The Doctor Weighs In

By Pat Salber, MD

We have known about the association between snoring and obesity for a long time. But we now know that sleep-disordered breathing (SBD) -- a sleep disturbance characterized by snoring and episodes of apnea or not breathing for periods of time -- is linked, independent of obesity, to insulin resistance, abnormal glucose metabolism, and Type 2 diabetes.

Sinziana Seicean, MD, MPH and colleagues published results of the Sleep Heart Health Study in the May 2008 issue of Diabetes Care. They studied 209 normal weight and 1,036 overweight/obese individuals who had a diagnosis of SDB, but did not have a diagnosis of diabetes. They found that SDB was associated with all of the manifestations of impaired glucose metabolism, including impaired fasting glucose, impaired glucose tolerance, and occult diabetes. The magnitude of the association between SDB and abnormal glucose metabolism was the same regardless of whether the individual was normal or overweight/obese.

This suggests that obesity is not the common cause of both insulin resistance and sleep-disordered breathing. Rather there appears to be an independent association between SDB and impaired glucose metabolism that is not explained by adiposity.

The authors suggest that the association of SDB with glucometabolic disturbances may relate to the “often-profound physiological stresses that occur overnight with sleep apnea.” They suggest that these stresses may transiently increase autonomic sympathetic activity, increase outpouring of the stress hormone, cortisol, and a decrease insulin sensitivity. Indeed, they point out that a human study of people with sleep apnea demonstrated improved insulin sensitivity after treatment of the SDB with continuous positive airway pressure (CPAP)

Why is this study important? Because it means that individuals with SDB who are normal weight may be at risk of impaired glucose metabolism. It also suggests that therapy aimed specifically at SDB and not just at obesity may be indicated to reverse that risk.

To learn if you are at risk of having SDB, answer the following questions based on the Berlin Questionnaire:

By Dov Michaeli MD, Ph.D

The April 14 online edition of the Proceedings of the National Academy of Sciences carried an intriguing article titled “ Endogenous steroids and financial risk taking on a London trading floor”. Both authors, J.M. Coates and J. Herbert are from the Dept. of Physiology, Development and Neuroscience at Cambridge University . But J.M.C. is also from the School of business at Cambridge , and his main research interests are summarized by him thusly: “ I have been sampling endogenous steroids from traders on a trading floor in the City to determine the role of both testosterone and cortisol in their decision making and in their performance. I compliment this field work with behavioral experiments set in the lab and in artificial asset markets”

Raging hormones and bubbles

The rationale for this field of research is both compelling and fascinating. As stated by J.M.C  “ the waves of irrational exuberance and pessimism that destabilize the financial markets ,may be driven by naturally produced steroid hormones. With receptors in almost every nucleated cell in the body, steroids such as testosterone and cortisol affect the moods we experience, the memories we store and recall, and the behavior we display in competitive and risk-taking situations”.

This is absolutely fascinating because for the first time we find a serious attempt to explain economic phenomena on the basis of human physiology.

What they found

The investigators took saliva samples from 17 male traders on a London stock trading floor twice daily over the course of eight days. They monitored the traders' levels of testosterone, the hormone most often associated with aggression and sexual behavior, and cortisol, the so-called stress hormone.

They tracked those levels against the amount of money that a trader made or lost, and against the variation in the market. What they found was that when the traders made more money, they had elevated levels of testosterone. When the markets were particularly variable, they had elevated levels of cortisol.

Aha, you might aver; how do you know what is cause and what is effect? Isn’t it just as possible that traders had their testosterone levels go up as a consequence of making money?

Good thought, but…

A further analysis showed that traders who started their days with elevated testosterone made more money than those who didn't. One trader went on a six-day winning streak, making twice as much money each day as the previous one. Over that period, his testosterone levels rose steadily, some 74 per cent! This guy must have been a raging bull by the end of the week. Just think of the rollicking weekend he must have had.

So should stock traders join the ranks of sports figures and take testosterone as a performance enhancer?

Not quite. There is a point of diminishing returns; too much testosterone leads to too much aggression and reckless decision making. In some it may even lead to criminal behavior.

