How much protein is enough?

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It seems, from clinical claims and numerous anecdotes, that protein intake has to be below some threshold for ketogenesis to continue, all else being equal.
(Conditions are rarely equal: the effects of fat intake, calorie intake, the profile of amino acids in your diet, the type of fat in your diet, exercise, and frequency of eating also matter!)
It is commonly assumed that excess protein gets immediately turned into glucose by gluconeogenesis.
However, we’ve shown in a series of articles (part 1, part 2, part 3, part 4)
that such a mechanism is highly unlikely —
excess protein does not just get immediately turned into glucose.
The evidence points to gluconeogenesis being driven by demand for glucose, not supply of protein.
However, it does appear that above a certain level of protein intake ketogenesis declines.
So regardless of mechanism, as ketogenic dieters, we probably still need to limit protein.
It’s not clear how much is too much.
But how much is enough?
It is important not to turn a healthy, ketogenic diet into an unhealthy starvation diet!
In this article we review some answers to this question, and some unanswered questions.

In Brief

  • It’s important to get enough protein.
  • The RDA for protein is too low: if you are like most people, your health will suffer if you eat as little protein as the RDA requires.
  • Getting the minimum may not be optimal, but getting less than the minimum would be a mistake.
  • There are several different conditions that are commonly believed to affect protein requirements.
    In particular, exercise and weight loss have both been said to increase protein needs.
    We couldn’t find definitive support for either of those beliefs.
  • We are most interested in studies that apply to keto dieters.
    Evidence from experiments on the Protein-Sparing Modified Fast is quite likely to apply to keto dieters.
    However, experiments on Protein-Sparing Modified Fasts leave out an important factor: fat intake, which may reduce protein requirements by reducing the need to use protein for energy.
  • We estimate that females should get at least 1.2 g/kg of ideal weight per day, and males at least 1.4 g/kg of ideal weight. [Edit 2014-01-11: (this may possibly be lowered by fat intake; see below)]
Measuring protein intake: per body weight, not percent of calories
Let’s head off confusion by distinguishing different ways to measure protein intake.
You’ll sometimes see protein intake expressed in terms of percent of total calorie intake.
For example, the USDA recommends 10-35% of calories from protein.
But this measures how much you are eating, not how much you are using!
If you are losing weight, then (hopefully!) some of the calories you are burning are coming from your body fat instead of from your diet.
Measuring protein requirements as a percent of intake ignores those calories.
In this case, the percent of protein you are eating would be higher than the percent you are using.
A better way to express protein requirements is in terms of body weight.
You are made in large part out of protein and so the more of you there is, the more protein you need to maintain your structures.
We have seen protein requirements in the form of percent of your ideal body weight, percent of your lean mass, or simply percent of your body weight.
These make more sense than percent of calories in this context.

Protein is essential to the body

Protein is necessary for virtually every biological process.
Enzymes, antibodies, cellular receptors, and collagen are just a few examples of protein structures, but there are maybe 2 million different proteins functioning in the body [1].
Getting too little protein to provide for these structures could adversely affect many aspects of health, especially growth and maintenance of bone and muscle, and immune function [2], [3], [4].
Although the body recycles the amino acids that proteins are built from (this is called protein “turnover”), there are also constant losses that need to be replaced (“obligatory nitrogen losses”) [5].

The RDA is not enough

The lowest estimates of minimum requirements we have seen is the USDA RDA (it’s now called RDI) of 0.8g per kg of body weight per day (for adults) [6].
Even they admit, in their 1000+ page explanation of macronutrient RDAs (RDAs for protein, fat and carbohydrate) from the Institute of Medicine, that the method they used to determine adequate protein levels (called “nitrogen balance”) is likely to result in underestimates [7].
Because of this, and because there was a flaw in the mathematical model that was used to derive the recommendations, a 2010 study reanalysed the same data that was used to generate the USDA RDA recommendations.
They concluded that the recommendations should be 50% higher than they are [8].
That is, they conclude that for most people, 1.2g/kg/day of protein intake is necessary.
There is also experimental evidence that suggests the RDA is inadequate [9].

Different conditions may require different amounts of protein

An issue with using the results of these studies, is that, as with any physiological experiments, when you change the base conditions, the results may suddenly no longer apply.
Changes that might make these conclusions inapplicable include what happens during high levels of physical activity, weight loss, or when consuming different levels of macronutrients. Specifically we want to know if protein requirements change when keto-adapted.
Exercise conditions
Whether higher levels of exercise increase protein needs is controversial.
Some studies suggest that endurance exercise increases the need for protein because protein is oxidised (used for energy) during the exercise [10].
However, there is also evidence that after a period of training this oxidation is limited by downregulation of the necessary enzymes [11].
That is, after doing it regularly, the body learns to spare the protein and stops letting it be used in that way.
In particular, it is the BCAAs (branched chain amino acids) that appear to be oxidised [11].
Since BCAAs are known to be elevated in keto dieters,
it’s possible that any such effect would be minimal for us in the first place or that the downregulation has already taken place.
In fact, infusing people with beta-hydroxybutyrate (the ketone body we check for in the blood to see if someone is in deep ketosis) reduces leucine oxidation and promotes protein synthesis [12].

