2014-04-07

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].)

Beta-hydroxybutyrate and acetoacetate in blood and cerebrospinal fluid during fasting

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.


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].

ketosis false negatives using urine acetoacetate

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

Flowchart to determine diabetic keto-acidosis.

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.


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


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

"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

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

[4]

Evidence type: experiment

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."

https://lh3.googleusercontent.com/-GFZldRQ9ZJ8/U0K3Tz42-4I/AAAAAAAAB5Y/GcRiXEaYAGc/w775-h555-no/epilepsy-acetoacetate-beta-hydroxybutyrate.png
[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:

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."

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"

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

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"

2014-02-10

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."

2014-02-01

Science Fiction

We humans are storytellers. When we want something to be memorable and meaningful, we make it into a story that can be interpreted causally. Our brains are just made that way [1], [2]. That may be why adding dramatic anecdotes to a book or article can make it more popular and persuasive than sticking solely to claims that have gone through rigorous tests. This can lead us to believe more strongly in a hypothesis than the evidence merits.

In Apologia we describe how we try to mitigate errors in our work by tracing our sources of evidence. We aim to at least label our hypotheses as such, and to point out when evidence we used comes only from observed correlations.

Beyond anecdote, there are other ways that storytelling is used in science: the plausible mechanism, and the evolutionary story. Both types are used in two ways: to explain an observation, or to lend weight to an hypothesis. A characteristic of this “science fiction” is that it can be argued against by making a different, more compelling story. The best narrator wins! Like any other hypothesis, though, an hypothesis supported by plausible mechanisms or evolutionary stories might be disproven by experimental evidence.

Plausible mechanisms

Plausible mechanisms are stories that involve chains of known scientific facts, integrated together into an expected result.


Here's an example of plausible mechanism that we used in a post a couple of years ago:

  1. "[BCAAs] are known to have positive effects on muscle growth and recovery.
  2. "One important effect of keto-adaptation is a dramatic increase in circulating BCAAs."
  3. "Therefore it is quite plausible that [...] a ketogenic diet will improve muscle growth and recovery relative to a glycolytic diet, something already anecdotally reported."

(We're glad to see that we drew attention to the type of argument we were making, with the word plausible, even as we threw in anecdote for good measure.)

A counter-story might go along these lines:

  1. Muscle growth is stimulated by insulin.
  2. Ketogenic diets lower insulin.
  3. Therefore muscle growth will be retarded on a ketogenic diet in comparison with a glycolytic diet.

We could spend a lot of energy expounding on one story or other, but only replicable, randomised, controlled trials can finally lay a story to rest.


Evolutionary stories

Evolutionary stories are stories that make plausible hypotheses about why certain adaptations could have been selected. They can be used to argue that a certain trait is adaptive, or, more subtly, that an organism has a certain trait.


Here's an example of an evolutionary story:

  1. Ketogenic metabolism is an adaptation to cope with conditions of scarcity.
  2. We get fat because our genes are thriftily hanging on to excess calories to use in famines.
  3. Therefore ketogenic diets must send stress signals to the body, indicating imminent famine.

We recently read a counter-story described by Anna of the blog “lifeextension”.

We can't do that whole post justice, so we recommend you read it. It's not long, and it contains citations supporting the premises. The gist of the story goes like this:

  1. We adapted to a diet largely consisting of meat.
  2. When meat is plentiful, our bodies keep fat at optimal levels for peak fitness and ability.
  3. Eating starch or fiber sends a strong stress signal, mediated by gut microbiota which are sensitive to small changes in diet, indicating that famine is imminent.
  4. This starts a cascade of fat storage.
  5. That is, starch digestion is an adaptation to cope with conditions of scarcity.

We could add more to that story. For example,

  • There is a follow-up post about work that demonstrates that amylase activity is a biomarker of stress.
  • We could point out that no other species responds to abundance by getting fat. Instead they reproduce more.

But these are just embellishments to one of the stories. The right question to ask is:

What kind of evidence could let us discriminate between these two stories?

One way to do that would be to understand stress, how to measure it, and how to tell when it is healthy and when it is detrimental.

Tune in next time for “Ketogenic diets, Cortisol, and Stress, Part II”: The Ketogenic Diet's Effect on Cortisol Metabolism, in which we provide evidence that ketogenic diets have a beneficial effect on cortisol metabolism.

Further Reading

  1. Darwin's Dangerous Idea by Daniel Dennett

    In which we are warned against “Just So Stories”—evolutionary stories that are plausible (at least to some people), and that would explain some observations, but that may or may not be true.

  2. Just So Stories by Rudyard Kipling

    Stories explaining how animals came to be the way they are, such as “How The Leopard Got His Spots”.

  3. The Black Swan by Nassim Nicholas Taleb

    In which we are warned against “The Narrative Fallacy“—the tendency to rely on explanations because they make good stories.

