The Effect of Ketogenic Diets on Thyroid Hormones

The previous generation of myths about low carb diets were focused on organ systems. They warned of things like kidney dysfunction, and osteoporosis. As these myths became untenable, new myths have swiftly taken their place: myths, for example, about hormone systems, and gut bacteria.

In previous posts, such as here, and here, we dispelled misinformation arising from fears about cortisol. In this post we address fears about thyroid.

The idea that ketogenic diets are “bad for thyroid” is spouted in keto-opposed and keto-friendly venues alike. Despite rampant parroting, it is difficult to find evidence to support this idea. The only evidence that we found even suggestive of this idea is the fact that T₃, the most active thyroid hormone, has repeatedly been shown to be lower in ketogenic dieters.

However, this lowered T₃ is not a sign of “hypothyroid”. In fact, it has a beneficial function! In this article, we explain why lower T₃ on a ketogenic diet is beneficial, rather than a sign of dysfunction or cause for alarm.

In Brief:

• Low T₃ is not hypothyroid.
• Lower T₃ spares muscle in conditions of weight loss or inadequate protein.
• Low T₃ is associated with longevity.

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Low T₃ is not hypothyroid.

Diagnosis

Let's first clear up some confusion about “low thyroid”.

Diagnosis is a tricky business. Diseases manifest in unwanted symptoms, and diagnosis is the art of determining the cause. Sometimes symptoms are very good discriminators. They are easy to verify, and they have only one or two common causes. Other times symptoms are common in a variety of illnesses, and by themselves don't help diagnosis much. Hypothyroid tends to be a cluster of these indiscriminate symptoms, and therefore, a lot of people are tempted, in understandable desperation, to diagnose themselves with it.

Ideally in medical research we want to find indicators and predictors of diseases: things we can measure that discriminate well between diseases, or predict the imminent manifestation of those diseases. Often they are measures that are not readily apparent to a patient, for example blood levels of various substances. To verify a suspicion of hypothyroid, we measure thyroid hormones in the blood.

As we have seen again and again, there are often different ways to measure something, and symptoms or outcomes correlated with one measure may or may not correlate with the others.

Hypothyroid

The most common thyroid measures are the levels of TSH (thyroid stimulating hormone), T₄ (a relatively inactive form of thyroid hormone), and T₃ (the more active form). TSH acts on the thyroid gland causing T₃ and T₄ to be produced. Further T₃ can be generated out of T₄. Hypothyroid is a problem in the gland, where not enough T₃ and T₄ are being produced. It is indicated by high values of TSH (along with low T₃ and T₄).

It is my suspicion that supplementing thyroid hormone in the general case of hypothyroidism may be as foolish as supplementing insulin in Non-Insulin-Dependent Diabetes. Insulin is appropriate in (aptly named) Insulin-Dependent Diabetes, just as thyroid hormone would remain appropriate in Hashimoto's.

The situation is analogous to high insulin in a Type II (Non-Insulin-Dependent) Diabetic: In that case, insulin at normal amounts is not effectively reducing blood sugar as it would in a healthy body, so more and more gets produced to have the needed effect. In the case of hypothyroid, more and more TSH is produced, because TSH is what acts on the thyroid gland to produce T₃ and T₄. In other words, when you have low T₃ and T₄ levels, this signals more TSH to be created, in order to cause more T₃ and T₄ to be made in the gland.

Low T₃ by itself, without high TSH or low T₄, has been studied extensively, and has various names, including “nonthyroidal illness syndrome” (NTIS) [1]. On modern, high carb diets, it appears to happen only in cases of critical illness [1].

Whether low T₃ in critical illness is adaptive or not is a point of controversy [1]. Clearly, either there is a disruption in production caused by the illness, or the body has a functional reason for not raising T₃; that is, that low T₃ helps recovery in some way. The adaptive hypothesis would be supported if supplementing T₃ caused harm. Unfortunately, results have been mixed.

The mixed results are probably an artefact of the lumping together of the various situations in which NTIS occurs. Although NTIS occurs with starvation, ketogenic diets, which share some metabolic similarities with starvation, have not so far been included in this area of research. However, research in calorie, carbohydrate, and protein restriction indicates that in these cases, as with starvation [1], lower T₃ is adaptive.

Lower T₃ spares muscle in conditions of weight loss or inadequate protein.

In weight loss, starvation, or protein deficiency conditions, lowered T₃ is thought to be a functional response that protects against muscle loss [2], [3]. When a diet creates a calorie deficit, or is low in protein, this creates a catabolic state (one in which the body tends to be breaking things down, rather than building them up). If the body does not respond to this by lowering T₃, then lean mass would be lost. Moreover, if T₃ is supplemented by a well-meaning person who interpreted this adaptation as a detrimental “hypothyroid” condition, this also results in loss of lean mass, as shown by Koppeschaar et al. [4]. Supplementing T₃ decreases ketosis, and increases the insulin-to-glucagon ratio [4], which, as we have previously discussed is tightly correlated with glucose production. This suggests that supplementing T₃ induces gluconeogenesis; as Koppeschaar et al. put it: "It must be concluded that triiodothyroxine also directly influenced glucose metabolism".

Not only are T₃ levels lower in calorie restriction, but T₃ receptors are downregulated [1], [5], suggesting a second mechanism by which the body adapts away from T₃ use under ketogenic conditions.

If you are on a low-carb diet in which you are losing weight, and your T₃ is low, don't assume you should correct this with supplementation. Lowered T₃ has a purpose, and supplementing it defeats the purpose.

Other research has shown a correlation between lower T₃ and higher ketosis [6], and between lower T₃ and very low carbohydrate levels [7], [8], [9]. It's all very consistent.

In other words, the more ketogenic a weight loss diet is the better it spares muscles, and lowered T₃ is thought to be part of the mechanism, because it is both correlated with higher βOHB, correlated with muscle sparing, and because supplementing with T₃ reverses the muscle sparing effect.

As alluded to above, T₃ will also be lowered in a situation where weight is not being lost, and carbs are not ketogenically low, if protein is inadequate [10]. This further underscores the function of T₃ lowering: to spare protein for lean mass.

We are not aware of a study showing the effects of a protein adequate, ketogenic maintenance diet (i.e. not calorie restricted) that measured T₃. Therefore, we are not certain whether lowered T₃ would continue in that context [11].

However, insofar as it may continue, that could be beneficial:

Low T₃ is associated with longevity.

It's possible that the lower T₃ found in ketogenic dieters is an indicator of a lifespan increasing effect.

First, T₃ is associated with longevity. Low T₃ has been found in the very long-lived [12]. This does not appear to be simply an effect of old age, though, because the correlation also shows up in a genetic study of longevity [13].

Moreover, just as with moderately elevated cortisol, low T₃ is found in animals who have their lifespans experimentally increased, and therefore (again, as with elevated cortisol) the low T₃ is hypothesised to be part of the mechanism in increasing lifespan [13], [14].

Conclusion

There is no evidence that we are aware of indicating that ketogenic diets cause hypothyroid, or negatively impact thyroid function. The fact that T₃ is lower in ketogenic dieters is probably part of the mechanism that protects lean mass when fat is being lost. Moreover, low T₃ may possibly even be an indicator of a life extending effect, an effect we have suggested elsewhere when examining the cortisol profile of ketogenic dieters.

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References:

[1]

Evidence type: review Thyroid function during critical illness. Economidou F1, Douka E, Tzanela M, Nanas S, Kotanidou A. Hormones (Athens). 2011 Apr-Jun;10(2):117-24. (Emphasis ours) “The metabolic support of the critically ill patient is a relatively new target of active research and little is as yet known about the effects of critical illness on metabolism. The nonthyroidal illness syndrome, also known as the low T₃ syndrome or euthyroid sick syndrome, describes a condition characterized by abnormal thyroid function tests encountered in patients with acute or chronic systemic illnesses. The laboratory parameters of this syndrome include low serum levels of triiodothyronine (T₃) and high levels of reverse T₃, with normal or low levels of thyroxine (T₄) and normal or low levels of thyroid-stimulating hormone (TSH). This condition may affect 60 to 70% of critically ill patients. The changes in serum thyroid hormone levels in the critically ill patient seem to result from alterations in the peripheral metabolism of the thyroid hormones, in TSH regulation, in the binding of thyroid hormone to transport-protein and in receptor binding and intracellular uptake. Medications also have a very important role in these alterations. Hormonal changes can be seen within the first hours of critical illness and, interestingly, these changes correlate with final outcome. Data on the beneficial effect of thyroid hormone treatment on outcome in critically ill patients are so far controversial. Thyroid function generally returns to normal as the acute illness resolves.” [...] “It remains controversial whether development of the aforementioned changes in thyroid metabolism reflects a protective mechanism or a maladaptive process during illness. If these changes constitute an adaptation mechanism, then treatment to restore thyroid hormone levels to the normal range could have deleterious effects. In contrast, if these changes are pathologic, treatment may improve an otherwise poor clinical outcome. Current literature data indicate that: Starvation-induced decrease in serum T₃ concentrations most likely reflects a process of adaptation.”