(Leucine is a BCAA — it is probably the most important BCAA for ketogenic metabolism. More on that another day.)

As for weight lifting,
it seems intuitive that if you are building muscle, you will need more protein.
Some studies seem to show this, but others actually show the reverse [13], [14], [15].
The subjects in those studies, of course, were not on keto diets.
These facts taken together seem to suggest that when you adapt to a hormonal state that favours muscle preservation or gain, whether it is a ketogenic state, or the state of regular exercise stimulus, it reduces the need for protein.
Indeed, ketosis is known to be protein-sparing, and that may mean that you actually need less protein.
Protein requirements and weight loss
We have seen it asserted that weight loss itself increases the need for protein.
However, the only studies we have seen that claim to prove it are flawed [16], [17].
It is still possible that weight loss requires more protein, but we haven’t yet been convinced either way.
Note that this is different from the claim that higher protein diets improve weight loss (even when carbohydrates are not ketogenically low), which has shown repeatedly [18], [19], [20], [21], [22].
Since protein is generally taking the place of carbohydrate, we would certainly expect that to be true.
Relatedly, it is often claimed that weight loss is necessarily accompanied by some loss of lean mass.
This has a plausible mechanism.
For one thing, in people with lots of excess fat, more muscle, bone, and other infrastrucure has been built to carry the excess weight, and as the stimulus of the weight of the fat recedes, the extra muscle built to hold it might atrophy.
Nonetheless, there are some studies of keto diets used for weight loss in which lean mass was preserved or even increased, for example in [24] and [25].

Protein requirements for keto dieters

Since retaining lean mass requires sufficient protein (among other things), studies in which keto dieters retained lean mass must have been protein adequate.
Note that the reverse is not true: if a study had keto dieters losing lean mass, that doesn’t imply that protein intake was inadequate.
Other factors, such as mineral intake [23], and activity level and type [24] can effect muscle retention.
The Protein-Sparing Modified Fast
One particular kind of ketogenic weight loss diet that specifically aims to provide just enough protein to prevent muscle loss is called a Protein-Sparing Modified Fast.
The developers of the Protein-Sparing Modified Fast were hypothesising that fasting would be the perfect therapy for the treatment of obesity, if it weren’t for the resulting detrimental and dangerous loss of lean mass.
They discovered that by adding enough protein, subjects lost fat effectively, but without losing lean mass.
In particular, it was found that males preserved lean mass at 1.4 g/kg ideal body weight, and females at 1.2 g/kg ideal body weight [25].
This is particularly relevant for us, since the Protein-Sparing Modified Fast is a ketogenic condition.
Adding fat into the mix
In addition to the effects of being keto-adapted, we would like to know what the effect of the amount of fat in the diet has, if any, on protein requirements.
It is plausible that if for some reason the rate of oxidation of fat stores were limited, that some dietary protein might be oxidised for fuel.
If this were the case, then the addition of fat should lessen protein requirements.
In other words, if there is a rate limit to getting fat out of fat stores, then adding sufficient dietary fat to make up for the energy requirements not met by adipose tissue would spare protein.
On a keto diet, since carbohydrates are limited, and protein levels that are too high are undesirable (though how high is “too high” is not well understood), energy balance is made up by dietary fat.
(And besides, fat is an important source of essential fatty acids and nutrients.)
Unfortunately, we don’t know of studies that test this in either weight loss or weight maintenance conditions.


It is important to get enough protein.
We looked at the RDA, and that is certainly too low, so we looked for other sources of evidence.
We also tried to determine if some common conditions would alter the amount needed, without coming to any strong conclusions.
We wanted to find evidence that would be relevant to ketogenic dieters in particular.
Studies based on the Protein-Sparing Modified Fast don’t match our needs exactly, since we eat lots of fat, but at least the participants were in ketosis.
Based on those studies, we think females need at least 1.2 g/kg of ideal body weight, and men at least 1.4.
However, we still don’t know how high protein can be before it interferes with ketosis, and this is likely to vary by individual.
Moreover, we don’t know if it would be better for your health to have just the minimum, or to have substantially more.
It is certainly plausible that having more would allow for better functioning.


[1] Evidence type: authority
“The word “proteome” is derived from PROTEins expressed by a genOME, and it refers to all the proteins produced by an organism, much like the genome is the entire set of genes. The human body may contain more than 2 million different proteins, each having different functions. As the main components of the physiological pathways of the cells, proteins serve vital functions in the body such as:

  • catalyzing various biochemical reactions, e.g. enzymes;
  • acting as messengers, e.g. neurotransmitters;
  • acting as control elements that regulate cell reproduction;
  • influencing growth and development of various tissues, e.g. trophic factors;
  • transporting oxygen in the blood, e.g. hemoglobin; and
  • defending the body against disease, e.g. antibodies.
[2] Evidence type: experimental

Castaneda C, Charnley JM, Evans WJ, Crim MC.
Am J Clin Nutr. 1995 Jul;62(1):30-9.

