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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.
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?

Figure 1 from “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.
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.

Further Reading

For a review of 11β-HSD1, see:

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

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

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.”

https://lh4.googleusercontent.com/-xs_juGoIO9w/UvfQYOArowI/AAAAAAAAB2E/v8XJUPOwvoY/w717-h612-no/Vogelzangs-2010-Fig1.png
[3] Evidence type: experiment

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

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

(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

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

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

(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

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)

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

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.

The Ketogenic Diet Reverses Indicators of Heart Disease

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The Ketogenic Diet Reverses Indicators of Heart Disease

Cardiovascular disease (CVD) is the leading cause of death worldwide
1.
Because of its prevalence and life-threatening nature, and because it appears that a keto diet is likely to reverse it, we consider it one of the most important conditions to discuss here.

In our last post, we argued that CVD, being a disease strongly associated with metabolic syndrome, is likely to be best treated with a ketogenic diet.
In this post we will present more evidence that ketogenic diets do improve heart disease risk factors.

Unfortunately, there is much confusion and misinformation about the impact of nutrition on CVD among scientists and non-scientists alike.
Not only does a high fat, keto diet not worsen heart disease risk — as would commonly be assumed — it actually improves it.
This confusion about dietary fat is probably the reason that we do not yet have clinical trials directly testing the effects of ketogenic diets on CVD outcomes.

However, we already have many trials of ketogenic diets that measured known CVD risk factors, especially cholesterol profiles.
It turns out that these trials show a powerful heart disease risk reduction in those following a ketogenic diet.
It is powerful both in absolute terms, and in comparison with low-fat diets, which tend to improve some weakly predictive factors while worsening stronger predictors.

As such, a high-fat ketogenic diet is currently the best known non-drug intervention for heart disease, as defined by mainstream measures of risk. It is arguably better than drug interventions, too.

In brief:

  • Total cholesterol and LDL cholesterol are only weak predictors of CVD.
  • Triglycerides, HDL, LDL particle size, and the HDL-to-triglyceride ratio are much stronger predictors of CVD.
  • Keto diets improve triglyceride levels, HDL, and LDL particle size — precisely those measures that strongly indicate risk.

Total cholesterol and LDL cholesterol are only weakly associated with CVD

The connection between blood cholesterol levels and the development of heart disease began to be explored in the last century.
Over the last several decades, our understanding of the predictive power of various blood lipids has gone through many refinements as our ability to measure finer and finer detail has advanced.

In the early years, it appeared that high levels of total cholesterol carried some risk of heart disease in many cases.
However, it is now well established that total cholesterol by itself is a weak predictor
2,
3,
4.

The reason is quite simple.
The different subtypes of cholesterol work together in an intricately balanced system.
There is a wide range of total cholesterol levels that are perfectly healthy, so long as the proportions of the subtypes are healthy ones.
By the same token, a given level of total cholesterol, even if it is perfectly normal, could be pathological when examined by subtype.
Strong evidence from recent decades suggests that the best known blood lipid measures for predicting future risk of CVD are HDL, triglycerides, and related ratios (see below).

Similarly, while LDL cholesterol is probably important, it appears that it does not have good predictive power when looking at its magnitude alone
5,
6,
7,
8.

One reason for this is that like total cholesterol, LDL is not uniform.
Just as we distinguish between HDL and LDL, the so-called “good” and “bad” cholesterol, LDL itself is now known to have two important subtypes with opposite risk
implications.
Having more large, light LDL particles (also called Pattern A), does not indicate high CVD risk, but having more small, dense particles (Pattern B) does
9,
10,
11,
12,
13.
Therefore high LDL by itself is not necessarily indicative of CVD.

Low HDL cholesterol is strongly associated with CVD

Having high blood levels of HDL is now widely recognized as predicting lower levels of heart disease.
The proportion of total cholesterol that is HDL cholesterol is a particularly strong predictor.
In 2007, a meta-analysis was published in the Lancet that examined information from 61 prospective observational studies, consisting of almost 900,000 adults.
Information about HDL was available for about 150,000 of them, among whom there were 5000 vascular deaths. According to the authors, “the ratio of total to HDL cholesterol is a substantially more informative predictor of IHD mortality than are total cholesterol, HDL
cholesterol, or non-HDL cholesterol.”
14

This is consistent with many other studies, for example this very recent analysis from the COURAGE trial
15.

High triglycerides are strongly associated with CVD

There has been drawn out controversy in the medical community as to the relationship of triglyceride levels to CVD.
There are two parts to the controversy: whether or not triglycerides are an independent predictor of CVD, and whether or not triglycerides play a causative role in CVD.

In both cases, however, it doesn’t matter in which way the controversy is resolved!
Whether or not triglycerides independently predict CVD
(and there is at least some evidence that they do),
and whether or not they cause CVD, there is no controversy about whether they predict CVD.
The association between triglyceride levels and CVD still holds and is strongly predictive
16,
17,
18.
In fact it is so predictive that those who argue that triglyceride levels are not an independent risk factor, call it instead a “biomarker” for CVD
19.
In other words, seeing high triglycerides is tantamount to seeing the progression of heart disease.

