Ring in the New Year

Whew.  A bit of a hiatus there.  I hadn't quite realized how much I had overextended myself until decamping to Texas for some serious sitting around.  There I had all sorts of unrealized ambitious plans to read and get caught up, visit some local Crossfits, answer some emails, etc.  I did very little at all besides the holiday stuff, a handful of morning runs, and reading some fiction.  Since the whole family was recovering from a steady onslaught of viral preschool nastiness that began before Thanksgiving, I sorely needed the rest.  A very mild but persistent case of walking pneumonia had settled in, so it was nice to take it easy and finally get well.

In the midst of the sitting around, I was able to visit two Austin "real food" restaurants, Hudson's on the Bend (where I had rattlesnake cakes - not gluten-free but very tasty, and Hudson's has several gluten-free options) and Foreign and Domestic (steak and pigs brains.  I have to say the brains at Animal were better, but the steak at F&D was fabulous, the yogurt with dill sauce sublime, and the atmosphere quintessential Austin).  I'm told the Noble Pig is also excellent (though it is a sandwich restaurant).

One of Lance Armstrong's yellow jerseys at Hudson's on the Bend

Pig brains and huckleberries

   

Yogurt with dill sauce

Perhaps the most ambitious thing I did all week was to go to the rail yard for the Austin Steam Train Association.  We were able to get a behind the scenes tour, and the kids were thrilled (kids love trains,  as do the adults at the Austin Steam Train Association).   

At this point I have numerous articles and a large stack of books waiting to be read.  I'm hoping that without my class, my schedule will be a bit more forgiving.  You never know what will turn up, however, and the backlog of emails and to-dos--formidable!

Time to Freak Out. Sensibly.

There is a reason I stick to relatively easily modifiable practices and how they might (possibly!) improve health and prevent disease.  I like fun exercise, real food, wool socks in the wintertime, and sunshine.  I don't like to think about the years of farm pesticide waste seeping into the groundwater, or the estrogenic compounds in plastic.  Plastic compounds are ubiquitous and incredibly convenient.  In all our packaged foods.  Sippy cups.  Tupperware.  IV bags and tubing.  Coating paper receipts.  In the lining of canned foods and soda.  The most famous is BPA (found primarily in receipts and number 7 plastic), but all sorts of plastic contain all sorts of weird compounds.

Image from Flickr Creative Commons

I like to live a relatively processed food and gluten free life - but philosophical ramblings about candy cigarettes aside, I don't dive across the table and grab the birthday cake out of my kid's hand at the party.  (I'm not generally tempted by the birthday cake myself, as it is generally of the grocery-store azol-dye soybean oil frosted variety.  There was an incredible ice cream cake at a recent party that I'll admit to stealing a few bites from).   There's a line between living a somewhat normal life and being completely obsessed and anxiety-ridden about food, and I certainly don't want the kids to be obsessed and anxiety-ridden about food.   Nor would I lie about my kids having celiac or peanut allergies - the last thing I want is a terrified preschool teacher calling me about the goldfish cracker my kid snatched from some other kid's lunch, and should she call an ambulance or what.  Nothing is totally off-limits within reason, though the healthy stuff has to be consumed first, before the leftover Halloween candy.  And yes, they do get gluten-free pretzels as a snack (they are cooked in palm oil).  And sometimes those sugar-bombs otherwise known as raisins.

So we muddle through, minimizing harm, and the way I approach plastics is to slowly transition away from them and avoid heating anything (or putting hot food) in them.  (I try not to think about those years and years of microwaved lean cuisines).  I get milk delivered from a local organic dairy in glass bottles.  Is that enough?  Some (many of you, perhaps) would say no.  But aluminum lunch containers are expensive (and have plastic lids that tend not to fit as closely as plastic on plastic), and many of the plastic ones I have are still serviceable and attractive.  Canned foods are also tricky - on a mostly "paleo" "real foods" "avoiding processed food" diet the major canned foods will be coconut milk and tomato products (maybe canned pumpkin?).  In general I made an effort to avoid these except for maybe once per week, figuring, again, the dose makes the poison, and tomato sauce makes anything more palatable for the kids (a variation of the old parenting trick of putting ketchup on everything.)