  4. Thrifty genes for obesity and the metabolic syndrome — time to call off the search?

  5. Salivary alpha-amylase in biobehavioral research: recent developments and applications.

Notes

[1]

The Neurology of Narrative

Kay Young, Jeffrey L. Saver
From: SubStance Issue 94/95 (Volume 30, Number 1&2), 2001 pp. 72-84

"Abstract

Narrative is the inescapable frame of human existence. Thinkers as diverse as Aristotle, Barthes, and Bruner have recognized the centrality of narrative in human cognition, but have scanted its neurobiologic underpinning. Recent advances in cognitive neuroscience suggest a regionally distributed neural network mediates the creation of narrative in the human central nervous system. Fundamental network components include: 1) the amygdalo-hippocampal system, responsible for initial encoding of episodic and autobiographical memories, 2) the left peri-Sylvian region, where language is formulated, and 3) the frontal cortices and their subcortical connections, where individuals and entities are organized into real and fictional temporal narrative frames. We describe four types of dysnarrativia, states of narrative impairment experienced by individuals with discrete focal damage in different regions of this neural network subserving human self-narrative. Patients with these syndromes illustrate the inseparable connection between narrativity and personhood. Brain- injured individuals may lose their linguistic or visuospatial competencies and still be recognizably the same persons. Individuals who have lost the ability to construct narrative, however, have lost their selves."

[2]

Causal coherence and memory for events in narratives

John B. Black Hyman Bern
Journal of Verbal Learning and Verbal Behavior. Volume 20, Issue 3, June 1981, Pages 267–275

"Causally related events in narratives were remembered better than events that were not causally related. In Experiment 1, subjects recalled sentences from stories when given the sentences that immediately preceded them as cues. Cued recall was better when the two sentences were causally related than when they were not. In Experiment 2, subjects free recalled the same stories. Again, recall was better for the sentences when they were part of a causally related pair. Also subjects were more likely to combine two sentences into one during recall when they were causally related."

2014-01-24

Babies thrive under a ketogenic metabolism

Some people, even some scientists who study ketogenic metabolism, have the idea that ketogenesis is somehow abnormal, or exceptional; an adaptation for emergencies only. We disagree.

One reason we think a ketogenic metabolism is normal and desirable, is that human newborns are in ketosis. Despite the moderate sugar content of human breast milk, breastfeeding is particularly ketogenic. This period of development is crucial, and there is extensive brain growth during it. Although the composition of breast milk can be affected by diet [1], it is reasonable to assume that breast milk has always been ketogenic, and this is not an effect of modernisation.

When the brain is in its period of highest growth, and when the source of food is likely to be close to what it evolved to be for that period, ketones are used to fuel that growth.

If nothing else, this suggests that learning is well supported by a ketogenic metabolism. It is also consistent with the ability of ketogenic diets to treat a variety of seemingly unrelated brain disorders and brain trauma.

In brief

  • Newborn infants are in ketosis. This is their normal state.
  • Breastfeeding is particularly ketogenic (compared to formula feeding).
  • Breastfeeding longer (up to a point) is associated with better health outcomes.
  • This suggests the hypothesis that weaning onto a ketogenic diet would be healthier than weaning onto a high-carb diet.
(Mark-up ours) https://lh4.googleusercontent.com/-Qkco6a-yHU4/UuLtMjR7QjI/AAAAAAAABzk/pGq63wexS2A/w1042-h468-no/ketonemiaTable.png

Human babies are in ketosis

Soon after birth, human babies are in ketosis, and remain so while breastfeeding [2]. They use ketones and fats for energy and for brain growth.

When this has been studied, in the first couple of hours after birth, babies aren't immediately in ketosis. There is a short delay [3]. During that brief period before ketogenesis starts, lactate (confusingly not to do with lactation) becomes an important fuel to suppport the brain [4]. Some researchers speculate that this delay in ketogenesis could be because of a limited supply of carnitine, which is supplied by milk, but they also note that glycogenolysis and gluconeogenesis (the process by which glucose is made out of protein) are not active immediately [5]. Therefore, it could simply be the case that ketogenesis takes time to get started. In other words, it may just be keto-adaptation.

Note, though, that the mothers of these babies were unlikely to have been ketogenic. As it happens, if the mother is in ketosis (as has been studied through fasting), ketone bodies will pass through the placenta and be used by the fetus [5], [6]. At the same time, gluconeogenesis is induced in the liver of the fetus, likely as a result of the insulin-to-glucagon ratio [7], [8]. Therefore, it is possible that the fetus of a ketogenic mother would already be independently ketogenic at birth.

Breastfeeding is probably healthy

Many positive associations between exclusive breastfeeding for at least 3-6 months and the later health of the child have been reported. For example, intelligence has been positively correlated with length of time breastfeeding. The data is conflicting and prone to confounds [9], although we found a few studies that appear to have addressed those confounds and still showed an effect [10], [11], [12]. There have also been correlations found between breastfeeding and protection from developing diseases, such as asthma and allergies [13], type 1 and type 2 diabetes [14], and epilepsy [15].