Ketogenic metabolism most closely resembles starvation, though, of course, with the important difference that it is nutritionally complete and there is no reason to believe it would be unhealthy indefinitely. — Amber

[2]

Evidence type: experiment Relationship between the changes in serum thyroid hormone levels and protein status during prolonged protein supplemented caloric deprivation. Kaptein EM, Fisler JS, Duda MJ, Nicoloff JT, Drenick EJ. Clin Endocrinol (Oxf). 1985 Jan;22(1):1-15. (Emphasis ours) “The relationship between the changes in serum thyroid hormone levels and nitrogen economy during caloric deprivation were investigated in ten obese men during a 40 d, 400 kcal protein-supplemented weight-reducing diet. This regimen induced increases in the serum levels of total T₄, free T₄ and total rTT₃and decreases of total T₃, while serum TSH remained unchanged. There were progressive decreases in total body weight and urinary losses of total nitrogen and 3-methylhistidine, with the early negative nitrogen balance gradually returning towards basal values during the 40 days. Subjects with the largest weight loss had the most increase in the serum levels of total T₄ and free T₄ index and the greatest decrease in T₃. The magnitude of the increase of the nitrogen balance from its nadir was correlated with the extent of the reduction of T₃ and increase of T₃ uptake ratio and free T₄ levels. The decrease in the urinary excretion of 3-methylhistidine correlated with the increase in free T₄ and rT₃ levels. Nadir serum transferrin values were directly related to peak rT₃ values, and the lowest albumin concentrations occurred in subjects with the highest total T₄ and free T₄ index values. Further, the maximum changes in the serum thyroid hormone levels preceded those of the nutritional parameters. These relationships suggest that: (1) increases in serum rT₃ and free T₄ and reductions in T₃ concentrations during protein supplemented weight reduction may facilitate conservation of visceral protein and reduce muscle protein turnover; and (2) the variation in the magnitude of these changes may account for the heterogeneity of nitrogen economy.”

[3]

Evidence type: experiment Variability in body protein loss during protracted, severe caloric restriction: role of triiodothyronine and other possible determinants Yang MU, van Itallie TB. Am J Clin Nutr. 1984 Sep;40(3):611-22. (Emphasis ours) “Although the rate of fat loss was relatively constant throughout the study, wide interindividual variations in cumulative protein (nitrogen) deficit were observed. Total nitrogen losses per subject ranged from 90.5 to 278.7 g. Cumulative nitrogen loss during the first 16 days tended to correlate negatively with initial mean fat cell size and positively with initial lean body mass. Most notable was the strong negative correlation between the size of the decrease in serum triiodothyronine over the 64-day study and the magnitude of the concurrent cumulative N deficit. During severe caloric restriction, one's ability to decrease circulating serum triiodothyronine levels may be critical to achievement of an adaptational decrease in body protein loss.”

[4]

Evidence type: experiment Metabolic responses in grossly obese subjects treated with a very-low-calorie diet with and without triiodothyronine treatment Koppeschaar HP, Meinders AE, Schwarz F. Int J Obes. 1983;7(2):133-41. (Emphasis ours) “Metabolic responses during a very-low-calorie diet, composed of 50 per cent glucose and 50 per cent protein, were studied in 18 grossly obese subjects (relative weights 131-205 per cent) for 28 d. During the last 14 d (period 2) eight subjects (Gp B) served as controls, while the other ten subjects (Gp A) in the low T₃ state were treated with triiodothyronine supplementation (50 micrograms, 3 times daily). During the first 14 d (period 1) a low T₃-high rT₃ state developed; there was an inverse relationship between the absolute fall of the plasma T₃ concentrations and the cumulative negative nitrogen balance as well as the beta-hydroxybutyrate (βOHB) acid concentrations during the semi-starvation period, pointing to a protein and fuel sparing effect of the low T₃ state. Weight loss in the semi-starvation period was equal in both groups; during T₃ treatment the rate of weight loss was statistically significant (Gp A 6.1 +/- 0.3 kg vs Gp B 4.2 +/- 0.2 kg, P less than 0.001). In the control group there was a sustained nitrogen balance after three weeks; in Gp A the nitrogen losses increased markedly during T₃ treatment. Compared to the control group, on average a further 45.4 g extra nitrogen were lost, equivalent to 1.4 kg fat free tissue. Thus, 74 per cent of the extra weight loss in the T₃ treated group could be accounted for by loss of fat free tissue. During the T₃ treatment period no detectable changes occurred regarding plasma triglycerides and plasma free fatty acids (FFA) concentrations; the plasma βOHB acid concentrations decreased significantly as compared to the control group. Plasma glucose concentrations and the immunoreactive insulin (IRI)/glucose ratio increased in Gp A in the T₃ treatment period, reflecting a state of insulin resistance with regard to glucose utilization. Our results warrant the conclusion that there appears to be no place for T₃ as an adjunct to dieting, as it enhances mostly body protein loss and only to a small extent loss of body fat.” [...] "The plasma βOHB concentration declined significantly during T₃ treatment. In accordance with the results of Hollingsworth et al. we observed a decline of the plasma uric acid levels; this decline occurred simulataneously with the decrease in the βOHB levels in the T₃ treated group; as renal tubular handling of uric acid and ketones are closely linked during fasting, this might implicate a diminished renal reabsorbtion of ketones. "It is known that renal conservation of ketones prevents large losses of cations during prolonged starvation without T₃ treatment; since ammonium is the major cation excreted in established starvation, the increased renal reabsorbtion of ketone bodies also minimizes nitrogen loss."

[5]

Evidence type: review Fasting decreases triiodothyronine receptor capacity. Schussler GC, Orlando J. Science. 1978 Feb 10;199(4329):686-8. "Fasting decreases the ratio of hepatic nuclear to serum triiodothyronine (T₃) by diminishing the binding capacity of nuclear T₃ receptors. In combination with the lower serum T₃ concentration caused by fasting, the decrease in receptor content results in a marked decrease in nuclear T₃-receptor complexes. The changes in T₃ receptor content and circulating T₃ in fasted animals appear to be independent synergistic adaptations for caloric conservation in the fasted state. Unlike changes in hormonal level, the modification of nuclear receptor content provides a mechanism that may protect cells with a low caloric reserve independently of the metabolic status of the whole animal."

[6]

Evidence type: controlled experiment Effect of caloric restriction and dietary composition on serum T₃ and reverse T₃ in man Spaulding SW, Chopra IJ, Sherwin RS, Lyall SS. J Clin Endocrinol Metab. 1976 Jan;42(1):197-200. “To evaluate the effect of caloric restriction and dietary composition on circulating T₃ and rT₃, obese subjects were studied after 7—18 days of total fasting and while on randomized hypocaloric diets (800 kcal) in which carbohydrate content was varied to provide from 0 to 100% calories. As anticipated, total fasting resulted in a 53% reduction in serum T₃ in association with a reciprocal 58% increase in rT₃. Subjects receiving the no-carbohydrate hypocaloric diets for two weeks demonstrated a similar 47% decline in serum T₃ but there was no significant change in rT₃ with time. In contrast, the same subjects receiving isocaloric diets containing at least 50 g of carbohydrate showed no significant changes in either T₃ or rT₃ concentration. The decline in serum T₃ during the no-carbohydrate diet correlated significantly with blood glucose and ketones but there was no correlation with insulin or glucagon. We conclude that dietary carbohydrate is an important regulatory factor in T₃ production in man. In contrast, rT₃, concentration is not significantly affected by changes in dietary carbohydrate. Our data suggest that the rise in serum rT₃ during starvation may be related to more severe caloric restriction than that caused by the 800 kcal diet.”

So at least in a very low calorie situation, T₃ becomes low only when the diet is sufficiently low in carbohydrate to be ketogenic, and its level correlates with ketogenesis. We are not told whether any of the diets were protein sufficient, but in this case it doesn't matter. The very low calories make it catabolic, and only when carbohydrate is at ketogenically low levels does the protein sparing effect occur. —Amber

[7]

Evidence type: controlled experiment The effect of varying carbohydrate content of a very-low-caloric diet on resting metabolic rate and thyroid hormones. Mathieson RA, Walberg JL, Gwazdauskas FC, Hinkle DE, Gregg JM. Metabolism. 1986 May;35(5):394-8. (Emphasis ours) “Twelve obese women were studied to determine the effects of the combination of an aerobic exercise program with either a high carbohydrate (HC) very-low-caloric diet (VLCD) or a low carbohydrate (LC) VLCD diet on resting metabolic rate (RMR), serum thyroxine (T₄), 3,5,3'-triiodothyronine (T₃), and 3,5,3'-triiodothyronine (rT₃). The response of these parameters was also examined when subjects switched from the VLCD to a mixed hypocaloric diet. Following a maintenance period, subjects consumed one of the two VLCDs for 28 days. In addition, all subjects participated in thrice weekly submaximal exercise sessions at 60% of maximal aerobic capacity. Following VLCD treatments, participants consumed a 1,000 kcal mixed diet while continuing the exercise program for one week. Measurements of RMR, T₄, T₃, and rT₃ were made weekly. Weight decreased significantly more for LC than HC. Serum T₄ was not significantly affected during the VLCD. Although serum T₃ decreased during the VLCD for both groups, the decrease occurred faster and to a greater magnitude in LC (34.6% mean decrease) than HC (17.9% mean decrease). Serum rT₃ increased similarly for each treatment by the first week of the VLCD. Serum T₃ and rT₃ of both groups returned to baseline concentrations following one week of the 1,000 kcal diet. Both groups exhibited similar progressive decreases in RMR during treatment (12.4% for LC and 20.8% for HC), but values were not significantly lower than baseline until week 3 of the VLCD. Thus, although dietary carbohydrate content had an influence on the magnitude of fall in serum T₃, RMR declined similarly for both dietary treatments.”