Ignorance is bliss, really.  At the end of November a research letter was published in JAMA- "Canned Soup Consumption and Urinary Bisphenol A: A Randomized Crossover Trial." In this little Harvard School of Public Health Study, student and staff volunteers consumed 12 ounces of either fresh (prepared without canned ingredients) or canned (Progresso brand) soup daily for lunch (they were vegetarian varieties of course - this is HSPH!).  For the first 5 day period, the soup was consumed daily.  After a 2-day washout, the treatment assignments were reversed.  Urine samples were taken on the 4th and 5th days of each phase.  Urinary BPA was found in 100% of Progresso consumers and 77% of fresh soup consumers, and following the 5 days of canned soup, urinary BPA was 1221% higher than the urinary BPA of the fresh soup consumers.

"The increase in urinary BPA concentrations following canned soup consumption is likely a transient peak of uncertain duration.  The effect of such intermittent elevations in urinary BPA concentration is unknown.  The absolute urinary BPA concentrations observed following canned soup consumption are among the most extreme reported in a nonoccupational setting."

I have to admit I'd canned (heh heh) Progresso and other pre-prepared soups from my eating list a long time ago due to the biochemistry-happy omega-6 fest in the list of ingredients… as expected from any processed food maker trying to scratch a profit by using the least expensive commodity items.  I try to use marinara sauce from a glass jar whenever possible (we'll ignore the plastic seal around the top), and I'm looking for good convenient alternatives to canned coconut milk… but the pantry still has some canned items, to be sure.  And certainly the cardboard box variety of foods has plastic in the lining as well, right?  I make more and more of my own bone broth, but sometimes you just need a bit of stock on hand.  Am I being hopelessly neurotic and silly worrying about plastics, BPA, and canned items (and handling receipts as little as possible)?

Well, 2011 has not been a friendly year for BPA.  A month before the research letter in JAMA alarmed the Progresso soup executives, another scary article was published in Pediatrics: Impact of Early-Life Bisphenol A Exposure and Executive Function in Children (free full text!).  A prospective observational study, so the typical caveats apply.

Urine was collected from pregnant women at 16 and 26 weeks, and at birth) and later from the resultant babies at 1, 2, and 3 years of age.  The results?  Well, BPA was detected in >97% of the gestational and child urine samples.  With adjustment for confounders, each 10-fold increase in gestational BPA concentrations was associated with more anxious and depressed behavior on standardized scales, along with poorer emotional control.  This was true more of girl babies than of boys.  The urinary levels in the children themselves didn't make much difference in behavior, and there was no difference between girls and boys.

There was another scary article about exposure of infants to breastfeeding moms replete with BPA that I can't find now, and this cute article from January in JAMA about nematodes and BPA.  I avoid gluten (for the most part) due to some skin effects and general creepiness, and I don't see why I should feel differently about estrogenic compounds leaching from plastics.

But no, I don't leap across the table and grab the Capri Sun out of my kid's hand at the birthday party either.  Nor will I add a machete to my list of standard kitchen tools so that I can make coconut milk from scratch.   I drink from a plastic-free water container at the gym and the next set of lunchbox containers will be metal… but life has to be lived.  And at least I can worry about these things affecting my children, rather than tuberculosis, mines, or revolution.

Evolution and Anorexia Nervosa

There was a bit of a dust-up in the paleo and low carb blogosphere about some comments Gary Taubes apparently made about anorexia and insulin in an interview.  He noted that insulin was used as a therapy for anorexia, thus suggesting that (perhaps) anorexia, like obesity, is a disorder of fat metabolism. My suspicion is that Gary was using those studies as an example of how insulin could cause weight gain.   On the other hand, one doesn't need exogenous insulin to refeed anorexics  - the time-tested method is to keep those far gone enough to have medically dangerous symptoms (unstable blood pressure, dropping electrolytes, or super slow heart rate) under lock and key and get calories in whatever way possible (including via a tube inserted into the stomach.)