Observational correlations are good sources of hypotheses, but can't establish causality. Unfortunately, these hypotheses are hard to test. We suppose that breastfeeding is healthy mainly because we clearly evolved to breastfeed.

Breastfeeding is ketogenic

The medical focus in the 20th century was heavily influenced by the discovery of micronutrients, and because of this, we have been looking for the secret of the healthfulness of breast milk by examining what nutrients it contains. However, one significant difference between breastfeeding infants and those drinking formula is that they are in deeper ketosis [16]. It is not known why. It could be a property of the milk, or something else about the feeding. In any case, regardless of mechanism, the fact is that breastfeeding is more ketogenic. It is possible that the reason that longer breastfeeding is generally associated with better health, is because it represents a longer time in ketosis.

Summary

  • The period in which human brains grow the most, and in which food is least likely to be different from evolutionary conditions, is a ketogenic period. This suggests that a ketogenic metabolism is excellent for learning and development.
  • Breastfeeding in humans is particularly ketogenic. We hypothesise that the positive associations between health and longer breastfeeding may be due to extending the period of ketosis in infancy.
  • A related hypothesis we offer is that extending the period of ketosis after breastfeeding, by weaning onto ketogenic foods such as homemade broth [*] and fatty meat, rather than cereal, fruit, and starchy vegetables, would further promote brain development and reduce risk of disease.
[*]Homemade, because it is rich in fat, unlike the boxed varieties which have almost none.

---

References and notes

[1]

Evidence type: review

Sheila M. Innis
Adv Nutr May 2011 Adv Nutr vol. 2: 275-283, 2011

"The fatty acids needed by the mammary gland for synthesis of TG for secretion in milk are obtained by uptake of fatty acids from plasma and de novo synthesis in the mammary gland (7). Fatty acid synthesis in the mammary gland, however, is unusual. Commencing with acetyl CoA, malonyl CoA 2 carbon units are added to the growing fatty acid with elongation terminated at a carbon chain length of 14 or less by the mammary gland-specific enzyme thioesterase II rather than at 16 carbons, as occurs in the liver and other tissues (7, 8). Synthesis and secretion of 10:0, 12:0, and 14:0 into milk is increased in lactating women consuming high-carbohydrate diets, whereas the secretion of the 18 carbon chain unsaturated fatty acids, which are derived by uptake from plasma, is decreased (4, 9, 10). Overall, reciprocal changes in mammary gland-derived medium-chain fatty acids (MCFA) and plasma-derived unsaturated fatty acids allows the milk fat content to be maintained under conditions of varying maternal dietary fat and carbohydrate intake. The levels of unsaturated fatty acids, including 18:1(n-9), 18:2(n-6), 18:3(n-3), 20:5(n-3), 22:6(n-3), and trans fatty acids in human milk, however, vary widely, with the maternal dietary fat composition being one of the most important factors contributing to the differences in the levels of unsaturated fatty acids in the milk of different women (4, 8, 11–14). In contrast, the levels of 16:0 in milk from women in different countries and with different diets is relatively constant at 20–25% of the milk fatty acids regardless of differences in the maternal diet fat content or composition (4). Possible exceptions include lower levels of 14–18% 16:0 described for milk from women in Gambia (15), some vegans and vegetarians (16, 17), and the Arctic Inuit (18)."

[2]

Evidence type: review of experiments in humans and rats

Medina JM, Tabernero A.
J Neurosci Res. 2005 Jan 1-15;79(1-2):2-10.

"Striking changes in the fuel supply to the tissues occur during the perinatal period because the transplacental supply of nutrients ends with a period of postnatal starvation (presuckling period) followed by adaptation to a fat-rich diet."

[...]

"Ketone bodies are a major fuel for the brain during the suckling period and hence the stimulation of ketogenesis at birth is an important metabolic event in adaptation of the newborn to extrauterine life. Ketogenesis is active during late gestation in human fetal liver and the activity of ketogenic enzymes sharply increases immediately after birth in the rat (Hahn and Novak, 1985; Bougneres et al., 1986). In addition to modulation of enzyme activities, the control of ketogenesis also depends on the availability of fatty acids. The increase in fatty acid concentrations that occurs after delivery is due to breakdown of triacylglycerol in white adipose tissue present in human newborns at birth. In the rat, however, plasma fatty acids mostly come from hydrolysis of triacylglycerols from the mother’s milk because of the lack of white adipose tissue at birth. Nevertheless, in both species, once lactation is active fatty acids come from the intestinal hydrolysis of milk triacylglycerols, which may be absorbed directly without passage through the lymph (Aw and Grigor, 1980)."

[...]

