Category Archives: Disease - Page 21

Danger of Zero-Carb Diets III: Scurvy

Posted by on November 20, 2010 207 comments

I started low-carb Paleo dieting in late 2005. I ate a lot of vegetables but no starches and hardly any fruit. In retrospect, I would call it a near zero-carb diet. At that time I was 12 years into a chronic illness that got a little worse each year and was quite mysterious to me. Adopting a low-carb diet brought immediate changes: it made what I would much later recognize as a chronic bacterial infection better (in parts of the body, not the brain) and made a chronic fungal infection worse.

Within about a year I had developed scurvy. It took me an embarrassingly long time to figure out what it was. By the time knew what it was, I had 3 cavities; had lost 25 pounds; had developed diverticulitis and an abdominal aorta that visibly swelled with every heartbeat; and had minor skin wounds – scrapes and scratches – that hadn’t healed in 6 months.

Developing scurvy was a surprise, because I was eating many vegetables plus taking a multivitamin containing 90 mg of vitamin C. I had never had any signs of vitamin C deficiency before adopting a low-carb diet.

Four grams a day of vitamin C for two months cured all the scurvy symptoms. It would be several more years before I figured out the infections, but this experience taught me the importance of micronutrition. The experience persuaded me that I needed to research diets and nutrition closely, and started us down the path of writing Perfect Health Diet.

Scurvy on a Ketogenic Diet

My experience is not unique. Here’s one case we mention in the book: the story of a young girl with epilepsy.

KM was a 9-year old girl … diagnosed with epilepsy at six months old. She started a ketogenic diet in October 2003, as her multiple antiepileptic drugs were proving to be less than effective; indeed she was having as many as 12 tonic seizures per day with prolonged periods of non-convulsive status epilepticus. After the diet was prescribed the seizure frequency reduced markedly and there were a number of long periods of time in which she had no seizures.

KM’s mother gave a history of her daughter having had bleeding gums since the beginning of September 2006; she described them as being very dark red, swollen and bleeding. In addition, she explained that her daughter had dry, crusted blood peri-orally. The family’s general dental practitioner had explained that this was probably caused by erupting teeth and instructed her to use 0.2% chlorhexidine gluconate gel and to continue her regular oral hygiene regimen; however this had no effect. About a month later the patient’s right arm became swollen. It was thought that she had sustained a fracture or a dislocation; however she was discharged from the local hospital’s fracture clinic because there was clinical improvement and radiographs showed no callus formation.

In early November KM inhaled a primary molar tooth while she was having her teeth cleaned (Fig. 1). This required an emergency bronchoscopy to retrieve it; at the same time the surgeons extracted her remaining primary teeth in order to avoid a recurrence of the problem….

At that time an appointment was made to attend a paediatric dentistry consultant clinic at the Leeds Dental Institute; however this was never kept as about three weeks after the extractions the patient was admitted to hospital with low grade fever, persistently bleeding gums, oedema of her hands and feet and a petechial rash on her legs. [1]

This girl was eating a typical amount of vitamin C: her dietary intake was calculated at 73 mg/day, well above the US RDA for 9-13 year olds of 45 mg/day. Yet her blood level was only 0.7 µmol/l. Scurvy is diagnosed at levels below 11 µmol/l.

The symptoms of scurvy are sufficiently insidious that it is easy to miss the diagnosis. In KM’s case, it happened that a “senior house officer” – a junior doctor in training – from India recognized the symptoms of scurvy. Otherwise, it might have never have occurred to the doctors to test her vitamin C level. [2]

What Is the Cause of Low-Carb Scurvy?

So what causes scurvy to develop on low-carb diets even with vitamin C intake well above the US RDA?

It seems to be a confluence of two factors:

  • An infection or some other stress (e.g. injury, cancer) leads to the oxidation of extracellular vitamin C; and
  • On a low-insulin or glutathione-deficiency-inducing diet, oxidized vitamin C is not recycled.

Infection and Vitamin C

The immune response to infections generates reactive oxygen species, which oxidize vitamin C. Oxidation removes a hydrogen atom from vitamin C, turning it into “dehydroascorbic acid,” or DHAA. If DHAA remains in the blood, it degrades with a half-life of 6 minutes. [3]

Infections can cause vitamin C deficiency on any diet. During the “acute phase response” to infection or injury, vitamin C often becomes deficient. Here is a nice paper in which French doctors surveyed their hospital patients for scurvy:

We determined serum ascorbic acid level (SAAL) and searched for clinical and biological signs of scurvy in 184 patients hospitalized during a 2-month period.

