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.
- 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 ⁴.
As an example of this stability, a study by Bisschop et al. in 2000 ⁵ 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.
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 ⁶. 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, ⁴. 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) ⁷, 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 ⁸. 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.
For clarification and further discussion of this topic, please see:
- We were talking about gluconeogenesis, not ketogenesis.
- Protein, Gluconeogenesis, and Blood Sugar
- Protein, Ketogenesis, and Glucose Oxidation
(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
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.
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.
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.
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
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
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.
⁴ 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.
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.
⁵ 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
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).
⁶ 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 (⁴) in text and in the table in the line marked :
[T]here was no change in glucose production after ingestion of 50 g of protein in the form of cottage cheese.
⁷ 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
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).
⁸ 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
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.
In this study (in mice) the ketogenic diet used to reverse renal failure in mice was also protein restrictied, because the protein was being converted to glucose, keeping glucose too high for the kidneys to heal:ReplyDelete
Reversal of Diabetic Nephropathy by a Ketogenic Diet
Here's an interview with Dr. Mobbs, in which he describes that protein restriction to limit gluconeogenesis was crucial.
Mice and (especially) rats seem to do more gluconeogenesis, so researchers sometimes need to restrict their protein heavily.Delete
Tuck, thank you for the links, and for bringing up some important points. I have a couple of comments.Delete
1) About Dr. Mobbs' statements in the interview:
Dr. Mobbs says two separable things. First he says that in mice, a 20% protein diet was not ketogenic, and that an 8% protein diet was ketogenic. These numbers certainly don't hold for humans, but the trend may be the same. That is, there may be decreasing ketosis in humans as protein increases. That's a subject for another post.
Then he says that this lack of ketogenesis is due to excess gluconeogenesis. This is the relevant part for our argument. Dr. Mobbs does not say he observed increased GNG, he only provided this as an explanation for the lower ketogenesis. I would be very interested to know why he says this, and I'd love to hear from him, but my suspicion is that he says it because he has heard it repeated, even in scientific literature, since, as we point out, that was the standard hypothesis for some time.
Incidentally, I am currently trying to find out the state of the evidence about protein levels and ketogenesis, but have seen only theoretical arguments so far.
2) These mice were diabetic. We didn't emphasize in the article, but in the case of insulin-dependent diabetes (either type 1, or very severe type 2), protein actually does increase GNG.
In the study, some but not all of the mice were type 1. As to type 2, Nephropathy in Patients with Type 2 Diabetes asserts that nephropathy affects 20-40% of people who have had type 2 for 15-20 years, so I would guess that the disease has to be quite far progressed before nephropathy develops. The further developed it is, the more likely insulin is no longer adequately produced.
As such, it's even possible that Dr. Mobbs did observe increased GNG from higher protein levels, but that wouldn't be a counter-example to our findings, as we are concerned with the case of people without insulin dependence, either non-diabetic, or only mildly type 2.
Ketosis will have an upper limit controlled by the rate of lipolysis of body fat and exogenous fat and the supply of same. So if you eat less fat and more protein, you will likely get fewer ketones if the rate of body fat lipolysis is at its max. Was the total amount of fat the same in both diets? Something to consider.Delete
Good point, Marnee. Protein, fat, and calories are interdependent.Delete
I'd like to discuss the effects of protein on ketosis in a subsequent post, and this is one of the reasons it is complicated.
Both lowering protein and lowering calories have been said to increase ketosis, and fat to increase it. I'm still looking, but I have yet to find primary experimental evidence for any of that. I just find theoretical equations, like the ketogenic ratio, and lots of repeating. I suspect in the case of ketosis, though, unlike for GNG, it may actually be true.
Suppose you want to test this, given a constant low carb level.
If you keep calories the same, then less protein is also more fat. If you want to keep fat the same while lowering protein, you've also lowered calories.
One condition that I think would be particularly informative is to hold protein constant and increase (or decrease) fat. This would also increase (decrease) calories. If ketosis increased (decreased), then this supports the belief that fat has a positive effect. If it decreased (increased), then this supports the belief that calories has a negative effect. Then those effects could be quantitatively controlled for when looking at protein.
All fair points.ReplyDelete
Mobb's study is an interesting counter-point, however.