"The increase in the activities of ketogenic enzymes together with the increase in the availability of fatty acids occurring immediately after delivery result in enhancement of ketogenic capacity of the liver (Girard,1990). This is responsible for the increase in ketone body concentrations observed postnatally. In fact, plasma ketone body concentrations are the main factor controlling the rate of ketone body utilization by neonatal tissues (Robinson and Williamson, 1980). In addition, activities of enzymes involved in ketone body utilization either increase during the first days of extrauterine life, as in the rat (Page et al., 1971), or are already induced during early gestation, as in the human brain (Patel et al., 1975). Moreover, newborn rat brain contains acetoacetyl-CoA synthetase, a unique enzyme that allows an important portion of carbon atoms from ketone bodies to be incorporated into lipid via a highly efficient cytosolic pathway (Williamson and Buckley, 1973). Indeed, there is a strong correlation between lipid synthesis and the activity of this enzyme during brain development (Yeh and Sheehan, 1985). Moreover, ketone body transport across the blood–brain barrier using the monocarboxylate carrier is maximal during the suckling period, in keeping with the idea that ketone bodies play an important role in brain development (Cremer, 1982; Conn et al., 1983). "Ketone bodies are utilized by the newborn brain as a source of energy and carbon skeletons and are incorporated into fatty acids, sterols, acetylcholine, and amino acids (Robinson and Williamson, 1980; Bougneres et al., 1986). Ketone bodies, however, seem to be the major source of carbon skeletons for sterol synthesis during brain development and play a decisive role in the synthesis of brain structures during myelinogenesis (Robinson and Williamson, 1980; Miziorko et al., 1990). Ketone bodies are utilized evenly by neurons, astrocytes, and oligodendrocytes (Edmond et al., 1987; Lopes-Cardozo et al., 1989; Poduslo and Miller, 1991), indicating that they are ubiquitous substrates for brain cells. Acetoacetyl-CoA synthetase activity, however, is higher in oligodendrocytes than in neurons or astrocytes, confirming the special role of oligodendrocytes in myelinogenesis (Pleasure et al., 1979; Lopes-Cardozo et al., 1989; Poduslo and Miller, 1991)."

[3]

Evidence type: review of experiments

Ward Platt M, Deshpande S.
Semin Fetal Neonatal Med. 2005 Aug;10(4):341-50.

"During the first 8 h after birth, newborn infants have been shown to have rather low plasma ketone body concentrations despite adequate levels of precursor free fatty acids (FFAs), reflecting limited capacity for hepatic ketogenesis.30 Thereafter, from 12 h of age, healthy term infants show high ketone body turnover rates (12e 22 mmol kg/min) approaching those found in adults after several days of fasting,14 and during days 2 and 3 after birth they exhibit high ketone body concentrations quantitatively similar to those observed after an overnight fast in older children (Fig. 2).15 Such ketone body concentrations may account for as much as 25% of the neonate’s basal energy requirements during this time. Thus vigorous ketogenesis appears to be an integral part of extrauterine metabolic adaptation in the term human neonate."

[4]

Evidence type: review of experiments in humans and rats

Medina JM, Tabernero A.
J Neurosci Res. 2005 Jan 1-15;79(1-2):2-10.

"Although the supply of metabolic substrates is maintained mostly during the perinatal period, there is an apparent lack of mobilization of energy reserves immediately after delivery; i.e., during the presuckling period. During this period, the maternal supply of glucose has ceased and alternative substrates have not yet been released. In the rat, fatty acids come exclusively from the mother’s milk because of the lack of white adipose tissue at birth. Consequently, free fatty acids are not available in the rat before the onset of suckling (Mayor and Cuezva, 1985; Girard, 1990). In the case of human newborns, however, fatty acid mobilization occurs immediately after birth, although the onset of ketogenesis is delayed, probably as a consequence of a limited supply of carnitine, which is provided mainly by the milk (Hahn and Novak, 1985; Schmidt-Sommerfeld and Penn, 1990). In addition, glycogenolysis and gluconeogenesis are not active immediately after birth, resulting in very low concentrations of plasma glucose (Mayor and Cuezva, 1985; Girard, 1990). In these circumstances, lactate may play an important role as an alternative substrate. In fact, lactate accumulates in fetal blood during the perinatal period and is removed rapidly immediately after delivery (Persson and Tunell, 1971; Juanes et al., 1986)."

[5]

Evidence type: presumably this is a review. We could not get the full text, so for us this is evidence by authority

Shambaugh GE 3rd.
Fed Proc. 1985 Apr;44(7):2347-51.