[8]

Evidence type: controlled experiment Effect of dietary carbohydrates during hypocaloric treatment of obesity on peripheral thyroid hormone metabolism Pasquali R, Parenti M, Mattioli L, Capelli M, Cavazzini G, Baraldi G, Sorrenti G, De Benedettis G, Biso P, Melchionda N. J Endocrinol Invest. 1982 Jan-Feb;5(1):47-52. (Emphasis ours) “The effect of different hypocaloric carbohydrate (CHO) intakes was evaluated in 8 groups of obese patients in order to assess the role of the CHO and the other dietary sources in modulating the peripheral thyroid hormone metabolism. These changes were independent of those of bw. Serum T₃ concentrations appear to be more easily affected than those of reverse T₃ by dietary manipulation and CHO content of the diet. A fall in T₃ levels during the entire period of study with respect to the basal levels occurred only when the CHO of the diet was 120 g/day or less, independent of caloric intake (360, 645 or 1200 calories). Moreover, reverse T₃ concentrations were found increased during the entire period of study when total CHO were very low (40 to 50 g/day) while they demonstrated only a transient increase when CHO were at least 105 g/day (with 645 or more total calories). Indeed, our data indicate that a threshold may exist in dietary CHO, independent of caloric intake, below which modifications occur in thyroid hormone concentrations. From these results it appears that the CHO content of the diet is more important than non-CHO sources in modulating peripheral thyroid hormone metabolism and that the influence of total calories is perhaps as pronounced as that of CHO when a “permissive” amount of CHO is ingested.”

[9]

Evidence type: controlled experiment Effect of dietary composition on fasting-induced changes in serum thyroid hormones and thyrotropin Azizi F. Metabolism. 1978 Aug;27(8):935-42. (Emphasis ours) “To assess the effect of starvation and refeeding on serum thyroid hormones and thyrotropin (TSH) concentrations, 45 obese subjects were studied after 4 days of fasting and after refeeding with diets of varying composition. All subjects showed an increase in both serum total and free thyroxine (T₄), and a decrease in serum total and free triiodothyronine (T₃) following fasting. These changes were more striking in men then in women. The serum T₃ declined during fasting even when the subjects were given oral L-T₄, but not when given oral L-T₃. After fasting, the serum reverse T₃ (rT₃) rose, the serum TSH declined, and the TSH response to thyrotropin-releasing hormone (TRH) was blunted. Refeeding with either a mixed diet (n = 22) or a carbohydrate diet (n = 8) caused the fasting-induced changes in serum T₃, T₄, rT₃, and TSH to return to control values. In contrast, refeeding with protein (n = 6) did not cause an increase in serum T₃ or in serum TSH of fasted subjects, while it did cause a decline in serum rT₃ toward basal value. “The present data suggest that: (1) dietary carbohydrate is an important factor in reversing the fall in serum T₃ caused by fasting; (2) production of rT₃ is not as dependent on carbohydrate as that of T₃; (3) men show more significant changes in serum thyroid hormone concentrations during fasting than women do, and (4) absorption of T₃ is not altered during fasting.”

Note that in this case, “refeeding” was with an 800 calorie diet, i.e., for protein, 200g. So the refeeding diet is still low calorie, and thus still catabolic —Amber

[10]

Evidence type: controlled experiment The role of dietary fat in peripheral thyroid hormone metabolism Otten MH, Hennemann G, Docter R, Visser TJ. Metabolism. 1980 Oct;29(10):930-5. “Short term changes in serum 3,3',5-triiodothyronine (T₃) and 3,3'5-triiodothyronine (reverse T₃, rT₃) were studied in four healthy nonobese male subjects under varying but isocaloric and weight maintaining conditions. The four 1500 kcal diets tested during 72 hr, consisted of: I, 100% fat; II, 50% fat, 50% protein; III, 50% fat, 50% carbohydrate (CHO), and IV, a mixed control diet. The decrease of T₃ (50%) and increase of rT₃ (123%) in the all-fat diet equalled changes noted in total starvation. In diet III (750 kcal fat, 750 kcal CHO) serum T₃ decreased 24% (NS) and serum rT₃ rose significantly 34% (p < 0.01). This change occurred in spite of the 750 kcal CHO. This amount of CHO by itself does not introduce changes in thyroid hormone levels and completely restores in refeeding models the alterations of T₃ and rT₃ after total starvation. The conclusion is drawn that under isocaloric conditions in man fat in high concentration itself may play an active role in inducing changes in peripheral thyroid hormone metabolism.”

Here, finally, is a study that is explicitly a maintenance diet. It says mostly what we would expect. It was a bit surprising, and contrary to some previous findings, that in the half carb, half fat diet, this high a carbohydrate level would still allow lower T₃. The authors suggest that this is evidence that high fat alone is responsible. Our interpretation, in contrast, is that it is the zero protein condition that led to the lower T₃. In the body of the paper, the authors, to their credit, acknowledge that they are speculating. We would love to see this example followed by more researchers. —Amber

[11]

Ebbeling et al. did make T₃ measurements, on a ketogenic diet intended to be weight stable, but the subjects were losing weight while on the ketogenic phase, and therefore no conclusion about T₃ in weight stable, protein adequate conditions can be drawn from that study. Effects of dietary composition on energy expenditure during weight-loss maintenance. Ebbeling CB, Swain JF, Feldman HA, Wong WW, Hachey DL, Garcia-Lago E, Ludwig DS. JAMA. 2012 Jun 27;307(24):2627-34. doi: 10.1001/jama.2012.6607. (Emphasis ours) “Participants Overweight and obese young adults (n=21). Interventions After achieving 10 to 15% weight loss on a run-in diet, participants consumed low-fat (LF; 60% of energy from carbohydrate, 20% fat, 20% protein; high glycemic load), low-glycemic index (LGI; 40%-40%-20%; moderate glycemic load), and very-low-carbohydrate (VLC; 10%-60%-30%; low glycemic load) diets in random order, each for 4 weeks.” [...] “Hormones and Components of the Metabolic Syndrome (Table 3) Serum leptin was highest with the LF diet (14.9 [12.1 to 18.4] ng/mL), intermediate with the LGI diet (12.7 [10.3 to 15.6] ng/mL) and lowest with the VLC diet (11.2 [9.1 to 13.8] ng/mL; P=0.0006). Cortisol excretion measured with a 24-hour urine collection (LF: 50 [41 to 60] μg/d; LGI: 60 [49 to 73] μg/d; VLC: 71 [58 to 86] μg/d; P=0.005) and serum TSH (LF: 1.27 [1.01 to 1.60] μIU/mL; LGI: 1.22 [0.97 to 1.54] μIU/mL; VLC: 1.11 [0.88 to 1.40] μIU/mL; P=0.04) also differed in a linear fashion by glycemic load. Serum T₃ was lower with the VLC diet compared to the other two diets (LF: 121 [108 to 135] ng/dL; LGI: 123 [110 to 137] ng/dL; VLC: 108 [96 to 120] ng/dL; P=0.006).”

[12]

Evidence type: observational Evaluation of neuroendocrine status in longevity. Baranowska B1, Wolinska-Witort E, Bik W, Baranowska-Bik A, Martynska L, Broczek K, Mossakowska M, Chmielowska M. Neurobiol Aging. 2007 May;28(5):774-83. Epub 2006 May 12. (Emphasis ours) “It is well known that physiological changes in the neuroendocrine system may be related to the process of aging. To assess neuroendocrine status in aging humans we studied a group of 155 women including 78 extremely old women (centenarians) aged 100-115 years, 21 early elderly women aged 64-67 years, 21 postmenopausal women aged 50-60 years and 35 younger women aged 20-50 years. Plasma NPY, leptin, glucose, insulin and lipid profiles were evaluated, and serum concentrations of pituitary, adrenal and thyroid hormones were measured. Our data revealed several differences in the neuroendocrine and metabolic status of centenarians, compared with other age groups, including the lowest serum concentrations of leptin, insulin and T₃, and the highest values for prolactin. We failed to find any significant differences in TSH and cortisol levels. On the other hand, LH and FSH levels were comparable with those in the elderly and postmenopausal groups, but they were significantly higher than in younger subjects. GH concentrations in centenarians were lower than in younger women. NPY values were highest in the elderly group and lowest in young subjects. We conclude that the neuroendocrine status in centenarians is markedly different from that found in early elderly or young women.”

[13]

Evidence type: observational Low serum free triiodothyronine levels mark familial longevity: the Leiden Longevity Study. Rozing MP1, Westendorp RG, de Craen AJ, Frölich M, Heijmans BT, Beekman M, Wijsman C, Mooijaart SP, Blauw GJ, Slagboom PE, van Heemst D; Leiden Longevity Study (LLS) Group. J Gerontol A Biol Sci Med Sci. 2010 Apr;65(4):365-8. doi: 10.1093/gerona/glp200. Epub 2009 Dec 16. “BACKGROUND: The hypothalamo-pituitary-thyroid axis has been widely implicated in modulating the aging process. Life extension effects associated with low thyroid hormone levels have been reported in multiple animal models. In human populations, an association was observed between low thyroid function and longevity at old age, but the beneficial effects of low thyroid hormone metabolism at middle age remain elusive. METHODS: We have compared serum thyroid hormone function parameters in a group of middle-aged offspring of long-living nonagenarian siblings and a control group of their partners, all participants of the Leiden Longevity Study. RESULTS: When compared with their partners, the group of offspring of nonagenarian siblings showed a trend toward higher serum thyrotropin levels (1.65 vs157 mU/L, p = .11) in conjunction with lower free thyroxine levels (15.0 vs 15.2 pmol/L, p = .045) and lower free triiodothyronine levels (4.08 vs 4.14 pmol/L, p = .024). CONCLUSIONS: Compared with their partners, the group of offspring of nonagenarian siblings show a lower thyroidal sensitivity to thyrotropin. These findings suggest that the favorable role of low thyroid hormone metabolism on health and longevity in model organism is applicable to humans as well.”