RESULTS: The prevalence of hypovitaminosis C (depletion: SAAL<5 mg/l or deficiency: SAAL<2 mg/l) was 47.3%. Some 16.9% of the patients had vitamin C deficiency. There was a strong association between hypovitaminosis C and the presence of an acute phase response (p=0.002). [4]

So half were at least depleted in vitamin C and 17% had outright deficiency, which if it persisted would produce scurvy.

We’ve previously written of how important it is to supplement with vitamin C during infections:

I might add here that in sepsis, an extremely dangerous inflammatory state brought on by bacterial infections, intravenous vitamin C reverses some of the worst symptoms. [5] If you have a loved one suffering from a dangerous infection, it might not be a bad idea to get them some vitamin C.

Insulin Dependence of Vitamin C Recycling

DHAA can be recycled back into vitamin C, but only inside cells.

In order to enter cells, DHAA needs to be transported by glucose transporters. GLUT1, GLUT3, and GLUT4 are the three human DHAA transporters; GLUT1 does most of the work. [6]

DHAA transport is crucial for brain vitamin C status. There is no direct transport of vitamin C into the brain, yet the brain is one of the most vitamin C-dependent tissues in the body. The brain relies entirely on GLUT1-mediated transport of DHAA from the blood for its vitamin C supply. Within the brain, DHAA is restored to vitamin C by glutathione.

Supplying DHAA to stroke victims (of the mouse persuasion) as late as 3 hours after the stroke can reduce the stroke-damaged volume by up to 95%:

DHA (250 mg/kg or 500 mg/kg) administered at 3 h postischemia reduced infarct volume by 6- to 9-fold, to only 5% with the highest DHA dose (P < 0.05). [7]

This is a fascinating reminder of the importance of vitamin C for wound repair and protection from injury.

Glucose transporters are activated by insulin. Thus, DHAA import into cells is increased by insulin, leading to more effective recycling of vitamin C [8]:

Insulin and IGF-1 promote recycling of DHAA into ascorbate. Source.

Confirming the role of insulin in promoting vitamin C recycling, Type I diabetics (who lack insulin) have lower blood levels of vitamin C, higher blood levels of DHAA, increased urinary loss of vitamin C metabolites, and greater need for dietary vitamin C. [9, 10]

Now we have a mechanism by which zero-carb diets reduce vitamin C recycling: by lowering insulin levels they inhibit the transport of DHAA into cells, preventing its recycling into vitamin C. Instead, DHAA is degraded and excreted. As a result, vitamin C is lost from the body.

Glutathione and Vitamin C Recycling

Once inside the cell, DHAA is recycled back to ascorbate, mainly by glutathione inside mitochondria:

Dehydroascorbate, the fully oxidized form of vitamin C, is reduced spontaneously by glutathione, as well as enzymatically in reactions using glutathione or NADPH. [11]

A GLUT1 transporter on the mitochondrial membrane is needed to bring DHAA into mitochondria, possibly squaring the effect of insulin on vitamin C recycling.

Since glutathione recycles vitamin C, glutathione deficiency is another possible cause of vitamin C deficiency.

Glutathione is recycled by the enzyme glutathione peroxidase, a selenium-containing enzyme whose abundance is sensitive to selenium status. One difficulty with zero-carb diets is that they seem to deplete selenium levels.

Selenium deficiency is a common side effect of ketogenic diets. Some epileptic children on ketogenic diets have died from selenium deficiency! [12]

So here we have a second mechanism contributing to the development of scurvy on a zero-carb diet. The diet produces a selenium deficiency, which produces a glutathione deficiency, which prevents DHAA from being recycled into vitamin C, which leads to DHAA degradation and permanent loss of vitamin C.

Conclusion

Zero-carb dieters are at high risk for vitamin C deficiency, glutathione deficiency, and selenium deficiency. Anyone on a zero-carb diet should remedy these by supplementation.

These deficiencies are exacerbated by chronically low insulin levels. Insulin helps recycle vitamin C, which supports glutathione status. Lack of insulin increases vitamin C degradation and loss.

The failure of the body to efficiently recycle vitamin C and maintain antioxidant stores on a zero-carb diet is evidence of an evolutionary maladaption to the zero-carb diet.

There was no reason why our ancestors should have become adapted to a zero-carb diet; after, all they’ve been eating starches for at least 2 million years. It seems a risky step to try to live this way.