"Pregnancy is characterized by a rapid accumulation of lipid stores during the first half of gestation and a utilization of these stores during the latter half of gestation. Lipogenesis results from dietary intake, an exaggerated insulin response, and an intensified inhibition of glucagon release. Increasing levels of placental lactogen and a heightened response of adipose tissue to additional lipolytic hormones balance lipogenesis in the fed state. Maternal starvation in late gestation lowers insulin, and lipolysis supervenes. The continued glucose drain by the conceptus aids in converting the maternal liver to a ketogenic organ, and ketone bodies produced from incoming fatty acids are not only utilized by the mother but cross the placenta where they are utilized in several ways by the fetus: as a fuel in lieu of glucose; as an inhibitor of glucose and lactate oxidation with sparing of glucose for biosynthetic disposition; and for inhibition of branched-chain ketoacid oxidation, thereby maximizing formation of their parent amino acids. Ketone bodies are widely incorporated into several classes of lipids including structural lipids as well as lipids for energy stores in fetal tissues, and may inhibit protein catabolism. Finally, it has recently been shown that ketone bodies inhibit the de novo biosynthesis of pyrimidines in fetal rat brain slices. Thus during maternal starvation ketone bodies may maximize chances for survival both in utero and during neonatal life by restraining cell replication and sustaining protein and lipid stores in fetal tissues."

[6]

Evidence type:

Herrera, Emilio
Endocrine, Volume 19, Number 1, October 2002 , pp. 43-56(14)

"During early pregnancy there is an increase in body fat accumulation, associated with both hyperphagia and increased lipogenesis. During late pregnancy there is an accelerated breakdown of fat depots, which plays a key role in fetal development. Besides using placental transferred fatty acids, the fetus benefits from two other products: glycerol and ketone bodies. Although glycerol crosses the placenta in small proportions, it is a preferential substrate for maternal gluconeogenesis, and maternal glucose is quantitatively the main substrate crossing the placenta. Enhanced ketogenesis under fasting conditions and the easy transfer of ketones to the fetus allow maternal ketone bodies to reach the fetus, where they can be used as fuels for oxidative metabolism as well as lipogenic substrates."

[...]

"Increased gluconeogenesis from glycerol and ketogenesis from NEFA may benefit the fetus, which at late gestation is at its maximum accretion rate and its requirements for substrates and metabolic fuels are greatly augmented. The preferential use of glycerol for gluconeogenesis and the efficient placental transfer of the newly formed glucose may be of major importance to the fetus under these fasting conditions (Fig. 2), in which the availability of other essential substrates such as amino acids is reduced (30,34). Placental transfer of ketone bodies is highly efficient (35), reaching fetal plasma at the same level as in maternal circulation (29). Ketone bodies may be used by the fetus as fuels (36) and as substrates for brain lipid synthesis (37)."

[7]

Evidence type: review We could not get the full text, so for us this is evidence by authority

Girard J.
Biol Neonate. 1986;50(5):237-58.

"Abstract

Birth in most mammalian species represents an abrupt change from a high-carbohydrate and low-fat diet to a high-fat and low-carbohydrate diet. Gluconeogenesis is absent from the liver of the fetus of well fed mothers, but can be induced prematurely by prolonged fasting of the mother. Gluconeogenesis increases rapidly in the liver of newborn mammals in parallel with the appearance of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme of this pathway. The rise in plasma glucagon and the fall in plasma insulin which occur immediately after birth are the main determinants of liver PEPCK induction. When liver PEPCK has reached its adult value, i.e. 24 h after birth, other factors are involved in the regulation of hepatic gluconeogensis. In order to maintain a high gluconeogenic rate, the newborn liver must be supplied with sufficient amount of gluconeogenic substrates and free fatty acids. An active hepatic fatty acid oxidation is necessary to support hepatic gluconeogenesis by providing essential cofactors such as acetyl CoA and NADH. The relevance of animal studies for the understanding of neonatal glucose homeostasis in man is discussed."

[8]

Evidence type: review of experiments:

Kalhan S, Parimi P.
Semin Perinatol. 2000 Apr;24(2):94-106.

(emphasis ours)

"Studies in human and animal models have consistently confirmed the dependence of the fetus on the mother for supply of glucose so that the fetus in utero under normal physiological circumstances does not produce glucose. However, most gluconeogenic and glycogenolytic enzymes have been shown to be present early in fetal development. The exception is the cytosolic phosphoenol pyruvate carboxykinase, which is expressed (at least in the rat) immediately after birth. 12-14 The appearance of gluconeogenic enzyme activity in the liver in relation to birth in the rat fetus and newborn is displayed in Figure 2. As shown, PC and glucose-6-phosphatase activity are expressed in the fetus, are relatively low at birth, and increase rapidly thereafter. Fructose 1,6-diphosphatase activity increases before birth. In contrast, phosphoenol pyruvate carboxykinase activity is absent in the fetus and rapidly increases immediately after birth, so that hepatic gluconeogenesis is completely absent in utero and appears in the immediate newborn period 2,14,5 GNG, however, can,be induced in utero by prolonged maternal starvation, prolonged hypoglycemia in the mother, or by direct injection of cyclic adenosine monophosphate (cAMP) into the fetus. 16-18 In addition, some studies have showed incorporation of tracer carbon from lactate into glucose in rat fetus and glutamine carbon into hepatic glycogen in sheep fetus. 4,5,19 The significance of these latter observations remains unclear."

