate control of intermediary metabolism in rat liver by the insulin/glucagon ratio during starvation and after glucose refeeding: Regulatory significance of long-chain acyl-CoA and cyclic AMP.
Archives of Biochemistry and Biophysics.
Volume 183, Issue 2, October 1977, Pages 647–663

(Emphasis ours)


The levels of serum insulin, glucagon, and free fatty acids (FFA) and the tissue concentrations of hepatic cyclic AMP, long-chain acyl-CoA (LCA), adenine nucleotides, inorganic phosphate, the intermediates of the Embden-Meyerhof pathway, the citric acid cycle (including acetyl-CoA and free CoA), and the cytoplasmic and mitochondrial redox couples were determined in the rat 12, 24, and 48 h after food withdrawal and 5, 10, 20, 40, 60, and 120 min after the refeeding of glucose. Using the measured metabolite contents in the liver, the alterations in the concentration of malate, oxaloacetate, citrate, and α-ketoglutarate and the changes in the energy state of the adenine nucleotide system and the redox state of the NAD system were attributed to the cytoplasmic and mitochondrial compartments by applying established calculation methods. Glucose refeeding provoked significant alterations in all parameters investigated. These changes occurred within minutes, reversing the hormone and metabolite pattern which had developed within 24 h in response to food withdrawal. Particularly, glucose refeeding resulted in a drastic increase in the insulin/glucagon ratio. Simultaneously, the level of serum FFA and the concentration of LCA in the liver declined. The latter alteration was accompanied by an increase in the cytoplasmic and a decrease in the mitochondrial ATP/ADP x P ratios. Moreover, the redox state of the cytoplasmic NAD system was shifted toward the oxidized state. When the appropriate data were plotted against each other, highly significant correlations were obtained (i) between the insulin/glucagon ratio and the serum FFA concentration, (ii) between the serum FFA concentration and the concentration of hepatic LCA, (iii) between the hepatic LCA concentration and the cytoplasmic energy state, and (iv) between the cytoplasmic energy state and the redox state of the cytoplasmic NAD system. These findings are interpreted to support the hypothesis derived from experiments carried out in vitro that the insulin/glucagon ratio via the FFA-dependent concentration of hepatic LCA might affect the translocation of adenine nucleotides between the cytoplasmic and the mitochondrial compartment, thereby regulating the cytoplasmic energy state and the redox state of the cytoplasmic NAD system, consequently. Glucose refeeding provoked rapid coordinate changes in the concentration of the intermediates of both the citric acid cycle and the Embden-Meyerhof chain, indicating the altered substrate flow through these pathways. Those metabolites, known to modulate the activity of key regulatory enzymes in vitro, were analyzed with respect to their suggested regulatory function. As to the established shift from pyruvate carboxylation to pyruvate decarboxylation after glucose refeeding, the data revealed that the decrease in pyruvate carboxylase activity can be attributed to the decrease in the intramitochondrial ATP/ADP ratio and the simultaneous fall in acetyl-CoA concentration, while the coordinate increase in pyruvate dehydrogenase activity can be ascribed to the decline in the concentration of LCA and, consequently, in the ratios of ATP/ADP , NADH/NAD, and acetyl-CoA/CoA within the mitochondria. As for the citric acid cycle, increased citrate synthesis from acetyl-CoA and oxaloacetate was supported by the rapid drop in the concentration of the established inhibitor of citrate synthesis, LCA. In contrast, the concentration of succinyl-CoA, an inhibitor of the enzyme in vitro, remained practically constant, questioning its regulatory function under the present experimental conditions. In addition to the activation of citrate synthase, the coordinate activation of isocitrate dehydrogenase was indicated by the LCA-mediated decline in both the mitochondrial ATP/ADP and the NADH/NAD ratios. Glucose refeeding immediately reduced urea excretion to basal values. This alteration was preceded by a drastic fall in the tissue concentration of cyclic AMP, supporting the physiological role of the nucleotide in the control of hepatic gluconeogenesis. In contrast, the observed changes in the concentration of the effectory acting metabolites (ATP, AMP, fructose 1,6-diphosphate, citrate, and alanine) were incompatible with the suggested function of these intermediates in switching over the substrate flow through the Embden-Meyerhof pathway from gluconeogenesis to glycolysis. The results are discussed in reference to the known rapid stimulation of fatty acid biosynthesis in the liver and to the transfer of reducing equivalents by the different shuttles of the inner mitochondrial membrane. In summary, it can be concluded that the insulin/glucagon ratio in a moment-to-moment fashion controls the glucose balance across the liver by regulating hepatic intermediary metabolism via the concentration of both LCA and cyclic AMP.

Evidence type: experiment (non-human animal)

Peret J, Foustock S, Chanez M, Bois-Joyeux B, Assan R.
Plasma glucagon and insulin concentrations and hepatic phosphoenolpyruvate carboxykinase and pyruvate kinase activities during and upon adaptation of rats to a high protein diet.
J Nutr. 1981 Jul;111(7):1173-84.

(Emphasis ours)


Plasma hormones, glucose and free fatty acids, liver glycogen and two key enzymes of glycolysis and gluconeogenesis were examined in adult rats during a 40-day period of high protein feeding. Plasma insulin fell within 1 day but returned to normal after 4 days. Glucagon changed more slowly, reaching a maximum on day 4 and declined to near the control value within 24 days. Consequently, the insulin to glucagon ratio was lower on days 1, 4 and 8 and was nearly normal on day 24. With respect to hepatic enzymes, phosphoenolpyruvate carboxykinase activity rose sharply on the 1st day and remained elevated for 40-day period; the L-isozyme of pyruvate kinase, although unchanged on the 1st day, decreased thereafter and from day 8 on represented 15–20% of control. Circadian variations in these parameters were also measured in rats adapted to the high protein diet. In such animals, the diurnal change in plasma hormones was less marked but tended to be inverted with respect to controls; the insulin/glucagon ratio was highest during daylight on high protein and in late night on the control diet. Over 24 hours, pyruvate kinase activity was related directly and phosphoenolpyruvate carboxykinase inversely to the hormone ratio. We concluded that in rats adapted to high protein, as in controls, the diurnal balance between glycolysis and gluconeogenesis is probably regulated by the same factor, namely the insulin/glucagon ratio.

Evidence type: authority

Eric C. Westman, John Mavropoulos, William S. Yancy and Jeff S. Volek
A review of low-carbohydrate ketogenic diets.
Current Atherosclerosis Reports
Volume 5, Number 6 (2003), 476-483, DOI: 10.1007/s11883-003-0038-6

The insulin/glucagon (I/G) ratio is a key determinant of lipolysis, glycogenolysis, and gluconeogenesis [14,15].

(We followed the references given for this assertion, and did not understand how they supported it, so we consider this evidence as authority-based, at least for us.)

Evidence type: in vitro experiment

S.R. Wagle.
Interrelationship of insulin and glucagon ratios on carbohydrate metabolism in isolated hepatocytes containing high glycogen.
Biochemical and Biophysical Research Communications.
Volume 67, Issue 3, 1 December 1975, Pages 1019–1027


The effect of physiological concentrations of glucagon and insulin on glycogenolysis was studied in the presence and absence of substrates in isolated hepatocytes containing high glycogen. In the absence of substrates glucagon stimulated glycogenolysis at 10−14M concentration, and addition of 100 μunits of insulin partially inhibited glucagon stimulated glycogenolysis (10−14M to 10−11M). However, in the presence of substrates, insulin completely inhibited glucagon stimulated glycogenolysis (10−14M to 10−11M), indicating that molar glucagon and insulin ratios control carbohydrate metabolism in liver. Additional studies showed incorporation of amino acid into protein was linear for only 3 to 4 hr in cells containing low glycogen, whereas in cells containing high glycogen, incorporation was linear for 8 to 10 hr.