HDL-to-Triglycerides Ratio: compounding evidence

Triglycerides and HDL levels statistically interact.
That means it is a mistake to treat one as redundant with respect to the other.
If you do, you will miss the fact that the effect of one on your outcome of interest changes depending on the value of the other.
Despite the fact that most heart disease researchers who study risk factors have not used methods tuned to find interactions between triglycerides and HDL, many studies have at least measured both.
This has allowed others to do the appropriate analysis.
When triglycerides and HDL have been examined with respect to each other, that is, when the effect of triglycerides is measured under the condition of low HDL, or when the effect of HDL is measured under the condition of high triglycerides, this combination of factors turns out to be even more indicative of CVD
20,
21,
22,
23.

One of the most interesting aspects of this finding from our perspective, is that the ratio of triglyceride levels to HDL is considered to be a surrogate marker of insulin resistance
(See The Ketogenic Diet as a Treatment for Metabolic Syndrome.)
In other words, the best lipid predictors of CVD are also those that indicate insulin resistance.

Ketogenic Diets improve risk factors for CVD

There is now ample evidence that a low carbohydrate, ketogenic diet improves lipid profiles, particularly with respect to the risk factors outlined above: triglycerides, HDL, and their ratio
24,
25,
26,
27,
28,
29,
30,
31.

Although a ketogenic diet typically raises LDL levels, which has been traditionally seen as a risk factor, it has also been shown to improve LDL particle size.
In other words, although the absolute amount of LDL goes
up, it is the “good” LDL that goes up, whereas the “bad” LDL goes down
31,
32.
This is hardly surprising, since LDL particle size is also strongly predicted by triglycerides
33,
34,
35.

Although there have not yet been intervention studies testing the effect of a ketogenic diet on the rate of actual CVD incidents (e.g. heart attacks), the evidence about lipid profiles is strong enough to make ketogenic diets more likely to reduce heart disease than any other known intervention.

Summary:

  • Current medical practice uses blood lipid measurements to assess the risk of heart disease.
  • Despite the continuing tradition of measuring total cholesterol and LDL, we have known for decades that triglycerides, HDL, and the ratio of the two, are much better predictors of heart disease.
    LDL particle size is also considered strongly predictive.
  • A ketogenic diet has a very favourable impact on these risk factors, and thus should be considered the diet of choice for those at risk of CVD.

In their 2011 paper, “Low-carbohydrate diet review: shifting the paradigm”, Hite et al. display the following graph (VLCKD stands for Very Low Carbohydrate Ketogenic Diet, and LFD for Low Fat Diet)
36 based on data from 31:

It makes an excellent visualization of the factors at stake, and how powerful a ketogenic diet is.
It also shows quite clearly that not only is restricting carbohydrate more effective for this purpose than a low fat diet, but that a low fat diet is detrimental for some important risk factors — apolipoprotein ratios, LDL particle size, and HDL — but a low carb diet is not.
The ketogenic diet resulted in a significant improvement in every measure.

References:

1 Evidence type: observational


World Health Organization Fact sheet N°317: Cardiovascular diseases (CVDs) September 2011

  • CVDs are the number one cause of death globally: more people die annually from CVDs than from any other cause.
  • An estimated 17.3 million people died from CVDs in 2008, representing 30% of all global deaths. Of these deaths, an estimated 7.3 million were due to coronary heart disease and 6.2 million were due to stroke.
  • Low- and middle-income countries are disproportionally affected: over 80% of CVD deaths take place in low- and middle-income countries and occur almost equally in men and women.
  • By 2030, almost 23.6 million people will die from CVDs, mainly from heart disease and stroke. These are projected to remain the single leading causes of death.

2 Evidence type: observational


Role of lipid and lipoprotein profiles in risk assessment and therapy.
Ballantyne CM, Hoogeveen RC.
Am Heart J. 2003 Aug;146(2):227-33.

Despite a strong and consistent association within populations, elevated TC [(total cholesterol)] alone is not a useful test to discriminate between individuals who will have CHD [(coronary heart disease)] events and those who will not.

3 Evidence type: observational


Relation of serum lipoprotein cholesterol levels to presence and severity of angiographic coronary artery disease.
Philip A. Romm, MD, Curtis E. Green, MD, Kathleen Reagan, MD, Charles E. Rackley, MD.
The American Journal of Cardiology Volume 67, Issue 6, 1 March 1991, Pages 479–483

Most CAD [(coronary artery disease)] occurs in persons who have only mild or moderate elevations in cholesterol levels. Total cholesterol level alone is a poor predictor of CAD, particularly in older patients in whom the major lipid risk factor is the HDL cholesterol level.

4 Evidence type: observational


Lipids, risk factors and ischaemic heart disease.
Atherosclerosis. 1996 Jul;124 Suppl:S1-9.
Castelli WP.

