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Evidence-Based Diabetes Management May 2014

The How and Why of Stress, Diabetes, and the Brain

Stanton R. Mehr
A Visit With Mark Feinglos, MD, and Richard Surwit, PhD
The interaction between stress and diabetes mellitus, though long established, has flown under the radar in a flurry of new pharmacologic therapies in recent years. Evidence-Based

Diabetes Management
revisited this important finding and its implications for patient care with 2 pioneers of the field from Duke University who have worked together to elucidate much of what we know today: Mark Feinglos, MD, professor of medicine, endocrinology, metabolism, and nutrition; and Richard Surwit, PhD, vice chairman and head professor, department of psychiatry and behavioral sciences.

A Relationship Between Levels of Stress and Blood Glucose

Evidence-Based Diabetes Management: You’ve been working on the effects of stress and blood sugar levels for 3 decades, but it has not received the kind of spotlight that pharmacologic

treatments routinely receive. Why do you think that is?

Richard Surwit, PhD: Speaking as the psychologist on the team, interest in many psychological issues, including stress, come and go in the popular press. People attend to them and then forget about them. We were on the cover of Newsweek magazine in 2004 regarding the role of stress and disease and there was a big to-do about it, but that faded.

Mark Feinglos, MD: As an endocrinologist, I believe physicians sometimes have a different approach to cognitive function. Some ignore it. Some tend to view their patients from the neck down, so to speak. They worry about the physiology and the anatomy but they don’t think about the brain’s involvement in disease.

Then there are other groups of physicians and care providers—and I believe endocrinologists are part of this group—who more often consider the role that brain and behavior play in diabetes care. You see evidence of that in the steady stream of articles on the topic appearing in the specialty journals and in the journals related to nursing care or the ancillary health professions. Unfortunately, most physicians tend to not think quite as much about behavior issues.

EBDM: I haven’t seen too many articles recently relating levels of stress to diabetes.

Feinglos: The reasons for this are: (1) It’s a complex area—what does stress mean? Everybody lives with some kind of stress; (2) It’s time consuming to delve into how much stress a patient

has and how that is interacting with someone’s diabetes. As you know, most physicians don’t have a great deal of time in today’s office environment; (3) Once you’ve even taken that time, how do you treat it? Richard and I have thought about that for a long time and have looked at both behavioral and pharmacological ways of thinking about those issues. But it’s very complicated. We’re frequently asked by attorneys whether a stressful event, like an auto accident, can trigger the onset of diabetes. What is more likely is that a stressful situation will not cause diabetes, but the event in the presence of underlying diabetes increases stress hormone levels, which raises glucose levels, perhaps more so in someone with diabetes.

Surwit: The direction of the work that Mark and I have been doing for over 30 years has led us to look at how the brain and the central nervous system are involved in the etiology of diabetes, and

not just in terms of stress. That’s the thrust of what we’re doing now. The fact that diabetes is a stress-responsive disease, as are other diseases like high blood pressure, suggested to us a long time ago that there may be something wrong in the neurologic control of blood glucose that makes a person susceptible to developing diabetes. Let me give you a specific example from some of our recent work. We have shown that, in some groups, epinephrine (adrenaline), a classic stress hormone circulating in the body, interacts with central adiposity in producing elevated fasting blood sugar levels. Lean people with high levels of epinephrine don’t seem to have this problem.

However, obese people who have low levels of epinephrine (whom you might say are not stress responsive, or are relatively laid back) don’t demonstrate this abnormality in blood sugar. So there may be an interaction between the factors that create obesity—and those are probably numerous—and the activity of the autonomic nervous system in producing abnormalities in blood glucose concentrations. We don’t really know what fraction of patients with type 2 diabetes mellitus (T2DM) is affected by this interaction.

What’s more interesting to us at this point is not so much that people with diabetes will show exacerbations of diabetes when they’re under stress, but rather, what does that tell us about the

pathophysiology of diabetes in general? That suggests to us that certain drugs commonly used for other things might actually be helpful in the management of people with T2DM, particularly the

significant group that is obese.

EBDM: What role does insulin resistance play in that interaction, and does the brain, directly or indirectly, regulate insulin resistance?