Evidence type: authority

Postprandial Blood Glucose.
doi: 10.2337/diacare.24.4.775 Diabetes Care April 2001 vol. 24 no. 4 775-778

Dissatisfying as it is, for now we will talk about safe as meaning not identified as correlating with current or subsequent development of diabetes.
We will talk more about blood sugar in a subsequent post.

(Emphasis ours)

The word postprandial means after a meal; therefore, PPG concentrations refer to plasma glucose concentrations after eating. Many factors determine the PPG profile. In nondiabetic individuals, fasting plasma glucose concentrations (i.e., following an overnight 8- to 10-h fast) generally range from 70 to 110 mg/dl. Glucose concentrations begin to rise ∼10 min after the start of a meal as a result of the absorption of dietary carbohydrates. The PPG profile is determined by carbohydrate absorption, insulin and glucagon secretion, and their coordinated effects on glucose metabolism in the liver and peripheral tissues.

The magnitude and time of the peak plasma glucose concentration depend on a variety of factors, including the timing, quantity, and composition of the meal. In nondiabetic individuals, plasma glucose concentrations peak ∼60 min after the start of a meal, rarely exceed 140 mg/dl, and return to preprandial levels within 2–3 h. Even though glucose concentrations have returned to preprandial levels by 3 h, absorption of the ingested carbohydrate continues for at least 5–6 h after a meal.

BCAAs and Keto diets

(Note: This article is a departure from our tradition of end-to-end citations, and other practices necessary for establishing high confidence in medical assertions. This departure is merely in the interest of publishing more ideas in less time, as our intensely busy lives have led to a huge backlog of unfinished articles for which the verification and explicit justification process has proved to be at least 80% of the work. Because of its importance to us, though, when we return to more fundamental ketogenic science articles, we will return that style.)

Benefits of BCAAs

If you follow the bodybuilding community, you are probably aware of some of the benefits of branched chain amino acids (BCAAs). That’s because they are known to have positive effects on muscle growth and recovery. (See for example Nutraceutical Effects of Branched-Chain Amino Acids on Skeletal Muscle, and Branched-Chain Amino Acids Activate Key Enzymes in Protein Synthesis after Physical Exercise.)

Less well known is that BCAAs have favourable effects on the brain, in particular the glial cells (brain cells that aren’t neurons, are more numerous than neurons, and turn out to be essential for supporting neurons — it seems probable that most brain afflictions are caused by problems in the glial cells). The beneficial effects of BCAAs come from their important role in the manufacture of neurotransmitters, and vital metabolic cycles such as the leucine-glutamate cycle.

Here are a couple of examples of beneficial effects of BCAA supplementation on the brain: Dietary branched chain amino acids ameliorate injury-induced cognitive impairment, Branched-chain amino acids may improve recovery from a vegetative or minimally conscious state in patients with traumatic brain injury: a pilot study, Recovery of brain dopamine metabolism by branched-chain amino acids in rats with acute hepatic failure..

The problems being helped by BCAA supplementation are similar to some of the benefits that have been shown to be helped by ketogenic diets, and this is no coincidence.

One important effect of keto-adaptation is a dramatic increase in circulating BCAAs.

This fact is one the many proposed mechanisms of the anti-epileptic properties of ketogenic diets. (See also The ketogenic diet and brain metabolism of amino acids: relationship to the anticonvulsant effect.)

There also appears to be a bit of a feedback loop, in that supplementing a ketogenic diet with BCAAs can itself increase ketogenesis relative to the same amount of other proteins.

Nonetheless, the important point to take away from this post is that a ketogenic diet itself achieves what others are striving for by ingesting expensive (and, frankly, revoltingtasting) powders. Therefore it is quite plausible that in addition to the more-studied positive nervous system effects, a ketogenic diet will improve muscle growth and recovery relative to a glycolytic diet, something already anecdotally reported.

We were talking about gluconeogenesis, not ketogenesis.

Our last post described the evidence that the rate of gluconeogenesis (GNG) is stable under a variety of metabolic conditions.
We also described several experiments in which large amounts of protein were ingested or infused and did not increase the rate.
We concluded that eating more protein than your body needs probably doesn’t increase GNG.

Many of our readers expressed confusion about the implications of this finding, and our purpose in posting it.

The reason we investigated this was to address the following concern. One of the reasons keto dieters want to minimize the amount of carbohydrate they eat is so that their bodies don’t have to deal with excess glucose in the blood.
Whenever we ingest carbohydrate, it becomes sugar in the blood&nbsp¹.
Since blood sugar must be kept within a narrow range for safety&nbsp², eating carbs then causes the body to release insulin in order to draw sugar quickly and safely out of the blood and into storage (as fat tissue)&nbsp³.

In our opinion, the ideal situation is to introduce no significant amount of sugar into the blood by eating, and instead allow the body to supply the blood with just the amount of glucose it needs by producing it at a slow and steady rate through GNG.
This is achieved by keto dieters who carefully count any carbohydrates they eat, with the goal of keeping them below a certain level, for example, 25g per day.

Because some people have said that when you eat protein above basic requirements it turns into sugar, the question some dieters have is whether they need to count excess protein toward their carb counts&nbsp.
They want to know if eating an extra 30 grams of protein means that they have added some 20 grams of sugar into their bloodstreams that now has to be dealt with just as if they had eaten 20 more grams of carbohydrate.
This is the conclusion we were setting out to deny.
Protein you eat in excess of your needs does not become extra blood sugar, unless you are severely diabetic.

However, this does not mean that eating too much protein has no adverse effects, or that keto dieters should be unconcerned about excess protein intake!
In particular, there is another important reason that keto dieters minimize the carbohydrate they eat — to increase the levels of ketones in the blood.
So a second question, and one that we did not address in the last post, is whether excess protein inhibits ketogenesis, the production of ketone bodies.
In contrast to the situation with gluconeogenesis, we suspect protein does inhibit ketogenesis.
If so, that’s a valid reason for not eating more than you need.


¹ Evidence type: authority

Marks’ Basic Medical Biochemistry: A Clinical Approach. Michael
A. Lieberman, Allan Marks. Lippincott Williams & Wilkins, Apr 21, 2008.
p. 479

The major carbohydrates of the diet (starch, lactose, and sucrose) are digested to produce monosaccharides (glucose, fructose, and galactose), which enter the blood.

² Evidence type: authority

Marks’ Basic Medical Biochemistry: A Clinical Approach. Michael
A. Lieberman, Allan Marks. Lippincott Williams & Wilkins, Apr 21, 2008.
p. 483

(Emphasis in original)

[I]nsulin and glucagon maintain blood glucose levels near 80 to 100 mg/dL, (90 mg/dL is the same as 5mM), despite the fact that carbohydrate intake varies considerably over the course of the day.

³ Evidence type: authority

Human Biochemistry and Disease. Gerald Litwack. Academic Press, Jan 4,
2008. p. 583

The anabolic effects of released insulin, after glucose is sensed by glucoreceptors of beta cells, are to cause the uptake of glucose and amino acids from the blood into muscle, and the uptake of glucose from the blood to form triglycerides in fat cells.

Evidence type: observation

Protein turns into glucose if you eat too much?!!

So I am trying to research a bit over the interwebs about just how much protein is to much and at what point your body will convert protein into glucose but there are so many different opinions on this… *pulls her hair out* This is where i think Calories in vs. calories out makes more sense… what yall think?