“A 9-wk study of adaptation to marginal protein intakes was conducted in 12 elderly women. Subjects were randomly assigned to two groups fed a weight-maintenance diet containing either 1.47 (low) or 2.94 (adequate) g body cell mass-1.d-1 (0.45 and 0.92 body wt-1.d-1, respectively). Mean nitrogen balance in the low-protein group remained negative throughout the study. These subjects experienced significant losses in lean tissue, immune response, and muscle function. The adequate-protein group was in nitrogen balance throughout the study, without changes in lean tissue, and with improvements in immune response, serum immunoglobulins, albumin, total protein values, and muscle function. Thus, elderly women fed the low-protein diet accommodated to the diet by compromising functional capacity, whereas those fed the adequate diet maintained functional capacity.”

[3] Evidence type: summary of experiments

Peng Li, Yu-Long Yin, Defa Li, Sung Woo Kim and Guoyao Wu.
British Journal of Nutrition (2007), 98, 237–252 doi: 10.1017/S000711450769936X

“A deficiency of dietary protein or amino acids has long been known to impair immune function and increase the susceptibility of animals and humans to infectious disease. However, only in the past 15 years have the underlying cellular and molecular mechanisms begun to unfold. Protein malnutrition reduces concentrations of most amino acids in plasma. Findings from recent studies indicate an important role for amino acids in immune responses by regulating: (1) the activation of T lymphocytes, B lymphocytes, natural killer cells and macrophages; (2) cellular redox state, gene expression and lymphocyte proliferation; and (3) the production of antibodies, cytokines and other cytotoxic substances. Increasing evidence shows that dietary supplementation of specific amino acids to animals and humans with malnutrition and infectious disease enhances the immune status, thereby reducing morbidity and mortality.”

[4] Evidence type: observational

Bonjour JP, Ammann P, Chevalley T, Rizzoli R.
Can J Appl Physiol. 2001;26 Suppl:S153-66.

“Among osteotrophic nutrients, proteins play an important role in bone development, thereby influencing peak bone mass. Consequently, protein malnutrition during development can increase the risk of osteoporosis and of fragility fracture later in life. Both animal and human studies indicate that low protein intake can be detrimental for both the acquisition of bone mass during growth and its conservation during adulthood. Low protein intake impairs both the production and action of IGF-I (Insulin-like growth factor-I). IGF-I is an essential factor for bone longitudinal growth, as it stimulates proliferation and differentiation of chondrocytes in the epiphyseal plate, and also for bone formation. It can be considered as a key factor in the adjustments of calcium-phosphate metabolism required for normal skeletal development and bone mineralization during growth. In healthy children and adolescents, a positive association between the amount of ingested proteins and bone mass gain was observed in both sexes at the level of the lumbar spine, the proximal femur and the midfemoral shaft. This association appears to be particularly significant in prepubertal children. This suggests that, like for the bone response to either the intake of calcium or weight-bearing exercise, the skeleton would be particularly responsive to the protein intake during the years preceding the onset of pubertal maturation.”

[5] Evidence type: summary of experiments

“As protein deficiency declines, the efficiency with which amino acids are reutilized increases, but small amounts of amino acids are continuously degraded, and their nitrogen is lost from the body even when no protein is being consumed. These losses are termed obligatory nitrogen losses. If protein intake declines below the amount of these obligatory losses, the amount of nitrogen excreted by the body will exceed the amount consumed, and the body will be in a state of negative nitrogen balance. As protein intake is increased, nitrogen balance will become less negative until, at some point, a steady state will be reached such that nitrogen intake will equal nitrogen loss; i.,e., nitrogen balance will be zero. An estimate of adult requirements for protein or amino acids can therefore be obtained from measurement of the minimum amount of protein or amino acid nitrogen that must be consumed to just balance body nitrogen losses.”

[6] Dietary Reference Intakes: Macronutrients

[7] Evidence type: summary of experiments

“The nitrogen balance method does have substantial practical limitations and problems. First, the rate of urea turnover in adults is slow, so several days of adaptation are required for each level of dietary protein tested to attain a new steady state of nitrogen excretion (Meakins and Jackson, 1996; Rand et al., 1976). Second, the execution of accurate nitrogen balance measurements requires very careful attention to all the details of the procedures involved. Since it is easy to overestimate intake and underestimate excretion, falsely positive nitrogen balances may be obtained (Hegsted, 1976). Indeed, an overestimate of nitrogen balance seems consistent throughout the literature because there are many observations of quite considerable apparent retention of nitrogen in adults (Oddoye and Margen, 1979). This observation is biologically implausible because (a) adults do not normally accrete body protein, and (b) the magnitude of the positive nitrogen balances is inconsistent with stability of body weight.”
Comment: That last statement is odd. It could be seen as denying the evidence. We actually find it plausible that adults could accrete protein to a greater extent than currently assumed (more on this in a subsequent post). And of course, as every dieter knows, body weight can be stable even while lean mass is increasing, if fat is simultaneously decreasing.