[14]

Evidence type: experiment Effect of long-term calorie restriction with adequate protein and micronutrients on thyroid hormones. Fontana L, Klein S, Holloszy JO, Premachandra BN. J Clin Endocrinol Metab. 2006 Aug;91(8):3232-5. Epub 2006 May 23. “CONTEXT: Caloric restriction (CR) retards aging in mammals. It has been hypothesized that a reduction in T₃ hormone may increase life span by conserving energy and reducing free-radical production. OBJECTIVE: The objective of the study was to assess the relationship between long-term CR with adequate protein and micronutrient intake on thyroid function in healthy lean weight-stable adult men and women. DESIGN, SETTING, AND PARTICIPANTS: In this study, serum thyroid hormones were evaluated in 28 men and women (mean age, 52 +/- 12 yr) consuming a CR diet for 3-15 yr (6 +/- 3 yr), 28 age- and sex-matched sedentary (WD), and 28 body fat-matched exercising (EX) subjects who were eating Western diets. MAIN OUTCOME MEASURES: Serum total and free T₄, total and free T₃, reverse T₃, and TSH concentrations were the main outcome measures. RESULTS: Energy intake was lower in the CR group (1779 +/- 355 kcal/d) than the WD (2433 +/- 502 kcal/d) and EX (2811 +/- 711 kcal/d) groups (P < 0.001). Serum T₃ concentration was lower in the CR group than the WD and EX groups (73.6 +/- 22 vs. 91.0 +/- 13 vs. 94.3 +/- 17 ng/dl, respectively) (P < or = 0.001), whereas serum total and free T₄, reverse T₃, and TSH concentrations were similar among groups. CONCLUSIONS: Long-term CR with adequate protein and micronutrient intake in lean and weight-stable healthy humans is associated with a sustained reduction in serum T₃ concentration, similar to that found in CR rodents and monkeys. This effect is likely due to CR itself, rather than to a decrease in body fat mass, and could be involved in slowing the rate of aging.”

Keto-adapted, but no ketones?

One of the cheapest and easiest ways to measure ketones is to use ketone test strips, e.g. Ketostix. Ketone test strips use a chemical reaction to measure acetoacetate (see below), usually in urine, though the same method can be used for blood. (Not to be confused with the blood strips used at home for beta-hydroxybutyrate.) However, acetoacetate test strips are of limited usefulness. For one thing, urine concentrations are affected by dilution, which means that they are affected by how much you drink.

But the problem is deeper than that. Acetoacetate is only one of the three ketone bodies (see below). Initially, when you start a ketogenic diet, acetoacetate will make up about half of the circulating ketones [1], but when you are keto-adapted, it makes up only about 20% of the ketone bodies in circulation (see below). Morover, the sensitivity of the strips is a little lower than optimal for our purposes. They register negative unless the concentration is quite high.

So, it is not uncommon for a keto-adapted person to measure negative for acetoacetate.

Different ketone bodies occur in different amounts

There are three compounds grouped together as ketone bodies: acetoacetate, beta-hydroxybutyrate, and acetone. In keto-adapted people, acetoacetate levels are relatively low even though beta-hydroxybutyrate is high. Typically, beta-hydroxybutyrate levels are 4–5 times as high as acetoacetate. (Acetone makes up only about 2% of total ketone bodies [2].)

The graph above shows that in the ketosis of fasting, the proportion of acetoacetate (the top, white part of the bar) is much smaller than that of beta-hydroxybutyrate (the black part). In the study here, after 21 days of fasting, the average level of blood acetoacetate was 1.04 mmol/L, while the beta-hydroxybutyrate level was 4.95 mmol/L [3]. In another study of epileptic children on ketogenic diets, after 3 months, the average acetoacetate level was 1.182 mmol/L, while the average beta-hydroxybutyrate level was 4.21 [4].

The level of ketosis in fasting and in epileptic treatment is a little bit higher than for the typical ketogenic dieter who is simply trying to lose weight, enhance athletic performance, or improve their cardiovascular risk profile, for example. In those cases, beta-hydroxybutyrate levels are typically 1–3 mmol/L.

Since the ratio of acetoacetate to beta-hydroxybutyrate is only about 1:4, acetoacetate levels will be only about 0.25–0.75 mmol/L for keto-adapted people. The acetoacetate measure does not register as positive until about 0.5-1.0 mmol/L [5], so those values will often register as negative for acetoacetate.

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Here are some examples of negative acetoacetate, even while beta-hydroxybutyrate is very high.

There is a dangerous state that diabetics can get into called keto-acidosis, which is crucially different from nutritional ketosis (a safe and healthy state), but is often confused with it, because they both involve activation of ketogenesis. Ketone levels in keto-acidosis are much higher than in nutritional ketosis, and it is the monitoring of this state that ketone strips are optimised for. Even though ketone levels in keto-acidosis are higher than in nutritional ketosis, in one report it was found that 57% of diabetics with negative acetoacetate measurements were suffering from keto-acidosis [6].

Most of the cases of high beta-hydroxybutyrate in this study were not also positive for urine acetoacetate.

This flowchart shows that it is clinically accepted that even with very high beta-hydroxybutyrate levels, acetoacetate in urine and blood can be negative. The reason acetoacetate is bothered with at all is that it is relatively cheap and easy to measure.

What's the best way to measure ketosis?

Ketone test strips are a cheap and easy way to confirm ketosis when you have very high levels, such as during keto-adaptation. However, we would expect the false negative rate to be high for keto-adapted people, and for infants, (who are normally in consistent but mild ketosis while exclusively breastfed). So although it can be a good tool when you are starting a ketogenic diet, it is not necessarily reliable as you progress.

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A negative acetoacetate measure does not imply that you are not in ketosis.

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If you are troubleshooting, and need more accurate measurements, we strongly recommend a blood ketone meter for beta-hydroxybutyrate. However, be aware that the strips themselves are very expensive.

A new breath acetone meter is now on the market. It costs about $100, but it doesn't require any strips, so you pay only once. Unfortunately, like the acetoacetate strips, the measure is only semi-quantitative, and appears to have a relatively high minimum threshold for showing positive. We also don't know how well acetone correlates to beta-hydroxybutyrate, or to therapeutic results. Nonetheless, it is a promising technology, and it requires no pinpricks or pants down. We'd love to hear from you if you've given it a try.

References:

[1]

Evidence type: authority The Art and Science of Low Carbohydrate Living: An Expert Guide to Making the Life-Saving Benefits of Carbohydrate Restriction Sustainable and Enjoyable Jeff Volek and Steven Phinney Publisher: Beyond Obesity LLC; 1St Edition edition (May 19, 2011) "Beta-hydroxybutyrate and acetoacetate are made in the liver in about equal proportions, and both are initially promptly oxidized by muscle. But over a matter of weeks, the muscles stop using these ketones for fuel. Instead, muscle cells take up acetoacetate, reduce it to beta-hydroxybutyrate, and return it back into the circulation. Thus after a few weeks, the predominant form in the circulation is beta-hydroxybutyrate, which also happens to be the ketone preferred by brain cells (as an aside, the strips that test for ketones in the urine detect the presence of acetoacetate, not beta-hydroxybutyrate). The result of this process of keto-adaptation is an elegantly choreographed shuttle of fuel from fat cells to liver to muscle to brain."

[2]

Evidence type: authority Henry's Clinical Diagnosis and Management by Laboratory Methods Richard A. McPherson, Matthew R. Pincus Elsevier Health Sciences, Sep 6, 201 "Whenever a defect in carbohydrate metabolism or absorption or an inadequate amount of carbohydrate is present in the diet, the body compensates by metabolizing increasing amounts of fatty acids. [...] In ketonuria, the three ketone bodies present in the urine are acetoacetic acid (20%), acetone (2%), and 3-hydroxybutyrate (about 78%)."

[3]	Evidence type: experiment Comparative measurements of glucose, beta-hydroxybutyrate, acetoacetate, and insulin in blood and cerebrospinal fluid during starvation. Owen OE, Reichard GA Jr, Boden G, Shuman C. Metabolism. 1974 Jan;23(1):7-14.