[9]

Evidence type: meta-analysis

Walfisch A, Sermer C, Cressman A, Koren G.
BMJ Open. 2013 Aug 23;3(8):e003259. doi: 10.1136/bmjopen-2013-003259.

"The association between breastfeeding and child cognitive development is conflicted by studies reporting positive and null effects. This relationship may be confounded by factors associated with breastfeeding, specifically maternal socioeconomic class and IQ.

Design Systematic review of the literature.

Setting and participants Any prospective or retrospective study, in any language, evaluating the association between breastfeeding and cognitive development using a validated method in healthy term infants, children or adults, was included.

Primary and secondary outcome measures Extracted data included the study design, target population and sample size, breastfeeding exposure, cognitive development assessment tool used and participants’ age, summary of the results prior to, and following, adjustment for confounders, and all confounders adjusted for. Study quality was assessed as well.

Results 84 studies met our inclusion criteria (34 rated as high quality, 26 moderate and 24 low quality). Critical assessment of accepted studies revealed the following associations: 21 null, 28 positive, 18 null after adjusting for confounders and 17 positive—diminished after adjusting for confounders. Directionality of effect did not correlate with study quality; however, studies showing a decreased effect after multivariate analysis were of superior quality compared with other study groupings (14/17 high quality, 82%). Further, studies that showed null or diminished effect after multivariate analysis corrected for significantly more confounders (7.7±3.4) as compared with those that found no change following adjustment (5.6±4.5, p=0.04). The majority of included studies were carried out during childhood (75%) and set in high-income countries (85.5%).

Conclusions Much of the reported effect of breastfeeding on child neurodevelopment is due to confounding. It is unlikely that additional work will change the current synthesis. Future studies should attempt to rigorously control for all important confounders. Alternatively, study designs using sibling cohorts discordant for breastfeeding may yield more robust conclusions."

[10]

Evidence type: observational

Florey CD, Leech AM, Blackhall A.
Int J Epidemiol. 1995;24 Suppl 1:S21-6.

"OBJECTIVE: To determine the relationship between type of infant feeding and mental and psychomotor development at age 18 months.

METHOD: A follow-up study of children born to primigravidae living in Dundee and booked into antenatal clinics in the City of Dundee (Local Authority District) from 1 May 1985 to 30 April 1986. The study population was 846 first born singletons, of whom 592 attended for developmental assessment at age 18 months. The main outcome measures were the Bayley Scales of Infant Mental and Motor Development.

RESULTS: Higher mental development was significantly related to breast feeding on discharge from hospital and according to the health visitors' notes at about 2 weeks after discharge after allowing for partner's social class, mother's education, height, alcohol and cigarette consumption; placental weight and the child's sex, birth weight and gestational age at birth. After adjustment for statistically significant variables, the difference in Bayley mental development index between breast and bottle fed infants was between 3.7 and 5.7 units depending on the source of feeding data. No differences were found for psychomotor development or behaviour.

CONCLUSION: The study provides further evidence of a robust statistical association between type of feeding and child intelligence. However, the literature is replete with suggestions for potential confounding variables which offer alternative causal explanations. To unravel what is an important clinical and public health question, further research should concentrate on randomized trials of supplemented formula feeds for children of mothers opting for bottle feeding and on epidemiological studies designed to disentangle the relation between method of feeding, parental intelligence and social environment."

[11]

Evidence type: observational

Belfort MB, Rifas-Shiman SL, Kleinman KP, Guthrie LB, Bellinger DC, Taveras EM, Gillman MW, Oken E.
JAMA Pediatr. 2013 Sep;167(9):836-44.

"Breastfeeding may benefit child cognitive development, but few studies have quantified breastfeeding duration or exclusivity, nor has any study to date examined the role of maternal diet during lactation on child cognition.

OBJECTIVES: To examine relationships of breastfeeding duration and exclusivity with child cognition at ages 3 and 7 years and to evaluate the extent to which maternal fish intake during lactation modifies associations of infant feeding with later cognition.

DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study (Project Viva), a US prebirth cohort that enrolled mothers from April 22, 1999, to July 31, 2002, and followed up children to age 7 years, including 1312 Project Viva mothers and children.

MAIN EXPOSURE: Duration of any breastfeeding to age 12 months. MAIN OUTCOMES AND MEASURES:

Child receptive language assessed with the Peabody Picture Vocabulary Test at age 3 years, Wide Range Assessment of Visual Motor Abilities at ages 3 and 7 years, and Kaufman Brief Intelligence Test and Wide Range Assessment of Memory and Learning at age 7 years.