My wife discovered that she had to restrict her protein intake to kick off her weight loss, at about the same time Jimmy Moore made the same discovery. Just because it's missing in the small amount of scientific literature about ketogenic diets doesn't mean it's false. ;) Or as they like to say, "Absence of evidence is not evidence of absence."
And neither my wife nor Jimmy are diabetic.
So I think that if someone fails to see the benefits they're expecting from a ketogenic diet, this is a useful trick to keep in mind.
Sure. I think there are still valid important reasons for keeping protein intake on the low side. The experiences of Jimmy Moore and your wife (and others) could be from an effect on ketogenesis, rather than on gluconeogenesis, for example.Delete
And yes, there are still gaps in the experimental evidence that prevent me from being as conclusive about the matter as I might otherwise be. The Title, the In Brief, and the Summary all emphasize this.
And it turns out that they treat certain diseases by increases protein intake to stimulate gluconeogenesis:ReplyDelete
"At 16 years of age, he developed a severe cardiomyopathy with a left ventricular mass index of 209 g/m(2). The cardiomyopathy remained stable on a protein intake of 20-25% of total energy. At age 22 years, the diet was changed to increase his protein intake to 30% of total energy and minimize his cornstarch therapy to only what was required to maintain normoglycaemia. Dramatic improvement in the cardiomyopathy occurred."
"Reversal of glycogen storage disease type IIIa-related cardiomyopathy with modification of diet."
From Peter, indirectly:
I am a big fan of Petro Dobromylskyj.Delete
One problem with this argument that high levels of protein increase GNG in GSD III, is that in glycogen storage diseases, GNG doesn't work the way it should, so we can't extrapolate, just like we can't extrapolate from insulin-dependent diabetes.
I don't know much about GSDs, but it looks like the problem in GSD III is that stored glycogen can't be properly accessed. If I understand correctly (and that's a big if), this would disrupt the Cori Cycle, which is an important contributor to GNG after the first few hours post-eating. (See, for example Cori cycle contribution to plasma glucose appearance in man.) So this would impair the ability of GNG to keep up its stable rate, and it would make sense that frequent and higher protein intake would help.
So I would say that the increased protein intake was not to "stimulate" GNG but to allow it. There is an important distinction to be made about the glucose made by the "excess" protein here. In GSD III, the patients don't have enough glucose. So doing whatever it takes to get GNG to work adequately is necessary to provide enough glucose. The concern for people without GSD on keto diets, is whether they are creating excess glucose.
This is related to the point about adequate substrate. When substrates are inadequate, increasing protein will increase GNG, because before that point, more is needed to supply blood sugar. I'm interested in the question of what happens when protein is more than adequate.
"I am a big fan of Petro Dobromylskyj"ReplyDelete
Aren't we all? ;)
"I don't know much about GSDs, but it looks like the problem in GSD III is that stored glycogen can't be properly accessed."
Right, it goes into glycogen, but can't be recovered. It's treated, so I understand, by providing sufficent glucose via an alternative mechanism to allow the muscles to function.
What I don't know is that there's any impact on the liver's ability to create glucose from protein. I assume there is not, because that's how they're treating the disease.
But I don't think you can assume that this behavior is abnormal (protein stimulating GNG)...
The other issue you're going to have in trying to make this case, is that no-one's going to study it in healthy people, because they're all supposed to be eating enough glucose, and ketosis will kill them. ;)
So I think that you can pretty clearly say that it's possible that excess protein in ketosis can cause excess glucose production: that's what happens in the mice, and what happens in people with the GSD.
Great article, btw. Keep up the good work.
To be completely clear, I disagree with your statement that excess protein in ketosis causes excess glucose production either in mice or in people with GSD.Delete
The mice in the experiment were severely diabetic, and furthermore the experimenters did not measure GNG, they measured ketosis.
The GSD patients never had excess glucose. They required excess protein to get adequate glucose. That's fundamentally different.
Here we go. (Sorry to trickle this out into your comments, but I do this in my limited spare time):ReplyDelete
"High-protein diets were previously shown to increase energy expenditure (EE) in healthy human volunteers (5–11). Gluconeogenesis has been hypothesized to contribute to this increased EE after a high-protein diet (5, 6, 9, 12). Although gluconeogenesis is thought to be relatively stable in humans, a high-protein diet, especially in the absence of carbohydrates, may stimulate gluconeogenesis (13). Because gluconeogenesis is an energetically costly pathway of protein metabolism with energy costs that are estimated to amount to 20% (6, 12), this process may contribute to an increased EE after a high-protein diet or after a highprotein,
"The objective was to study whether a high-protein, carbohydrate-free diet (H diet) increases gluconeogenesis and whether this can explain the increase in EE. Therefore, gluconeogenesis and EE were measured when healthy subjects consumed an H diet or a normal-protein (N) diet....