Is there a rule of thumb to what the bodies tipping point is for when it will convert protein into glucose?

How much protein can you eat before it turns to glucose?

muffin_maiden: I’ve read before that eating too much protein at once can cause it to turn to glucose, but how much protein can you eat before that happens?
I tend to eat two larger meals (or one big one) during the day with between 10 and 16 ounces of protein at a time.
Would that amount turn to glucose or are we talking that you’d have to eat a LOT of meat before that happens?


redtoile: Thanks for this post. I worry about this all the time.


CarolynF: According to Dr. Atkins, it is around 52 percent of protein gets converted to glucose.

So, if you overeat protein at each meal, it will act like carbs.

If You Eat Excess Protein, Does It Turn Into Excess Glucose?

Gluconeogenesis is Demand-Driven, not Supply-Driven

We have seen the claim that any protein you eat in excess of your immediate needs will be turned into glucose by spontaneous gluconeogenesis ¹.
(Gluconeogenesis (GNG) is the process by which glucose is made out of protein in the liver and kidneys.) Some people think that because protein can be turned into glucose, it will, once other needs are taken care of, and that therefore keto dieters should be careful not to eat too much protein.

While we believe there are valid reasons for limiting protein intake, experimental evidence does not support this one.
In our opinion, it makes sense physiologically for GNG to be a demand-driven rather than supply-driven process, because of the need to keep blood glucose within tight bounds.

In brief

  • Gluconeogenesis is a slow process and the rate doesn’t change much even under a wide range of conditions.
  • The hypothesis that the rate of gluconeogenesis is primarily regulated by the amount of available material, e.g. amino acids, has not been supported by experiment.
    Having insufficient material available for gluconeogenesis will obviously limit the rate, but in the experiments we reviewed, having excess material did not increase the rate.
  • We haven’t found any solid evidence to support the idea that excess protein is turned into glucose.
  • More experiments are needed to confirm that this still holds true in keto dieters.

Gluconeogenesis has a Stable Rate

Gluconeogenesis (GNG) is a carefully regulated process for increasing blood sugar.
It is stimulated by different hormones, including glucagon — the primary hormone responsible for preventing low blood sugar.
GNG produces glucose slowly and evenly ².
It was once thought that the main determination of the rate of GNG was how much glucogenic substrate, that is, raw materials for it, was available, but further experiments have shown that this is not the case ³.
Instead, it now appears that GNG is relatively constant over a large variety of conditions .

As an example of this stability, a study by Bisschop et al.
in 2000  showed that subjects following a keto diet for 11 days had only a small (14%) increase in glucose production from GNG after overnight fasting, as shown in this graph.
This works out to a difference of less than a gram of glucose per hour.

Note that 11 days might be too little time for all of the subjects to keto-adapt, and it is possible that the rate of GNG would change in subsequent weeks.

Negative Results

In another experiment (this time in subjects on a glycolytic, or carb-based, rather than a ketogenic diet), ingesting 50g of protein resulted in the same amount of glucose production as drinking water .
In other words, the amount of glucose that was made after ingesting that protein wasn’t any more than would have been produced without it.
While it’s possible that this protein doesn’t count as “excess”, it was likely to be nearly half of their daily required protein intake, and eaten in one sitting, and so it is enough to cast serious doubt on the idea.

There are other experiments in which increasing the available material for GNG to high levels didn’t increase GNG ³.
In these experiments GNG substrates were infused directly into the blood rather than eaten.

The problem with applying the results of these experiments to the question of excess protein consumption is that infusion might bypass some mechanism that increases GNG when the protein is actually eaten.
For instance, it is known that protein consumption stimulates a great deal of glucagon (along with insulin) , and it might be suggested that this glucagon would thereby increase GNG.
A counterargument to that possibility is that although glucagon stimulates GNG in many conditions, its action appears to always be overridden by insulin .
This means that the insulin that is produced when eating protein will counteract the glucagon and GNG will not be affected (except in the case of insulin-dependent diabetes, where insulin is neither created nor responded to in the normal fashion).

Both the argument from infused substrates and the counter-arguments outlined here are plausible mechanism arguments — taking physiological processes known to occur in one context and arguing that they will occur in another context.
Plausible mechanism arguments should be used with caution.


In sum, then, there is no evidence that we could find that consuming excess protein will increase glucose production from GNG.
On the other hand, there is much suggestive evidence that it does not.

Further experiments need to be carried out to answer the question completely.
In particular, we would like to see a comparison of the rate of GNG in keto-adapted dieters consuming no protein, adequate protein, or a large quantity of protein, with and without dietary fat.

Follow-up posts

For clarification and further discussion of this topic, please see:


(We owe a debt of gratitude to a special friend from Windy City for helping us access full texts, as our previous access has expired.
Thank you!)

¹ Evidence type: observation
Please note
We have cited some people here as making what we believe to be an unsupported assertion.
This does not imply any disrespect for the authors!
To the contrary, we believe that writers such as these contribute to scientific knowledge even when they make mistakes.
By writing specific and falsifiable statements and by posting them publicly where others can cite them, they give others a chance to learn from both their accurate statements and their mistakes.

We, too are fallible, and we expect that errors of our own will come to light sooner or later; such is the nature of science.
There is no shame in this, and we intend none.
Please see Apologia for our philosophy about this.

Scientific progress is made in large part through discovering errors and correcting them.
We sincerely hope that those we have quoted will be glad to either learn from this post, or conversely, to point out to us where we have erred.
In either case, an issue that was obscure will have been clarified for everyone.

Nora Gedgaudas

Also, keep in mind that a significant percentage of protein consumed that is in excess of what you actually need for your daily maintenance and repair will convert to sugar and get used exactly the same way.

Mark Sisson

As I’ve said before, I’m trying to minimize my use of glucose, whether exogenous or endogenously produced.
If I’m eating so much protein that the excess is being converted to glucose, I’m not really minimizing it, am I?

Eric Westman in an interview with Jimmy Moore


JM: Well, and I would think that if you’re sensitive to carbohydrate then you would be sensitive to eating too much protein as well, because you want to stave off the effects of gluconeogenesis from happening, which would provide too much glucose in your body, tantamount to eating a lot of carbs.

EW: That’s a good point, that some of the protein that we eat can be turned into the glucose through gluconeogenesis, and that may be a reason why someone is not able to get to ketosis — that too much protein is being converted to glucose.

(Update 2012-08-21)

The Rosedale Diet, p82.

When you eat more protein than your body needs to replace and repair body parts, excess protein is largely converted into glucose and burned as fuel.

² Evidence type: experimental

Jerome W. Conn, L. H. Newburgh. The Glycemic Response to Isoglucogenic Quantities of Protein and Carbohydrate. J Clin Invest. 1936; 15(6):665–671 doi:10.1172/JCI100818

(Emphasis ours)

In the process of protein metabolism, the complex protein molecule is split in the intestinal tract to amino-acids. These are absorbed into the blood stream and transported to the liver where oxidative deamination occurs. Here the glycogenic amino-acids are split to form urea and glucose. That this process is a slow one is shown in the charts by the slowly rising blood urea nitrogen. Glucose is, therefore, liberated into the blood stream in this process at a slow and even rate over a prolonged period of time. Under these conditions the diabetic is able to utilize a greater total amount of glucose without glycosuria in the eight hour period. Therefore, the inability of a diabetic to dispose of large quantities of glucose is partially compensated if the glucose is presented for utilization slowly and evenly. There appears, then, to be some advantage to the diabetic of this slow liberation of glucose from protein foods.

