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

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

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

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

In Brief:

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

Gluconeogenesis

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

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

In fact, it turns out that the level of blood sugar that has to be reached to significantly increase cortisol is so low that clinical symptoms of hypoglycemia also start to appear at that level ³. Not only are reports of hypoglycemic episodes in studies of keto dieters rare, it has been known since at least 1936 that keto diets with adequate protein help prevent hypoglycemia ⁶. (It is reported in that paper that keto diets with lower protein help somewhat, but not enough.) A more recent paper from 1975 asserts that the best treatment for hypoglycemia is a low carbohydrate diet with frequent small meals, though they note that this worsens the condition in occasional cases where the patient has one of the above-mentioned or similar disorders ⁷. The only other examples of hypoglycemia we could find referred to the initial fasting or severely calorie-restricted phases of ketogenic diets for epilepsy.

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

What you can do

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

Summary:

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

References:

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

• “Ketogenic and very low carbohydrate diets necessarily increase cortisol expression in order to create glucose for the few cells in the body that cannot run on ketone bodies.”
• “To summarize: long-term gluconeogenesis can work, but you will be operating on a consistently high level of cortisol, which may not be ideal.”
• “[I]ncrease starchy carbs to ~20% of calories (lowers cortisol from gluconeogenesis)”
• “The body interprets a low-carb diet as “a starvation signal” secreting cortisol”
• “Mat Lalonde discusses how carb restriction signals starvation, specifically in regards to the cortisol release from gluconeogenesis. In my previous post I suggested a minor carb excess is probably better than minor carb restriction in order to prevent gluconeogenesis (from carb restriction), which I think is probably worse than de novo lipogenesis (from carb excess). Excess cortisol can hinder your weight loss efforts.”

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


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

(Emphasis ours.)

The importance of maintaining a fairly constant level of serum glucose is reflected in the elaborate system for defending against falling glucose concentrations. Four major counterregulatory hormones are of varying importance and effectiveness in counteracting a hypoglycemic threat, and there is a hierarchy of response of the factors that counterbalance the threat of hypoglycemia. Each factor has a somewhat different threshold for activation (39 ³, 40 ⁴) and the physiological importance of each component in the system of defense against hypoglycemia tends to be reflected by its position in the hierarchy. Small decreases in the plasma glucose concentration to the threshold of 65 mg/dL (3.6 mM/L) are usually sufficient to trigger the secretion of glucagon and epinephrine (40 ⁴,41 ⁵), the hormones that are of greater counterregulatory importance. Cortisol levels do not increase until the blood glucose falls below 55 mg/dL.


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

The relevant references from that passage are:

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

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

⁴(Ober's 40.) Evidence type: experimental.
Mitrakou A, Ryan C, Veneman T, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 1991;260:E67-E74.

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

⁵(Ober's 41.) Evidence type: experimental.
Bolli GB, Fanelli CG. Unawareness of hypoglycemia. N Engl J Med 1995;333:1771-1772.

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

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

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

...

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

...

Conclusions

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

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

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

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

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

⁷ Evidence type: experiment.
Hofeldt FD. Reactive hypoglycemia. Metabolism. 1975 Oct;24(10):1193-208.
(Emphasis ours)

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

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