"...In conclusion, increased gluconeogenesis contributes to increased EE after consumption of an H diet for 1.5 d following a decrease in body glycogen stores. Forty-two percent of the increase in EE after the H diet was explained by an increase in gluconeogenesis. The energy cost of gluconeogenesis was 33% of the energy content of glucose."
"Gluconeogenesis and energy expenditure after a high-protein, carbohydrate-free diet"
I think there are several things being conflated here.Delete
One is whether a keto diet increases the rate of (fasting) GNG, which it does by a small amount as seen in the graph.
The other, which they are measuring in this study, is the total amount of GNG. Of course this goes up on a keto diet, because that's where we get all of the glucose we use. In non-keto dieters, high insulin after each carb-containing meal suppresses GNG, and the carbs that were eaten raise blood sugar. So keto diets and non-keto diets have different GNG totals over the day. I'm not arguing that total GNG isn't increased on a keto diet. They certainly didn't compare adequate and high levels of protein under constant ketogenic conditions in this study, so they can't address our question based on this experiment.
The study they cite as (13), Thermodynamics and metabolic advantage of weight loss diets, doesn't suggest anywhere that high protein itself increases GNG. It only says that low carb diets entail a reliance on GNG for glucose. It says:
"In summary, the need to meet the obligate demand for glucose means that a nominally eucaloric low carbohydrate diet can lead to increased gluconeogenesis from protein. Increased gluconeogenesis will, in turn, lead to protein turnover. Together, these processes will lead to
So in this case I think there is a conflation of the term high-protein meaning a low carb diet, and high-protein meaning excess intake. When they say "a high-protein diet, especially in the absence of carbohydrates, may stimulate gluconeogenesis", they mean a keto diet as opposed to a non-keto diet, not high protein vs. adequate protein.
"Sorry to trickle this out into your comments, but I do this in my limited spare time"Delete
Haha, well, this is essentially a hobby for me (see About Us), so I make no turn-around time guarantees either.
I low-carbed for over two decades as a T2 diabetic, which is, of course, supposed to prevent diabetes from progressing.ReplyDelete
Once my bG went over 300 mg/dL regularly, even when fasting for several days, I had to go on insulin. So I've been using a Lantus/Humalog multiple daily injection regimen for about 5 years now.
Most T2s only have to dose Humalog for carbohydrate, but many T1s have to dose for protein also. I have to dose for protein even though I'm a T2, if I want to keep my postprandials under 140 mg/dL.
I discovered this because while learning to dose, I ate a number of carb-only and protein-only meals to figure it out.
My "mixed" meals are breakfast at around 20 grams carb, lunch and dinner at around 40 grams carb, and all meals at around 30-40 grams protein, and random amounts of fat depending on hunger. I dose for BOTH the carb and protein in mixed meals to control my postprandials.
I dose 1 unit for 5 grams of carb or 10 grams protein. So for me, protein "needs" about half as much insulin as carb does.
My only explanation for this is that after a very long time doing the low-carb thing, my body got VERY good at gluconeogenesis. Heck, sometimes it seems I can make glucose out of air! Obviously, that's an exaggeration, but...
The only macronutrient that doesn't need insulin is fat. If I eat a snack that is almost entirely fat, like a couple strips of bacon, or a coconut fat/cocoa/stevia candy concoction, I don't need to take insulin and there's almost no effect on bG (within the error of my meter, I can't measure a difference).
I recently read that not only the glycerol of fat molecules can be converted to glucose, but the fatty acids too, which is apparently new information. I'm keeping my fingers crossed that no one tells my liver about this!