[8] Evidence type: meta-analysis of experiments

Elango R, Humayun MA, Ball RO, Pencharz PB.
Curr Opin Clin Nutr Metab Care. 2010 Jan;13(1):52-7.

“This review discusses recent evidence that suggests a significant underestimation of protein requirements in adult humans.
Traditionally, total protein requirements for humans have been determined using nitrogen balance. The recent Dietary Reference Intake recommendations for mean and population-safe intakes of 0.66 and 0.8 g/kg/day, respectively, of high-quality protein in adult humans are based on a meta-analysis of nitrogen balance studies using single linear regression analysis. We reanalyzed existing nitrogen balance studies using two-phase linear regression analysis and obtained mean and safe protein requirements of 0.91 and 0.99 g/kg/day, respectively. The two-phase linear regression analysis is considered more appropriate for biological analysis of dose-response curves. Considering the inherent problems associated with the nitrogen balance method, we developed an alternative method, the indicator amino acid oxidation technique, to determine protein requirements The mean and population-safe requirements in adult men were determined to be 0.93 and 1.2 g/kg/day and are 41 and 50%, respectively, higher than the current Dietary Reference Intakes recommendations.
The indicator amino acid oxidation-based requirement values of 0.93 and 1.2 g protein/kg/day and the reanalysis of existing nitrogen balance studies are significantly higher than current recommendations. Therefore, there is an urgent need to reassess recommendations for protein intake in adult humans.”

[9] Evidence type: experimental

Anna E. Thalacker-Mercer,1 James C. Fleet,1 Bruce A. Craig,2 and Wayne W. Campbell
J Nutr Biochem. 2010 November; 21(11): 1076–1082.

“Previous studies have suggested that the current RDA for protein (0.8 g•kg−1•d−1) is inadequate to maintain protein homeostasis [5, 32-34], fat-free mass, and skeletal muscle cross-sectional area in older adults [7, 35] while protein intake above the RDA may be needed to maintain lean body mass and type I muscle fiber cross sectional area in older women [5, 6]. The results of our study reveal a molecular signature of a biological response to inadequate dietary protein intake that is consistent with this hypothesis. We believe that the observation that transcripts for “muscle and organ development” and “cell differentiation” increase when the protein intake is greater than the RDA (i.e. cluster C5 in Figure 1) and previous phenotypic data [5-7, 32-35] suggest that there are positive responses to consuming protein in quantities greater than the RDA in skeletal muscle. Thus, our array data are consistent with previous reports that suggest a higher protein intake contributes to a healthier physiological profile [5, 6, 36] and better muscle responses to resistance training [37]. The study duration was not, however, sufficient to directly link changes in the skeletal muscle transcript profile with previously reported phenotypes of adaptation and accommodation [5-7, 32-35].”

[10] Evidence type: experiment

Lemon PW, Dolny DG, Yarasheski KE.
Can J Appl Physiol. 1997 Oct;22(5):494-503.

“Six healthy men completed three 1-hr bouts of treadmill walk-jogging at low (L; 42 +/- 3.9% VO2max), moderate (M; 55 +/- 5.6%), and high (H; 67 +/- 4.5%) exercise intensity in order to determine whether moderate physical activity affects dietary protein needs. Both sweat rate and sweat urea N loss were greater (p < .10) with increasing exercise intensity. Seventy-two hour postexercise urine urea N excretion was elevated (p < .05) over nonexercise control (26.6 +/- 2.96 g) with both M (31.0 +/- 3.65) and H (33.6 +/- 4.39), but not L (26.3 +/- 1.86), intensities. Total 72-hr postexercise urea N excretion (urine + sweat) for the M and H exercise was greater than control by 4.6 and 7.2 g, respectively. This suggests that 1 hr of moderate exercise increases protein oxidation by about 29-45 g, representing approximately 16-25% of the current North American recommendations for daily protein intake. These data indicate that the type of exercise typically recommended for health/wellness can increase daily protein needs relative either to sedentary individuals or to those who exercise at lower intensities.”

[11] Evidence type: review of experiments

Tarnopolsky M.
Nutrition. 2004 Jul-Aug;20(7-8):662-8.

“Human skeletal muscle can oxidize at least eight amino acids (alanine, asparagine, aspartate, glutamate, isoleucine, leucine, lysine, and valine; 70); however, during exercise, the branched-chain amino acids (BCAA: isoleucine, leucine, and valine) are preferentially oxidized (43, 49, 58, 70). The BCAA are transaminated to their keto-acids via branched-chain aminotransferase (BCAAT), with subsequent oxidation occurring via branched-chain oxo-acid dehydrogenase enzyme (BCOAD; 8, 9). The amino-N group is usually transaminated with α-ketoglutarate to form glutamate, which is then transaminated with pyruvate to form alanine or aminated via glutamine synthase to form glutamine (15, 57). The BCOAD enzyme is rate limiting in BCAA oxidation, with about 5 to 8% being active (dephosphorylated) at rest, and 20 to 25% being active during exercise (8, 49).”