Related Posts

Other posts in this series:

  1. Dangers of Zero-Carb Diets, I: Can There Be a Carbohydrate Deficiency? Nov 10, 2010.
  2. Dangers of Zero-Carb Diets, II: Mucus Deficiency and Gastrointestinal Cancers A Nov 15, 2010.
  3. Dangers of Zero-Carb Diets, IV: Kidney Stones Nov 23, 2010.

References

[1] Willmott NS, Bryan RA. Case report: Scurvy in an epileptic child on a ketogenic diet with oral complications.  Eur Arch Paediatr Dent. 2008 Sep;9(3):148-52. http://pmid.us/18793598.

[2] Willmott NS, personal communication.

[3] “Dehydroascorbate,” Wikipedia, http://en.wikipedia.org/wiki/Dehydroascorbate.

[4] Fain O et al. Hypovitaminosis C in hospitalized patients. Eur J Intern Med. 2003 Nov;14(7):419-425. http://pmid.us/14614974.

[5] Tyml K et al. Delayed ascorbate bolus protects against maldistribution of microvascular blood flow in septic rat skeletal muscle. Crit Care Med. 2005 Aug;33(8):1823-8. http://pmid.us/16096461.

[6] Rivas CI et al. Vitamin C transporters. J Physiol Biochem. 2008 Dec;64(4):357-75. http://pmid.us/19391462.

[7] Huang J et al. Dehydroascorbic acid, a blood-brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke. Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11720-4. http://pmid.us/11573006.

[8] Qutob S et al. Insulin stimulates vitamin C recycling and ascorbate accumulation in osteoblastic cells. Endocrinology. 1998 Jan;139(1):51-6. http://pmid.us/9421397.

[9] Will JC, Byers T. Does diabetes mellitus increase the requirement for vitamin C? Nutr Rev. 1996 Jul;54(7):193-202. http://pmid.us/8918139.

[10] Seghieri G et al. Renal excretion of ascorbic acid in insulin dependent diabetes mellitus. Int J Vitam Nutr Res. 1994;64(2):119-24. http://pmid.us/7960490.

[11] Linster CL, Van Schaftingen E. Vitamin C. Biosynthesis, recycling and degradation in mammals. FEBS J. 2007 Jan;274(1):1-22. http://pmid.us/17222174.

[12] Bank IM et al. Sudden cardiac death in association with the ketogenic diet. Pediatr Neurol. 2008 Dec;39(6):429-31. http://pmid.us/19027591. (Hat tip Dr. Deans.)

Dangers of Zero-Carb Diets, II: Mucus Deficiency and Gastrointestinal Cancers

Posted by on November 15, 2010 308 comments

Jan Kwasniewski developed his Optimal Diet something like 40 years ago and it has become extremely popular in Poland.

Kwasniewski recommended that adults should eat in the ratio

60 g protein – 180 g fat – 30 g carbohydrate
(Source).

In terms of calories this is roughly 240 calories protein / 1640 calories fat / 120 calories carbohydrate on a 2000 calorie diet.

The Perfect Health Diet proportions are more like 300 calories protein / 1300 calories fat / 400 calories carbohydrate.  So the diets would be similar if about 300 calories, or 15% of energy, were moved from fat to carbohydrate in the form of glucose/starch (not fructose/sugar!).

Note that we recommend obtaining at least 600 calories per day from protein and carbs combined. This ensures adequate protein for manufacture of glucose and ketones in the liver. But the Optimal Diet prescribes only 360 calories total (less in women), suggesting that gluconeogenesis cannot, over any long-term period, fully make up for the dietary glucose deficiency.

In the book, we note that a healthy body typically utilizes and needs about 600 glucose calories per day. On the Bellevue All-Meat Trial in 1928 Vilhjalmur Stefansson ate 550 protein calories per day, which is probably a good estimate for the minimum intake needed to prevent lean tissue loss on a zero-carb diet.

With only 360 carb plus protein calories per day, the Optimal Diet forces ketosis if lean tissue is to be preserved. Since at most 200 to 300 calories per day of the glucose requirement can be displaced by ketones, the Optimal Diet is living right on the margin of glucose deficiency.

Gastrointestinal Cancers in Optimal Dieters

I learned over on Peter’s blog that Optimal Dieters have been dying of gastrointestinal cancers at a disturbing rate. Recently Adam Jany, president of the OSBO (the Polish Optimal Dieters’ association), died of stomach cancer at 64 after 17 years on the Optimal Diet. Earlier Karol Braniek, another leader of the OSBO, died at 68 from duodenal cancer.