³ Evidence type: review of experiments

F. Jahoor, E. J. Peters, and R. R. Wolfe. The relationship between gluconeogenic substrate supply and glucose production in humans. AJP – Endo February 1, 1990 vol. 258 no. 2 E288-E296
(Emphasis ours)

Gluconeogenesis plays an integral role in the maintenance of glucose homeostasis in humans, contributing about one-third of glucose produced in the postabsorptive state and all glucose produced when hepatic glycogen is depleted by starvation (6, 23-25). Because the results of in vivo experiments in humans and animals (12-15, 20) and in vitro perfused rat liver studies (11, 27) have demonstrated a close correlation between the rate of glucose production and the flux of gluconeogenic substrates, it is believed that gluconeogenic precursor supply plays a major role in the regulation of glucose production (12,13,20). Several studies in vivo support this concept. For example, we and others have demonstrated that the hyperglycemic response to severe burn injury and sepsis is a direct result of an increased rate of glucose production, which is associated with a concomitant increase in the fluxes of alanine and lactate, major gluconeogenic substrates (15, 39). The proposed regulatory role of precursor supply received further support in the quest to rationally explain the paradox of a reduced glucose production rate (and hypoglycemia) in starvation, despite a hormonal-substrate milieu that would normally favor stimulation of gluconeogenesis (2, 7, 12, 13, 28), thus glucose production. After prolonged starvation (3-4 wk), human subjects had low levels of gluconeogenic precursors associated with hypoglycemia and a reduced glucose production rate (6, 7, 12, 25). Infusion of unlabeled alanine caused hyperglycemia and an increased incorporation of [ 14C]label from alanine into glucose in this circumstance (12,13). It was therefore proposed by Cahill, Felig, and Marliss and their associates (7, 12, 13, 20) that the reduced glucose production rate in starvation was due to the reduced availability of gluconeogenic substrates; hence, gluconeogenic precursor supply was rate-limiting for glucose production rate.

In contrast, the findings of several kinetic studies performed in human and dog do not support this proposal (1, 30, 34, 38). These studies in postabsorptive subjects employed either the isotope dilution or hepatic vein catheterization techniques and failed to show any significant change in glucose production rate in response to infusions of substantial quantities of alanine, lactate, and glycerol even when there was a fivefold increase in the hepatic uptake of the infused substrate (1, 30, 34, 38)

These conflicting findings suggest that the relationship between gluconeogenic substrate supply and gluconeogenic enzyme activity in prolonged starvation may be different from that of the postabsorptive state. Alternatively, it is possible that the response to an increase in precursor supply is different from the response to a decrease. This latter possibility could occur if the endogenous supply of gluconeogenic precursors is just sufficient to maximally satisfy the capacity of the gluconeogenis enzyme system or of a particular key-limiting enzyme.


Our data so far indicate that under almost any physiological situation, an increase in gluconeogenic precursor supply alone will not drive glucose production to a higher level, suggesting that factors directly regulating the activity of the rate-limiting enzyme(s) of glucose production normally are the sole determinants of the rate of production; hence, there will be no increase in glucose production if the increase in gluconeogenic precursor supply occurred in the absence of stimulation of the gluconeogenic system. On the other hand, results of the DCA experiments suggest a coupling between precursor supply and gluconeogenic enzyme capacity. In this light, if there is a stimulation in gluconeogenic enzyme capacity (for example because of hyperglucagonemia of severe trauma), then there will have to be an increased rate of uptake of gluconeogenic precursors to meet the requirements of such a stimulated system. Thus the rate of uptake of gluconeogenic substrates and the rate of glucose production will be closely related, but the increased uptake of gluconeogenic precursors will be a consequence of a stimulated gluconeogenic enzyme system rather than the cause of an increased rate of gluconeogenesis.

Evidence type: review of experiments

Frank Q. Nuttall, Angela Ngo, Mary C. Gannon. Regulation of hepatic glucose production and the role of gluconeogenesis in humans: is the rate of gluconeogenesis constant? Diabetes Metab Res Rev 2008; 24: 438–458.

(Emphasis ours)

Current data support the hypothesis that the rate of glucose appearance changes but the rate of gluconeogenesis remains remarkably stable in widely varying metabolic conditions in people without diabetes. In people with diabetes, whether gluconeogenesis remains unchanged is at present uncertain. Available data are very limited. The mechanism by which gluconeogenesis remains relatively constant, even in the setting of excess substrates, is not known. One interesting speculation is that gluconeogenic substrates substitute for each other depending on availability. Thus, the overall rate is either unaffected or only modestly changed. This requires further confirmation.

Evidence type: experimental

P. H. Bisschop, A. M. Pereira Arias, M. T. Ackermans, E. Endert, H. Pijl, F. Kuipers, A. J. Meijer, H. P. Sauerwein and J. A. Romijn. The Effects of Carbohydrate Variation in Isocaloric Diets on Glycogenolysis and Gluconeogenesis in Healthy Men. The Journal of Clinical Endocrinology & Metabolism May 1, 2000 vol. 85 no. 5 1963-1967

(Emphasis ours)


To evaluate the effect of dietary carbohydrate content on postabsorptive glucose metabolism, we quantified gluconeogenesis and glycogenolysis after 11 days of high carbohydrate (85% carbohydrate), control (44% carbohydrate), and very low carbohydrate (2% carbohydrate) diets in six healthy men. Diets were eucaloric and provided 15% of energy as protein. Postabsorptive glucose production was measured by infusion of [6,6-2H2]glucose, and fractional gluconeogenesis was measured by ingestion of 2H2O. Postabsorptive glucose production rates were 13.0 ± 0.7, 11.4 ± 0.4, and 9.7 ± 0.4μ mol/kg·min after high carbohydrate, control, and very low carbohydrate diets, respectively (P < 0.001 among the three diets). Gluconeogenesis was about 14% higher after the very low carbohydrate diet (6.3 ± 0.2 μmol/kg·min; P = 0.001) compared to the control diet, but was not different between the high carbohydrate and control diets (5.5± 0.3 vs. 5.5 ± 0.2 μmol/kg·min). The rates of glycogenolysis were 7.5 ± 0.5, 5.9 ± 0.3, and 3.4± 0.3 μmol/kg·min, respectively (P < 0.001 among the three diets).

Evidence type: experimental
M A Khan, M C Gannon and F Q Nuttall. Glucose appearance rate following protein ingestion in normal subjects. J Am Coll Nutr December 1992 vol. 11 no. 6 701-706

Unfortunately, we have been unable to access the full text of this paper.
However, the results are described by the authors in the paper above () in text and in the table in the line marked [108]:

[T]here was no change in glucose production after ingestion of 50 g of protein in the form of cottage cheese.

If anyone having access to this paper would like to share it with us, we would be grateful, because it is the most relevant experiment we could find on the topic, and further details may be important.

Evidence type: experimental

Richard D. Carr, Marianne O. Larsen, Maria Sörhede Winzell, Katarina Jelic, Ola Lindgren, Carolyn F. Deacon, and Bo Ahrén. Incretin and islet hormonal responses to fat and protein ingestion in healthy men. AJP – Endo October 2008 vol. 295 no. 4 E779-E784

(Emphasis ours)

Fasting glucose levels were 4.6 ± 0.2 mmol/l, and glucose levels did not change significantly during any of the tests. Fasting insulin levels were 55 ± 3 pmol/l. Insulin levels were unaltered after water ingestion, whereas they increased after fat and protein ingestion. The increased plasma insulin concentrations were seen between 30 and 240 min after fat ingestion (P = 0.031 vs. water) and between 15 and 240 min after protein ingestion (P = 0.018 vs. water). When compared with water ingestion, fat and protein ingestion both significantly increased early and late insulin responses (Table 1). These responses were more pronounced after protein than after fat ingestion (P < 0.001 for all). Fasting glucagon levels were 65 ± 3.7 ng/l. Glucagon levels were unaltered after water ingestion. In contrast, glucagon levels were increased by both fat and protein ingestion, with significant elevations from minute 120 and onward after fat ingestion (P = 0.019 vs. water) and from minute 30 and onward after protein ingestion (P = 0.005 vs. water). The late glucagon response was increased by fat ingestion, whereas, after protein ingestion, both early and late responses were significantly increased. As for insulin, early and late glucagon responses were higher after protein ingestion than after fat ingestion (both P < 0.001; Fig. 1).