One of my attendings in at Children's Hospital characterized anorexia as "a desperate disease."  Often purging and starvation are combined (though this combination would be more correctly called "eating disorder not otherwise specified" or "anorexia nervosa, bingeing-purging subtype" than strict anorexia nervosa), and there were many cases of young teenagers hiding vomit and stool in places in their rooms to conceal purging and to get laxatives (not surprisingly, constipation is a symptom of anorexia).

Cowboy Junkies - Bea's Song (one of the better songs ever written - right click to open in new tab)

My evolutionary psychiatry interest has always been in how psychiatric disorders have changed over the past 100 years of rapidly changing lifestyle and diet.  Anorexia nervosa is one of those illnesses that was exceedingly rare until 50 years ago, then escalated rapidly, then leveled off so far as prevalence, though those who are affected encompass more children and more men now than ever before.  My educated guess is that only a small percentage of us are capable of starving ourselves outright without being under lock and key, and that vulnerable population shows symptoms earlier and earlier in life as societal pressures and the obesogenic environment increases.

A quote from my previous blog post linked above (the medical literature references can be found there):

All eating disorders remain relatively rare [though in total they are more common than schizophrenia and bipolar I disorder]. Anorexia afflicts about 0.5% of women and 0.1% of men. Bulimia around 1-3% of women (also 0.1% of men), and binge eating disorder 3.3% of women and 0.8% of men. Anorexia nervosa remains the most deadly of all psychiatric disorders, with a 5-10% death rate within 10 years of developing the symptoms, and an 18-20% death rate within 20 years. Anorexia is endemic in the fashion industry, to the point where models are now being airbrushed to add curves. Another model, Isabelle Caro, died at age 28 of anorexia, and Ana Reston of Brazil died at age 20, still modeling with a BMI of less than 14.

Photo of Isabelle Caro from Wikipedia

The current state of the art treatment of anorexia begins with refeeding, mostly because we know that semi-starvation itself causes obsessions, depression, and fixation on food.   In the hospital, patients work closely with dietitians, trying to learn how to eat a healthy amount and to establish a better relationship with food.  While medicines that promote weight gain are prescribed, antidepressants and other agents are fairly useless in a starvation situation.

You can imagine the typical well-meaning dietician designed diets for these sick young people.  It's the food pyramid with way too many grains, too little fat, and a focus on "healthy" rather than good old fashioned farm fresh food.  And while I don't really have any objections a food pyramid Mediterranean-style whole foods diet (autoimmune issues with grains notwithstanding), I know that what happens in real life is not skipping breakfast, a light lunch, and a late supper of mussels, olive oil, roasted peppers, tapenade and homemade sourdough bread, but rather three meals and two snacks a day, a version of Weight Watchers™ with Skinny Cow ice cream sandwiches, whole grain Rice o Roni, cans of beans, omega-6 laden commercial salad dressing, boneless skinless chicken breasts,  and "lite" yogurt.

The problem with so many meals a day is that one has to think about food constantly.  I don't think that is the best way to recover from an eating disorder, though one would have to be careful with fasting as well.  I believe intermittent fasting is a valuable practice, a way to lower food reward and to ultimately establish a good relationship with food - I don't have to have it right now, but later would probably be fine too - however, fasting can trigger binges in those who are vulnerable.  It is not verboten in those of normal or excess weight, but should be undertaken with care and support.  In my mind, the healthiest diet is one that you don't have to think about all that much - poached eggs, a beef stew with some liver chunks you cook once and eat all week long.  Cold potatoes and butter.  Forgetting to eat every now and again.

M83  Midnight City (right click to open in new tab)

I believe Jamie sent me this recent paper, Role of the evolutionarily conserved starvation response in anorexia nervosa.  It is a fascinating piece, with an in-depth consideration of biology, evolution, and insulin.

The authors speculate that "AN [anorexia nervosa] may be caused by defects in the evolutionarily conserved response to food and nutrient shortage associated with reduced calorie intake."