Those individuals who had TC [(total cholesterol)] levels of 150-300 mg/dl (3.9-7.8 mmol/1) fell into the overlapping area (Fig. 1), demonstrating that 90% of the TC levels measured were useless (by themselves) for predicting risk of CHD [(coronary heart disease)] in a general population. Indeed, twice as many individuals who had a lifetime TC level of less than 200 mg/dl (5.2 mmol/1) had CHD compared with those who had a TC level greater than 300 mg/dl (7.8 mmol/l) (Fig. 1).

5 Evidence type: observational


Range of Serum Cholesterol Values in the Population Developing Coronary Artery Disease.
William B. Kannel, MD, MPH.
The American Journal of Cardiology, Volume 76, Issue 9, Supplement 1, 28 September 1995, Pages 69C–77C

The ranges of serum cholesterol and LDL cholesterol levels varied widely both in the general population and in patients who had already manifested CAD (Figures 1 and 2). Because of the extensive overlap between levels, it was impossible to differentiate the patients with CAD from the control subjects.

6 Evidence type: observational


Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease.
Jacques Genest Jr., MD,FACC, Judith R. McNamara, MT, Jose M. Ordovas, PhD, Jennifer L. Jenner, BSc, Steven R. Silberman, PhD, Keaven M. Anderson, PhD, Peter W.F. Wilson, MD, Deeb N. Salem, MD, FACC, Ernst J. Schaefer, MD.
Journal of the American College of Cardiology Volume 19, Issue 4, 15 March 1992, Pages 792–802.

Our data suggest that total and LDL cholesterol may not be the best discriminants for the presence of coronary artery disease despite the strong association between elevated cholesterol and the development of coronary artery disease in cross-sectional population studies and prospective epidemiologic studies.

7 Evidence type: observational


Apolipoprotein B and apolipoprotein A-I: risk indicators of coronary heart disease and targets for lipid-modifying therapy.
Walldius, G. and Jungner, I. (2004),
Journal of Internal Medicine, 255: 188–205. doi: 10.1046/j.1365-2796.2003.01276.x

(Emphasis ours.)

For over three decades it has been recognized that a high level of total blood cholesterol, particularly in the form of LDL cholesterol (LDL-C), is a major risk factor for developing coronary heart disease (CHD) [1–4]. However, as more recent research has expanded our understanding of lipoprotein function and metabolism, it has become apparent that LDL-C is not the only lipoprotein species involved in atherogenesis. A considerable proportion of patients with atherosclerotic disease have levels of LDL-C and total cholesterol (TC) within the recommended range [5, 6], and some patients who achieve significant LDL-C reduction with lipid-lowering therapy still develop CHD [7].

Other lipid parameters are also associated with elevated cardiovascular risk, and it has been suggested that LDL-C and TC may not be the best discriminants for the presence of coronary artery disease (CAD) [5].

8 Evidence type: observational


Plasma Lipoprotein Levels as Predictors of Cardiovascular Death in Women.
Katherine Miller Bass, MD, MHS; Craig J. Newschaffer, MS; Michael J. Klag, MD, MPH; Trudy L. Bush, PhD, MHS.
Arch Intern Med. 1993;153(19):2209-2216.

Using a sample of 1405 women aged 50 to 69 years from the Lipid Research Clinics’ Follow-up Study, age-adjusted CVD death rates and summary relative risk (RR) estimates by categories of lipid and lipoprotein levels were calculated. Multivariate analysis was performed to provide RR estimates adjusted for other CVD risk factors.

RESULTS: Average follow-up was 14 years. High-density lipoprotein and triglyceride levels were strong predictors of CVD death in age-adjusted and multivariate analyses. Low-density lipoprotein and total cholesterol levels were poorer predictors of CVD mortality. After adjustment for other CVD risk factors, HDL levels less than 1.30 mmol/L (50 mg/dL) were strongly associated with cardiovascular mortality (RR = 1.74; 95% confidence interval [CI], 1.10 to 2.75). Triglyceride levels were associated with increased CVD mortality at levels of 2.25 to 4.49 mmol/L (200 to 399 mg/dL) (RR = 1.65; 95% CI, 0.99 to 2.77) and 4.50 mmol/L (400 mg/dL) or greater (RR = 3.44; 95% CI, 1.65 to 7.20). At total cholesterol levels of 5.20 mmol/L (200 mg/dL) or greater and at all levels of LDL and triglycerides, women with HDL levels of less than 1.30 mmol/L (< 50 mg/dL) had CVD death rates that were higher than those of women with HDL levels of 1.30 mmol/L (50 mg/dL) or greater.

9 Evidence type: plausible mechanism and observational review


Particle size: the key to the atherogenic lipoprotein?
Rajman I, Maxwell S, Cramb R, Kendall M.
QJM. 1994 Dec;87(12):709-20.

Using different analytical methods, up to 12 low-density lipoprotein (LDL) subfractions can be separated. LDL particle size decreases with increasing density. Smaller, denser LDL particles seem more atherogenic than the larger, lighter particles, based on the experimental findings that smaller LDL particles are more susceptible for oxidation in vitro, have lower binding affinity for the LDL receptors and lower catabolic rate, have a higher concentration of polyunsaturated fatty acids, and potentially interact more easily with proteoglycans of the arterial wall. Clinical studies have shown that a smaller LDL subfraction profile is associated with an increased risk of heart disease, even when total cholesterol level is only slightly raised. There is a strong inverse association between LDL particle size and triglyceride concentrations. Although LDL particle size is genetically determined, its phenotypic expression may also be affected by environmental factors such as drugs, diet, obesity, exercise or disease. Factors that shift the LDL subfractions profile towards larger particles may reduce the risk of heart disease.