RESULTS: Adjusting for sociodemographics, maternal intelligence, and home environment in linear regression, longer breastfeeding duration was associated with higher Peabody Picture Vocabulary Test score at age 3 years (0.21; 95% CI, 0.03-0.38 points per month breastfed) and with higher intelligence on the Kaufman Brief Intelligence Test at age 7 years (0.35; 0.16-0.53 verbal points per month breastfed; and 0.29; 0.05-0.54 nonverbal points per month breastfed). Breastfeeding duration was not associated with Wide Range Assessment of Memory and Learning scores. Beneficial effects of breastfeeding on the Wide Range Assessment of Visual Motor Abilities at age 3 years seemed greater for women who consumed 2 or more servings of fish per week (0.24; 0.00-0.47 points per month breastfed) compared with less than 2 servings of fish per week (−0.01; −0.22 to 0.20 points per month breastfed) (P = .16 for interaction).

CONCLUSIONS AND RELEVANCE: Our results support a causal relationship of breastfeeding duration with receptive language and verbal and nonverbal intelligence later in life."

[12]

Evidence type: observational

Julvez J, Guxens M, Carsin AE, Forns J, Mendez M, Turner MC, Sunyer J.
Dev Med Child Neurol. 2014 Feb;56(2):148-56. doi: 10.1111/dmcn.12282. Epub 2013 Oct 1.

"AIM: This study investigated whether duration of full breastfeeding is associated with child neuropsychological development and whether this association is explained by social, psychological, and nutritional factors within families.

METHOD: Participants in this study were a population-based birth cohort in the city of Sabadell (Catalonia, Spain). Females were recruited during the first trimester of pregnancy between July 2004 and July 2006. Information about parental characteristics and breastfeeding was obtained through questionnaires. Full breastfeeding was categorized as never, short term (≤4mo), long term (4-6mo), or very long term (>6mo). A trained psychologist assessed the neuropsychological development of children at 4 years of age (n=434) using the McCarthy Scales of Children's Abilities (MSCA).

RESULTS: Full breastfeeding showed an independent association with child general MSCA scores after adjusting for a range of social, psychological, and nutritional factors (>6mo, coefficient=7.4 [95% confidence interval=2.8-12.0], p=0.011). Maternal social class, education level, and IQ were also associated with child neuropsychological scores, but did not explain breastfeeding associations. Omega-3 (n3) fatty acid levels were not associated with child neuropsychological scores.

INTERPRETATION: Very long-term full breastfeeding was independently associated with neuropsychological functions of children at 4 years of age. Maternal indicators of intelligence, psychopathology, and colostrum n3 fatty acids did not explain this association."

[13]

Evidence type: observational

I Kull, M Wickman, G Lilja, S Nordvall, and G Pershagen
Arch Dis Child. 2002 December; 87(6): 478–481. doi: 10.1136/adc.87.6.478 PMCID: PMC1755833

"Aims: To investigate the effect of breast feeding on allergic disease in infants up to 2 years of age.

Methods: A birth cohort of 4089 infants was followed prospectively in Stockholm, Sweden. Information about various exposures was obtained by parental questionnaires when the infants were 2 months old, and about allergic symptoms and feeding at 1 and 2 years of age. Duration of exclusive and partial breast feeding was assessed separately. Symptom related definitions of various allergic diseases were used. Odds ratios (OR) and 95% confidence intervals (CI) were estimated in a multiple logistic regression model. Adjustments were made for potential confounders.

Results: Children exclusively breast fed during four months or more exhibited less asthma (7.7% v 12%, ORadj = 0.7, 95% CI 0.5 to 0.8), less atopic dermatitis (24% v 27%, ORadj = 0.8, 95% CI 0.7 to 1.0), and less suspected allergic rhinitis (6.5% v 9%, ORadj = 0.7, 95% CI 0.5 to 1.0) by 2 years of age. There was a significant risk reduction for asthma related to partial breast feeding during six months or more (ORadj = 0.7, 95% CI 0.5 to 0.9). Three or more of five possible allergic disorders—asthma, suspected allergic rhinitis, atopic dermatitis, food allergy related symptoms, and suspected allergic respiratory symptoms after exposure to pets or pollen—were found in 6.5% of the children. Exclusive breast feeding prevented children from having multiple allergic disease (ORadj = 0.7, 95% CI 0.5 to 0.9) during the first two years of life.

Conclusion: Exclusive breast feeding seems to have a preventive effect on the early development of allergic disease—that is, asthma, atopic dermatitis, and suspected allergic rhinitis, up to 2 years of age. This protective effect was also evident for multiple allergic disease."

[14]

Evidence type: review of observational studies

Pereira PF, Alfenas Rde C, Araújo RM.
J Pediatr (Rio J). 2014 Jan-Feb;90(1):7-15. doi: 10.1016/j.jped.2013.02.024. Epub 2013 Oct 16.

"Objective the aim of this study was to perform a review to investigate the influence of breastfeeding as a protective agent against the onset of diabetes in children.

Sources non-systematic review of SciELO, LILACS, MEDLINE, Scopus, and VHL databases, and selection of the 52 most relevant studies. A total of 21 articles, specifically on the topic, were analyzed (nine related to type 1 diabetes and 12 to type 2 diabetes).