Some more facts about eating disorders - in 10-20% of patients, the disorder is short-lived.  In 20-30% it is chronic and unremitting.  The most seriously affected are at greatest risk for hypothyroidism, loss of bone density, electrolyte disturbances, low blood cell counts, amenorrhea, suicide, and death.

In anorexia, the physiology of starvation is paramount.  Both brain and peripheral metabolism responses come into play, orchestrated by the brain and the endocrine system (I don't think obesity is far different - I see no reason that obesity would be regulated by fat tissue or the liver when the brain and endocrine system are doing their thing).

The goal of the starvation response is to conserve energy, delay growth, preserve ATP (by increasing efficiency of energy metabolism) and to minimize oxidative damage.  In starvation, changes in the hypothalamus of the brainstem result in a fall in blood insulin levels and a suppression of other anorexogenic factors.  Once ketosis occurs with the depletion of glycogen stores, there is an increase in output from the sympathetic nervous system and stimulation of food-seeking behaviors.  These multiple pathways explain why fasting can be healthy, but also stressful.

One of the major biochemical pathways activated is the IGF-1/FOXO response (an insulin growth factor 1 pathway).  So the authors of this paper postulate something a bit similar to Gary Taubes - anorexia arises when there is defective regulation in the starvation pathway, similar to how insulin deficiency (due to insulin resistance) is a factor in diabetes.  Meaning there is a lot going on with respect to home life, environment, stress, and temperament in eating disorders, but only a select few have the genetic capability to deliberately starve themselves is response to the environment, and those few may have differences in the IGF-1/FOXO pathway.  The researchers were able to find some yeast, fruit flies, worms, and mice with defects in that pathway who tend to restrict food and develop more slowly (or, alternatively, eat more and spontaneously gain weight), and who have genetic differences in the IGF-1/FOXO pathway.

Evidence for genetic vulnerability to anorexia includes the fact that eating disorders are highly heritable. (Uruguayan model Luisel Ramos and her sister both died from anorexia in recent years).   When doing genome-wide linkage analysis of families with eating disorders, many components of the starvation response pathway are located in highly suspect genetic areas.  In practical terms, the increased impetus on thinness and subsequent dieting brings out the reinforcing starvation response as a result of the genetic vulnerability.  A single episode of excessive caloric restriction seems to bring out long-term changes in the neurotransmitter production mediated by FOXO.

Thus caloric restriction and weight loss predispose to additional episodes of dieting, especially in susceptible individuals wih defective regulation of their starvation response, or with perseverative bias in behavior, reflected in obsessive thoughts and compulsivity.

How do these general ideas affect treatment?  Family therapy, distress tolerance, and cognitive behavioral therapy around distorted body image is a cornerstone of therapy for eating disorders, along with the refeeding.

Should we use insulin to treat anorexia?  Well, the reactive hypoglycemia and other risks are problematic.  A more sophisticated approach is to use IGF-1 itself - it can increase appetite and reverse bone loss seen in anorexia.  Long term treatment tends to result in hyperplasia of the lymphatic tissue, tumor promotion, and excess accumulation of body fat.  

Better that we never begin dieting in the first place.  Skipping the processed foods and ensuring there are plenty of healthy fat and nutrients for the brain and muscles seems like the optimal and common sensical approach in that regard.  I'm not sure what to do about the fashion industry...

Beyond the Chemical Imbalance Part 2

Love the new song from the new album by the Black Keys:  Lonely Boy (from El Camino)   I know this guy's video will get slashed soon enough, but for now… enjoy!  The Black Keys said Lonely Boy is a departure from their typical style, as it is up-tempo.  I wish they would do more like this one!

Are you peppy yet?  You ought to be, because we are going to dive back in to this paper (sent to me by Jamie some weeks ago):  Beyond the serotonin hypothesis: Mitochondria, inflammation, and neurodegeneration in major depression and affective spectrum disorders.

There's all this talk about pathogenesis, chickens, and eggs.  Well, I know where it ends.  We chase the trail back to the beginnings (is it abuse?  temperament? soda?  ho-hos?  winter? rancid vegetable oil?  bad reality TV?  the jury is still out).