10 Evidence type: nested case-control study


Association of Small Low-Density Lipoprotein Particles With the Incidence of Coronary Artery Disease in Men and Women.
Christopher D. Gardner, PhD; Stephen P. Fortmann, MD; Ronald M. Krauss, MD
JAMA. 1996;276(11):875-881. doi:10.1001/jama.1996.03540110029028.

Incident CAD cases were identified through FCP surveillance between 1979 and 1992. Controls were matched by sex, 5-year age groups, survey time point, ethnicity, and FCP treatment condition. The sample included 124 matched pairs: 90 pairs of men and 34 pairs of women.

LDL size was smaller among CAD cases than controls (mean ±SD) (26.17±1.00nm vs 26.68±0.90nm;P

The Ketogenic Diet as a Treatment for Metabolic Syndrome

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The Ketogenic Diet for Metabolic Syndrome

Metabolic Syndrome (MetS) can be viewed as a set of symptoms of insulin resistance.
Taken together, those symptoms signify a threat of heart disease, diabetes, cancer, and other diseases that appear to be different manifestations of a common cause.
That common cause is likely to be insulin resistance.

This hypothesis is supported by evidence that ketogenic diets not only normalize insulin sensitivity and the symptoms of MetS, but they treat (or have promise in treating) many MetS-associated diseases.

In light of this, it seems plausible that adopting a ketogenic diet will significantly improve your chances of avoiding these diseases in the first place.

* * *

In brief

  • Metabolic Syndrome is a cluster of symptoms, not a disease.
    Those symptoms are useful to class together, because their association with a variety of different diseases strongly suggests a common cause.
    In other words, it has provided us with a compelling hypothesis.
  • If there were a common cause, then a therapy that treats that cause should help them all.
    Moreover, it should reduce the symptoms of Metabolic Syndrome itself.
    Further, treatments that work for one but not the others should be considered inferior, “band-aid” treatments.
  • A ketogenic diet improves Metabolic Syndrome.
    Also, for every disease associated with MetS that we have investigated, a keto diet has either been shown to help, has shown preliminary evidence in its favour, or has not been sufficiently tested to rule out.
  • This supports the hypothesis that those diseases have a common cause, and that a ketogenic diet addresses it.

* * *

What is Metabolic Syndrome?

Metabolic Syndrome is a cluster of symptoms that commonly occur together and indicate increased risk of cardiovascular disease (CVD), type 2 diabetes (T2D), cancer, and other diseases.
Clinically, to be diagnosed with MetS, you have to score above (or in the case of HDL, below) a healthy threshold in at least 3 of the following 5 measurements: waist size, fasting blood glucose, blood pressure, triglycerides, and HDL.
All of these are associated with insulin resistance, although some are more predictive than others
1,
2,
3
, and so metabolic syndrome might be more accurately described as insulin resistance syndrome (and it sometimes is)
4,
5.

Just as with any such measure, it can be misleading to draw a threshold at such a particular point.
The cost of ignoring warning signs because they fall below a threshold may be worse than the benefit of giving a special diagnosis to those who have multiple symptoms, each of which could be recognized as warranting treatment on its own
6.

Nonetheless, it is useful to have a name for a set of associations for two reasons.

  1. It allows us to recognize the commonalities in symptoms of a variety of disease states which is suggestive of common mechanisms.
  2. It promotes the insight that any treatment that is purported to improve risk of CVD or T2D ought to have a beneficial impact on all of the associated symptoms.
    If it doesn’t, there is a risk that it is a band-aid solution that temporarily hides the problem rather than fixing it.

Because these symptoms so often occur together, and because they are all risk factors for a group of diseases which in turn are risk factors for each other, it is the contention of many scientists that they have a common cause.
Some argue that this common cause is obesity itself.
A separate cause is postulated for obesity, which then is supposed to cause the other risk factors.
However, other researchers, ourselves among them, believe that obesity and the other symptoms have a common cause related to insulin signalling.
For this reason, we have grouped together several diseases which appear to have insulin signalling at their root, and which have elevated risk in the presence of Metabolic Syndrome symptoms.
These diseases include (but are not limited to) cardiovascular disease
7,
type 2 diabetes
8,
polycystic ovarian syndrome
9,
Alzheimer’s disease
10, and cancer.
11.


In other words, we believe that Metabolic Syndrome is not itself a disease, but is a class of warning signs associated with the progression of several other diseases. If this is true, then when you treat the underlying cause of these symptoms, they will all normalize together, and the risk of all associated diseases will simultaneously be reduced.

* * *

Ketogenic diets treat insulin resistance and therefore are expected to treat all diseases that have Metabolic Syndrome as a symptom.