[4]

Evidence type: experiment A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Neal EG1, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH. Epilepsia. 2009 May;50(5):1109-17. doi: 10.1111/j.1528-1167.2008.01870.x. Epub 2008 Nov 19. "One hundred forty-five children with intractable epilepsy were randomized to receive a classical or an MCT diet." [...] "Classical diets were started at a 2:1 ratio and gradually increased to a 4:1 ratio as tolerated over 1–2 weeks; in a few children the ratio was kept at 3:1 for longer because of tolerance problems. Protein was generally kept at World Health Organization (WHO) minimum requirements for age (World Health Organization, 1985). MCT diets were commenced on a full prescription for carbohydrate (generally 15% energy), protein (usually 10% energy), and long-chain fatty acids (usually 30% energy). The MCT fat was increased incrementally over a 7–10 day period as tolerated, to an initial level that was usually 40–45% of total dietary energy. Diets were fully supplemented with vitamins and minerals. "Subsequent to starting the diet, all children were reviewed as outpatients at 3, 6, and 12 months. They were also closely monitored by telephone between clinic visits. Diets were fine-tuned as necessary to improve ketosis and optimize seizure control. The parameters within which the two diets could be modified were defined before study commencement. Overall energy prescription was adjusted on both diets as needed. Ketogenic ratio on the classical diets was kept between 2:1 and 5:1 (most classical diet children were on a 4:1 ratio, a few were on a 3:1 ratio, and two children needed a 2:1 ratio for a short period). Fine-tuning on the MCT diets involved adjusting the proportion of MCT and carbohydrate in the prescription. MCT was usually started at 40–45% of energy, and was increased up to 60% if necessary and tolerated. Carbohydrate was usually started at 15% of energy, and was reduced to a lowest value of 12% if necessary. Carbohydrate was reduced to improve ketosis only if an increase in MCT was not possible because of poor tolerance. Other modifications on both diets were fluid intake and meal distribution. Protein intake was increased as needed to meet requirements."

[5]

Evidence type: authority Ketostrips use nitroprusside to detect acetoacetate levels. We have seen claims that they can detect as little as 5 mg/dl (0.5 mmol/L), only 10 mg/dl, or, most commonly, the minimum is given as the range 5–10 mg/dl. Here is an example of each: From: Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Walker HK, Hall WD, Hurst JW, editors. Boston: Butterworths; 1990. "Nitroprusside is available as a test tablet (Acetest) and as a coated reagent strip (Ketostix), both manufactured by the Ames Division of Miles Laboratories, Inc., Elkhart, Indiana. With Acetest, after 30 seconds the color development is compared to a chart and judged negative, small, moderate or large. The tablet will detect 5 to 10 mg/dl of acetoacetate and 20 mg/dl of acetone. The quantitative range included in each category is 5 to 20 mg/dl for small, 20 to 40 mg/dl for moderate, and 40 mg/dl or greater for large. With Ketostix, the strip is momentarily dipped into the urine specimen or passed through in the urinary stream and compared to a color chart 1 minute later. The scale is negative, trace, small, moderate, and large. The strip is capable of detecting 5 mg/dl acetoacetate but is not reactive to acetone. The ranges are wider and shifted somewhat to the right in the higher zones compared to Acetest so that only 16% of samples containing 20 mg/dl acetoacetate are read as moderate while 24% of samples containing 80 mg/dl acetoacetate are still called moderate. Only 15% of the samples containing 40 mg/dl acetoacetate are judged to be large; 76% are large at 80 mg/dl and 100% at 160 mg/dl. The Ketostix test is most accurate when urines are tested with a high specific gravity (between 1.010 and 1.020) and low-pH. Highly pigmented urine specimens may yield false positive readings. Levodopa will also cause a false positive result. Ketostix strips are less sensitive than Acetest tablets and have a high degree of variability between lots. Acetest, with sensitivity in the 5 mg/dl range, is the preferable method." From: Medical Laboratory Science : Theory And Practice Ochei Et Al. Tata McGraw-Hill Education, Aug 1, 2000. p 134 "Ketostix (Ames) This test strip will detect 0.5–1.0 mmol/L (5–10 mg/dl) of acetoacetic acid" From: Blackwell's Five-Minute Veterinary Consult: Laboratory Tests and Diagnostic Procedures Shelly L. Vaden, Joyce S. Knoll, Francis W. K. Smith, Jr., Larry P. Tilley John Wiley & Sons, Jun 13, 2011 "Only acetoacetate and acetone are detectable by reagent strips or tablet tests, which are based on the reaction of acetoacetate (more reactive) and acetone (less reactive) with nitroprusside. "Urine (and blood) can be screened for ketones by using either reagent strips or tablets [...] The [tablet] is more sensitive than reagent strips and will detect 5 mg/dL of ketones compared with 10 mg/dL for dipsticks."

[6]

Evidence type: authority, since we can't access the full text From: Development of Paper-strip Test for 3-Hydroxybutyrate and its Clinical Application Yutaka Harano, M.D., Masaaki Suzuki, M.D., Hideto Kojima, M.D., Atsunori Kashiwagi, M.D. Ph.D., Hideki Hidaka, M.D. Ph.D. and Yukio Shigeta, M.D. Ph.D. Diabetes Care September/October 1984 vol. 7 no. 5 481-485 "MacGillivray et al. recently reported that 57% of the urine tests that were negative for ketone bodies by acetest were associated with elevated plasma 3-OHBA in insulin-dependent diabetes. [...] "MacGillivray, M. H., Voorhess, M. L., Putnam, T. I., Li, P. K., Schaefer, P. A., and Bruck, E.: Hormone and metabolic profiles in children and adolescents with Type I diabetes mellitus. Diabetes Care 1982; 5(Suppl .l):38-47"

The Ketogenic Diet's Effect on Cortisol Metabolism

(Related post: Red Light, Green Light: responses to cortisol levels in keto vs. longevity research)

One of the myths surrounding ketogenic diets comes from misunderstanding the role of cortisol — the "stress hormone".

In a previous post, we addressed one of the arguments behind this myth: the idea that to activate gluconeogenesis (to make glucose out of protein), extra cortisol must be recruited. That is just factually incorrect, as we showed in the post.

The other argument, which we address here, is more complex.

Like the previous cortisol myth, it involves a faulty chain of reasoning. Here are the steps:

1. Ketogenic diets may raise certain measures of cortisol.
2. Chronically elevated cortisol is correlated with metabolic sydrome, and therefore higher cortisol measures may indicate the onset of metabolic syndrome.
3. Therefore, ketogenic diets could cause metabolic syndrome.

Metabolic syndrome is a terrible and prevalent problem today. It is that cluster of symptoms most strongly identified with diabetes — excess abdominal fat, high blood sugar, and a particular cholesterol profile — but also correlated with other life-threatening conditions such as heart disease and cancer.

In this post, we're going to explain some of the specifics of cortisol metabolism. We'll show how this argument is vague, and how clarifying it leads to the opposite conclusion. The confusion may all stem from misunderstanding one important fact: different measures of cortisol are not equivalent.

First, though, there is an important reason why the argument doesn't make sense.

We already know that a ketogenic diet effectively treats metabolic syndrome. As we will describe below, it turns out that certain cortisol patterns are strongly linked to metabolic syndrome, and might even be a cause of metabolic syndrome. If the cortisol pattern that develops in response to a ketogenic diet were the kind that was associated with metabolic syndrome, then we would expect people on ketogenic diets to show signs of abdominal fat gain, rising blood sugar, and a worsening cholesterol profile, but we see the opposite. This by itself makes it highly unlikely that ketogenic diets raise cortisol in a harmful way.

In other words, because cortisol regulation is so deeply connected to metabolic syndrome, the fact that ketogenic diets reverse symptoms of metabolic syndrome is itself strong evidence that they improve cortisol metabolism.

In Brief

• There are many different measures of cortisol, because researchers have identified many different processes in cortisol metabolism.
• Increases in some of those measurements are consistently linked to metabolic syndrome, and others are not.
• Some researchers believe that cortisol dysregulation is a key underlying factor in metabolic syndrome.
• The cornerstone of this connection may be the activity of an enzyme, 11β-HSD1. It converts from the inactive form cortisone to the active cortisol.
• In metabolic syndrome, 11β-HSD1 is underactive in liver tissue and overactive in fat tissue. This results in a high rate of cortisol clearance, and low rate of regeneration.
• These symptoms of cortisol dysregulation associated with metabolic syndrome were found to be reversed by a keto diet in a study that made the necessary measurements.

Does a ketogenic diet raise cortisol?

Boston Children's Hospital graphic (with our markup in black). Click for the original.

In a widely-cited study [1], from the Harvard-affiliated Boston Children's Hospital, published in the Journal of the American Medical Association, three different diets were tested: a low-fat diet, a low-carb diet, and a low-glycemic-index diet. The study showed that the different diets had substantially different metabolic effects, with the low-carbohydrate diet having the best results. To our surprise, the researchers then recommended the low-glycemic-index diet instead. As they explained in the accompanying press release:

“The very low-carbohydrate diet produced the greatest improvements in metabolism, but with an important caveat: This diet increased participants' cortisol levels, which can lead to insulin resistance and cardiovascular disease.”

The Boston Children's Hospital then went on to produce a graphic advising patients to follow the low-glycemic-index diet, and giving this as the primary reason not to choose the low-carb diet. Here is that graphic, which we've marked (in black) to show our disagreement. (Click for the full version without our markup.)

The cortisol levels are an understandable concern, because high urinary cortisol has been epidemiologically associated with a greatly increased risk of death from heart attacks [2].

However, because a ketogenic diet effectively treats metabolic syndrome, we should expect that it also reduces those specific cortisol patterns that are associated with metabolic syndrome (and therefore heart disease). As we show below, this has, in fact, been found.

How is cortisol associated with metabolic syndrome?

Just as we now understand that measuring an individual's total cholesterol without looking at its component parts is inadequate for assessing cardiovascular health, there are different ways to measure cortisol, and only specific patterns of measurements are found with metabolic syndrome.