Cortisol, anxiety and risk management

Cortisol is one of the stress hormones. It rises when stress levels are up, which is stating the obvious. But what is less apparent is its role in limiting risk. Let’s go back to the savannah for a minute. You spot a lion striding toward you. Being the testosterone macho that you are you’d be perfectly willing to take the beast on. One guy, Samson, actually did it and lived to tell the tale, so why can’t you? Fortunately, your eyes send the brain another message: don’t kid yourself, this is dangerous! The order goes out to the adrenal glands and a flood of cortisol is released into the circulation, raising your anxiety level and making you have some second thoughts: after all, this is a tale from the bible, and you know how believable those are; besides, this guy Samson- did anybody see him kill the lion? Maybe he was just using it as a line to get Delilah to do what Philistine girls do better than the Israelite ones do? So you hedge your bets and climb up the closest tree. In other words, cortisol made you manage your risks more rationally.

Indeed, when the markets stopped going in one direction and started fluctuating, as markets always do, cortisol levels went up and trading became more restrained.

Of course there is a downside to cortisol as well, especially when exposure to it is chronic.

The downside of cortisol

A few days ago we reported on a Kaiser Permanente study that showed increased risk of dementia in males over 40 who had an increased central obesity, or abdominal girth that is 35 inches in women and 40 inches in men. Even men with a normal BMI had a 2 fold increase in risk if their abdominal fat was excessive. Now, if you think that you are in great shape because your BMI is within the normal limits, and you proudly display your six-pack abs to anybody who would care to look, think again . Experts now think that subcutaneous fat -- the flabby variety under the skin in areas like the buttocks, legs and arms -- while unfashionable, is fairly benign. Researchers at the Washington University School of Medicine in St. Louis demonstrated that when they removed an average of 22 pounds of subcutaneous fat via liposuction from 15 overweight women, they found no change in the women's cholesterol levels, triglycerides, insulin sensitivity or other health risks. We are talking here about visceral fat, or fat that underlines your awsome abs, lining your intestines and other internal organs. This fat in excess can be deadly. It is associated with the diseases of metabolic syndrome, but also with gall bladder disease, sleep apnea, numerous cancers, and dementia. So even if you are not flabby (you cannot pinch your skin and subcutaneous fat), but your belly is sticking out – you probably have excess visceral fat.

A major factor in determining this deadly distribution of fat is cortisol. This is probably why people under chronic stress are more prone to all the diseases we just mentioned.

But wait, there is more. Cortisol also causes increased risk of arthritis. It also leads to shrinkage of the prefrontal cortex and hippocampus, brain regions associated with decision making and factual memory, meanwhile it contributes to growth in the amygdala, a region associated with emotional memory and anxiety. Not good stuff.

The good news

Cortisol levels can be controlled by reducing stress levels. And visceral fat is the first to go when someone loses weight in general. Aerobic exercise, like walking or running, is particularly effective. Doing sit-ups, abdominal crunches and pilates can strengthen your abdominal muscles, and help hold your stomach in, but they won't target visceral fat specifically.

Some final thoughts on stock trading

Here are some questions that beg for a study.

· Are women better traders because they are less prone to wild speculation?

· Are stock traders more prone to heart disease and diabetes? Or more critically for their clients, are they likelier to become demented?

· Should clients insist on a broker’s full disclosure of his health record?

Or may be the answer is a lot simpler: get a woman broker.

By Dov Michaeli MD, Ph.D

Alcoholism is a major public health problem. This we all know. But did you know that as alcoholism evolves, stress systems in the brain play an increasing role in motivating continued alcohol use and relapse. In other words, someone who is a moderate drinker will drink more if subjected to stress. And that, in turn would increase her sensitivity to stress, which would result in yet an additional increase in alcohol consumption, which in turn… you get the picture.

The stress response

Deficiency of a stress response is life threatening. For instance, in response to stress blood pressure goes up, heart rate increases and more blood is pumped into the brain and skeletal muscles. On the other hand, less blood is pumped into the GI tract or the kidneys. What’s the physiological rationale? Just imagine you are about to be mugged by a gun totting robber—a common American stress. You would like to assess the risk and think of an appropriate response, and then run as fast as you can to save your life, or stand your ground and fight, and maybe die a hero. Or if you are philosophically inclined, you might muse about the second amendment and its role in your predicament. All these considerations go through your mind at lightning speed, which requires blood supply and the energy (oxygen and glucose) that it provides. Either way, the last thing your body needs during this emergency is to waste precious blood supply and energy on digesting your last meal, or making urine.

The usual suspect for hormonal response to stress is the stress hormone cortisol. This hormone is released into the circulation after a rise in the level of another brain hormone called Corticotrophin Releasing Hormone (CRH). And rise in cortisol level in the blood will cause all the effects we have described.