The following is just a sample of evidence showing that not only does a keto diet address the symptoms of MetS itself, but also those conditions associated with it.
This is not meant to be comprehensive — there are many more supporting experiments in each category!

  • Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low fat diet12.
  • A ketogenic diet favorably affects serum biomarkers for cardiovascular disease in normal-weight men
    13.
  • In addition to decreasing body weight and improving glycemia, a ketogenic diet can be effective in decreasing antidiabetic medication dosage
    14 .
  • In a pilot study, a ketogenic diet led to significant improvement in weight, percent free testosterone, LH/FSH ratio, and fasting insulin in women with obesity and PCOS over a 24 week period
    15
    .
  • An oral ketogenic compound, AC-1202, was tested in subjects with probable Alzheimer’s disease, and resulted in a significant improvement to cognitive scores
    16.
  • It seems a reasonable possibility that a very-low-carbohydrate diet could help to reduce the progression of some types of cancer, although at present the evidence is preliminary
    17.

* * *

Summary

  • The ketogenic diet is a powerful therapy that exerts its healing effect in a wide variety of conditions that may seem superficially unrelated.
  • These conditions are linked by their connection to insulin resistance, and therefore their association with MetS.
  • This supports not only the hypothesis that a keto diet treats MetS, but also that insulin resistance is the underlying cause of many devastating diseases, and that the way a keto diet is treating those is
    by intercepting and correcting the underlying cause.

* * *

References:

1 Evidence type: observational analysis
Evidence type:


Insulin resistance in aging is related to abdominal obesity.
Kohrt WM, Kirwan JP, Staten MA, Bourey RE, King DS, Holloszy JO.
Diabetes. 1993 Feb;42(2):273-81.

(emphasis ours)

Abstract

Studies have shown that insulin resistance increases with age, independent of changes in total adiposity. However, there is growing evidence that the development of insulin resistance may be more closely related to abdominal adiposity. To evaluate the independent effects of aging and regional and total adiposity on insulin resistance, we performed hyperinsulinemic euglycemic clamps on 17 young (21-33 yr) and 67 older (60-72 yr) men and women. We assessed FFM and total and regional adiposity by hydrodensitometry and anthropometry. Insulin-stimulated GDRs at a plasma insulin concentration of approximately 450 pM averaged 45.6 +/- 3.3 mumol.kg FFM-1 x min-1 (mean +/- SE) in the young subjects, 45.6 +/- 10.0 mumol.kg FFM-1 x min-1 in 24 older subjects who were insulin sensitive, and 23.9 +/- 11.7 mumol.kg FFM-1 x min-1 in 43 older subjects who were insulin resistant. Few significant differences were apparent in skin-fold and circumference measurements between young and insulin-sensitive older subjects, but measurements at most central body sites were significantly larger in the insulin-resistant older subjects. Waist girth accounted for > 40% of the variance in insulin action, whereas age explained only 10-20% of the total variance and < 2% of the variance when the effects of waist circumference were statistically controlled. These results suggest that insulin resistance is more closely associated with abdominal adiposity than with age."]

2 Evidence type: retrospective observation


Use of waist circumference to predict insulin resistance: retrospective study.
Wahrenberg H, Hertel K, Leijonhufvud BM, Persson LG, Toft E, Arner P.
BMJ. 2005 Jun 11;330(7504):1363-4. Epub 2005 Apr 15.

In the multiple regression model, waist circumference was the strongest regressor of the five significant covariates (standardised partial regression coefficients: waist circumference β1 = 0.37; log-plasma triglycerides β2 = 0.23; systolic blood pressure β3 = 0.10, high density lipoprotein cholesterol β4 = -0.09; and body mass index β5 = 0.15 (P < 0.001)).

3 Evidence type: observational analysis


Biomarkers in Fasting Serum to Estimate Glucose Tolerance, Insulin Sensitivity, and Insulin Secretion
Allison B. Goldfine, Robert W. Gerwien, Janice A. Kolberg, Sheila O’Shea, Sarah Hamren, Glenn P. Hein, Xiaomei M. Xu, and Mary Elizabeth Patti
Clinical Chemistry 57:2 326–337 (2011)

A subset of 5 markers was associated with insulin sensitivity (assessed using the dynamic CISI measure): fasting glucose, insulin, Fas ligand, complement C3, and PAI-1. As shown in Fig. 3C, 91% of variance between predicted and observed CISI values was accounted for by these 5 markers alone (P 0.0001). In addition, a bootstrap R 2 value of 0.90 (IQR 0.83–0.94) indicates that the model could be expected to perform well on an independent data set. By comparison, HOMA-IR, a widely accepted estimate of insulin resistance based on fasting glucose and insulin, explained 88% of the variance of the dynamic measure of insulin sensitivity.

4 Evidence type: observation


A.D.A.M. Medical Encyclopedia.

Metabolic syndrome; Insulin resistance syndrome; Syndrome X

5 Evidence type: observation


Diabetes Health Center Insulin Resistance and Diabetes

If you have pre-diabetes or diabetes, chances are that you’ve heard of the medical term insulin resistance syndrome or metabolic syndrome. Insulin resistance or metabolic syndrome describes a combination of health problems that have a common link — an increased risk of diabetes and early heart disease.