Evidence type: review of experiments

Hua V. Lin and Domenico Accili. Hormonal Regulation Of Hepatic Glucose Production In Health And Disease. Cell Metab. 2011 July 6; 14(1): 9–19

(Emphasis ours)

Tracer studies in dogs have defined hormonal regulation of HGP [Hepatic Glucose Production] in detail. As in the isolated rodent liver, HGP is exquisitely sensitive to glucagon and insulin. Glucagon sets the basal tone, but insulin trumps glucagon at any concentration–just as it does in vitro. Both hormones affect primarily glycogenolysis by reciprocal changes of glycogen synthase and glycogen phosphorylase, and by modulating glycolysis through glucokinase, fructose-bisphosphatase and pyruvate kinase (see below) (Cherrington, 1999). Hormonal regulation of gluconeogenesis has proven difficult to demonstrate.

Ketogenic Diets, Cortisol, and Stress: Part I — Gluconeogenesis

One recent myth, prevalent in the Paleo Diet community, is that the keto diet is stressful to the body ¹. This idea arises from misunderstandings about cortisol — “the stress hormone”. There are two different arguments we know of, and this post will address the first one, the “gluconeogenesis requires cortisol” myth.

This myth comes from a mistaken chain of reasoning with three steps in it, only one of which is correct:

  1. On a keto diet, because you get very little glucose from carbohydrate in your diet, your body makes its own glucose on demand, in a process called gluconeogenesis. (This is correct.)
  2. Gluconeogenesis requires elevated cortisol. (This is not correct.)
  3. Chronically elevated cortisol damages the body. (This is not precisely true. In a subsequent article in this series, we will explore the relationship between cortisol levels and health. Nonetheless, it makes no difference for this argument — because gluconeogenesis does not in fact require excess cortisol.)

In Brief:

  • Gluconeogenesis does not require high levels of cortisol.
  • When blood sugar begins to get low, glucagon — the primary hormone responsible for ensuring adequate blood sugar — is produced. This promotes gluconeogenesis, and it happens before blood sugar gets low enough to trigger increases in cortisol.
  • When blood sugar gets so low that excess cortisol is produced, it is also low enough that symptoms of hypoglycemia (“low blood sugar”) appear — anxiety, palpitations, hunger, sweating, irritability, tremor; or in more extreme cases, dizziness, tingling, blurred vision, difficulty in thinking, and faintness. So hypoglycemic signs are a good way to judge if cortisol is involved.
  • Since keto dieters do not normally appear to suffer from hypoglycemic episodes, especially when eating enough protein and not fasting for long periods (indeed, hypoglycemic episodes appear to be reduced by keto diets), it is unlikely that cortisol comes into play to regulate blood sugar for normal keto dieters.
  • If you are concerned about your blood sugar, and whether cortisol is being called upon to regulate it, we recommend you measure your blood sugar levels with a glucometer such as this one (but any drug store should offer several models). If your blood sugar is sometimes too low, then we recommend that you experiment with increasing your protein or how frequently you eat.


On a keto diet, your body makes the modest amount of glucose it needs out of protein in a process called gluconeogenesis (GNG). There is a widely-held misconception that for GNG to occur, there must be high levels of the stress hormone cortisol in the blood. This mistake comes out of the fact that cortisol stimulates GNG. Therefore, it is reasoned, whenever you rely on GNG, your body has to produce and circulate more cortisol. This, however, is like arguing that since a reliable way to make people laugh is to tickle them, that every time you hear someone laughing it means they are being tickled. It turns out there are other ways to make people laugh, and there are other hormones that induce GNG.

The usual hormone to stimulate GNG is glucagon. Glucagon is produced when blood sugar gets low, and its primary function is to restore blood sugar to optimal levels. Cortisol levels rise when blood sugar reaches an even lower level. That is, the blood sugar threshold for cortisol production (55 mg/dL) is lower than the threshold for glucagon (65 mg/dL) ². This lower threshold could be reached if GNG was somehow obstructed. There are some rare disorders that prevent GNG, such as Fructose 1,6-Diphosphatase Deficiency or Glycogen Storage Disease, but in most people, GNG is a straightforward, unimpeded process.

In fact, it turns out that the level of blood sugar that has to be reached to significantly increase cortisol is so low that clinical symptoms of hypoglycemia also start to appear at that level ³. Not only are reports of hypoglycemic episodes in studies of keto dieters rare, it has been known since at least 1936 that keto diets with adequate protein help prevent hypoglycemia. (It is reported in that paper that keto diets with lower protein help somewhat, but not enough.) A more recent paper from 1975 asserts that the best treatment for hypoglycemia is a low carbohydrate diet with frequent small meals, though they note that this worsens the condition in occasional cases where the patient has one of the above-mentioned or similar disorders. The only other examples of hypoglycemia we could find referred to the initial fasting or severely calorie-restricted phases of ketogenic diets for epilepsy.

Based on this collection of observations, it appears that in keto dieters, the glucagon response is enough stimulate adequate GNG to restore blood sugar, unless they have rare GNG disorders, are eating insufficient protein, or have been engaging in extended fasting.

What you can do

If you experience symptoms that could indicate hypoglycemia, and you are concerned about the possibility that cortisol is being activated to regulate your blood sugar, we recommend you purchase a blood glucometer. It is an inexpensive device that measures the sugar in a drop of blood you get from your finger. Excess cortisol is not deployed for blood sugar regulation unless your blood sugar drops below about 55 mg/dL. If you notice this happening, you could experiment with increasing your protein intake or the frequency of eating.


  • GNG is stimulated by glucagon, and as long as the GNG response to glucagon is enough to restore blood sugar before it goes down to about 55mg/dL, cortisol will not be called upon to regulate blood sugar.
  • By the time blood sugar levels have gotten so low that cortisol is deployed to help fix it, hypoglycemic symptoms also appear.
  • Keto dieters don’t appear to experience hypoglycemic symptoms (except in some cases involving inadequate protein or prolonged fasting). In fact keto diets, especially protein-adequate keto diets, have been used to reduce the occurrence of hypoglycemic episodes in susceptible people.
  • Therefore it is not true that because keto diets use GNG for blood sugar regulation, they cause stress to the body.
  • Since blood sugar is easily measured, you can indirectly test for whether cortisol is being used to regulate your blood sugar yourself. If you find it to be low, there are other strategies you can try to alleviate it that don’t involve giving up your keto diet.


¹ Statements that imply this argument can be found in quotes like these:

That latter one seems to be a mistaken generalization that came from taking Mat Lalonde’s comments out of context. Lalonde was describing his experience of severe hypoglycemia that happened after extremely intense exercise. He said: “Gluconeogenesis gets turned on by cortisol and other hormones and it’s not that fast. In order for gluconeogenesis to ramp up, cortisol has to ramp up.” By “ramp up”, we infer he means ramp up enough to keep up with the excessive intensity he had induced — a situation unlikely to occur in most keto dieters. We hope to return to the subject of keto diets and athletics another time.