Thank you for sharing your experience! I have found the same thing and I don't even need insulin yet. My liver can produce glucose out of thin air and give it a 8oz steak and it will go to town...Delete
Since switching to a ketogenic diet and heavily restricting protein, I've achieved even better blood glucose control (fasting and PP) than on a simple low-carb diet. Fingers crossed that buys me even more "working pancreas time". :)
The situation in severe diabetes is different. According to the paper in reference number 4 above, a diabetic with fasting glucose above about 9.0 mmol/l will have increased GNG.Delete
jpatti, while on low carb were you in ketosis, and did you measure ketones with a ketone meter?Delete
Really nice article here. I am glad to see somebody take the metal stake to guys like RR who think protein is poison. Lab testing I have done clinically back this data set up too.ReplyDelete
Although we did cite some people as repeating this idea, it is the idea we are questioning, not the people. The idea is prevalent among many well-respected scientists for historical reasons. We feel it is a mistake, but our aim is to share awareness, not to place blame.Delete
I understand that. But when you are in the business of re engineering people when other try to cut your legs out from under your feet is makes the job much more difficult. Articles like this one one will help the lay public look at the data and the science and ask why is not the advice congruent, no matter whose lips they are uttered from. Again, thanks for writing it all up.Delete
Thank you for the encouragement.Delete
@Jack; I never said that protein is a poison. We must use it to regenerate our our components, however it is not a healthy fuel to burn. A low carb, high protein diet is NOT a healthy diet, raising mTOR along with other extremely detrimental effects. See;Delete
Many people have, since reading that article/powerpoint, changed their mind about high protein diets. You should listen to the science also, and save the metal stake for yourself.
I'm slightly confused. hope you can help clarify this.
In your post you wrote: "For instance, it is known that protein consumption stimulates a great deal of glucagon (along with insulin) ⁷, and it might be suggested that this glucagon would thereby increase GNG."
I know the post is concerned with GNG, but in reality, isn't the real concern the rise in insulin? Whatever the pathway is to raise insulin, once it's up, fat cells are (from what I understand) blocked (or at least partially) from releasing fat for use as energy.
I guess my question is, if we know that protein raises glucagon and insulin, should we eat less protein to have generally lower insulin levels? Or is weight loss dictated by the level of blood sugar and not insulin?
That's a good question, and I'm sure it is burning in many other minds.Delete
This post has a very limited scope. We are simply arguing that this particular reason for limiting protein doesn't seem to be supported.
However, there may be other reasons for keeping protein low, so long as it is adequate. We will be exploring these reasons in subsequent posts, but since we haven't finished writing them, we're not yet sure of the conclusions.
The bottom line is that excess protein gets burned as fuel and that's not healthy. The amount that is first converted into glucose depends on the protein and the composition of amino acids that make it up. Some amino acids convert directly into glucose. Others enter energy pathways as intermediate hydrocarbons; not literally glucose but shorter carbon fragments of same. Either way, one must deaminate the amino acid, transferring the nitrogen to ammonia and urea that circulates as a poison until it can be excreted in the urine (hence the name). If nothing else, protein will cause harm by having to burn the excess one way or another and therefore not burn fatty acids or ketones. Then there are the important effects on metabolic hormones and pathways. It raises glucagon that raises glucose and also growth hormone that does the same and then it raises insulin; talk about metabolic schizophrenia. It profoundly raises mTOR increasing risk of cancer. I will answer more thoroughly when I have time. Thanks.ReplyDelete
Dr. Rosedale, I definitely didn't mean that this was the bottom line on protein. I agree that there are many good reasons to limit it. I only wanted to separate the supported reasons from the unsupported ones. I was getting weary of hearing that eating protein above some level is just like eating carbohydrates. This, I don't feel is justified.Delete
My conclusions about essentially every aspect of keto diets are very closely aligned with yours, and this was meant to be just a clarification of a minor point.
Thanks, and I appreciate this post, many of your others, and your search for knowledge.Delete
Dr. Rosedale - How much is too much?Delete
That's the big question, though, isn't it?Delete
"We haven't found any solid evidence to support the idea that excess protein is turned into glucose". end of story :)Delete
It's Aviv from the ZIOH group.
I am on the same diet like you, zero carbs, carnivorous diet. I am trucking my diet in any aspect and blogging about it in Hebrew.
I am a big fan of Ron Rosedale, if only for the fact that much of what he says affecting me in the exact way he predicting it.
For 3 straight months, I trucked blood glucose in the morning and in the evening, and blood B-OHB, morning and evening on this diet, daily. (many times, more the twice a day - not a cheap habit).