6 Evidence type: observation


The metabolic syndrome: is this diagnosis necessary?
Gerald M Reaven.
Am J Clin Nutr June 2006 vol. 83 no. 6 1237-1247

The goal of diagnosing the metabolic syndrome is to identify persons at increased risk of CVD. Because each component that makes up the versions of the metabolic syndrome increases CVD risk (34, 36, 37, 62, 68, 69), it seems prudent to treat any of these abnormalities that are present. Furthermore, it would not be too surprising that the more abnormalities present in any given person, the greater would be his or her risk of CVD. The question can be raised, however, as to whether identifying a person as having metabolic syndrome necessarily indicates that he or she is at greater risk of CVD than is a person who may not qualify for that designation. This did not seem to be the case when the ATP III criteria were applied to the Framingham Study database (117); a recent report pointed out that persons meeting any 2 criteria were at no less risk than were those meeting 3 criteria. Indeed, it would be possible to describe a number of prototypic clinical situations in which a person with 1 or 2 abnormalities would be at greater risk of CVD than would a patient who met the metabolic syndrome diagnostic criteria.

7 Evidence type: retrospective observation


The Metabolic Syndrome and Total and Cardiovascular Disease Mortality in Middle-aged Men.
Hanna-Maaria Lakka, MD, PhD; David E. Laaksonen, MD, MPH; Timo A. Lakka, MD, PhD; Leo K. Niskanen, MD, PhD; Esko Kumpusalo, MD, PhD; Jaakko Tuomilehto, MD, PhD; Jukka T. Salonen, MD, PhD
JAMA. 2002;288(21):2709-2716. doi:10.1001/jama.288.21.2709.

The metabolic syndrome, a concurrence of disturbed glucose and insulin metabolism, overweight and abdominal fat distribution, mild dyslipidemia, and hypertension, is associated with subsequent development of type 2 diabetes mellitus and cardiovascular disease (CVD).

The prevalence of the metabolic syndrome ranged from 8.8% to 14.3%, depending on the definition. There were 109 deaths during the approximately 11.4-year follow-up, of which 46 and 27 were due to CVD and CHD, respectively. Men with the metabolic syndrome as defined by the NCEP were 2.9 (95% confidence interval [CI], 1.2-7.2) to 4.2 (95% CI, 1.6-10.8) times more likely and, as defined by the WHO, 2.9 (95% CI, 1.2-6.8) to 3.3 (95% CI, 1.4-7.7) times more likely to die of CHD after adjustment for conventional cardiovascular risk factors. The metabolic syndrome as defined by the WHO was associated with 2.6 (95% CI, 1.4-5.1) to 3.0 (95% CI, 1.5-5.7) times higher CVD mortality and 1.9 (95% CI, 1.2-3.0) to 2.1 (95% CI, 1.3-3.3) times higher all-cause mortality. The NCEP definition less consistently predicted CVD and all-cause mortality. Factor analysis using 13 variables associated with metabolic or cardiovascular risk yielded a metabolic syndrome factor that explained 18% of total variance. Men with loadings on the metabolic factor in the highest quarter were 3.6 (95% CI, 1.7-7.9), 3.2 (95% CI, 1.7-5.8), and 2.3 (95% CI, 1.5-3.4) times more likely to die of CHD, CVD, and any cause, respectively.

Cardiovascular disease and all-cause mortality are increased in men with the metabolic syndrome, even in the absence of baseline CVD and diabetes.

8 Evidence type: retrospective observation


Risks for All-Cause Mortality, Cardiovascular Disease, and Diabetes Associated With the Metabolic Syndrome: A summary of the evidence.
Earl S. Ford, MD, MPH
Diabetes Care July 2005 vol. 28 no. 7 1769-1778

For studies that used the exact NCEP definition of the metabolic syndrome, random-effects estimates of combined relative risk were 1.27 (95% CI 0.90–1.78) for all-cause mortality, 1.65 (1.38–1.99) for cardiovascular disease, and 2.99 (1.96–4.57) for diabetes. For studies that used the most exact WHO definition of the metabolic syndrome, the fixed-effects estimates of relative risk were 1.37 (1.09–1.74) for all-cause mortality and 1.93 (1.39–2.67) for cardiovascular disease; the fixed-effects estimate was 2.60 (1.55–4.38) for coronary heart disease.

CONCLUSIONS—These estimates suggest that the population-attributable fraction for the metabolic syndrome, as it is currently conceived, is ∼6–7% for all-cause mortality, 12–17% for cardiovascular disease, and 30–52% for diabetes.