The stress of alcoholism

Since the demonstration that alcoholism can result from repeated bouts of stress and drinking, several experimental drugs were tested to see if one could break the vicious cycle by inhibiting release of CRH. Alas, not much success.

Apparently, the CRH/cortisol system is not the only one alerting our body that it is subjected to stress and causing it to physiologically adapt quickly. Another brain hormone system, substance P (SP) and its receptor neurokinin 1 receptor (NK1R) is highly expressed in brain areas involved in stress responses and drug reward, including the hypothalamus, amygdala, and nucleus accumbens. In rodents, psychological stressors induce release of SP in the amygdala, whereas genetic deletion or pharmacological blockade of NK1R inhibits the associated behavioral responses. Interestingly, SP is also involved in the transmission of pain from the peripheral nervous system to the brain. And the expression of SP/NK1R system is especially high in the vomiting center in the brain stem. Food for thought.

In a paper published in the latest Science issue ( March 14, 2008 ) a group of scientists from the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , tested the hypothesis that the NK1/NK1R system is largely responsible stress-induced alcoholism. They went about it in two ways. First, they “knocked out” (inactivated) the gene that codes for NK1R in mice, so in effect they created mice that lack this system of stress response. They then subjected wild type (normal) mice and mice deficient in NK1R to escalating concentrations of alcohol, starting at 3% and ending with 15% over 60 days. Lo and behold, they created what amounts to holier than thou mice: the wild type mice consumed an average of 10g/kg body weight, whereas the “knocked out” mice consumed only 6g/kg. They also showed an increased sensitivity to the sedative effects of alcohol. In other words, they drank little, and they couldn’t “hold their liquor” very well. Party poopers.

What about us, humans?

In a randomized controlled experimental study, recently detoxified alcoholic inpatients were treated with an NK1R antagonist (LY686017; n = 25) or placebo (n = 25). LY686017 suppressed spontaneous alcohol cravings, improved overall well-being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial LY686017 effects.

Small population, so it’s too early to pop the champagne. But the results are truly impressive, and as the authors state with typical scholarly restraint: “Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism”.

Judging from results of treatments of other psychiatric conditions, a combination of drug and behavioral therapy is likely to prove more effective than drug alone. So, no—we are not likely to see AA go out of business any time soon. But the ready availability of effective drugs may make the excuse of scoundrels who “check in for rehabilitation” a lot less believable.

By Dov Michaeli MD, Ph.D

I remember a wonderful lecture at UCSF, about 30 years ago, by Dr. Dennis Burkitt, on “Diseases of Civilization”. Dr. Burkitt was a missionary doctor in the bush in what at the time was Rhodesia (today’s Zimbabwe ). He was also an extraordinarily astute clinical observer (he was the first to describe a hitherto unknown cancer, aptly called Burkitt’s lymphoma). At the end of the lecture somebody asked whether Africans in the bush, being free of modern world stress, are healthier. Dr. Burkitt retorted that wondering every night whether that was the night the lion was going to have you for lunch is hardly an anxiety-free thought. The message was that stress recognizes no boundaries of geography, education, income, sex or national origin.

What is stress?

To paraphrase Potter Stewart, a supreme court justice who grappled with the definition of pornography: “I know it when I see it”. But there is a more ‘scientific’ definition: Psychological stress occurs when an individual perceives that environmental demands tax or exceed his or her adaptive capacity”. Interestingly, an elaboration of this definition includes two elements: high psychological demands coupled with low decision latitude. In other words, stress as we commonly understand it, high and unrelenting demand, is not enough. It is the lack of control, the feeling of helplessness, which tips the scale to the feeling of stress.

Can psychological stress cause disease?

I have to admit: being a firm believer in the physical causes of disease, I was highly skeptical. I readily admitted that stress could exacerbate disease; I have seen countless cases of acute asthma attacks or acute MI precipitated by acute psychological stress. But chronic, low intensity stress? I wanted to see hard evidence.

The title of a recent article, and an accompanying commentary in the JAMA, “Job Strain and Risk of acute Recurrent Coronary Heart Disease Events”, tweaked my curiosity. The authors followed 206 patients who have had an MI, for a period of 2.5 years following their initial episode. After statistically adjusting for 26 potentially confounding factors (smoking history, hypertension, high LDL etc.) they concluded that job strain increased the risk of recurrent coronary heart disease or CHD by 100%!

How can it happen?