But here is where it ends.  Ground zero.  Ratty neurons, smoking mitochondria, and brain damage.  Inflammation.

Inflammation is the term for the complex biological response of tissues to harmful stimuli, such as pathogens, damages cells, or irritants.  Inflammation is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue.

I knew there was a reason I liked this paper so much.  Two sentences of real wisdom.   The paper continues on to talk about cell death, mitochondria, and the cell "executioners" called capases.  They are cysteine proteases that bring it when a cell needs offing.  These are the cellular equivalent of the Necro-whatevers from Chronicles of Riddick.   Overproduction of reactive oxygen species by shoddy, inefficiently-acting mitochondria is a central feature of neuron cell death.   The tricky wicket is that mitochondrial dysfunction and cell death leads to more inflammation, dysfunction, and cell death.

The presence of an inflammatory response in major depression… is evidenced by, amongst other things, increased plasma levels of pro-inflammatory cytokines and acute phase reactants, oxidative damage to red blood cell membranes and serum phospholipids, and lowered serum zinc.

Pro-inflammatory cytokines can induce depression in 70% of people treated with such agents.  Elevations of cytokines have been reported in depression, anxiety, fibromyalgia, migraines, IBS, chronic fatigue syndrome, diabetes, autoimmune arthritis… of course, says any doctor.  The so-called "mitochondrial cocktail" can improve mitochondrial function after a few months and includes the following:  CoQ10, riboflavin, and at least one additional antioxidant (vit C, E, or alpha lipoic acid), and l-carnitine or creatine.

Older school psychopharmacologists will try the following:

Tricyclic antidepressants - they act as classical mitochondrial decouplers by hindering ATP synthesis and enhance ATPase activity.  They tend to change how mitochondria function in a neuroprotective way.

SSRIs: some seem to be toxic to mitochondria at large doses, but protective at lower doses.  In animal models, all antidepressants attenuate inflammation-induced brain cytokine production and prevent the development of depression induced by high dose interferon.  In fact, antidepressants seem to have this effect regardless of mechanism (SSRI, tricyclic, lithium) - which is a major argument against the monoamine theory of depression.

Lithium: seems to enhance mitochondrial function in humans and rats.  Long-term is even better than short-term.  Lithium is the favored medicine of the gray-haired psychopharmacologist.  Between the neuroprotective effects and the anti-suicide benefit, you might expect people to encourage lithium to be in the water…

Shock therapy:  Yes, it is still around.  Frankly, there is no faster treatment for depression and it works in refractory cases, thus is often a lifesaver.  It has terrible side effects, there's no denying it.  And it seems to increase the mitochondrial efficiency in rats.

Up to 50% of patients with major depression are unresponsive to medications… here is a poem from old Egyptian papyrus (from the anchor paper)

Disease has sneaked into me.  I feel my limbs heavy.  I no longer know my own body.  Should the master physician come to me… My heart is not revived by his medicines. 

Depression - Beyond the Chemical Imbalance (Part 1)

Today we go back to the basics of depression.  Borodin's Nocturne (right click to open in new tab).

I would say there are three main theories held by the general public about the causes of depression:

1) Bootstrap theory:  you are a lazy good-for-nothing who just needs to snap out of it and get up and get yourself better.

2) Trauma theory: too much stress, death, trauma, etc.

3) The chemical imbalance:  You have an SSRI deficiency and your serotonin needs to be regulated (see this memorable old zoloft commercial)

Of course, I don't subscribe to any of these theories entirely, though there are elements to each of them that hold a kernel of truth - my belief and one that is largely supported by the literature is that stress and genetic susceptibility leads to depressive symptoms, which are mediated by inflammatory means in the brain.  And certainly if one is capable, getting up and getting out and exercising and eating right can be very helpful, but sometimes asking a depressed person to wake up early and exercise is like asking someone with a broken ankle to go for a run.  The frontal lobe isn't firing on all cylinders.  There's no motivation, no zazz.