9 Evidence type: retrospective observation


Prevalence and Characteristics of the Metabolic Syndrome in Women with Polycystic Ovary Syndrome.
Teimuraz Apridonidze, Paulina A. Essah, Maria J. Iuorno and John E. Nestler.
The Journal of Clinical Endocrinology & Metabolism April 1, 2005 vol. 90 no. 4 1929-1935

The polycystic ovary syndrome (PCOS) is characterized by insulin resistance with compensatory hyperinsulinemia. Insulin resistance also plays a role in the metabolic syndrome (MBS). We hypothesized that the MBS is prevalent in PCOS and that women with both conditions would present with more hyperandrogenism and menstrual cycle irregularity than women with PCOS only.

We conducted a retrospective chart review of all women with PCOS seen over a 3-yr period at an endocrinology clinic. Of the 161 PCOS cases reviewed, 106 met the inclusion criteria. The women were divided into two groups: 1) women with PCOS and the MBS (n = 46); and 2) women with PCOS lacking the MBS (n = 60).

Prevalence of the MBS was 43%, nearly 2-fold higher than that reported for age-matched women in the general population. Women with PCOS had persistently higher prevalence rates of the MBS than women in the general population, regardless of matched age and body mass index ranges.

10 Evidence type: retrospective observation


Association of metabolic syndrome with Alzheimer disease: A population-based study.
M. Vanhanen, PhD, K. Koivisto, MD, PhD, L. Moilanen, MD, PhD, E. L. Helkala, PhD, T. Hänninen, PhD, H. Soininen, MD, PhD, K. Kervinen, MD, PhD, Y. A. Kesäniemi, MD, PhD, M. Laakso, MD, PhD and J. Kuusisto, MD, PhD
Neurology September 12, 2006 vol. 67 no. 5 843-847

Of the study subjects, 418 (43.6%) had MetS. Probable or possible AD was diagnosed in 45 subjects (4.7%). AD was more frequently detected in subjects with MetS than in subjects without MetS (7.2 vs 2.8%; p < 0.001). The prevalence of AD was higher in women with MetS vs women without the syndrome (8.3 vs 1.9%; p < 0.001), but in men with MetS, the prevalence of AD was not increased (3.8 vs 3.9%; p = 0.994). In univariate logistic regression analysis, MetS was significantly associated with AD (odds ratio [OR] 2.71; 95% CI 1.44 to 5.10). In multivariate logistic regression analysis including also apolipoprotein E4 phenotype, education, age, and total cholesterol, MetS was significantly associated with AD (OR 2.46; 95% CI 1.27 to 4.78). If only nondiabetic subjects were included in the multivariate analysis, MetS was still significantly associated with AD (OR 3.26; 95% CI 1.45 to 7.27).

11 Evidence type: review and meta-analysis


Metabolic syndrome and risk of cancer: a systematic review and meta-analysis.
Esposito K, Chiodini P, Colao A, Lenzi A, Giugliano D.
Diabetes Care. 2012 Nov;35(11):2402-11. doi: 10.2337/dc12-0336.

RESULTS: We analyzed 116 datasets from 43 articles, including 38,940 cases of cancer. In cohort studies in men, the presence of metabolic syndrome was associated with liver (relative risk 1.43, P < 0.0001), colorectal (1.25, P < 0.001), and bladder cancer (1.10, P = 0.013). In cohort studies in women, the presence of metabolic syndrome was associated with endometrial (1.61, P = 0.001), pancreatic (1.58, P < 0.0001), breast postmenopausal (1.56, P = 0.017), rectal (1.52, P = 0.005), and colorectal (1.34, P = 0.006) cancers. Associations with metabolic syndrome were stronger in women than in men for pancreatic (P = 0.01) and rectal (P = 0.01) cancers. Associations were different between ethnic groups: we recorded stronger associations in Asia populations for liver cancer (P = 0.002), in European populations for colorectal cancer in women (P = 0.004), and in U.S. populations (whites) for prostate cancer (P = 0.001). CONCLUSIONS: Metabolic syndrome is associated with increased risk of common cancers; for some cancers, the risk differs betweens sexes, populations, and definitions of metabolic syndrome.

12 Evidence type: controlled experiment


Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low fat diet.
Volek JS, Phinney SD, Forsythe CE, Quann EE, Wood RJ, Puglisi MJ, Kraemer WJ, Bibus DM, Fernandez ML, Feinman RD.
Lipids. 2009 Apr;44(4):297-309. doi: 10.1007/s11745-008-3274-2. Epub 2008 Dec 12.

Abstract

We recently proposed that the biological markers improved by carbohydrate restriction were precisely those that define the metabolic syndrome (MetS), and that the common thread was regulation of insulin as a control element. We specifically tested the idea with a 12-week study comparing two hypocaloric diets (approximately 1,500 kcal): a carbohydrate-restricted diet (CRD) (%carbohydrate:fat:protein = 12:59:28) and a low-fat diet (LFD) (56:24:20) in 40 subjects with atherogenic dyslipidemia. Both interventions led to improvements in several metabolic markers, but subjects following the CRD had consistently reduced glucose (-12%) and insulin (-50%) concentrations, insulin sensitivity (-55%), weight loss (-10%), decreased adiposity (-14%), and more favorable triacylglycerol (TAG) (-51%), HDL-C (13%) and total cholesterol/HDL-C ratio (-14%) responses. In addition to these markers for MetS, the CRD subjects showed more favorable responses to alternative indicators of cardiovascular risk: postprandial lipemia (-47%), the Apo B/Apo A-1 ratio (-16%), and LDL particle distribution. Despite a threefold higher intake of dietary saturated fat during the CRD, saturated fatty acids in TAG and cholesteryl ester were significantly decreased, as was palmitoleic acid (16:1n-7), an endogenous marker of lipogenesis, compared to subjects consuming the LFD. Serum retinol binding protein 4 has been linked to insulin-resistant states, and only the CRD decreased this marker (-20%). The findings provide support for unifying the disparate markers of MetS and for the proposed intimate connection with dietary carbohydrate. The results support the use of dietary carbohydrate restriction as an effective approach to improve features of MetS and cardiovascular risk.