I can definitely say, that on me, no matter the 'mechanism' behind it, too much protein will get me higher blood glucose for a day or two, and will take me even longer to get back to ketosis after.
I am not sure people realizing how much is "too much". At my experience, a big steak at more than 12oz is too much. Many people will consider it a good low carb option.
In fact I can say, that in my case (emphasizing - my own case), if I eat more than 30-40g of protein a meal, or 80-100 grams a day, it will be too much. I need good 5-6 hours between. Do not eat breakfast, had an HgA1C 5.8 before the diet on a low carb paleo diet, before switching to a zero carb ketogenic diet. I am an active 30 years old man.
After too much protein, even with NO carbs on my diet, I will feel bloated, gain weight, get out of ketosis, feel dizzy etc.
I actually made a graph with daily blood glucose and ketones every month as compare to my diet.
I might just convert the graph with English notes, so you'll understand how significant it is to me.
Look at the graph bellow at my second month summary:
It looks to me, that the more metabolically derange one is and the more insulin resistant one is, excess protein is a bigger problem than what people believe.
BTW I checked the next post about the mechanisms of GNG and what effects blood glucose you posted.
Regardless of the 'reason', nothing like real life experience for me.
So as a zero carber to another, you doing a great job, and I love exploring your blog, keep 'em coming!
And yes - meat is all I eat, but fat is what I really want. :)
Hi, Aviv, thank you for the data! I do agree that ketosis is adversely affected by protein after some threshold, regardless of mechanism.Delete
Thank you for sharing your experience, Aviv. Very interesting.Delete
Dr. Rosedale, does eating more protein than the body needs for maintenance and repair also increase leptin production? Thanks.Delete
Dr Rosedale, I note that Wilder's ketoginic formula allows for a little more than half of protein to be converted to glucose (see http://perfecthealthdiet.com/2011/02/ketogenic-diets-i-ways-to-make-a-diet-ketogenic/). I haven't been able to find anything that describes why this is the case and whether some proteins are more or less prone to GNG based on their amino acid profile. Are you aware if this data exists. My analysis of the available food insulin index data shows that a bit more than half of the protein is converted to glucose and affects insulin but I'm not sure if this is dose dependent or protein type dependent (see https://www.dropbox.com/s/ninuwyreda0epix/Optimising%20nutrition%2C%20managing%20insulin.docx?dl=0).Delete
Some amino acids can be converted in to glucose. They are called gluconeogenic amino acids. Some can be converted in ketone bodies (ketogenic amino acids). Only a few are both. Formulas like that are based on what the amino acid profile of a protein is like.Delete
But that's only half of the story. The thing is, just because an amino acid CAN be converted into gluose, doesn't mean it WILL. You should look at a formula like that as expressing a maximum, a *worst case*. Metabolising protein for energy is the last thing your body wants to do with it.
If you read the rest of the articles in this series, I hope you will get a better sense of why the absolute amount of protein you eat is a very poor predictor of your GNG. GNG is demand driven, not supply driven.
Thank you both.. Rosedale and Amber..ReplyDelete
From my personal observation I can tell you that eating excess lean protein raises my blood sugar more then when I'm eating less of the same protein. I'm not diabetic, not even close, so why is this happening if you are saying that excess protein doesn't stimulate GNG?ReplyDelete
Have you tried buying a glucose meter and see if it affects your blood sugar?