[12] (Thank you to Bill Lagakos for pointing us to this study.)
Evidence type:

Nair KS, Welle SL, Halliday D, Campbell RG.
J Clin Invest. 1988 Jul;82(1):198-205.

“Because intravenous infusion of beta-hydroxybutyrate (beta-OHB) has been reported to decrease urinary nitrogen excretion, we investigated in vivo metabolism of leucine, an essential amino acid, using L-[1-13C]leucine as a tracer during beta-OHB infusion. Leucine flux during beta-OHB infusion did not differ from leucine flux during normal saline infusion in nine normal subjects, whereas leucine oxidation decreased 18-41% (mean = 30%) from 18.1 +/- 1.1 (P less than 0.01), and incorporation of leucine into skeletal muscle protein increased 5-17% (mean = 10%) from 0.048 + 0.003%/h (P less than 0.02). Since blood pH during beta-OHB infusion was higher than the pH during saline infusion, we performed separate experiments to study the effect of increased blood pH on leucine kinetics by infusing sodium bicarbonate intravenously. Blood pH during sodium bicarbonate infusion was similar to that observed during the beta-OHB infusion, but bicarbonate infusion had no effect on leucine flux or leucine oxidation. We conclude that beta-OHB decreases leucine oxidation and promotes protein synthesis in human beings.”

[13] Evidence type: uncontrolled experiment

Pikosky M, Faigenbaum A, Westcott W, Rodriguez N.
Med Sci Sports Exerc. 2002 May;34(5):820-7.

“Healthy children (N = 11, 8.6 +/- 1.1 yr, 33.7 +/- 9.4 kg, 131 +/- 9.6 cm, BMI = 19.1 +/- 3.4) participated in a supervised resistance-training program 2 times.wk-1 for 6 wk. 15N glycine methodology was used to assess nitrogen flux (Q), protein synthesis (PS), protein breakdown (PB), and net turnover ([NET] = PS – PB) before (PRE) and after (POST) resistance training. Percent body fat (%BF), fat-free mass (FFM), fat mass (FM), and energy and protein intakes were also determined. PRE/POST measurements of 1RM for the chest press and leg extension were used to examine strength gains.
Gains associated with the chest press and leg extension were 10% and 75% (P < 0.001), respectively. Significant increases (P < 0.05) were noted for weight, height, FFM, and FM. Energy and protein intake remained constant. Significant decreases (PRE vs POST) were observed for Q (1.22 +/- 0.1 vs 0.75 +/- 0.05, P < 0.001), PS (6.48 +/- 0.47 vs 3.55 +/- 0.30, P < 0.001), and PB (5.24 +/- 0.41 vs 2.96 +/- 0.30, P < 0.01) after 6 wk of resistance training. NET was also reduced (P = 0.07, 1.24 +/- 0.31 vs 0.59 +/- 0.20
Resistance training resulted in a downregulation in protein metabolism, which may be energy based. Future studies are needed to clarify energy, as well as protein, needs in young children participating in this form of exercise.”

[14] Evidence type: uncontrolled experiment

Hartman JW, Moore DR, Phillips SM.
Appl Physiol Nutr Metab. 2006 Oct;31(5):557-64.

“It is thought that resistance exercise results in an increased need for dietary protein; however, data also exists to support the opposite conclusion. The purpose of this study was to determine the impact of resistance exercise training on protein metabolism in novices with the hypothesis that resistance training would reduce protein turnover and improve whole-body protein retention. Healthy males (n = 8, 22 +/- 1 y, BMI = 25.3 +/- 1.8 kg.m(-2)) participated in a progressive whole-body split routine resistance-training program 5d/week for 12 weeks. Before (PRE) and after (POST) the training, oral [15N]-glycine ingestion was used to assess nitrogen flux (Q), protein synthesis (PS), protein breakdown (PB), and net protein balance (NPB = PS-PB). Macronutrient intake was controlled over a 5d period PRE and POST, while estimates of protein turnover and urinary nitrogen balance (N(bal) = N(in) – urine N(out)) were conducted. Bench press and leg press increased 40% and 50%, respectively (p < 0.01). Fat- and bone-free mass (i.e., lean muscle mass) increased from PRE to POST (2.5 +/- 0.8 kg, p < 0.05). Significant PRE to POST decreases (p <0.05) occurred in Q (0.9 +/- 0.1 vs. 0.6 +/- 0.1 g, PS (4.6 +/- 0.7 vs. 2.9 +/- 0.3, and PB (4.3 +/- 0.7 vs. 2.4 +/- 0.2 Significant training-induced increases in both NPB (PRE = 0.22 +/- 0.13; POST = 0.54 +/- 0.08 and urinary nitrogen balance (PRE = 2.8 +/- 1.7 g N.d(-1); POST = 6.5 +/- 0.9 g N.d(-1)) were observed. A program of resistance training that induced significant muscle hypertrophy resulted in reductions of both whole-body PS and PB, but an improved NPB, which favoured the accretion of skeletal muscle protein. Urinary nitrogen balance increased after training. The reduction in PS and PB and a higher NPB in combination with an increased nitrogen balance after training suggest that dietary requirements for protein in novice resistance-trained athletes are not higher, but lower, after resistance training.”