The scientifically minded probably are most familiar with theory number three.  In medical terms, the "chemical imbalance" theory is called the "monoamine hypothesis" of depression.  The monoamine theory is (I would say) largely accepted by doctors of a certain age (even psychiatrists), but it holds about as much water as the carbohydrate-insulin theory of obesity.  Back in the day there was a medication for blood pressure called reserpine.  Among other things it depletes the brain of serotonin, and does indeed tend to cause depression (it is rarely used nowadays).

The first antidepressant, a drug used to treat tuberculosis, was found serendipitously.  One of its actions was to change the concentrations of monoamines (such as serotonin and norepinephrine) in the synapse between nerves.   And thus, the monoamine hypothesis of depression was born along with a billion dollar antidepressant industry.  All the antidepressants affect the monoamines one way or another, and they work… if you are lucky, often with side effects, and maybe they protect your brain during one episode of depression, but they don't seem to protect you from the next episode if you go off the medicine when you feel better (talk therapy when compared to medicines seems to have more long term benefit, not surprisingly).

Along the way, the monoamine theory picked up a bunch of other diseases (called the affective spectrum disorders) including major depressive disorder's anxious twin, generalized anxiety disorder, migraines, irritable bowel syndrome, bipolar disorders, social phobia, PTSD, OCD fibromyalgia, and chronic fatigue syndrome among others (1).  All of these diseases have been shown to respond (somewhat) to three or more different classes of antidepressant medication.

Problem is, when you measure serotonin in depressed people, the levels are often all over the map.  In fact, low serotonin doesn't really correlate with depression very well at all, though low serotonin in the central nervous system does correlate with suicide, violence, and insomnia.   Brain researchers quickly figured out that the monoamine hypothesis has some pretty big holes, and the mechanism of antidepressants is not about increasing serotonin and other monoamines in the synapse but rather changing the efficiency with which monoamine signals are transmitted.

Instead, the current literature-supported theory of the brain pathology of depression and the other affective spectrum disorders leads us to two things going awry - the immune system (inflammation) and mitochondrial dysfunction.

How messy is the study of depression?  Consider these facts - if we look at the modern criteria, the classic unipolar major depression is a smallish subset of the whole.  31-62% of people with depression have symptoms of "atypical depression" (leaden feelings in the arms and legs, increased appetite, increased sleep, as opposed to the classic weight loss and insomnia).  64-72% of those with atypical depression meet criteria for bipolar spectrum disorders.  Depressive disorders are often comorbid with ADHD, anxiety, and substance abuse disorders.  You can see if we try to study a group of patients with "major depressive disorder" by criteria that represents the typical clinical outpatient, we will get a mix of people with various complicating neuropsych problems, and any studies of so-called "pure" major depressive disorders where other problems are excluded (which is typical for pharmaceutical studies) will not necessarily be generalizable to the actual population.

Add in frequent comorbid medical conditions, and you have a whole soup of pathology.  92% of depressed inpatients have pain, typically headaches or muscle aches.  Irritable bowel and migraines are often found, along with metabolic syndrome, pre-diabetes and diabetes, and obesity.

However, rather than be taken aback by the complexities, theories of mitochondrial dysfunction and inflammation can scoop up the entire variable pathology (which makes these theories very pleasing to me).

So let's start with mitochondria.  As we know, these are the energy factories of the cells, and their primary mission is to make the cellular equivalent of gasoline, ATP.  Problems with the mitochondria tend to show up as symptoms with the most energetically hungry cells of the muscle and nerves.   Nutritionally, CoQ10, carnitine, B-vitamin, and selenium deficiencies can also cause mitochondrial dysfunction directly.  Mitochondria desperately need these micronutrients to do their work efficiently.

Symptoms of mitochondrial dysfunction can be non-specific, but the cognitive symptoms are very similar to those found in depression, including impairments in attention and executive function and memory.  Tellingly, in families with known genetic problems with mitochondria, the symptoms worsen around times of stress - overwork, fasting, over-exercise, and environmental temperature extremes.  Children with mitochondrial disorders are more likely to be depressed than control children, and among adults, folks with known mitochondrial disorders are more likely to have depression, chronic fatigue, major depressive disorders, bipolar disorder, and panic disorder than the general population.