Anna, this deserves a detailed reply. I have some other things I need to do first, but I will get back to it soon.Delete
Amber, I was rereading your article trying to make more sense of this issue. do you have some time to may be give me a short reply as to my observation about excess protein raising blood sugar? thank you very much.Delete
Hi, Anna. I'm sorry for the wait. We've made a post addressing itDelete
thank you very much for the reply!Delete
people are dieing to be able to say eat more protein and no or low carb and get the same results...to this day where is there solid proof ? please direct me to it.,..its almost as credible as the HCG morons who say in a non pregnant person your body feeds it self your fat stores..lol ha ha ha still my favorite.protein will never be proven as good a fuel in active people..'you' people have been trying for years...ReplyDelete
What Dr. Rosedale said about protein we have discovered in developing a ketogenic lifestyle to manage type 1 diabetes. Our diet is very limited in meat consumption (the first year and a half we ate no animal products). Noe we limit to to a couple of small portions per week. People we help manage their diabetes almost always discover the same thing: meat raises their blood sugars, particularly 4, 6 even 8 hours later. With diabetics who still have beta cell function, yet it is compromised, this becomes an issue if their goal is to keep insulin demand as low as possible. Such is our goal and we have been able to stay off exogenous insulin for 6 years now.ReplyDelete
Dan, my wife is a type 1 diabetic and we have been on a similar journey. My view though is that you would still need some level of protein to obtain adequate amino acids, just as you would need some level of carbs (perhaps in the form of non-starchy vegetables) to obtain adequate vitamins and minerals.Delete
Protein is absolutely necessary to survival. Carbs are not. There is no nutrient we need that can't be obtained from meat. In fact meat is much more nutrient dense than plants, and those nutrients are more bioavailable. Moreover, plants often interefe with nutrient absorption. See, eg. Dr. Ede's infographic from her article on vegetables.Delete
I am growing more confused about protein the more I read, as some say don't limit protein, and others that protein must be limited, although most of what I'm seeing about protein and increased BG mainly comes from T2 diabetics. So far I seem to gravitate by appetite to between 65-110g per day (less than most recommendations), and I was on a varied keto diet, now on all protein. I have concluded that our reactions to food-diet are mainly trial and error experiments, and there is no sense in looking for a perfect macro.ReplyDelete
Fascinating discussion. So much to remains to understand about how our bodies work. Ultimately, I think it all comes down to how we feel personally (N=1), but it is nice to have other people (both clinicians and practitioners) to learn from.ReplyDelete
Also, I have found that in order for my body to digest the protein I consume, I NEED to eat a certain amount of fat with it. For example, if I eat hard cheese by itself, I will burp it up for hours afterwords and feel really lousy. But, if I eat it in a 1 to 1 ratio (ounce to ounce) with butter, I digest it fine and experience no digestive distress. I have the same experience with raw ground beef. If I eat lean grassfed ground beef by itself, I will experience digestive distress and feel terrible for hours. but if I add an ounce of butter per 4 ounces of ground beef, then it digests perfectly fine. I never understood this until now. I think it is my body's way of regulating my protein intake. If I eat the amount of fat needed to help me digest the protein, then it is harder to over-consume the protein because satiety kicks in sooner. Anyone else notice this?ReplyDelete
The food insulin index data in Appendix 3 of http://ses.library.usyd.edu.au/handle/2123/11945 suggests that protein generates a little more than half the insulin as carbohydrates on a gram for gram basis as healthy people.ReplyDelete
I think it’s reasonable to say that excess protein is not generally an issue because it takes time to digest and most people can secrete enough insulin to keep blood sugars low. However my wife is a type 1 diabetic and we know from personal experience with her and others that there is a “protein spike” in blood sugar that occurs some hours after eating a low carb high protein meal that requires insulin.
I have done some analysis of the food insulin index data to try to understand the effect of protein and fibre on insulin demand – see https://www.dropbox.com/s/ninuwyreda0epix/Optimising%20nutrition%2C%20managing%20insulin.docx?dl=0 . I found the results interesting!
I think people trying to achieve ketosis should be conscious of their overall “insulinogenic load” (as opposed to their glycaemic load) if they want to minimise insulin and attain ketosis.
What effect does the glucogenic / ketogenic potential of the various amino acids in this?ReplyDelete
Based on my review of the USDA foods database spreadsheet it appears that about 70 to 80% of the amino acids in protein have the potential to turn to glucose in the blood if they are not used for muscle growth and repair first (http://en.wikipedia.org/wiki/Glucogenic_amino_acid).
It seems to me that the only reason that blood sugar is not raised is that protein is digested slowly and most peoples' pancreas can keep up, though this is not the case in type 1 diabetics.
Regardless of the blood sugar rise though the sugar from gluconeogenesis still requires insulin which switches off ketogenesis which is what you're all about isn't it?
While it's true that most amino acids are gluconeogenic, the point here is that GNG is not driven by the availability of source material. It's driven by demand, which is under hormonal control. Just because it *can* doesn't mean it *will*.Delete
Thanks for the response Amber.Delete
I have now read the rest of your posts in this series and from what I can see the essence of your argument is: because ingested protein does not significantly raise blood glucose you have concluded that excess protein does not turn into glucose via gluconeogenesis.
