Thursday, August 19, 2010

Stress is Metabolic Syndrome

In a previous post I described a little bit about the HPA axis. That's hypothalamic-pituitary-adrenal axis, or master glands of stress and how they rule the body and the world. In today's post I want to explore a little more about how stress affects our metabolism and our minds.

Just to review, we have a stress response system in case something dangerous happens. And it works great for that kind of situation - send out a wave of stress hormone, a grandmother can lift the car off the trapped toddler. We can run faster, have better stamina, bleed less. What actually happens is that glucocorticoids (cortisol) and epinephrine (adrenaline) are released from the adrenal glands, and these hormones have a wide variety of effects on the body - increasing our cardiovascular capacity, decreasing our immune function, and increasing our ability to mobilize energy. Our own personal temporary superhero juice.

Acute stress has effects in the brain, too (1). Glucocorticoids bind to receptors in particular regions of the brain that encode memory (the hippocampus and the amygdala), so that years later, we can often remember stressful events as if they happened yesterday. This mechanism is part of the basis of flashbacks for people with PTSD.

And then there's chronic stress. Exposure to adrenaline and cortisol on a chronic basis can have disastrous effects on the body and brain. It is thought to contribute to the pathology of cardiovascular disease, high blood pressure, the spreading of cancer, immune system problems, and type I and type II diabetes. Chronic stress is of course also thought to cause, in part, many anxiety disorders and depressive disorders.

Cushing's syndrome is a disease caused by excess cortisol. Imaging studies have shown that people with Cushing's syndrome have a shrunken hippocampus. People with PTSD, and depression also tend to have a shrunken hippocampus. As I've described before, the hippocampus is the epicenter of how depression is toxic to the brain.

It's hard to study neurochemical goings-on in the the brains of living people, as we have the tedious tendency to be using our brains (though sometimes it is not obvious). For that reason, animal models are often used for experiments to really find out what is going on in a depressed or anxious brain. And the typical way to induce depression in a rat, for example, is to expose it to stress. And sure enough, the rat will begin to have changes in weight, disrupted sleep cycles, altered HPA axis function, and neurological changes in the hippocampus and the amygdala. Lithium and some antidepressants seem to protect the brains from the stress in animal models, reducing the amount of neurological changes in the brains. Chronic stress also causes an increase in glutamate in rat brains, which is one of the mechanisms we explored in Depression 2 - Inflammation Boogaloo. Humans will have elevated glutamate in their spinal fluid if they have anxiety.

All right. Blah blah blah. Stress makes you depressed. News flash! But here's where it gets interesting. Because, turns out, people with diabetes have many of the same neurological and morphological changes in the brain as depressed and anxious people do. Hyperglycemia accelerates brain aging and causes irreversible neuron loss in the hippocampus.

Cortisol seems to cause insulin resistance not only in the muscles and liver (which most paleo-minded folks will be aware of), but also in the hippocampus. Diabetics with poor glucose control have elevated cortisol, too. It's all a disastrous circle of sugary hormonal bodily terror. In an insulin-sensitive person, increases in insulin levels cause our cells to whip out the GLUT4 transporter, so that glucose is sucked from the blood into the muscle and fat. Cortisol seems to wreck the function of the GLUT4 transporters to some extent, leaving increasing levels of glucose floating around in the blood. Once you have hyperglycemia, you begin to favor oxidation over antioxidation. In the brain, glutathione (supreme antioxidant) levels are decreased in the hippocampus, leading to the rule of toxic glutamate. The NMDA receptor seems to increase. Not favorable to a healthy state of mind. All these changes decrease synaptic plasticity and repair. Exercise, estrogen, and antidepressants seem to be protective against this effect.

Now let's talk about the insulin receptor itself. The cerebellum, hypothalamus, and hippocampus all have insulin receptors, and insulin itself seems to be involved in mood states and cognition. If someone is insulin-resistant, adding insulin will help a person think more clearly. Insulin sensitivity seems to be associated with appropriate movement of glucose transporters GLUT4 and GLUT8 in the hippocampus to the cell membrane and the endoplasmic reticulum. Jamie Scott had a recent post on the cognitive effects of insulin resistance and diabetes.

Okay. Well, none of these findings are a huge surprise. We knew stress was bad. We knew insulin resistance was bad. Experimental animal models show that pharmacological interventions can reverse or slow down some of the damage. But hey, wouldn't it be better to avoid the chronic stress and insulin resistance in the first place? Better for the brain, better for the body.

Modern life requires work before play. Productivity before relaxation. Ability to afford the time to exercise before one actually gets the time to exercise. Hey, that's life, but take it to the automaton extreme (and add processed food and partially hydrogenated fat), and it rots our brains and ruins our bodies. But we will spend and spend until we have no more credit left. We need to change some of the incentives out there. Chronic, expensive disease is on the back burner, and it will bankrupt us.


  1. Ketamine

    I see "special K" may be coming back in the form of a new improved version.

    Did you ever come this Irish Psych - Ivor Browne ?

    Here is a link:

    I attended a few sessions on returning to Dublin in the '90s. He also used MDMA therapeutically before it became a party drug.

  2. WOW.... i think you just described me in a nutshell... i already eat paleo and high fat. is there anything can focus on besides sleep to help the hypercortisolism that lingers with anorexia??

  3. Leon - I always wondered why ketamine wasn't studied more for depression in an effort to make the treatment more practical. The only other way to cure resistant suicidal depression nearly as quickly is shock treatment, after all, so ketamine seems less risky and crazy when one takes that into consideration. I hadn't heard of Dr. Browne specifically, though that type of regression therapy is now generally frowned upon, as many false trauma memories were planted, it seems, along the way. I know of a very unusual case where chloral hydrate hypnosis was used and cleared by the ethics committee. It was well documented and there will be no destruction, however. A rule of thumb practicing medicine in the USA - never write anything you wouldn't want your patient and his or her lawyer to see.

    Malpaz - I know there are some treatments for hypercortisolism, but an endocrinologist would be the one to consult about that. It is common with anorexia, though other causes (adrenal issues) should be ruled out.

  4. Dr.Deans your blog is splendiferous. I wish all research papers were written with such... pep. I have a question though. Are the shrunken hippocampus in depressed individuals irreversible and permanent? Know of any studies that may shed light on this?

  5. Hi Jaedong. As far as I know the adult human hippocampus is the only part of the adult brain that may be able to regenerate at least a little (though other parts of the brain can shift functions to take over for damaged parts). I don't have the seminal paper on tap but here's a related paper:

    Hmm - silly ipad wont copy paste into the comment field here but the pubmed ID is 15680705


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