But all of that is the typical chicken and egg clinical stuff.  Maybe people with genetic mitochondrial problems have a lot of stress, and are thus more depressed.  What's the biochemical evidence for mitochondrial dysfunction in major depressive disorders (and bipolar disorder)?  Autopsies show all sorts of interesting problems with mitochondrial proteins, unusual mitochondrial DNA mutations, and poor mitochondrial complex activity (2).  ATP production rates and respiratory chain enzyme ratios seem to be decreased in the muscle of biopsied patients with major depressive disorder and pain.  In fact, several studies have shown that patients with a high degree of somatic complaints (typically muscle aches) have much lower ATP production than average in the muscle.  In chronic fatigue patients, some similar abnormalities have been found.

And finally, in some mouse models of mitochondrial dysfunction, the mice have bipolar-like symptoms and altered levels and turnover of the monoamines.  The researchers worked out that the mitochondrial dysfunction was the cause of the monoamine depletion, leading to the mouse mood disorders.

So mitochondrial problems (which can be brought about genetically, but also by micronutrient deficiencies) can cause oxidative stress, and eventually lead to nerve damage and psychiatric symptoms.  More on the specifics of this pathology and the role of inflammation in the next post.

Tales of the Metabolically Deranged

Happy Thanksgiving!  I'm probably in too good of a mood to write this post properly, but I have a moment right now and must seize the opportunity, and I'm going to try to make this short but cogent.  A few days ago I noted that I don't agree with Mercola and Rosedale about their characterization (paraphrased, as it wasn't quite as black and white) of glucose as toxic and human beings as on a linear path to diabetes.  Whether or not anyone cares about my opinion as a psychiatrist is another question :-) Commenter js290 wrote the following:

You should read more carefully what Dr. Rosedale wrote in the link you supplied. Your characterization of it is entirely [sic] accurate.

I wrote that I read the articles a couple of times, and found them flabbergasting.  Js290 wrote back:

The way I read it, Dr. Rosedale offered the most generalized solution. The abstraction he makes is we simply define a gradient of metabolic derangement from 0% (healthy) to 100% deranged (diabetic). His argument seems to be simply, the diet that is therapeutic for fully metabolically deranged cannot be unhealthy for the metabolically healthy.

Analogously, it's similar to most of the paleo stance on gluten grains: just because it's tolerable doesn't make it optimal.

Given that you have written about brains function on ketones, that for the same number of carbon atoms, fatty acids produce more ATP than glucose, that the body is capable of producing all the glucose it needs, Dr. Rosedale's view is by far the most generalized and better abstraction from a health perspective. 

Why come up with many different models for different use cases when a single model will work? This is how evolution and natural selection does things: the best abstraction wins.

I think js290 encompasses in a nutshell exactly why I find the theories so puzzling.  I don't see why we should use sick people to tell us what is optimal for all people.  Nor do I know the definition of "metabolically deranged" - do we mean pre-diabetic and type II diabetic?  Obese?  Metabolic syndrome?

I disagree with the characterization that the "derangements" are linear.  My understanding of physiology is that those with healthy beta cell function can do very well with a wide variety of carbohydrate intake and it shouldn't matter that much for optimal health.  We are obligated to use glucose for fuel - we have systems in place to deal with physiologic amounts of glucose.  I also don't think that post-prandial glucose "spikes" are particularly abnormal or dangerous unless they are very high and last a long time.  I don't think glucose or carbohydrates as a macronutrient class per se cause diabetes.  Once you get past a tipping point and start taking out beta cells, hyperglycemia, insulin resistance, and increasing damage occurs, then you have fewer options, dietarily speaking.  Even then, a hard core ketotic zero carber who never cheats may be in good stead, but those who cheat are now (physiologically) even more insulin resistant than they would have been if they ate enough carbs to keep them out of deep ketosis all the time… so glucose "spikes" and area under the curve for glucose and insulin would be even higher than if there were more carbs eaten on a regular basis.