[15] Evidence type: uncontrolled experiment

Moore DR, Del Bel NC, Nizi KI, Hartman JW, Tang JE, Armstrong D, Phillips SM.
J Nutr. 2007 Apr;137(4):985-91.

“We aimed to determine the impact of intense resistance training, designed to increase lean body mass (LBM), on both fasted and fed whole body protein kinetics in untrained young men. Twelve healthy males (22 +/- 2 y of age; BMI, 24.3 +/- 2.4 kg/m(2)) participated in a 12-wk (5-d/wk) resistance training program. Before and after training, a primed constant infusion of [1-(13)C]leucine was used to measure whole body leucine turnover, protein breakdown, and nonoxidative leucine disposal in the fasted and fed states. Participants were studied during 5-d controlled diet periods that provided a moderate protein intake [1.4 g/(kg body wt . d)]. We estimated protein turnover and nitrogen balance. Training increased LBM (61.6 +/- 6.9 vs. 64.8 +/- 6.7 kg, P < 0.05). After training, whole body leucine turnover was reduced (P < 0.01) in both fasted (167 +/- 18 vs. 152 +/- 17) and fed (197 +/- 23 vs. 178 +/- 21) states [all values micromol/(kg LBM . h)]. Training-induced decreases (P < 0.01) in protein breakdown occurred in the fasted (165 +/- 18 vs. 144 +/- 17) and fed (111 +/- 23 vs. 93 +/- 20) states. Following training, nonoxidative leucine disposal was similarly reduced (P < 0.01) in the fasted (144 +/- 18 vs. 126 +/- 18) and fed (151 +/- 20 vs. 133 +/- 19) states. Nitrogen balance was more positive after training (13.7 +/- 8.1 vs. 33.4 +/- 12.5 g/(kg LBM . d), P < 0.01) indicating an increased retention of dietary nitrogen. Intense resistance training alters whole body protein kinetics in novice weightlifters regardless of feeding status. The increase in nitrogen balance after training demonstrates a more efficient utilization of dietary nitrogen, suggesting that protein requirements for novice weightlifters are not elevated.”

[16] Evidence type: experimental

L J Hoffer, B R Bistrian, V R Young, G L Blackburn, and D E Matthews.
J Clin Invest. 1984 March; 73(3): 750–758.

“A randomized comparison trial of two very low calorie weight reduction diets was carried out for 5 or 8 wk in 17 healthy obese women. One diet provided 1.5 g protein/kg ideal body weight; the other provided 0.8 g protein/kg ideal body weight plus 0.7 g carbohydrate/kg ideal body weight. The diets were isocaloric (500 kcal). Amino acid metabolism was studied by means of tracer infusions of L-[1-13C]leucine and L-[15N]alanine. After 3 wk of adaptation to the diets, nitrogen balance was zero for the 1.5 g protein diet but -2 g N/d for the 0.8 g protein diet. Postabsorptive plasma leucine and alanine flux decreased from base line by an equal extent with both diets by approximately 20 and 40%, respectively. It was concluded that protein intakes at the level of the recommended dietary allowance (0.8 g/kg) are not compatible with nitrogen equilibrium when the energy intake is severely restricted, and that nitrogen balance is improved by increasing the protein intake above that level. Basal rates of whole body nitrogen turnover are relatively well maintained, compared with total fasting, at both protein intakes. However, turnover in the peripheral compartment, as evidenced by alanine flux, may be markedly diminished with either diet.”
Comment: The authors have assumed that the RDA is adequate, which would imply that the condition of weight loss had increased protein needs. However, since we have seen that the RDA is not, in fact adequate, the conclusion is unwarranted. I.e., the study was not controlled for people not losing weight.