Cortisol can be measured in fluids, such as urine, saliva, or blood. Within those fluids, the amount of free cortisol can be measured, but so can cortisone, the inactive form, or the metabolites that are the result of enzyme action, and the ratios of any of these to the others can be measured (see Figure 1). Moreover, these measurements have a diurnal rhythm, being higher and lower at different times of the day.

The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) can convert back and forth between cortisol and cortisone. 11β-HSD1—a subtype of 11β-HSD—converts cortisone to cortisol. When inactive cortisone is converted to the active cortisol, it is called regeneration. The other enzymes in the illustration break cortisone or cortisol down into metabolites. That process is called clearance. It turns out that measurements of these enzyme are important for evaluating cortisol metabolism.

The cortisol profile that has been associated with metabolic syndrome includes the following characteristics:

• high cortisol production rates [3].
• high cortisol clearance rates [4], [5].
• high 11β-HSD1 expression in fat cells, and low 11β-HSD1 expression in the liver [6], [7], which determines when and where cortisol is regenerated.

Similarly to the way total cholesterol measurement is correlated with heart disease, but only because it is roughly correlated with more informative cholesterol measurements, 24-hour urinary cortisol may be a proxy for production or clearance, but a poor one [3], [4], [7].

Cortisol levels are affected by production, but they are also affected by regeneration and clearance. In other words, if regeneration were increased, or clearance decreased, levels could go up even if production stayed the same or went down. (We previously discussed a similar situation with blood glucose and faulty inference about glucose production rates.) This means that levels can look similar, even when cortisol metabolism is very different.

Implication for those following the “adrenal fatigue” hypothesis: if you measure your cortisol, and it is high, you can't conclude that your adrenal glands are working correspondingly hard. It could be due to increased regeneration and reduced clearance by enzyme activity. Higher cortisol could actually mean the adrenals are working less!

In obesity, it appears that production goes up to compensate for high clearance and impaired regeneration, although sometimes not enough to compensate; blood cortisol is sometimes actually lower in obese subjects [8].

How does a ketogenic diet affect the relevant cortisol measures?

In [9], investigators put obese men on either a high-fat/low-carb (fat 66%, carb 4%) or a moderate-fat/moderate-carb (fat 35%, carb 35%) diet ad libitum (eating as much as they wanted). Note that both diets had the same protein percent, and both were lower carb than a standard American diet, but only the high-fat/low-carb diet was at ketogenically low levels.

For the high-fat/low-carb group, “the metabolic syndrome pattern” was reversed: blood cortisol went up, clearance went down, and regeneration went up. This was apparently due to an increase of 11β-HSD1 activity in liver tissue.

(Activity of 11β-HSD1 did not go down in fat tissue of those subjects, but the authors point out that the activity in fat tissue tends to go down when more fat is eaten, and the high-fat/low-carb group weren't actually eating more fat in absolute terms than at baseline, only lower carb.)

This reversal didn't happen in the moderate-fat/moderate-carb group, even though they lost a similar amount of weight.

So the ketogenic diet actually improved the cortisol profile of the participants, making it less like the cortisol profile seen in metabolic syndrome.

Summary

There is some reason to believe that cortisol dysregulation is a key underlying factor in metabolic syndrome [10], [11]. The dysregulation has a particular pattern that seems to be caused by a tissue-specific expression of the enzyme 11β-HSD1.

There is a belief among some researchers that ketogenic diets worsen cortisol metabolism (which could lead to metabolic syndrome and heart disease), but an examination of the specific pattern of cortisol metabolism related to metabolic sydrome shows the opposite.

This is what should have been expected in the first place, since ketogenic diets have already been shown to improve insulin sensitivity (the defining symptom of metabolic syndrome) in repeated randomized controlled trials.

One mechanism by which keto diet improves metabolic syndrome may be its beneficial effect on cortisol metabolism.

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Further Reading

For a review of 11β-HSD1, see:

11β-hydroxysteroid dehydrogenase 1: translational and therapeutic aspects.

Gathercole LL, Lavery GG, Morgan SA, Cooper MS, Sinclair AJ, Tomlinson JW, Stewart PM.

Endocr Rev. 2013 Aug;34(4):525-55. doi: 10.1210/er.2012-1050. Epub 2013 Apr 23.

References:

[1]

Evidence type: controlled experiment Effects of dietary composition on energy expenditure during weight-loss maintenance. Ebbeling CB, Swain JF, Feldman HA, Wong WW, Hachey DL, Garcia-Lago E, Ludwig DS. JAMA. 2012 Jun 27;307(24):2627-34. doi: 10.1001/jama.2012.6607. (Emphases ours) "Participants Overweight and obese young adults (n=21). "Interventions After achieving 10 to 15% weight loss on a run-in diet, participants consumed low-fat (LF; 60% of energy from carbohydrate, 20% fat, 20% protein; high glycemic load), low-glycemic index (LGI; 40%-40%-20%; moderate glycemic load), and very-low-carbohydrate (VLC; 10%-60%-30%; low glycemic load) diets in random order, each for 4 weeks. … "Hormones and Components of the Metabolic Syndrome (Table 3) "Serum leptin was highest with the LF diet (14.9 [12.1 to 18.4] ng/mL), intermediate with the LGI diet (12.7 [10.3 to 15.6] ng/mL) and lowest with the VLC diet (11.2 [9.1 to 13.8] ng/mL; P=0.0006). Cortisol excretion measured with a 24-hour urine collection (LF: 50 [41 to 60] μg/d; LGI: 60 [49 to 73] μg/d; VLC: 71 [58 to 86] μg/d; P=0.005) and serum TSH (LF: 1.27 [1.01 to 1.60] μIU/mL; LGI: 1.22 [0.97 to 1.54] μIU/mL; VLC: 1.11 [0.88 to 1.40] μIU/mL; P=0.04) also differed in a linear fashion by glycemic load. Serum T3 was lower with the VLC diet compared to the other two diets (LF: 121 [108 to 135] ng/dL; LGI: 123 [110 to 137] ng/dL; VLC: 108 [96 to 120] ng/dL; P=0.006). "Regarding components of the metabolic syndrome, indexes of peripheral (P=0.02) and hepatic (P=0.03) insulin sensitivity were lowest with the LF diet. Serum HDL-cholesterol (LF: 40 [35 to 45] mg/dL; LGI: 45 [41 to 50] mg/dL; VLC: 48 [44 to 53] mg/dL; P<0.0001), triglycerides (LF: 107 [87 to 131] mg/dL; LGI: 87 [71 to 106] mg/dL; VLC: 66 [54 to 81] mg/dL; P<0.0001), and PAI-1 (LF: 1.39 [0.94 to 2.05] ng/mL; LGI: 1.15 [0.78 to 1.71] ng/mL; VLC: 1.01 [0.68 to 1.49] ng/mL; P for trend=0.04) were most favorable with the VLC diet and least favorable with the LF diet. … "Although the very low-carbohydrate diet produced the greatest improvements in most metabolic syndrome components examined here, we identified two potentially deleterious effects of this diet. Twenty-four hour urinary cortisol excretion, a hormonal measure of stress, was highest with the very low-carbohydrate diet. Consistent with this finding, Stimson et al reported increased whole-body regeneration of cortisol by 11β-HSD1 and reduced inactivation of cortisol by 5α-and 5β-reductases over 4 weeks on a VLC vs. a moderate-carbohydrate diet. Higher cortisol levels may promote adiposity, insulin resistance, and cardiovascular disease, as observed in epidemiological studies." Comment: It is ironic that the authors bring up Stimson et al. as an example of a study that corroborates their findings. This is the very study [9] that, in our opinion, exonerates the VLC diet with respect to cortisol.

[2]

Evidence type: epidemiological observation Urinary cortisol and six-year risk of all-cause and cardiovascular mortality. Vogelzangs N, Beekman AT, Milaneschi Y, Bandinelli S, Ferrucci L, Penninx BW. J Clin Endocrinol Metab. 2010 Nov;95(11):4959-64. doi: 10.1210/jc.2010-0192. Epub 2010 Aug 25. "Context: The stress hormone cortisol has been linked with unfavorable cardiovascular risk factors, but longitudinal studies examining whether high levels of cortisol predict cardiovascular mortality are largely absent. Objective: The aim of this study was to examine whether urinary cortisol levels predict all-cause and cardiovascular mortality over 6 yr of follow-up in a general population of older persons. Design and Setting: Participants were part of the InCHIANTI study, a prospective cohort study in the older general population with 6 yr of follow-up. Participants: We studied 861 participants aged 65 yr and older. Main Outcome Measure: Twenty-four-hour urinary cortisol levels were assessed at baseline. In the following 6 yr, all-cause and cardiovascular mortality was ascertained from death certificates. Cardiovascular mortality included deaths due to ischemic heart disease and cerebrovascular disease. Results: During a mean follow-up of 5.7 (sd = 1.2) yr, 183 persons died, of whom 41 died from cardiovascular disease. After adjustment for sociodemographics, health indicators, and baseline cardiovascular disease, urinary cortisol did not increase the risk of noncardiovascular mortality, but it did increase cardiovascular mortality risk. Persons in the highest tertile of urinary cortisol had a five times increased risk of dying of cardiovascular disease (hazard ratio = 5.00; 95% confidence interval = 2.02–12.37). This effect was found to be consistent across persons with and without cardiovascular disease at baseline (p interaction = 0.78). Conclusions: High cortisol levels strongly predict cardiovascular death among persons both with and without preexisting cardiovascular disease. The specific link with cardiovascular mortality, and not other causes of mortality, suggests that high cortisol levels might be particularly damaging to the cardiovascular system."