² Evidence type: repeated experimental evidence.
Ober, K. Patrick (Ed.) Endocrinology of Critical Disease. 1997 Humana Press.

(Emphasis ours.)

The importance of maintaining a fairly constant level of serum glucose is reflected in the elaborate system for defending against falling glucose concentrations. Four major counterregulatory hormones are of varying importance and effectiveness in counteracting a hypoglycemic threat, and there is a hierarchy of response of the factors that counterbalance the threat of hypoglycemia. Each factor has a somewhat different threshold for activation (39 ³, 40) and the physiological importance of each component in the system of defense against hypoglycemia tends to be reflected by its position in the hierarchy. Small decreases in the plasma glucose concentration to the threshold of 65 mg/dL (3.6 mM/L) are usually sufficient to trigger the secretion of glucagon and epinephrine (40,41), the hormones that are of greater counterregulatory importance. Cortisol levels do not increase until the blood glucose falls below 55 mg/dL.

The single most important counteregulatory hormone is glucagon, which enhances hepatic glycogenolysis and gluconeogenesis; without glucagon, full recovery from hypoglycemia does not occur (1). Epinephrine, which has an additional action of inhibiting insulin secretion, is not necessary for counterregulation of hypoglycemia when glucagon is present, but it becomes essential in the absence of glucagon (a common occurrence in the patient with insulin-dependent diabetes). Growth hormone and cortisol are slower to act as counterregulatory agents, and these hormones do not make any substantial contribution to glucose counterregulation during acute insulin-induced hypoglycemia (42); since growth hormone and cortisol cannot compensate effectively for hypoglycemia in the absence of glucagon and epinephrine, they are of secondary importance in the counterregulatory scheme (34).

The relevant references from that passage are:

³(Ober’s 39.) Evidence type: experimental.
Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic threshold for activation of glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest 1987;79:777-781.
(Emphasis ours.)

Arterialized venous plasma glucose concentrations were used to calculate glycemic thresholds of 69 +/- 2 mg/dl for epinephrine secretion, 68 +/- 2 mg/dl for glucagon secretion, 66 +/- 2 mg/dl for growth hormone secretion, and 58 +/- 3 mg/dl for cortisol secretion. In contrast, the glycemic threshold for symptoms was 53 +/- 2 mg/dl, significantly lower than the thresholds for epinephrine (P less than 0.001), glucagon (P less than 0.001), and growth hormone (P less than 0.01) secretion.

(Ober’s 40.) Evidence type: experimental.
Mitrakou A, Ryan C, Veneman T, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 1991;260:E67-E74.

The glycemic thresholds for increases in plasma growth hormone, glucagon, epinephrine, and norepinephrine were not significantly different from one another (-67 mg/dl) but were significantly higher than that for cortisol (55 t 2 mg/dl, P < 0.004-0.0003) and for the appearance of autonomic symptoms (58 t 2 mg/ dl, P c 0.039-0.001).

(Ober’s 41.) Evidence type: experimental.
Bolli GB, Fanelli CG. Unawareness of hypoglycemia. N Engl J Med 1995;333:1771-1772.

In normal humans, small decreases in the plasma glucose concentration to the threshold of 65 mg per deciliter (3.6 mmol per liter) elicit the secretion of the rapid-acting counterregulatory hormones glucagon and epinephrine, which oppose the glucose-lowering effects of insulin in plasma within minutes. Should plasma glucose levels decrease further, to about 55 mg per deciliter (3.1 mmol per liter), the secretion of counterregulatory hormones increases, and autonomic symptoms (anxiety, palpitations, hunger, sweating, irritability, and tremor) appear, as well as neuroglycopenic symptoms (dizziness, tingling, blurred vision, difficulty in thinking, and faintness).

Evidence type: case studies
Jerome W. Conn. THE ADVANTAGE OF A HIGH PROTEIN DIET IN THE TREATMENT OF SPONTANEOUS HYPOGLYCEMIA: Preliminary Report. Published in Volume 15, Issue 6, J Clin Invest. 1936; 15(6):673 doi:10.1172/JCI100819

Waters(5) in 1931 advised strict curtailment of the carbohydrate in the diet, most of the calories being derived from fat. Following this a high fat, low carbohydrate diet with feedings divided into six daily meals was generally adopted. On this regime there was often prompt improvement; but while hypoglycemic attacks were diminished in number, they still occurred with alarming frequency.

It was realized, then, that the ingestion of large amounts of protein would supply glucose to the blood stream at a constant, slow rate, without the production of a hyperglycemia.


1. The slow rate at which glucose is liberated into the blood stream during the metabolism of protein is of advantage in the treatment of spontaneous hypoglycemia because —

(a) It causes no hyperglycemia and thus avoids excessive production of insulin and secondary hypoglycemia.

(b) It provides a source of glucose over a prolonged period of time.

(c) It allows in severe cases further restriction in carbohydrate than could otherwise be effected.

2. These facts justify the use of a diet high in protein and low in carbohydrate in the treatment of this condition.

Evidence type: experiment.
Hofeldt FD. Reactive hypoglycemia. Metabolism. 1975 Oct;24(10):1193-208.
(Emphasis ours)

The backbone of successful management of reactive hypoglycemia is the diet. A 100-g carbohydrate diet, isocaloric (25 calories per kilogram body weight) with six equal feedings with avoidance of refined carbohydrates will be successful in the majority of cases. Some authors report a beneficial effect by the restriction of caffeine-containing beverages(33,39,53,60,32-134) and alcohol.(33,35) Alcohol utilizes important gluconeogenic NAD substrate (17,136,137) for its metabolism, depresses the activity of important gluconeogenic enzymes,(138,139) limits alanine and substrate availability.(140)

An occasional case may show worsening on the low-carbohydrate, high-protein diet. Since there is an aminogenic influence on insulin secretion, this could potentially aggravate the reactive hypoglycemia in some patients. However, the concurrent protein stimulation of glucagon release could offset the effects of insulin.(18,23,145) Our studies on hepatic gluconeogenesis have shown that in patients with the fructose 1-6 diphosphatase deficiency there is characteristically a worsening of symptoms when stressed with a low-carbohydrate (ketogenic) diet. These patients, in order to maintain blood-glucose levels early in the fasting state, must call on adrenergic mechanisms to release glycogen stores. Similarly, an occasional patient will develop intolerant symptoms while on the low-carbohydrate, weight reduction Stillman or Atkins diet. These patients may well show similar hepatic enzyme defects. In this special low-carbohydrate intolerant subgroup, the stress of any ketotic diet is avoided and dietary carbohydrates are increased to 150 g or greater. We are presently conducting studies on the therapeutic effectiveness of folic acid (15 mg/day) in these patients with beneficial results.

Keto-adaptation: what it is and how to adjust

What is keto-adaptation?

Keto-adaptation is the process of shifting your metabolism from relying mostly on glucose for fuel, to relying mostly on fat-based sources of fuel. Not only does fat oxidation itself increase, but your body starts producing enough ketones that they can be used as a significant source of fuel as well. Ketones are derived from partially metabolized fat, and they can be used in many of the same tissues of the body as glucose can, including much of the brain. The benefits of using fat and ketones rather than glucose for fuel are many, and are the main subject of this site. However, it takes time for the metabolism to adjust to producing and using ketones at a significant rate. Even though changes are evident within days of carbohydrate restriction, improvements continue for weeks.