[17] Evidence type: experimental

W J Smith, L E Underwood and D R Clemmons.
The Journal of Clinical Endocrinology & Metabolism February 1, 1995 vol. 80 no. 2 443-449

“Sixteen adult subjects (7 males and 9 females), aged 22-40 yr, were recruited and assessed in the same manner as the children [i.e. by advertisement, and determined to be healthy by a battery of tests.] They consumed a diet that provided 35 Cal/kg IBW and 1 g protein/kg IBW for the first 3 study days. Nonprotein calories were provided as 70% carbohydrate and 30% lipid. On study days 4-9, half of the 16 subjects received only 17 Cal/kg IBW, but continued to receive 1 g protein/kg IBW.
“During the 6 days of calorie restriction, the adults lost 1.7 2 0.1 kg (mean 2 SD) […]. Baseline nitrogen balance in the adults (mean of days 2 and 3) was -82 2 47 mmol/day (mean + SE) and declined to -196 2 40 mmol/day (the mean of study days 8 and 9; P < 0.05).”
Comment: The authors showed that when healthy adults were given a constant amount of protein, but two different levels of calories, nitrogen balance was more negative in the lower calorie condition. However, both diets were still high enough in carbohydrate to be non-ketogenic, and the difference between the diets was primarily a carbohydrate difference. In a non-keto-adapted state, carbohydrates can spare protein, because your metabolism is much more dependent on glucose for fuel. That means that reducing carbohydrates will require more protein for gluconeogenesis. After keto-adaptation, many tissues use ketones instead, and this spares protein. So we would expect that lowering carbohydrates without keto-adapting would negatively affect nitrogen balance. Therefore, we can’t conclude that the negative nitrogen balance in this study reflects increased protein needs from caloric restriction alone, because it could be that the same caloric deficit in a keto-adapted state would have different results. It would be interesting to see an analogue of this study in keto-adapted people. We are not aware of any such study.

[18] Evidence type: randomised controlled trial

Baba NH, Sawaya S, Torbay N, Habbal Z, Azar S, Hashim SA.
Int J Obes Relat Metab Disord. 1999 Nov;23(11):1202-6.

“Thirteen male obese hyperinsulinemic normoglycemic subjects were divided into two groups and fed hypoenergetic diets providing 80% of their resting energy expenditure (REE). One group received a high-protein diet (HP; 45% protein, 25% carbohydrates, and 30% fat as percent of dietary energy) and the other a high-carbohydrate diet (HC; 12% protein, 58% carbohydrates and 30% fat).
“Weight loss was higher in the HP than HC group (8.3+/-0.7 vs 6.0+/-0.6 kg, P<0. 05). There was a decrease in body fat in both groups, whereas body water decreased significantly more in the HP group. REE decreased more in the HC than the HP group (-384.3+/-84.6 vs -132.3+/-51.0 kcal, P<0.05). Serum total cholesterol, triglycerides and LDL cholesterol decreased significantly to a similar extent in both diet groups, while HDL cholesterol was decreased significantly only in the HP group. Mean fasting insulin decreased significantly in both diet groups and reached the normal range only in the HP group.”

[19] Evidence type: randomized controlled trial

Labayen I, Díez N, González A, Parra D, Martínez JA.
Forum Nutr. 2003;56:168-70.

Eleven obese (BMI>30) women were randomly assigned to a 10w dietary intervention study comparing HP (30% protein) or HC (55% carbohydrate) energy restricted diets providing 30% energy fat content. Substrate utilisation was evaluated by indirect calorimetry. Body weight and composition (Bod Pod) and blood measurements were performed before and after weight loss.
On average, the individuals on the HP dietary group lost 4.4 kg more than those in the HC program (p<0.50), which was mainly due to a fat mass loss (3.7 kg, p<0.05) with no statistical differences in lean body mass reduction. These losses were accompanied by a significant decrease in fasting leptin in the HP group (-52%; P<0.05). On the other hand post-absorptive lipid oxidation decreased in the HC group (-48%) and remained unchanged in the HP groups.
The replacement of some dietary carbohydrate by protein in energy restricted diets, improves weight and fat losses and specifically promotes lipid oxidation in the fasting state, without major different in lean body mass depletion.”

[20] Evidence type: randomized controlled trial

Evangelista LS, Heber D, Li Z, Bowerman S, Hamilton MA, Fonarow GC.
J Cardiovasc Nurs. 2009 May-Jun;24(3):207-15. doi: 10.1097/JCN.0b013e31819846b9.

“[T]his feasibility study was conducted to compare the effects of an HP, hypoenergetic diet (40% total energy from carbohydrates, 30% from protein, and 30% from fat), a standard protein (SP), hypoenergetic diet (55% total energy from carbohydrates, 15% from protein, and 30% from fat), and a conventional diet (high carbohydrates, low fat, high fiber, with no energy restrictions) on body weight and adiposity in patients with HF and increased BMI greater than or equal to 27 kg/m2 and DM.
“The current report reflects data from the first 14 patients who consented to participate in the study; recruitment and enrollment are still ongoing. The patients were randomized to the HP (n = 5), SP (n = 5), and conventional diets (n = 4), respectively.
[…] Gee, look at that cholesterol. Not quite statistically significant (because the group size was small) but highly suggestive.

[21] Evidence type: experimental

Pasiakos SM, Cao JJ, Margolis LM, Sauter ER, Whigham LD, McClung JP, Rood JC, Carbone JW, Combs GF Jr, Young AJ.
FASEB J. 2013 Sep;27(9):3837-47. doi: 10.1096/fj.13-230227.