[3]

Evidence type: experiment Enhanced cortisol production rates, free cortisol, and 11β-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss Jonathan Q. Purnell, Steven E. Kahn, Mary H. Samuels, David Brandon, D. Lynn Loriaux, and John D. Brunzell Am J Physiol Endocrinol Metab. 2009 February; 296(2): E351–E357. "Controversy exists as to whether endogenous cortisol production is associated with visceral obesity and insulin resistance in humans. We therefore quantified cortisol production and clearance rates, abdominal fat depots, insulin sensitivity, and adipocyte gene expression in a cohort of 24 men. To test whether the relationships found are a consequence rather than a cause of obesity, eight men from this larger group were studied before and after weight loss. Daily cortisol production rates (CPR), free cortisol levels (FC), and metabolic clearance rates (MCR) were measured by stable isotope methodology and 24-h sampling; intra-abdominal fat (IAF) and subcutaneous fat (SQF) by computed tomography; insulin sensitivity (SI) by frequently sampled intravenous glucose tolerance test; and adipocyte 11β-hydroxysteroid dehydrogenase-1 (11β-HSD-1) gene expression by quantitative RT-PCR from subcutaneous biopsies. Increased CPR and FC correlated with increased IAF, but not SQF, and with decreased SI. Increased 11β-HSD-1 gene expression correlated with both IAF and SQF and with decreased SI. With weight loss, CPR, FC, and MCR did not change compared with baseline; however, with greater loss in body fat than lean mass during weight loss, both CPR and FC increased proportionally to final fat mass and IAF and 11β-HSD-1 decreased compared with baseline. These data support a model in which increased hypothalamic-pituitary-adrenal activity in men promotes selective visceral fat accumulation and insulin resistance and may promote weight regain after diet-induced weight loss, whereas 11β-HSD-1 gene expression in SQF is a consequence rather than cause of adiposity. "Previous studies have shown that compared with women, men have increased CPR (29), cortisol levels (29, 44), and visceral adiposity (9, 13). Given that hypercortisolemia can induce central obesity in disease states such as Cushing's syndrome, elevated endogenous cortisol secretion has been considered a potential mechanism that contributes to the expression of visceral adiposity in humans. However, of four previous reports that used 24-h urinary excretion rates of cortisol as a surrogate for cortisol production, only one found significant relationships between urinary secretion of total glucocorticoids, truncal fat, and insulin sensitivity in men and women (39), while three other studies in men have failed to show associations between urinary glucocorticoid secretion and either WHR (16, 26) or visceral fat (48). These studies, however, did not measure cortisol production directly, did not include blood FC, and did not test for differences in circadian variations of blood levels of cortisol, and in only one study was visceral fat specifically measured. [...] "In summary, we found in men that increased CPR and circulating FC are associated with accumulation of IAF, but not SQF, and with insulin resistance and impaired islet β-cell compensation (DI)."

[4]

Evidence type: observational Cortisol clearance and associations with insulin sensitivity, body fat and fatty liver in middle-aged men Holt HB, Wild SH, Postle AD, Zhang J, Koster G, Umpleby M, Shojaee-Moradie F, Dewbury K, Wood PJ, Phillips DI, Byrne CD. Diabetologia. 2007 May;50(5):1024-32. Epub 2007 Mar 17. "AIMS/HYPOTHESIS: The regulation of cortisol metabolism in vivo is not well understood. We evaluated the relationship between cortisol metabolism and insulin sensitivity, adjusting for total and regional fat content and for non-alcoholic fatty liver disease. "MATERIALS AND METHODS: "Twenty-nine middle-aged healthy men with a wide range of BMI were recruited. We measured fat content by dual-energy X-ray absorptiometry and magnetic resonance imaging (MRI), liver fat by ultrasound and MRI, the hypothalamic-pituitary-adrenal axis by adrenal response to ACTH(1-24), unconjugated urinary cortisol excretion, corticosteroid-binding globulin, and cortisol clearance by MS. We assessed insulin sensitivity by hyperinsulinaemic-euglycaemic clamp and by OGTT. "RESULTS: "Cortisol clearance was strongly inversely correlated with insulin sensitivity (M value) (r = -0.61, p = 0.002). Cortisol clearance was increased in people with fatty liver compared with those without (mean+/-SD: 243 +/- 10 vs 158 +/- 36 ml/min; p = 0.014). Multiple regression modelling showed that the relationship between cortisol clearance and insulin sensitivity was independent of body fat. The relationship between fatty liver and insulin sensitivity was significantly influenced by body fat and cortisol clearance. "CONCLUSIONS/INTERPRETATION: "Cortisol clearance is strongly associated with insulin sensitivity, independently of the amount of body fat. The relationship between fatty liver and insulin sensitivity is mediated in part by both fatness and cortisol clearance." [...] "Since we showed no strong associations between measures of insulin sensitivity and 09.00 h cortisol levels, ACTH-stimulated cortisol concentrations, and unconjugated urinary cortisol excretion, these findings suggest that the relationship between these other aspects of cortisol metabolism and insulin sensitivity is relatively weak."

[5]

Evidence type: experiment Association of 24-hour cortisol production rates, cortisol-binding globulin, and plasma-free cortisol levels with body composition, leptin levels, and aging in adult men and women. Purnell JQ, Brandon DD, Isabelle LM, Loriaux DL, Samuels MH. J Clin Endocrinol Metab. 2004 Jan;89(1):281-7. (emphasis ours) "The present study was designed to examine the hypothesis that hypothalamic-pituitary-adrenal axis activity as measured by 24-h cortisol production rate (CPR) and plasma levels of free cortisol is linked to increased body fat in adults, and that increased cortisol levels with aging results from increased CPR. Fifty-four healthy men and women volunteers with a wide range of body mass indexes and ages underwent measurement of CPR by isotope dilution measured by gas chromatography-mass spectroscopy, cortisol-binding globulin, and free cortisol in pooled 24-h plasma, body composition, and leptin. Cortisol clearance rates were determined from the 10-h disappearance curves of hydrocortisone after steady-state infusion in a separate group of lean and obese subjects with adrenal insufficiency. Although CPR significantly increased with increasing body mass index and percentage body fat, free cortisol levels remained independent of body composition and leptin levels due to increased cortisol clearance rates. CPR and free cortisol levels were, however, significantly higher in men than women. In addition, 24-h plasma free cortisol levels were increased with age in association with increased CPR, independent of body size. This increase in hypothalamic-pituitary-adrenal axis activity may play a role in the alterations in body composition and central fat distribution in men vs. women and with aging."

[6]

Evidence type: review of human and non-human animal experiments Adipose tissue expression of 11beta-hydroxysteroid dehydrogenase type 1 in Cushing's syndrome and in obesity. Espíndola-Antunes D, Kater CE. Arq Bras Endocrinol Metabol. 2007 Nov;51(8):1397-403. "Human studies "The bulk of evidences points both to an overexpression and an increased activity of 11bHSD1 in subcutaneous (SAT) and visceral adipose tissue (VAT) of obese subjects, although biopsies of the omentum were conducted in but a few studies. Several groups have shown higher 11bHSD1 mRNA expression in obese compared to non-obese subjects (29-32), although not all studies agree (33). Direct in vivo measurements using microdialysis in SAT also suggest an increase in the conversion rate of cortisone to cortisol (34). Moreover, 11bHSD1 mRNA expression positively correlates with obesity (body mass index and abdominal circumference), body composition, insulin resistance (30-32), resistins and other cytokines, as TNFa, IL-6, and leptin (35). "The whole body 11bHSD1 activity reflects mainly hepatic expression. Initial studies that relied on measurements of cortisol-to-cortisone metabolites in urine (23,36) should be taken with caution as indicative of 11bHSD1 activity, because several other cortisol and cortisone metabolizing enzymes are deregulated in obesity (36). Of greater importance is the finding of reduced hepatic 11bHSD1 activity measured by the conversion of orally administered cortisone to cortisol (23,37). Thus, 11bHSD1 upregulation in obesity seems not to be a generalized process. In both the whole body and the splanchnic circulation there are no differences between obese and lean subjects regarding cortisol regeneration rates (as measured by [2H4]-cortisol tracer), presumably because an upregulation in adipose tissue is counterbalanced by a downregulation in the liver (15). "Polymorphisms in the 11bHSD1 gene were identified in an attempt to clarify the basis for the increased activity of adipose tissue 11bHSD1 in obesity. In two populations, polymorphisms were associated with an increased risk of diabetes and hypertension, but not obesity (38,39). A polymorphism was also found that predicts lower 11bHSD1 expression and protection against diabetes (40)."