Data synthesis the duration and exclusivity of breastfeeding, as well as the early use of cow's milk, have been shown to be important risk factors for developing diabetes. It is believed that human milk contains substances that promote the maturation of the immune system, which protect against the onset of type 1 diabetes. Moreover, human milk has bioactive substances that promote satiety and energy balance, preventing excess weight gain during childhood, thus protecting against the development of type 2 diabetes. Although the above mentioned benefits have not been observed by some researchers, inaccuracies on dietary habit reports during childhood and the presence of interfering factors have been considered responsible for the lack of identification of beneficial effects.

Conclusion given the scientific evidence indicated in most published studies, it is believed that the lack of breastfeeding can be a modifiable risk factor for both type 1 and type 2 diabetes. Strategies aiming at the promotion and support of breastfeeding should be used by trained healthcare professionals in order to prevent the onset of diabetes."

[15]

Evidence type: observational

Sun Y, Vestergaard M, Christensen J, Olsen J.
J Pediatr. 2011 Jun;158(6):924-9. doi: 10.1016/j.jpeds.2010.11.035. Epub 2011 Jan 13.

"OBJECTIVE: We asked whether breastfeeding reduces the risk of epilepsy in childhood.

STUDY DESIGN: We included 69 750 singletons born between September 1997 and June 2003 in the Danish National Birth Cohort and observed them to August 2008. Information on breastfeeding was reported by mothers in two computer-assisted telephone interviews at 6 and 18 months after birth. Information on epilepsy (inpatients and outpatients) was retrieved from the Danish National Hospital Register. Cox proportional hazards regression models were used to estimate incidence rate ratios and 95% CIs.

RESULTS: Breastfeeding was associated with a decreased risk of epilepsy, with a dose-response like pattern. For example, children breastfed for 3 to 5, 6 to 8, 9 to 12, and ≥ 13 months had a 26%, 39%, 50%, and 59% lower risk of epilepsy after the first year of life, respectively, compared with children who were breastfed for <1 month. The association remained when we excluded children who had adverse neonatal conditions or children who were exposed to adverse maternal conditions during pregnancy.

CONCLUSIONS: The observed protective effect of breastfeeding may be causal. Breastfeeding may decrease epilepsy in childhood, thereby adding another reason for breastfeeding."

[16]

Evidence type: controlled human experiments

"Our summary statistic, median peak kb [(ketone body)] concentration (Table 6), is significantly higher in the BF [(breastfed)] group compared with other feed groups for the SGA [(small for gestational age)] infants analyzed separately. We further explored the relationship between the blood glucose concentration and kb response by finding the kb concentration at the lowest blood glucose level for each infant at >24 hours of age (Fig 3, Table 6). Especially at low blood glucose values, infants who receive breast milk show some of the highest values for blood kb concentration. Our data show that exclusive formula feeding does not necessarily protect against low blood glucose values. Hence, the SGA FF [(formula fed)] infant could be doubly at risk of both low blood glucose values with a reduced kb response. No BF infant had both low blood glucose and low kb levels. For LGA [(large for gestational age)] infants, low blood glucose values were offset by kb concentrations of the same order of magnitude previously demonstrated for AGA [(appropriate for getstaional age)] infants6 (Fig 3)."

[...]

"Mammalian animal studies have shown that the postnatal induction of the enzymes involved in β-oxidation within the mitochondria requires the presence of long-chain fatty acids.15 The carnitine palmitoyltransferase system, which controls movement of long-chain fatty acids into the mitochondria, represents a major rate-limiting step in ketogenesis in the suckling rat. Long-chain fatty acids play a pivotal role in the posttranscriptional regulation of carnitine palmitoyltransferase 1 during the immediate postnatal period. We speculate that a factor present in breast milk but absent in formula milk augments ketogenesis in human neonates in the same way. Carnitine is known to have a central role in β-oxidation of fats: it is responsible for the transport of fatty acyl-coenzyme A across the inner mitochondrial membrane.16 During the suckling period, the demand for carnitine exceeds the rate of endogenous synthesis by up to 50%.17 Indeed, healthy, full-term infants fed formulas devoid of carnitine showed reduction in ketogenesis and an accumulation of fatty acid precursors in the plasma. Although breast milk– and cow’s milk– derived formulas contain equivalent amounts of carnitine,18 it may well be that there are significant differences in bioavailability. When compared with breastfed control subjects, infants who were fed a standard formula that was not supplemented with carnitine demonstrated markers of carnitine deficiency.19 Furthermore, we hypothesized that high intakes of energy and protein associated with early formula feeding may “switch off” or dampen the crucial glucagon surge, central to regulation of fuel availability in the immediate postnatal period."

http://2.bp.blogspot.com/-LwawYJnqhfY/UuLrg-XQbTI/AAAAAAAABzE/1IsxQzCuQHg/s1600/breastfeedingketosis.png