“The purpose of this work was to determine the effects of varying levels of dietary protein on body composition and muscle protein synthesis during energy deficit (ED). A randomized controlled trial of 39 adults assigned the subjects diets providing protein at 0.8 (recommended dietary allowance; RDA), 1.6 (2×-RDA), and 2.4 (3×-RDA) g kg(-1) d(-1) for 31 d. A 10-d weight-maintenance (WM) period was followed by a 21 d, 40% ED. Body composition and postabsorptive and postprandial muscle protein synthesis were assessed during WM (d 9-10) and ED (d 30-31). Volunteers lost (P<0.05) 3.2 ± 0.2 kg body weight during ED regardless of dietary protein. The proportion of weight loss due to reductions in fat-free mass was lower (P<0.05) and the loss of fat mass was higher (P<0.05) in those receiving 2×-RDA and 3×-RDA compared to RDA. The anabolic muscle response to a protein-rich meal during ED was not different (P>0.05) from WM for 2×-RDA and 3×-RDA, but was lower during ED than WM for those consuming RDA levels of protein (energy × protein interaction, P<0.05). To assess muscle protein metabolic responses to varied protein intakes during ED, RDA served as the study control. In summary, we determined that consuming dietary protein at levels exceeding the RDA may protect fat-free mass during short-term weight loss.”

[22] Evidence type: randomised prospective study

Flechtner-Mors M, Boehm BO, Wittmann R, Thoma U, Ditschuneit HH.
Diabetes Metab Res Rev. 2010 Jul;26(5):393-405. doi: 10.1002/dmrr.1097.

“Obese subjects received instructions for an energy-restricted diet with a calorie deficit of 500 kcal/day and were randomly assigned to either high-protein (1.34 g/kg body weight) or conventional protein (0.8 g/kg body weight) diets for 12 months. Protein-enriched meal replacements were used to enrich one arm of the diet with protein throughout the study. In all, 67% of the participants completed the 1-year study.
Subjects following the high-protein diet lost more body weight and more fat mass compared with those on the conventional protein diet, whereas the loss of fat-free mass was similar in both diet groups. Biochemical parameters associated with the metabolic syndrome improved in both diet groups. Improvements were modestly greater in subjects with the high-protein diet. After 12 months of treatment, 64.5% of the subjects in the high-protein diet group and 34.8% of the subjects in the conventional diet group no longer met three or more of the criteria for having the metabolic syndrome.”

[23] Evidence type: explanation and comparison of experiments.

Stephen D Phinney.
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.”

[24] Evidence Type: experiment

Volek, Jeff S., Erin E. Quann, and Cassandra E. Forsythe.
Strength & Conditioning Journal 32.1 (2010): 42-47.

“We performed a similar experiment in overweight/obese men who were placed in a low-fat diet group that restricted fat to less than 25% of energy or a very low–carbohydrate ketogenic diet group that reduced carbohydrate to less than 15% energy. Both groups also participated in a resistance training program (see Practical Applications) (16). Body composition was assessed using dual energy x-ray absorptiometry before and after the 12-week program. The results were compared with non-training diet only groups. As expected, the low-carbohydrate diet group lost more fat, which was associated with greater decreases in insulin. Resistance training, independent of diet, resulted in increased lean body mass without compromising fat loss in both diet groups. The most dramatic reduction in percent body fat was in the low-carbohydrate diet resistance training group (25.3%), followed by low-fat resistance training(23.5%), low-carbohydrate diet only (23.4%), and low-fat diet only (22.0%) groups. These data show for the first time that resistance training is a potent stimulus to protect lean body mass in men consuming a low-carbohydrate diet, while still allowing for significantly greater fat loss.”

[25] Evidence type: summary of experiments

PG Lindner, GL Blackburn.
Obesity/Bariatric Med, 1976, pp. 198–216

“The question that remained to be answered was what amount of protein was necessary to maintain positive energy nitrogen balance ⁹³ for a time sufficient to allow the obese individual to reach his normal size.
“Blackburn, et al investigated this question while also measuring the biochemical and clinical aspects of what he termed the protein-sparing modified fast (PSMF). One hundred forty-six patients (111 outpatients) were followed at the Massachusetts Institute of Technology Clinical Research Center while undergoing a comprehensive weight reduction program that included nutritional education, behavior modification, exercise, and the PSMF. ⁹⁴’⁹⁵ He found that in males, nitrogen (N) balance was obtained at 1.4 gm protein daily/kg ideal body weight (IBW) and in females, N balance was obtained at 1.2 gm/kg IBW. Outpatients tolerated the PSMF well in a wide variety of lifestyles and occupations and invariably found it easier than a balanced deficit diet. Ingestion of 40 to 80 gm of carbohydrate in addition to protein, however, markedly reduced ketosis and reistated hunger.⁹⁶”

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.

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.