13 Evidence type: non-randomized experiment


A Ketogenic Diet Favorably Affects Serum Biomarkers for Cardiovascular Disease in Normal-Weight Men.
Matthew J. Sharman, William J. Kraemer, Dawn M. Love, Neva G. Avery, Ana L. Gómez, Timothy P. Scheett, and Jeff S. Volek.
J. Nutr. July 1, 2002 vol. 132 no. 7 1879-1885

The primary objective of this study was to examine how healthy normolipidemic, normal-weight men respond to a ketogenic diet in terms of fasting and postprandial CVD biomarkers. Ketogenic diets have been criticized on the grounds they jeopardize health (8); however, very few studies have directly evaluated the effects of a ketogenic diet on fasting and postprandial risk factors for CVD. Subjects consumed a diet that consisted of 8% carbohydrate (27 kg/m2 and a clinical diagnosis of PCOS were recruited from the community. They were instructed to limit their carbohydrate intake to 20 grams or less per day for 24 weeks. Participants returned every two weeks to an outpatient research clinic for measurements and reinforcement of dietary instruction. In the 5 women who completed the study, there were significant reductions from baseline to 24 weeks in body weight (-12%), percent free testosterone (-22%), LH/FSH ratio (-36%), and fasting insulin (-54%). There were non-significant decreases in insulin, glucose, testosterone, HgbA1c, triglyceride, and perceived body hair. Two women became pregnant despite previous infertility problems.

16 Evidence type: randomized, double-blind, placebo-controlled, multicenter trial


Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled, multicenter trial.
Samuel T Henderson, Janet L Vogel, Linda J Barr, Fiona Garvin, Julie J Jones and Lauren C Costantini.
Nutrition & Metabolism 2009, 6:31

AC-1202 significantly elevated a serum ketone body (β-hydroxybutyrate) 2 hours after administration when compared to Placebo. In each of the population groups, a significant difference was found between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45: 1.9 point difference, p = 0.0235 in ITT; 2.53 point difference, p = 0.0324 in per protocol; 2.6 point difference, p = 0.0215 in dosage compliant. Among participants who did not carry the APOE4 allele (E4(-)), a significant difference was found between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45 and Day 90. In the ITT population, E4(-) participants (N = 55) administered AC-1202 had a significant 4.77 point difference in mean change from Baseline in ADAS-Cog scores at Day 45 (p = 0.0005) and a 3.36 point difference at Day 90 (p = 0.0148) compared to Placebo. In the per protocol population, E4(-) participants receiving AC-1202 (N = 37) differed from placebo by 5.73 points at Day 45 (p = 0.0027) and by 4.39 points at Day 90 (p = 0.0143). In the dosage compliant population, E4(-) participants receiving AC-1202 differed from placebo by 6.26 points at Day 45 (p = 0.0011, N = 38) and 5.33 points at Day 90 (p = 0.0063, N = 35). Furthermore, a significant pharmacologic response was observed between serum β-hydroxybutyrate levels and change in ADAS-Cog scores in E4(-) subjects at Day 90 (p = 0.008).

17 Evidence type: review of experiments and case-studies


Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets.
A Paoli, A Rubini, J S Volek and K A Grimaldi.
European Journal of Clinical Nutrition (2013) 67, 789–796; doi:10.1038/ejcn.2013.116; published online 26 June 2013

[I]t seems a reasonable possibility that a very-low-carbohydrate diet could help to reduce the progression of some types of cancer, although at present the evidence is preliminary. In the 1980s, seminal animal studies by Tisdale and colleagues demonstrated that a ketogenic diet was capable to reduce tumour size in mice, whereas more recent research has provided evidence that ketogenic diets may reduce tumour progression in humans, at least as far as gastric and brain cancers are concerned. Although no randomized controlled trials with VLCKD have yet been conducted on patients and the bulk of evidence in relation to the influence of VLCKD on patient survival is still anecdotal, a very recent paper by Fine et al. suggests that the insulin inhibition caused by a ketogenic diet could be a feasible adjunctive treatment for patients with cancer. In summary, perhaps through glucose ‘starvation’ of tumour cells and by reducing the effect of direct insulin-related actions on cell growth, ketogenic diets show promise as an aid in at least some kind of cancer therapy and is deserving of further and deeper investigation—certainly the evidence justifies setting up clinical trials.