A Polish former Optimal Dieter who has now switched to something closer to the Perfect Health Diet noted that gastrointestinal cancers seem to be common among Optimal Dieters:

The impression we get is that there’s rather high occurrence of gut cancer, including stomach, duodenum, colon … [source]

I want to talk about why I think that is, since the danger that the Optimal Dieters are discovering was one of the key factors leading us to formulate and publish the Perfect Health Diet.

Zero-Carb Diets Can Induce Mucus Deficiency

I ate a high-vegetable but extremely low-carb diet from December 2005 to January 2008. At the time I thought I was getting about 300 carb calories a day, but I now consider this to have been a zero-carb diet, since I don’t believe carb calories are available from most vegetables. Vegetable carbs are mostly consumed by gut bacteria, whose assistance we need to break down vegetable matter, or by intestinal cells which consume glucose during digestion.

Throughout my 2 years on this zero-carb diet, I had dry eyes and dry mouth. My eyes were bloodshot and irritated, and I had to give up wearing contact lenses. Through repeated experiments, I established that two factors contributed to the dry eyes – vitamin C deficiency and glucose deficiency. After I solved the vitamin C issue, I did perhaps 50 experiments over the following few years, increasing carbs which made the dry eyes go away and reducing them which made them immediately come back. This established unequivocally that it was a glucose deficiency alone that caused the dry eyes.

Rebecca reports similar symptoms in herself and her low carb friends.

This is also a well-known symptom during starvation. As a review cited by LynMarie Daye (and referenced by CarbSane in the comments) notes,

Since hepatic glycogen stores are depleted within 24 h of fasting, blood glucose concentrations are maintained thereafter entirely through gluconeogenesis. Gluconeogenesis is mainly dependent on protein breakdown (a small amount comes from the glycerol released during lipolysis) and it thus results in protein wasting. It is the effects of protein malnutrition that lead to the eventual lack of ability to cough properly and keep the airways clear, in turn leading to pneumonia and death during prolonged starvation; hypoglycaemia does not occur. [1]

Another common symptom of very low carb diets is constipation. This is often attributed to lack of fiber, but I am skeptical. I will get to the various possible causes of constipation in a future post, but for now I’ll just point out that a deficiency of gastrointestinal mucus would create a dry colon and cause constipation.

What connects a zero-carb diet to dry eyes, dry mouth, dry airways, and dry gastrointestinal tract?

Tears, saliva, and mucus of the sinuses, airways, and gastrointestinal tract are all comprised substantially of glycoproteins called mucins. Mucins are primarily composed of sugar; they typically have a number of large sugar chains bound to a protein backbone.

For instance, the main mucin of the gastrointestinal tract, MUC2, is composed of a dimerized protein – each protein weighing 600,000 Daltons individually, so 1.2 million Daltons for the pair – plus about 4 million Daltons of sugar, for a total mass of 5 million Daltons. In the mucus, these large molecules become cross-linked to form “enormous net-like covalent polymers.” (source)

If, for whatever reason, mucin production were halted for lack of glucose, we would have no tears, no saliva and no gastrointestinal or airway mucus.

Mucin Deficiency Causes Cancer

There is a strong association between mucus deficiency and gastrointestinal cancers.

H. pylori is the strongest known risk factor for stomach cancer. [2] H. pylori infection is found in about 80% of gastric cancers. [3] One reason H. pylori promotes stomach cancer so strongly may be that it diminishes mucus in the stomach, as this photo shows:

Top: Normal stomach mucosa. Bottom: Stomach mucosa in an H. pylori infected person.

Scientists have created mice who lack genes for the main digestive tract mucins. These give us direct evidence for the effects on cancer of mucin deficiency.

Experiments in Muc1 knockout mice and mice with Muc1 knockdown have shown that under Helicobacter infection, mice deficient in Muc1 develop far more cancer-promoting inflammation than normal mice. [4]

The main mucin of the intestine is Muc2. The group of Leonard Augenlicht of the Albert Einstein Cancer Center in New York has studied mice lacking Muc2. They develop colorectal cancer. [5]

Tracing backward one step toward the source of mucin deficiency, the sugars in mucin are built from smaller pieces called O-glycans. It has been shown that mice that are deficient in O-glycans are prone to colorectal cancer: “C3GnT-deficient mice displayed a discrete, colon-specific reduction in Muc2 protein and increased permeability of the intestinal barrier. Moreover, these mice were highly susceptible to experimental triggers of colitis and colorectal adenocarcinoma.” [6]

Nutrient Deficiencies Can Also Play a Role

Some micronutrients are required for mucin production – notably vitamin D. [7, 8] Poland is fairly far north, and many of the Optimal Dieters could have been low in vitamin D.