I think the point you are trying to get across is the concept that eating lots of protein rather than carbs is fine and not unhealthy and it will not raise your blood sugars. I’m fine with that and I think that’s for the most part correct.
I can also agree that GNG is a demand driven process when it comes to using the body’s own muscle (along with fat) in a calorie restricted state.
However when your site is called ketotic.org and you’re taken to be an authoritative source on the ketogenic diet I think you need to go a bit deeper than just observing blood sugars which are just a symptom, not the root of the issue.
Maintaining blood sugars in the normal range is not, to my mind, is not the same thing as being ketogenic. Ketogenesis occurs when our insulin is low enough that we can easily use fat for fuel rather than storing it. It occurs when the glycogen are not overfull and we need to rely on fat for fuel.
So the discussion needs to be about INSULIN and not blood sugar.
So moving forward, the testing of the food insulin index shows that protein containing foods generate insulin. Tests in healthy people indicate that protein generates a bit more than half the insulin in normal healthy people as carbohydrate (see https://optimisingnutrition.wordpress.com/2015/03/23/most-ketogenic-diet-foods/). It should be noted that this is AFTER the needs of the body (e.g. growth, repair, brain function etc) are taken into account. Hence it is likely that protein has the potential to create significantly more than half as much insulin as carbohydrate gram for gram.
My wife is a type 1 diabetic and I hang out diabetes forums. One of the major issues for type 1 diabetics is how to deal with the glucose effect of protein. Due to the slower digestion time of protein what you tend to see is a slower and later rise in blood sugar compared to carbohydrate.Delete
A normal non-diabetic person would be able to tackle this rise in blood sugar (due to GNG?) with insulin because they have normal pancreatic function, however for a type 1 they have to either calculate a dose up front based on some assumption of how much protein turns to glucose or continually microdose if they have the luxury of a continuous glucose metre to keep the blood sugars in normal range. See https://optimisingnutrition.wordpress.com/2015/04/18/is-the-insulin-reaction-to-protein-dose-dependent/
If you listen to people like Jimmy More in the keto scene you will hear him continually banging on about is that you have to keep carbs low and MODERATE PROTEIN if you’re going to achieve significant blood ketone readings (due to reduced insulin levels).
I think managing insulin (not just achieving blood normal blood sugar) is a subtle but important distinction. The ACCORD study recently showed that optimising blood sugar via high levels of insulin were diabolical for health (i.e. it’s the insulin not the blood sugar that is a bigger health concern). Elevated insulin levels are also typical characteristics of the obese. It’s important to be have times of low insulin levels if you’re going to be healthy and normal weight.
The other question is, if protein in excess of the body’s requirements does not turn into glucose via amino acid, then where does it go? Is it all excreted as ammonia and / or nitrogen? Does it magically disappear because protein a magical macronutrient that does not make you fat? Does it all turn into ketones that are used for energy?
You’re no doubt aware that some amino acids are ketogenic, some amino acids are glycogenic and some can be both. The vast majority of the amino acids that make up protein are glucogenic and only two are ketogenic. See http://en.wikipedia.org/wiki/Glucogenic_amino_acid
There’s not a lot written out there so I thought I’d tally up the glucogenic, ketogenic and “both” amino acids in the USDA foods database. I’d love you to check out my numbers (https://www.dropbox.com/s/bxjcoegtlw4l05o/USDA%20foods%20database%20-%20ketogenic%20versus%20glucogenic%20amino%20acids.xlsx?dl=0), but it appears that if you assume that all the “both” aminos are ketogenic we end up with about 78% of the amino acids being glucogenic. If we assume that all the “both” amino acids are glucogenic then we end up with about 90% of the amino acids having the potential to turn into glucose if in excess of the body’s requirements. So it appears to me that about 85% of excess protein will be turned to glucose and eventually require insulin!
So in sum:
1. The vast majority of the protein that in excess to the body’s needs will turn into glucose via GNG.
2. You don’t see a sharp blood sugar rise in most normal healthy people because it is stored as glycogen in the liver and muscle for later use and any excess that spills into the blood over and above what is required for the body’s repair and refilling glycogen stores.
3. When this glucose from glycogen is used for energy or stored as fat it will require insulin.
4. Excessive GNG due to high levels of protein ingestion will not lead to a ketogenic state.
Let me just address a couple of points here.