In brief:

  • Carbohydrate-based fueling is a self-perpetuating cycle: it runs out quickly, and every time you eat more carbs you delay adaptation to fat-burning.
  • Fat-based fueling is sustainable, because it allows access to a very large store of energy without you frequently stopping to refuel. Blood sugar is maintained though precise internal processes without wild swings. These two together create a desirable flow of even, stable energy, mood, and alertness.
  • There is a delay between first reducing the amount of carbohydrates that you eat, and having a smoothly running fat metabolism. In the intervening days, you may feel slow, or even unwell. These symptoms can be minimized by making sure to eat lots of fat, staying hydrated, and using salt liberally. Other electrolytes may also be helpful to add — homemade broth makes a good supplement. Keep carbs consistently low, or you will never adapt and the process will go on indefinitely.

Carbohydrate-based fueling is a self-perpetuating cycle.

The body can store only relatively small amounts of glucose, in the form of glycogen. About 100 grams can be stored in the liver, and about 400 grams can be stored in the muscles. Muscle glycogen can only be used by the muscle it is stored in — it can’t go back to the bloodstream — so the liver glycogen is the only source that can be used to keep blood sugar stable, and provide fuel for the brain. If you are not making use of ketones for fuel, then this is not enough glucose to get through a typical day, let alone a day when you are doing something strenuous. If you depend on glucose metabolism, then you have to frequently replenish your glycogen stores or you will begin to feel tired, physically and mentally.

There are basically two ways to get the necessary glucose, and only one of them involves eating it. The first is to eat carbohydrate. Unfortunately, every time you ingest more than a small amount of carbohydrate, it stops all progression toward keto-adaptation. So this strategy is a Catch-22. It makes you continually dependent on dietary carbohydrate. It locks you in, because supply is limited, but restocking prevents other fuels from becoming available.

The other way to get glucose is to let the body make its own on demand out of protein. This process is called gluconeogenesis. Gluconeogenesis is the reason that eating carbohydrate is not necessary, even though some amount of glucose is manufactured and used internally. This is analogous to any other internally produced nutrient, such as vitamin D, which we don’t need to ingest, because the body makes it in response to sun exposure, or to a hormone, like adrenaline, that we make and use every day, but don’t need to get from food.

One of the benefits that comes directly from this physiological mechanism is that on a keto diet you will no longer need to eat so often. Skipping a meal does not become an emergency, or even a problem. A lot of people have problems with mood, cognition, and wakefulness if they don’t eat frequently. On a keto diet your blood sugar will naturally become steady, and the advice to eat every 3 hours to prevent hypoglycemia will become irrelevant.

What exactly happens during keto-adaptation?

In their recent book The Art and Science of Low Carbohydrate Living, Volek and Phinney describe two stages of keto-adaptation. In the first few days of a keto diet, your body is still running on glycogen stores. This is the toughest part of the process, because in order to break the vicious cycle of glucose-based metabolism, you have to avoid eating carbohydrates, even though your glycogen stores are dwindling. Fat metabolism is still not optimized, and ketone production hasn’t become significant.

Another noticeable effect in the first days is water loss. One of the inefficiencies of glycogen storage is that it needs to be stored with water. It takes about 3 or 4 grams of water to store a gram of glycogen [1] . This means that as you deplete your glycogen stores you could lose up to 2 kg of water! Not only that, but high circulating insulin levels cause water retention by inhibiting sodium excretion (see e.g. [2]). The keto diet lowers insulin levels and increases insulin sensitivity, allowing excess fluid to be released. These combined effects are the origin of the claim that the weight lost on keto diets is due to water loss. In the very beginning, this is true, but subsequently, of course, it is not.

When glycogen runs out, you start producing ketones, and some are excreted in the urine. This is easy to measure, and some keto dieters use it to know if they are hitting a low enough level of carbohydrate restriction. This also marks the beginning of the second stage of keto-adaptation. Ketones are now becoming available for fuel, but they haven’t yet risen to their stable adapted level. There is an interesting interplay between ketone use in the muscles and the brain. When ketone levels are low, the muscles tend to use them directly for fuel, but as levels increase, the muscles use them less, turning to fat for fuel instead. The brain, on the other hand, uses ketones proportionally to their concentration in the blood. This means that at low levels of ketones, the brain’s supply is not much affected, because the muscles intercede, but above some threshold, the brain’s supply rapidly becomes much higher. At this point, the brain can rely on ketones, and since it is no longer susceptible to running out of fuel, the need to eat frequently throughout the day to maintain mental function disappears. The muscles in turn now rely on fat: they finally have access to a virtually unlimited supply of energy, which is particularly valuable for athletes.

Much confusion has been generated by scientists not recognizing one or both stages of keto-adaptation. A few studies have been publicized claiming that low carbohydrate diets worsen mental or physical performance (e.g. [3], [4]). On reading the details, it turns out that the testing was done in the first few days of carbohydrate restriction. Obviously, these studies are not valid criticisms of the keto diet, except as measurements of the initial adaptation cost. They do not reflect the longer-term outcome.

How to make keto-adaptation as quick and painless as possible

As noted above, the difficult part of keto-adaptation is the first stage. There are two reasons. The first is that glucose is less available, but fat and ketone metabolism haven’t effectively taken over. The best strategy for coping with this is to eat a lot of fat. Even if you eventually wish to get most of your fat from your fat stores, you do not normally need to restrict it in the diet, and especially not now. Fat is an important source of essential fatty acids and nutrients. Moreover, ingesting fat with protein helps to moderate the insulin response. A keto diet is not a high protein diet, it is a high fat diet. Do not fear it. Eat plenty of fat during keto-adaptation to ensure you have energy available.

The second difficulty is a result of the sodium excretion and transient rapid water loss we mentioned. If care is not taken to replenish sodium and water, both sodium and potassium are sometimes lost too rapidly. This can cause tiredness, weakness, and headaches. Be sure to get enough sodium: about 5 grams per day, or 2 teaspoons of table salt, will help prevent these symptoms.

Adequate potassium may be necessary to preserve lean mass [5], and magnesium deficiency can lead to muscle cramps, as well as fatigue and dizziness. Both of these minerals are abundant in meat, but are easily lost though cooking: into the water, if the meat was boiled, or the drippings otherwise. In addition to taking care to preserve the liquid from meat, acute effects can be cut short through supplementing potassium and magnesium by capsule. We recommend regularly drinking broth.

Finally, keep your dietary carbohydrates low. The worst scenario is to eat some every few days — you will set yourself back, and be in perpetual limbo. Now is not the time to experiment with your carbohydrate tolerance, or eat foods you aren’t sure about the content of. Commit to a very low level of carbohydrate intake, and stay with it consistently for at least long enough to get ketone production in full force. Most people we have talked to, if they experienced any discomfort at all, felt fully functional within 4 or 5 days. However, metabolic changes continue for at least two weeks and often more [6]. We recommend a 30 day trial at near zero levels of carbohydrate, to give yourself a chance to experience a completely keto-adapted state.


  • The USDA National Nutrient Database for Standard Reference is a large database of nutrients including carbohydrate levels of whole foods and fast foods both.
  • Testing strips for urine ketones are useful for figuring out if you are getting into ketosis. We haven’t tried this brand, but it’s currently a good price. We’ve used Ketostix, and they work fine.
  • A fancier tool is a blood ketone meter. It works just like a glucose meter. In fact it doubles as one. This is better than urine testing, because it is more accurate, and it measures actual blood concentration. However, the test strips are pretty expensive.