Other important micronutrients for cancer prevention are iodine and selenium. Poland in particular had the lowest iodine intake and among the highest stomach cancer death rates in Europe. After Poland in 1996 began a program of mandatory iodine prophylaxis, stomach cancer rates fell:

In Krakow the standardized incidence ratio of stomach cancer for men decreased from 19.1 per 100,000 to 15.7 per 100,000, and for women from 8.3 per 100,000 to 5.9 per 100,000 in the years 1992-2004. A significant decline of average rate of decrease was observed in men and women (2.3% and 4.0% per year respectively). [9]

So among the Polish Optimal Dieters, the elevated gastrointestinal cancer risk caused by mucin deficiency may have been aggravated by iodine and sunlight deficiencies.

Conclusion

A healthy diet should be robust to faults. The Optimal Diet is not robust to glucose deficiency.

There’s good reason to suspect that at least some of the Optimal Dieters developed mucin deficiencies as a result of the body’s effort to conserve glucose and protein. This would have substantially elevated risk of gastrointestinal cancers. Thus, it’s not a great surprise that many Optimal Dieters have been coming down with GI cancers after 15-20 years on the diet.

We recommend a carb plus protein intake of at least 600 calories per day to avoid possible glucose deficiency. It’s plausible that a zero-carb diet that included at least 600 calories per day protein for gluconeogenesis would not elevate gastrointestinal cancer risks as much as the Optimal Diet. But why be the guinea pig who tests this idea?  Your body needs some glucose, and it’s surely less stressful on the body to supply some glucose, rather than forcing the body to manufacture glucose from protein.

Fasting and low-carb ketogenic diets are therapeutic for various conditions. But anyone on a fast or ketogenic diet should carefully monitor eyes and mouth for signs of decreased saliva or tear production. If there is a sign of dry eyes or dry mouth, the fast should be interrupted to eat some glucose/starch. Rice is a good source. The concern is not only cancer in 15 years; a healthy mucosal barrier is also essential to protect the gut and airways against pathogens.

Related Posts

Other posts in this series:

  1. Dangers of Zero-Carb Diets, I: Can There Be a Carbohydrate Deficiency? Nov 10, 2010.
  2. Danger of Zero-Carb Diets III: Scurvy Nov 20, 2010.
  3. Dangers of Zero-Carb Diets, IV: Kidney Stones Nov 23, 2010.

References

[1] Sonksen P, Sonksen J. Insulin: understanding its action in health and disease. Br J Anaesth. 2000 Jul;85(1):69-79. http://pmid.us/10927996.

[2] Peek RM Jr, Crabtree JE. Helicobacter infection and gastric neoplasia. J Pathol. 2006 Jan;208(2):233-48. http://pmid.us/16362989.

[3] Bornschein J et al. H. pylori Infection Is a Key Risk Factor for Proximal Gastric Cancer. Dig Dis Sci. 2010 Jul 29. [Epub ahead of print] http://pmid.us/20668939.

[4] Guang W et al. Muc1 cell surface mucin attenuates epithelial inflammation in response to a common mucosal pathogen. J Biol Chem. 2010 Jul 2;285(27):20547-57.  http://pmid.us/20430889.

[5] Velcich A et al. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science. 2002 Mar 1;295(5560):1726-9. http://pmid.us/11872843.

 [6] An G et al. Increased susceptibility to colitis and colorectal tumors in mice lacking core 3-derived O-glycans. J Exp Med. 2007 Jun 11;204(6):1417-29.  http://pmid.us/17517967.

 [7] Paz HB et al. The role of calcium in mucin packaging within goblet cells. Exp Eye Res. 2003 Jul;77(1):69-75. http://pmid.us/12823989.

[8] Schmidt DR, Mangelsdorf DJ. Nuclear receptors of the enteric tract: guarding the frontier.  Nutr Rev. 2008 Oct;66(10 Suppl 2):S88-97. http://pmid.us/18844851.

[9] Go?kowski F et al. Iodine prophylaxis–the protective factor against stomach cancer in iodine deficient areas. Eur J Nutr. 2007 Aug;46(5):251-6. http://pmid.us/17497074.

Choline Deficiency and Plant Oil Induced Diabetes

Posted by on November 12, 2010 70 comments

I’m going to deviate from my original plan for the “Dangers of a Zero-Carb Diet” series to discuss a topic that came up in the comments to the first post.