First, I can't discuss every single topic. I have a computer science day job and three children, and I have extremely high standards of evidence for just about everything I write—much higher than just pointing to a site or paper, because they often don't support their claims in turn. This takes a lot of time and effort compared to just sharing what I know. So, while insulin is definitely important, I chose this topic a few years ago because I saw it as a common point of misunderstanding at that time, even among experts. This site has often been geared more toward experts than toward the general lay audience. I highly recommend Ketogenic Diet Resource for a comprehensive, and easy to understand approach guide to the diet.
That said, I have discussed insulin in relation to this issue, and more relevantly, the insulin-to-glucagon ratio. When you bring up the insulin effect of protein, you are omitting the very important measurement of glucagon. The ultimate effect of taking in a protein on blood sugar itself can't be seen without measuring both, because the ratio is also important. Nonetheless, high insulin tends to turns off glucose production (GNG) itself, even under high glucagon.
You still seem to be confusing what *can* happen and what *does* happen. I am well aware of the gluconeogenic and ketogenic profiles of different amino acids, and have nowhere stated that I assume that amino acids that are both gluconeogenic and ketogenic will be used in one way or the other. That misses the point entirely. In fact, I mostly assume they will be used for neither!
Nor have I ever said that higher protein doesn't result in more gluconeogenesis ultimately. It may, through the mechanism of lowering ketogenesis through insulin-to-glucagon ratio. Insofar as it does, that is by increasing demand. That was discussed in more detail here. This post is really more about refuting an assumed mechanism than anything else.
I have seen the "where does it go?" argument before, and it's a good question for science, but not knowing the answer doesn't prove anything one way or another. We don't know all the mechanisms, so you can't just do a process of elimination. I don't have my collection at hand, but I have seen experiments that clearly show that the more protein you take in, the more is used for repair and maintenance. It's not linear at all, so you can't just figure out how much went to maintenance at one level, and assume that eating more would all be "excess", for example.
As to your summary:Delete
1. is vague and circular, because we don't know what makes protein excess. It's almost true by definition, but the implied causality is backwards. A more accurate statement might be that any protein that gets shunted into being metabolised for glucose must be excess. I would, if pressed, guess that the body strongly disprefers this use of protein, and would be evolutionarily driven to use it any other way it can first. My point is similar to Taubes point about calories. Yes, fat is made of excess calories. Does that tell you anything about causality, or what makes a calorie excessive in the first place? No.
2. lacks evidence, it's a hypothesis. Some of the experiments I've cited measure whether the glycogen came from "new" glucose via GNG. (I apologise; I can't check which ones right now.) The evidence is not just inferred from measuring blood sugar, but whether new glucose was actually being produced to be stored as glycogen. Again, insulin levels tend to reduce GNG (no matter where the resulting glucose is going). So, I don't think that hypothesis will hold up as is.
I agree with 3.
4. assumes what you are trying to prove, that high levels of protein cause excessive GNG. As I've said above, it appears that any such relationship would have to have causality in this order: higher protein --> decreased ketogenesis --> increased demand for GNG to fill the energy demand not met by ketones.
That's the point of this series of articles.
Thanks for your response Amber.Delete
My hope is that there will be more investigation / research into these topics so we can move past theorizing and annecdote, particularly given the revelations around dangers of high insulin levels.
Thanks for playing a significant part in moving the needle in that direction.
Thank you. Marty. That is also my hope. I don't know if I've made any real difference, but I appreciate the kind words.Delete
It is still not clear to me whether the dangers of diabetes are actually related to insulin itself or whether the correlation of insulin levels is only linked through the common cause of glucose oxidation. That is, if the ACCORD study showed that increasing insulin to control blood sugar wasn't a win, maybe that is because it is harmful to metabolise that much glucose, even if it doesn't build up in the blood. It is certainly suggestive. In fact, it is very consistent with the idea that while diabetes is one outcome of eating too much carbohydrate, CVD is another. That is, there is a large subset of people who don't get the diabetes symptoms, but do get the heart disease symptoms, and maybe that's because their insulin production never breaks down, but the high levels of glucose throughput is still harmful. Or maybe, as your idea suggests, it is a function of their own endogenously produced insulin. It would be nice to have a study that differentiated those.
As a society, for some reason we seem to take diabetes much less seriously than heart disease, even though it is no less devastating.