There are many theories, but the most plausible and the best documented is the stress hormone theory. We have two systems that get activated during stress: the HPA (hypothalamic-pituitary- adrenocortical axis) and the SAM (sympathetic- adrenal- medullary) systems. HPA secretes cortisol, SAM secretes epinephrine aka adrenaline. Both are known as stress hormones.

 If stress is so common in life, how is it that evolution allowed the hormonal response to stress to be so deleterious? And the answer is: it didn’t. Besides facilitating the fight or flight response, they increase innate immunity, our first line of defense against pathological invaders, and decrease the inflammatory response. But all this is true for acute stress (e.g. the lion is coming at you). Chronic stress is something quite different. For reasons yet unknown, chronic stress causes a decrease of the immune response and an increase of the inflammatory response—exactly the opposite effects of acute stress. Whatever the reasons may be—the effect is destructive. As an example: coronary heart disease is basically an inflammatory process, and chronic stress aids and abets it. Furthermore, macrophages, which are white blood cells that are central to the formation of a coronary plaque, were recently discovered to secrete their own adrenaline, adding insult to injury.

Does a low dose of NSAID (non-steroidal anti inflammatory drugs) to prevent CHD make sense now?

What other diseases are associated with stress?

Depression is the most obvious one. To cite some compelling statistics: approximately 20-25% of persons who experience major stressful events develop depression. And when a cohort of depressed persons was examined, it was found that 50-80% have had a major “life event” in the preceding 3-6 months. To close the loop: most depressed individuals suffer from a depressed immune response and from chronic, low grade inflammation. Based on this we still cannot conclude that there is a cause and effect relationship here; but it is an intriguing correlation nontheless.

HIV/AIDS has also been suggested to progress faster, even when taking anti HIV medications, if the patient is under chronic stress. Again, one shouldn’t be surprised if the explanation will turn out to be a depressed immune response.

In Conclusion

On the biological level, this is yet another demonstration of the mind-body relationship. In fact, a whole field of research called psychoneuroimmunology (I know, it’s a mouthful, but if you break it up to its component words, psycho-neuro-immunology, it makes sense) is thriving and is uncovering new connections between brain, mind and immune response on an almost daily basis.

On the clinical level, the strengthening evidence of the effect of stress on health and disease suggests new modalities and approaches to treatment.

What is most intriguing and potentially far-reaching, are the societal consequences. Now that we accrue more and more evidence on the effects of stress on health, it would make economic sense to pay attention to the work environment. An enlightened manager would insist on stress reduction in the workplace in order to increase productivity. Conversely, could a company be found liable if an employee is subjected to an abusive supervisor and suffers a heart attack? The medical evidence is already here.

Dov Michaeli MD, Ph.D is in the biotech industry.

I am at the Family Violence Prevention Fund’s National Conference on Health and Domestic Violence.  One of the panels that I attended examined the impact of child maltreatment on brain development.

David McCollum, MD, President of the Academy on Violence and Abuse, reviewed the medical literature on brain changes that occur after child abuse … and I am not talking about brain injury due to being hit on the head, rather I am talking about structural and functional changes in the brain that occur as a result of being exposed to the terror of family violence

Dr. McCollum briefly reviewed the biology of human brain maturation. Infants are born with an over  abundance of nerve cells, called neurons, and connections between nerve cells, called synapses. As the child gets older, there is a significant “pruning” of neurons as well as synapses.

Another process that occurs as the child’s brain matures is that the neurons become myelinated, a process that makes neuron-to-neuron transmission more efficient.

Myelination is inhibited when there are high levels of brain glucocorticoids, one class of hormone that is elevated during stress. There is no question -- being abused as a child or growing up in a home where your mother is abused is stressful…and, for many children, it is stressful over prolonged periods of time.

When the brains of children exposed to abuse are looked at anatomically, using imaging techniques, it turns out that there is a reduction in size of a number of key brain structures, including the amygdala, the hippocampus (mainly on the left side), and the cerebellar vermis. There is also a reduction in the size of the corpus callosum, the area that allows the two sides of the brain to communicate with each other. There is also an increase in the size of the putamen and the lateral ventricles (the cavities in the brain that contain cerebral spinal fluid). According to Dr. McCollum, many of these changes are explained by the inhibiting effect of glucocorticoids on myelination of neurons.

The areas of the brain impacted by glucocorticoid excess are components of the limbic system and related connections. The limbic system is involved in response to perceived danger.  It is also involved in our emotional response. The limbic system evolved to protect us from the dangers of the wild, and most likely played a role in our surviving attacks by predators. These stressful events were likely less common and less persistent than what is experienced by children trying to survive in a violent home.