Leonie’s Diabetes and the Rose Corn Oil Trial

What prompted this diversion is Leonie’s interesting comment from Wednesday’s post:

I developed diabetes several years after being on a low carb diet. Continuing low carb to manage the diabetes did not halt its progress. It has taken about 18 months of adding more carbs (60 – 100 gr/day) to my diet to bring my fasting glucose down by a couple of mmol and eating more carbs has also lowered my Hba1c and post meal spikes significantly. I wonder if the liver is another organ that may be affected by carbohydrate deficiency.

I had not heard of such cases before, or so I thought, but Dr. Deans in the comments reminded us that Peter at Hyperlipid had noticed two similar cases in the Rose Corn Oil trial. [1] (The Rose Corn Oil trial, of course, figures prominently in our book’s discussion of PUFA toxicity.)

In the Rose Corn Oil trial, there were three arms – a normal diet arm, a high corn oil arm, and a high olive oil arm. The normal dieters were expected to eat “fried foods, fatty meat, sausages, … ice cream, cheese, … milk, eggs, and butter” while the oil arms were supposed to restrict these foods and replace them with corn or olive oil.

Here’s what happened:

Four patients were removed from the trial for other reasons. Two developed non-cardiac thromboembolism and were given anticoagulant therapy. The other two were removed because of diabetes mellitus. One of them already had mild diabetes, but glycosuria increased considerably soon after he started oil. Oil was stopped and glycosuria disappeared. Oil was restarted, but was stopped a month later because heavy glycosuria recurred. The other patient, not a previously recognized diabetic, developed glycosuria with a diabetic glucose-tolerance test a few weeks after starting oil. [1]

The patients who developed diabetes came one from the corn oil arm and one from the olive oil arm. Likewise, the patients who developed thromboembolisms came one from the corn oil arm and one from the olive oil arm. No such disasters occurred on the “fatty meat” arm.

Since all three diets were similarly fatty, it doesn’t appear to be the quantity of fat that was the issue. Rather it was the type of lipid, or some micronutrient that was present in the animal and dairy foods but lacking in the plant oils.

For insight into what the problem might be, let’s look at how scientists poison lab animals.

Insights from Diet Animal Poisoning Research

You have to pity diet researchers. It takes 60 years for bad diets to poison humans enough to significantly raise mortality rates. Yet a diet researcher is supposed to gain a Ph.D. in 4 years (or in 5 while simultaneously obtaining an MD!), do a postdoc in 2 years, win a grant in the first years of an entry-level position with PI status, and then demonstrate productive results within the term of a 2-to-5 year grant. Deadlines are pressing: A study needs to start rats or mice on two diets, and have one diet produce much better health than the other, in considerably less than a two-year time frame.

Just comparing McDonald’s fast food with a Mediterranean diet won’t do. Two years later both sets of mice will die happily of old age, with no significant differences between groups. Peer reviewers judge you to have discovered no new results. No new results means no paper, no grant, no job.

So “diet” researchers first have to become experts at quickly inducing disease in rats and mice. Find a diet that poisons animals in a few months, compare it to another diet that doesn’t, and you have a paper. Look for variations that slow or hasten the poisoning, and you have more papers. To be a highly productive scientist, one must be a skilled animal poisoner.

Various techniques have been developed for this purpose, including: knocking out some crucial gene; breeding a mutant strain that naturally develops disease; giving the animals poison with their food; or depriving them of crucial nutrients. Almost every study of diet in mice or rats uses one of these techniques.

If a missing nutrient can cause diabetes within a few years for Leonie and 12 to 18 months for the Rose Corn Oil trial volunteers, it’s likely to be pretty good at inducing disease in animals too. There’s a good chance diet animal poisoning researchers have already stumbled upon it in rats or mice.

Choline Deficiency Diseases

One of the most popular deficiency diets among researchers is the choline-deficient diet. A useful paper by Dutch scientists [2] gives a nice look at the impact of choline deficiency on rats.

Choline deficiency (CD) by itself induces metabolic syndrome (indicated by insulin resistance and elevated serum triglycerides and cholesterol) and obesity.

A combined methionine and choline deficiency (MCD) actually causes weight loss and reduces serum triglycerides and cholesterol, but induces more severe liver damage. The MCD diet prevents the body from manufacturing choline from methionine, vitamin B12, and folate, so MCD diets severely reduce choline levels; and without choline VLDL particles are not produced. Without VLDL particles, fats and cholesterol are trapped in the liver and never reach the blood and adipose cells.