[7]

Evidence type: observational Local and systemic impact of transcriptional up-regulation of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue in human obesity. Wake DJ, Rask E, Livingstone DE, Söderberg S, Olsson T, Walker BR. J Clin Endocrinol Metab. 2003 Aug;88(8):3983-8. (emphasis ours) "In idiopathic obesity circulating cortisol levels are not elevated, but high intraadipose cortisol concentrations have been implicated. 11beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyzes the conversion of inactive cortisone to active cortisol, thus amplifying glucocorticoid receptor (GR) activation. In cohorts of men and women, we have shown increased ex vivo 11HSD1 activity in sc adipose tissue associated with in vivo obesity and insulin resistance. Using these biopsies, we have now validated this observation by measuring 11HSD1 and GR mRNA and examined the impact on intraadipose cortisol concentrations, putative glucocorticoid regulated adipose target gene expression (angiotensinogen and leptin), and systemic measurements of cortisol metabolism. From aliquots of sc adipose biopsies from 16 men and 16 women we extracted RNA for real-time PCR and steroids for immunoassays. Adipose 11HSD1 mRNA was closely related to 11HSD1 activity [standardized beta coefficient (SBC) = 0.58; P < 0.01], and both were positively correlated with parameters of obesity (e.g. for BMI, SBC = 0.48; P < 0.05 for activity, and SBC = 0.63; P < 0.01 for mRNA) and insulin sensitivity (log fasting plasma insulin; SBC = 0.44; P < 0.05 for activity, and SBC = 0.33; P = 0.09 for mRNA), but neither correlated with urinary cortisol/cortisone metabolite ratios. Adipose GR-alpha and angiotensinogen mRNA levels were not associated with obesity or insulin resistance, but leptin mRNA was positively related to 11HSD1 activity (SBC = 0.59; P < 0.05) and tended to be associated with parameters of obesity (BMI: SBC = 0.40; P = 0.09), fasting insulin (SBC = 0.65; P < 0.05), and 11HSD1 mRNA (SBC = 0.40; P = 0.15). Intraadipose cortisol (142 +/- 30 nmol/kg) was not related to 11HSD1 activity or expression, but was positively correlated with plasma cortisol. These data confirm that idiopathic obesity is associated with transcriptional up-regulation of 11HSD1 in adipose, which is not detected by conventional in vivo measurements of urinary cortisol metabolites and is not accompanied by dysregulation of GR. Although this may drive a compensatory increase in leptin synthesis, whether it has an adverse effect on intraadipose cortisol concentrations and GR-dependent gene regulation remains to be established."

[8]

Evidence type: review Extra-adrenal regeneration of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1: physiological regulator and pharmacological target for energy partitioning Brian R. Walker Proceedings of the Nutrition Society / Volume 66 / Issue 01 / February 2007, pp 1-8 (emphasis ours) "The parallels between the clinical features of Cushing’s syndrome and the features of the metabolic syndrome (visceral obesity, hyperglycaemia, hypertension) led to the hypothesis that obesity is associated with glucocorticoid excess (Bjorntorp, 1991). In several monogenic rodent models obesity is accompanied by elevated circulating glucocorticoid levels, and the obesity is prevented by adrenalectomy. Hyperactivity of the HPA axis was thought to reflect chronic stress. However, although there is some evidence for greater stress responsiveness of the HPA axis in obesity (Rosmond et al . 1998; Epel et al . 2000), stress does not appear to explain HPA axis activation in metabolic syndrome (Brunner et al . 2002). Most importantly, in human obesity it appears that cortisol secretion (Marin et al . 1992; Pasquali et al . 1993) is increased to match elevated metabolic clearance (Strain et al . 1982; Andrew et al . 1998; Lottenberg et al . 1998), and does not result in increased plasma cortisol concentrations. Indeed, plasma cortisol concentrations are generally lower amongst obese subjects (Ljung et al . 1996; Walker et al . 2000; Reynolds et al . 2003), i.e. inverse to the effects on the HPA axis seen during starvation (see earlier; p. 2)."

[9]

Evidence type: randomised controlled trial Dietary macronutrient content alters cortisol metabolism independently of body weight changes in obese men. Stimson RH, Johnstone AM, Homer NZ, Wake DJ, Morton NM, Andrew R, Lobley GE, Walker BR. J Clin Endocrinol Metab. 2007 Nov;92(11):4480-4. Epub 2007 Sep 4. "CONTEXT: Dietary macronutrient composition influences cardiometabolic health independently of obesity. Both dietary fat and insulin alter glucocorticoid metabolism in rodents and, acutely, in humans. However, whether longer-term differences in dietary macronutrients affect cortisol metabolism in humans and contribute to the tissue-specific dysregulation of cortisol metabolism in obesity is unknown. OBJECTIVE: The objective of the study was to test the effects of dietary macronutrients on cortisol metabolism in obese men. DESIGN: The study consisted of two randomized, crossover studies. SETTING: The study was conducted at a human nutrition unit. PARTICIPANTS: Participants included healthy obese men. INTERVENTIONS, OUTCOME MEASURES, AND RESULTS: Seventeen obese men received 4 wk ad libitum high fat-low carbohydrate (HF-LC) (66% fat, 4% carbohydrate) vs. moderate fat-moderate carbohydrate (MF-MC) diets (35% fat, 35% carbohydrate). Six obese men participated in a similar study with isocaloric feeding. Both HF-LC and MF-MC diets induced weight loss. During 9,11,12,12-[(2)H](4)-cortisol infusion, HF-LC but not MF-MC increased 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity (rates of appearance of cortisol and 9,12,12-[(2)H](3)-cortisol) and reduced urinary excretion of 5alpha- and 5beta-reduced [(2)H](4)-cortisol metabolites and [(2)H](4)-cortisol clearance. HF-LC also reduced 24-h urinary 5alpha- and 5beta-reduced endogenous cortisol metabolites but did not alter plasma cortisol or diurnal salivary cortisol rhythm. In sc abdominal adipose tissue, 11beta-HSD1 mRNA and activity were unaffected by diet. CONCLUSIONS: A low-carbohydrate diet alters cortisol metabolism independently of weight loss. In obese men, this enhances cortisol regeneration by 11beta-HSD1 and reduces cortisol inactivation by A-ring reductases in liver without affecting sc adipose 11beta-HSD1. Alterations in cortisol metabolism may be a consequence of macronutrient dietary content and may mediate effects of diet on metabolic health."

[10]

Evidence type: authority (review article) 11β-Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus. Pereira CD, Azevedo I, Monteiro R, Martins MJ. Diabetes Obes Metab. 2012 Oct;14(10):869-81. doi: 10.1111/j.1463-1326.2012.01582.x. Epub 2012 Mar 8. (emphasis ours) "Recent evidence strongly argues for a pathogenic role of glucocorticoids and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in obesity and the metabolic syndrome, a cluster of risk factors for atherosclerotic cardiovascular disease and type 2 diabetes mellitus (T2DM) that includes insulin resistance (IR), dyslipidaemia, hypertension and visceral obesity. This has been partially prompted not only by the striking clinical resemblances between the metabolic syndrome and Cushing’s syndrome (a state characterized by hypercortisolism that associates with metabolic syndrome components) but also from monogenic rodent models for the metabolic syndrome (e.g. the leptin-deficient ob/ob mouse or the leptin-resistant Zucker rat) that display overall increased secretion of glucocorticoids. However, systemic circulating glucocorticoids are not elevated in obese patients and/or patients with metabolic syndrome. The study of the role of 11β-HSD system shed light on this conundrum, showing that local glucocorticoids are finely regulated in a tissue-specific manner at the pre-receptor level. The system comprises two microsomal enzymes that either activate cortisone to cortisol (11β-HSD1) or inactivate cortisol to cortisone (11β-HSD2). Transgenic rodent models, knockout (KO) for HSD11B1 or with HSD11B1 or HSD11B2 overexpression, specifically targeted to the liver or adipose tissue, have been developed and helped unravel the currently undisputable role of the enzymes in metabolic syndrome pathophysiology, in each of its isolated components and in their prevention. In the transgenic HSD11B1 overexpressing models, different features of the metabolic syndrome and obesity are replicated."

[11]

Evidence type: non-human animal experiment Chronic inhibition of 11 β -hydroxysteroid dehydrogenase type 1 activity decreases hypertension, insulin resistance, and hypertriglyceridemia in metabolic syndrome. Schnackenberg CG, Costell MH, Krosky DJ, Cui J, Wu CW, Hong VS, Harpel MR, Willette RN, Yue TL. Biomed Res Int. 2013;2013:427640. doi: 10.1155/2013/427640. Epub 2013 Mar 18. (emphasis ours) "Metabolic syndrome is a constellation of risk factors including hypertension, dyslipidemia, insulin resistance, and obesity that promote the development of cardiovascular disease. Metabolic syndrome has been associated with changes in the secretion or metabolism of glucocorticoids, which have important functions in adipose, liver, kidney, and vasculature. Tissue concentrations of the active glucocorticoid cortisol are controlled by the conversion of cortisone to cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Because of the various cardiovascular and metabolic activities of glucocorticoids, we tested the hypothesis that 11β-HSD1 is a common mechanism in the hypertension, dyslipidemia, and insulin resistance in metabolic syndrome. In obese and lean SHR/NDmcr-cp (SHR-cp), cardiovascular, metabolic, and renal functions were measured before and during four weeks of administration of vehicle or compound 11 (10 mg/kg/d), a selective inhibitor of 11β-HSD1. Compound 11 significantly decreased 11β-HSD1 activity in adipose tissue and liver of SHR-cp. In obese SHR-cp, compound 11 significantly decreased mean arterial pressure, glucose intolerance, insulin resistance, hypertriglyceridemia, and plasma renin activity with no effect on heart rate, body weight gain, or microalbuminuria. These results suggest that 11β-HSD1 activity in liver and adipose tissue is a common mediator of hypertension, hypertriglyceridemia, glucose intolerance, and insulin resistance in metabolic syndrome."