In addition, since the liver will make a bunch of glucose via gluconeogenesis, I don't see much harm in eating moderate amounts of glucose so our liver doesn't need to make it, unless you are needing to stay in deep ketosis for medical reasons. Six of one, half a dozen the other.

And, of course, I think there are certain brain illnesses that could very well benefit from deep ketosis (for some of these conditions it is merely theoretical, for others there are case studies or even pilot data, for epilepsy there is a lot of data) - brain cancers, migraines, epilepsy, bipolar disorder, dementia, autism, and schizophrenia.

In general, I think it is reasonable that fasting and autophagy should be engaged in on an intermittent basis for all individuals, including heathy ones - I know that if on one particular day I personally eat high carb or low carb, I wake up the next morning in ketosis.  That is a sign of metabolic flexibility, which is a positive sign of a healthy metabolism.

Well, that is my opinion.  Starchy root vegetables and fruit are good sources of nutrients and in general less expensive than good quality meat, though perhaps not less expensive or easier to store than than good quality fat, calorie for calorie.  The nutrients in starch tend to be somewhat different than the ones in fat.   I find them pleasurable to eat, personally, and my kids certainly prefer the starch and fruit to just fat, green leafy vegetables, and meat.  Perhaps they would truly want mountains of candy and chocolate and their preferences shouldn't guide our health speculations… well, that's my opinion.  I simply don't think there is enough evidence to suggest that zero carb diets are optimal for everyone for longevity and health, either from an experimental perspective or from a common sense, physiologic perspective.

Soda Begets Zombies

Okay, not likely.  But the sugary variety might well be causing depression in those vulnerable to fructose malabsorption.  Have a look at my previous post on the subject.

Today I have a mere observational study that adds to a pile of evidence that soda ain't the best thing in the world to be drinking, behaviorally speaking. "The Twinkie Defense: the relationship between carbonated non-diet soft drinks and violence perpetration among Boston high school students."

Here's an appropriate song (right click in new tab to open):  Kiss With a Fist

Some bad news about behavior and soda, associatively speaking:  In Norwegian adolescents, soda consumption correlated with poor mental health.  Among American college students, those who drank more soda were less likely to be social, less able to understand emotional cues, and more likely to favor individualism (is that bad?).  There are several reasons soda might cause problems - the sugar could lead to a low blood sugar "crash" which is associated with violence (as I discussed in this post).  In addition, soda is a pretty poor source of nutrition other than straight-up calories, so if it replaces more nutritious food in the diet, big soda-drinkers could end up with micronutrient deficiencies.  And yeah, micronutrient deficiencies could lead to more violence.  No one measured if anyone was a fructose malabsorber.

The experimental design of the Boston study was pretty simple - Boston public high school students were randomly selected and asked to answer a survey.  Those who answered that they drank five or more cans of non-diet soda every week comprised 30% of the sample.  They controlled for a bunch of covariates (but I can think of several million more).  Alcohol, age, gender,  race, sleep, smoking, family dinners.

Heavy soda drinkers had similar BMIs to less heavy soda drinkers, and were no more likely to have less than 6 hours sleep.  White, Black, and Hispanic kids are all equally likely to be heavy soda drinkers, but Asians were significantly less likely to be quaffing 5 or more cans a week.

Heavy soda users were far more likely to smoke or drink alcohol, and were far more likely to carry around a knife, have been violent with a sibling, a date, or another young person. When the sample was split into 4 quartiles rather than two, the violence link remained linear, suggesting a dose response relationship.

And that's pretty much it.  A rather limited self-report study with some statistical crunching, no causal relationship can be inferred; though there are some sensible physiologic explanations as to why soda could make you knife your sister, it isn't proven here.  Brain-eating was not examined.

More posts this week!  I need to answer js290 regarding the whole linear glucose thing, and I figured it would warrant a short post rather than a comment.  Jamie has sent me a few papers, and I pulled some reviews on inflammation, atopy, and behavior.