Here is a measure of insulin resistance on the two diets:

The induction of insulin resistance by the CD diet is very rapid, requiring less than a week.

Induction of insulin resistance is thought to be mediated by elevated TNF-alpha production by adipose cells and by hypertriglyceridemia. Since the MCD diet neither raised serum triglycerides nor caused obesity which induces TNF-alpha production in adipose cells, it did not cause insulin resistance.

What Does This Have to Do With Diabetes?

Insulin resistance is a key step in the development of diabetes:

  • Insulin resistance in the liver causes the liver to release more glucose into the blood (since insulin inhibits glucose release by the liver). This is discussed in a nice paper [3] found by LynMarie Daye and cited in the comments by CarbSane.
  • Peripheral insulin resistance means that the rest of the body is less sensitive to insulin. The pancreas has to produce more insulin to dispose of the excess glucose that the liver is releasing.

This elevation of insulin and glucose levels is a crucial step toward diabetes; it is “pre-diabetes.”

Persistently elevated glucose levels can then poison the beta cells of the pancreas, diminishing insulin secretion capability and causing diabetes. [4]

The Rose Corn Oil trial was not a low-carb diet, so postprandial glucose levels could easily have risen to toxic levels.

If a CD diet can cause insulin resistance in a week, it’s plausible that it might cause diabetes in 12 to 18 months, which is when the Rose Corn Oil trial patients developed it.

What About the Thromboembolism Cases?

MCD diets induce fibrinogenesis. In the blood, excess fibrin formation leads to clotting, and clots can block vessels to cause thromboembolisms. It may be that the thromboembolism cases in the Rose Corn Oil trial had methionine, folate, or B12 deficiencies to go with their choline deficiency.

Why Do Plant Oils Induce Diabetes But Not Animal Fats?

So why did diabetes develop in the corn and olive oil arms of the Rose Corn Oil trial but not the “fatty meat and dairy” arm?

Well, look at the choline content of these foods:

Choline content of one cup (~200 g) oil or fat or 227 g (1/2 lb) meat

Beef liver 968.0 mg
Cube steak (beef) 290.0 mg
Beef tallow 164.0 mg
Butter 42.7 mg
Olive oil 0.6 mg
Corn oil 0.4 mg

Source: http://nutritiondata.com.

Take away meat and dairy and replace them with plant oils, and it’s very easy to have a choline deficiency.

What Does This Have to Do With Zero-Carb Diets?

Maybe nothing … without carb consumption, postprandial glucose levels are not as high, and beta cell poisoning is less likely … but it may be that a zero-carb diet aggravates a choline deficiency in some fashion. I will leave this as a topic for further research.

UPDATE: Leonie in a new comment gives us more information: she has PCOS, goiter with nodules, and auto-antibodies. This suggests autoimmunity as a more likely explanation for her zero-carb diabetes.

Conclusion

In the book, we recommend the use of animal fats such as beef tallow for cooking, and recommend that pregnant women and vegetarians supplement with choline. We thought seriously about recommending that everyone supplement choline, but were reluctant to recommend too many supplements.

In retrospect, we should have recommended choline supplements for everyone who is overweight, has elevated blood glucose or lipids, or has elevated liver enzymes.

We have been using beef tallow as our cooking oil for several months now. It might be good practice for everyone to favor animal fats like beef tallow over plant oils for cooking.

References

[1] Rose GA et al. Corn oil in the treatment of ischaemic heart disease.  Br Med J. 1965 Jun 12;1(5449):1531-3. http://pmid.us/14288105.

[2] Veteläinen R et al. Essential pathogenic and metabolic differences in steatosis induced by choline or methione-choline deficient diets in a rat model. J Gastroenterol Hepatol. 2007 Sep;22(9):1526-33. http://pmid.us/17716355.

[3] Sonksen P, Sonksen J. Insulin: understanding its action in health and disease. Br J Anaesth. 2000 Jul;85(1):69-79. http://pmid.us/10927996.

[4] Leibowitz G et al. Glucose regulation of ?-cell stress in type 2 diabetes. Diabetes Obes Metab. 2010 Oct;12 Suppl 2:66-75. http://pmid.us/21029302.

Dangers of Zero-Carb Diets, I: Can There Be a Carbohydrate Deficiency?