Other chemical changes have been attributed to chronic stress, include overproduction of dopamine, a substance that, in excess, causes reduced attention, increased vigilance, impaired ability to learn new material, and increasing paranoid and psychotic behavior.

Serotonin levels are decreased as a result of stress. Suicidal behavior, depression, and aggression have been shown to result from low serotonin levels. Substance P, a neuropeptide that participates in pain response and inflammation, has been found at higher levels in the spinal fluid of abused, compared with non-abused individuals.

All of these findings have potentially profound implications for healthcare professionals. No longer can we say that family violence is not a health care issue. When your brain structure and function changes, for the worst, as a result of exposure to violence, I would say without a doubt that it is a healthcare issue of the highest magnitude.

We don’t yet know if these changes can be reduced with treatment. But our new understanding of the neurobiology of abuse is sure to lead to new therapies, some of which may be pharmacological and some of which may be behavioral. Hopefully, these new findings will also lead to more aggressive and more effective efforts identify kids at risk and to help families learn to live violence-free.

Finally, it is my profound wish that studies such as these will stimulate research into new ways to prevent violence in the first place. Primary prevention research in the field of family violence is woefully underfunded. It is time to get our priorities straight -- our kids brains are at risk.

If you would like to read more about this fascinating and important topic, take a look at Dr. McCollum's article on "Child Maltreatment and Brain Development" published in Minnesota Medicine in March 2006.

Pat Salber, MD

We have known for a long time that the distribution of fat in the body is important in determining important health risks, such as type 2 diabetes and cardiovascular disease. “Apples” (or the abdominally obese) are at much greater risk than pear-shaped people who tend to deposit their fat in the hips, thighs and butts.

More recently, researchers have determined that one type of belly fat, called visceral fat, is worse than belly fat just below skin.  Visceral fat is deposited the omentum, the tissue that drapes around the intestines and other abdominal cavity organs (or viscera). You don’t have to be obese to have visceral fat. One the other hand, not all people who are obese develop significant amounts of this “bad fat.”

An article in the San Francisco Chronicle reports that recent research suggests that abdominal fat is related to the release of the stress hormone, cortisol. According to UCSF’s assistant professor of psychiatry, Elissa Epel, an expert on the physiological effects of stress, cortisol which is released when people are under stress, seems to interact with the pancreatic hormone, insulin, to create visceral fat. At the same time, cortisol stimulates a craving for “comfort foods” – the sweet stuff and the stuff high in fat. This is a double whammy – you desire and, as a result, often consume high calorie foods and you deposit those excess calories as bad fat in your belly.

To test the hypothesis that stress is related the deposition of visceral fat, researchers at the University of California San Francisco are recruiting 50 overweight women to participate in a study on the impact of stress relief techniques on body fat, particularly visceral fat. The study is not designed to help the participants lose weight per se, rather it is designed to reduce stress and stress-related eating.

The 50 women will be divided into two groups. One group will start stress reduction classes right away, the other won’t start these classes until after 6 months have passed. The classes will teach women stress reduction techniques and will also teach them how to recognize triggers that prompt stress-related eating. They will also be taught “mindful eating.”

I described mindful eating in my recent post “Getting in touch with your feelings…about raisins.” In that post, I describe a “raisin exercise” developed by the author of Soul-Full Eating, Maureen Whitehouse. This approach to eating involves really engaging with the foods you eat. As opposed to gulping them down as many of us do in the course of our hectic lives, you are taught to visually examine the food and then explore it with your fingers and hands. When you put it in your mouth, you explore it with your tongue and chew it, ever so slowly, letting the flavors linger in your mouth and in your mind.

According to a co-researcher on the UCSF study, Jennifer Daubenmier, a postdoctoral fellow with the UCSF Center for Obesity Assesment, Study and Treatment, mindful eating helps participants to think about how and why they eat. The goal of the UCSF program is to ultimately help the participants make better, smarter food choices. Although weight loss is not the goal, it is hoped that the program will result in a reduction of bad belly fat.

To qualify for the study, women must weigh less than 300 pounds and have apple-shaped figures. They must be between 21 and 50 years old. They must not be recently pregnant, diabetic or have heart disease. If you fit these criteria and are interesting in participating in the study, send an email to ucsfcalmmstudy@yahoo.com. If you want to learn more about what it means to participate in a clinical trial, click here.