Further Reading:


[1] Evidence type: experimental.
Olsson, K.-E. and Saltin, B. (1970), Variation in Total Body Water with Muscle Glycogen Changes in Man. Acta Physiologica Scandinavica, 80: 11–18. doi: 10.1111/j.1748-1716.1970.tb04764.x

“19 subjects performed prolonged heavy arm and leg exercise after which they had a protein and fat diet for three days. Thereafter they switched to a carbohydrate enriched diet during a 4-day period. The measurements were performed on the 3rd day and then repeated on the 7th day. The glycogen concentration in the thigh and the arm muscles was 4.5 and 2.6 g/kg wet muscle on the 3rd day and increased with the carbohydrate enriched diet to 19.9 and 16.9 g/kg wet muscle, respectively. Body weight increased 2.4 kg during this period of 4 days. The total body water increased 2.2 1 which is assumed to be caused by the glycogen storage in the muscles and the liver. The amount of glycogen stored was calculated to be at least 500 g, which means that 3-4 g of water is bound with each gram of glycogen.”

[2] Evidence type: review of a variety of experimental conditions.
R. A. DeFronzo (1981) The effect of insulin on renal sodium metabolism: A review with clinical implications. Diabetologia Volume 21, Number 3, 165-171, DOI: 10.1007/BF00252649

Data are discussed which demonstrate that insulin plays an important role in sodium metabolism. The primary action of insulin on sodium balance is exerted on the kidney. Increases in plasma insulin concentration within the physiological range stimulate sodium reabsorption by the distal nephron segments and this effect is independent of changes in circulating metabolites or other hormones. Several clinical situations are reviewed: sodium wasting in poorly controlled diabetics, natriuresis of starvation, anti-natriuresis of refeeding and hypertension of obesity, in which insulin-mediated changes in sodium balance have been shown to play an important pathophysiological role.”

[3] Langfort J, Zarzeczny R, Pilis W, Nazar K, Kaciuba-Uścitko H. The effect of a low-carbohydrate diet on performance, hormonal and metabolic responses to a 30-s bout of supramaximal exercise. Eur J Appl Physiol Occup Physiol. 1997;76(2):128-33.

The aim of this study was to find out whether a low-carbohydrate diet (L-CHO) affects: (1) the capacity for all-out anaerobic exercise, and (2) hormonal and metabolic responses to this type of exercise. To this purpose, eight healthy subjects underwent a 30-s bicycle Wingate test preceded by either 3 days of a controlled mixed diet (130 kJ/kg of body mass daily, 50% carbohydrate, 30% fat, 20% protein) or 3 days of an isoenergetic L-CHO diet (up to 5% carbohydrate, 50% fat, 45% protein) in a randomized order.

The main conclusions of this study are: (1) a L-CHO diet is detrimental to anaerobic work capacity, possibly because of a reduced muscle glycogen store and decreased rate of glycolysis; (2) reduced carbohydrate intake for 3 days enhances activity of the sympathoadrenal system at rest and after exercise.

[4] D’Anci KE, Watts KL, Kanarek RB, Taylor HA. Low-carbohydrate weight-loss diets. Effects on cognition and mood. Appetite. 2009 Feb;52(1):96-103. Epub 2008 Aug 29.

In the present experiment, cognitive effects of a low-carbohydrate diet were compared to those of another popular weight reduction diet over a 3-week period.

These data suggest that after a week of severe carbohydrate restriction, memory performance, particularly on difficult tasks (e.g., backward compared to forward digit span; spatial memory), is impaired.

Comment: This paper is interesting. The low carb dieters experienced memory deficits one week into the diet, and long term memory problems later, but the long term memory experiments were from memories that were formed at that same one week point, and so the problems were likely to be from poor memory formation, not poor recall ability. The authors suggest that cognition was better after more carbohydrate was added, but in the latter two weeks of the experiment the amount of carbohydrate added was very low, and the subjects were still well within ketogenic levels. So this isn’t a very compelling explanation. It seems much more plausible to us that this improvement was from keto-adaptation. While we don’t completely agree with the analysis of the authors, they did not state such a ridiculous interpretation of their findings in their paper as they did in the press: Science Daily reports:

A new study from the psychology department at Tufts University shows that when dieters eliminate carbohydrates from their meals, they performed more poorly on memory-based tasks than when they reduce calories, but maintain carbohydrates. When carbohydrates were reintroduced, cognition skills returned to normal.

“This study demonstrates that the food you eat can have an immediate impact on cognitive behavior,” explains Holly A. Taylor, professor of psychology at Tufts and corresponding author of the study. “The popular low-carb, no-carb diets have the strongest potential for negative impact on thinking and cognition.”

Whereas the abstract itself was more factual:

“Results showed that during complete withdrawal of dietary carbohydrate, low-carbohydrate dieters performed worse on memory-based tasks than ADA dieters. These impairments were ameliorated after reintroduction of carbohydrates. Low-carbohydrate dieters reported less confusion (POMS) and responded faster during an attention vigilance task (CPT) than ADA dieters. Hunger ratings did not differ between the two diet conditions. The present data show memory impairments during low-carbohydrate diets at a point when available glycogen stores would be at their lowest. A commonly held explanation based on preoccupation with food would not account for these findings. The results also suggest better vigilance attention and reduced self-reported confusion while on the low-carbohydrate diet, although not tied to a specific time point during the diet. Taken together the results suggest that weight-loss diet regimens differentially impact cognitive behavior.”

In other words, except for the memory problems that can be accounted for by keto-adaptation, the low carb dieters had equal or better cognitive performance than the ADA dieters, and yet this is cited as proof of the opposite!

[5] Evidence type: explanation and comparison of experiments.
Stephen D Phinney (2004) Ketogenic diets and physical performance. Nutrition & Metabolism 2004, 1:2 doi:10.1186/1743-7075-1-2

“An example of what happens when these mineral considerations are not heeded can be found in a study prominently published in 1980 [18]. This was a study designed to evaluate the relative value of “protein only” versus “protein plus carbohydrate” in the preservation of lean tissue during a weight loss diet. The protein only diet consisted solely of boiled turkey (taken without the broth), whereas the protein plus carbohydrate consisted of an equal number of calories provided as turkey plus grape juice. Monitored for 4 weeks in a metabolic ward, the subjects taking the protein plus carbohydrate did fairly well at maintaining lean body mass (measured by nitrogen balance), whereas those taking the protein only experienced a progressive loss of body nitrogen.

A clue to what was happening in this “Turkey Study” could be found in the potassium balance data provided in this report. Normally, nitrogen and potassium gains or losses are closely correlated, as they both are contained in lean tissue. Interestingly, the authors noted that the protein only diet subjects were losing nitrogen but gaining potassium. As noted in a rebuttal letter published soon after this report [19], this anomaly occurred because the authors assumed the potassium intake of their subjects based upon handbook values for raw turkey, not recognizing that half of this potassium was being discarded in the unconsumed broth. Deprived of this potassium (and also limited in their salt intake), these subjects were unable to benefit from the dietary protein provided and lost lean tissue. Also worthy of note, although this study was effectively refuted by a well-designed metabolic ward study published 3 years later [20], this “Turkey Study” continues to be quoted as an example of the limitations of low carbohydrate weight loss diets.”

[6] Evidence type: experiment.
Oliver E. Owen, Philip Felig, Alfred P. Morgan, John Wahren, and George F. Cahill, Jr. Liver and kidney metabolism during prolonged starvation. J Clin Invest. 1969 March; 48(3): 574–583.

“Blood glucose and insulin concentrations fell acutely during the 1st 3 days of fasting, and alpha amino nitrogen after 17 days. The concentration of free fatty acids, β-hydroxybutyrate, and acetoacetate did not reach a plateau until after 17 days.”