Posted by on November 10, 2010 161 comments

It’s frequently said in the Paleo blogosphere that carbs are unnecessary. Here’s an example from Don Matesz, an outstanding blogger who eats a diet extremely close to ours:

Protein is essential, carbs are not…. You can only cut protein so much, but you can cut carbs dramatically.

Dr. Michael Eades has mocked the idea of a carbohydrate deficiency disease:

Are there carbohydrate deficiency diseases, Mr. Harper, that you know about that the rest of the nutritional world doesn’t?  I’ll clue you in: there aren’t.  But there are both fat and protein deficiency diseases written about in every internal medicine textbook.

Such statements made an impression on me when I first started eating Paleo five years ago. But several years and health problems later, I realized that this view was mistaken.

Why Aren’t Carbohydrate Deficiency Diseases Known?

How do doctors discover the existence of a nutrient deficiency disease?

It’s not as easy as you might think. For example, the existence of essential fatty acid deficiency diseases in humans was in doubt right up into the 1950s, even though omega-6 deficiency disease had been discovered and characterized in rats in the 1920s. [1] The reason is that omega-6 and omega-3 deficiencies can occur only on unnatural diets. It was infants fed fat-free formula in the 1940s and 1950s who ended up proving the existence of omega-6 deficiency disease in humans.

Two difficulties have made it challenging for science to recognize a carbohydrate deficiency syndrome:

  1. Lack of an animal model.
  2. The rarity of zero-carb diets among humans.

Until recently, few people save the Inuit ate very low-carb diets, and the Inuit didn’t leave good medical records. As a result, few or no humans developed recorded carbohydrate deficiency syndromes.

This wouldn’t be a problem if it were possible to induce carbohydrate deficiency in animals. However, it isn’t.

Animals don’t get carbohydrate deficiency diseases because they have small brains, meaning low glucose needs, and big livers, meaning high glucose manufacturing capacity. Animals can generate all the glucose they need from protein or from volatile acids like propionate produced by bacterial fermentation in their digestive tracts.

But, as we note in the book, humans are more fragile. We have small livers and big brains, and so the possibility of glucose deficiency is real.

Here is a comparison of brain, liver, and gut sizes in humans and other primates [2]:

Organ % body weight, humans % body weight, other primates
Brain 2.0 0.7
Liver 2.2 2.5
Gut 1.7 2.9

The brain is the biggest determinant of glucose needs.  While other primates need only about 7% of energy as glucose or ketones, humans need about 20%.

Compared to other primates, humans have a 12% smaller liver. This means we can’t manufacture as much glucose from protein as animals can. Humans also have a 40% smaller gut. This means we can’t manufacture many short-chain fatty acids, which supply ketones or glucogenic substrates, from plant fiber.

So, while animals can meet their tiny glucose needs (5% of calories) in their big livers, humans may not be able to meet our big glucose needs (20-30% of calories) from our small livers.

So any carbohydrate deficiency disease will strike humans only, not animals.

How Should We Look for a Carbohydrate Deficiency Disease?

To find a carbohydrate deficiency syndrome in humans, we should look at populations that eat very low-carb diets, such as:

  • The Inuit on their traditional hunting diet.
  • Epilepsy patients being treated with a ketogenic diet.
  • Optimal Dieters in Poland, who have been following a very low-carb diet for more than 20 years.
  • Very low-carb dieters in other countries, who took up low-carb dieting in the last 10 years as the Paleo movement gathered steam.

We should also have an idea what kind of symptoms we should be looking for. Major glucose-consuming parts of the body are:

  • Brain and nerves.
  • Immune system.
  • Gut.

The body goes to great lengths to assure that the brain and nerves receive sufficient energy, so shortfalls in glucose are most likely to show up in immune and gut function.

So, we’ve mapped our project. Over the coming week, or however long it takes before we get tired, we’ll investigate the evidence for carbohydrate deficiency conditions in humans.

Related Posts

Other posts in this series:

  1. Dangers of Zero-Carb Diets, II: Mucus Deficiency and Gastrointestinal Cancers A Nov 15, 2010.
  2. Danger of Zero-Carb Diets III: Scurvy Nov 20, 2010.
  3. Dangers of Zero-Carb Diets, IV: Kidney Stones Nov 23, 2010.

References

[1] Holman RT. The slow discovery of the importance of omega 3 essential fatty acids in human health. J Nutr. 1998 Feb;128(2 Suppl):427S-433S. http://pmid.us/9478042

[2] Aiello LC, Wheeler P. The expensive tissue hypothesis: the brain and the digestive system in human and primate evolution. Current Anthropology 1995(Apr); 36(2):199-211.