Surwit: The simplified explanation is that when adrenalin interacts with fat mass, it elevates free fatty acids, which then stimulate the liver to produce more sugar—essentially creating insulin resistance.

Feinglos: And this isn’t an abnormal response—it’s the old fight-or-flight response. If you’re running or fighting, you need a source of energy. These hormones help you release energy from the liver and put it just where you need it. In that scenario, insulin resistance isn’t necessarily abnormal, but it’s an exacerbation of what was designed through evolution as a normal response.

Surwit: The idea that stress only affects people with a proclivity to the disease—in this case, people with substantial central adiposity—is not new. In fact, that’s probably true for every disease linked to stress. Stress will not cause hypertension or irritable bowel syndrome in and of itself. If someone has an autoimmune disease affecting the gastrointestinal system, that person will be more susceptible to the effects of stress. Stress should be viewed as working through one of the lesions, if you will, that predisposes a person to disease. Not something that causes disease de novo.

EBDM: In your research, you found certain subgroups that seem to have a greater stress response than other groups.

Surwit: Right. We found this to be the case for African American women. There are 2 possible reasons why African American women have a greater problem with this. One is that they have much higher levels of central adiposity than either Caucasian women and men or African American men. As a group, they have high levels of central adiposity. The other potential contributing factor that could play a role is that they have more sensitive beta-adrenergic receptors, which lead to the release of free fatty acids and are stimulated by adrenalin. So those 2 factors are probably conspiring to make them more susceptible.

Feinglos: What we’re seeing is not unusual in other diseases: an interaction of a genetic predisposition with factors that will bring out that genetic predisposition.

EBDM: In this same research, I found it interesting that you measured hostility, or markers of hostility. Is that a proxy for stress levels?

Surwit: I don’t really know. Hostility is defined by a 27-item scale that was de-rived from the Minnesota Multiphasic Personality Inventory. The scale tends to describe people who are relatively

untrusting of what’s going on around them. That more defines suspiciousness than it does hostility, although that’s the name the scale was given.

We don’t really understand why that is related, particularly in African American women, to abnormalities in blood glucose levels. It may be related to the fact that they are more responsive to high

epinephrine levels, that their autonomic nervous systems are more attuned to the fight-or-flight response. But that’s an open question. It’s an observation we and other groups have seen on multiple occasions. Exactly what it means and why it’s more common in African American women is not clear at this point.

Stress Management and Diabetes Care

EBDM: Let’s take this link between stress and glucose management into the physician’s office. What does the doctor or nurse educator tell the patient with diabetes about stress in the

management of the disease? What should patients do about it?

Feinglos: I wish there were a simple answer to that. Someone who takes the time to question patients about environmental stressors will often find fertile territory. But everyone has stress. Some

people live in a much more stressful environment than others and you can’t necessarily change the environment.

Nor do you want to put all kinds of people on pharmacologic therapies to alter their cognitive responses to stress. Beyond attempting behavioral approaches to modifying stress, making

people aware of what’s happening is important. If they can’t avoid the stress, they can modify their diabetes treatment to better cope with it. For example, if you know your blood sugar level is rising because of stress, you should try to bring your stress level down, knowing that this will positively affect your glucose concentrations.

If that is not possible, it may be necessary to modify the medication regimen for periods of increased stress.

Surwit: The system for payment of services in medicine and psychiatry is really tying our hands, because we can’t see people and bill them for a couple of sessions and teach them stress management for their diabetes unless they carry an outright psychiatric diagnosis. Most people with minor stress problems don’t have that diagnosis.

One of the things that we’re looking at now is using the beta-blocking drug carvedilol as a way of helping people whose glucose levels are more sensitive to stress. The drug may have very positive effects on glucose concentrations in these patients, because it blocks the mobilization of free fatty acids caused by adrenalin release. Mark and I are trying to get this study funded. If carvedilol works as we hope, we would have a very low cost intervention that wouldn’t make people drowsy or affect their cognitive function, but could blunt their glucose response to stress quite significantly.

Feinglos: Realize that at this point, our ideas are unencumbered by data! We have to be a little careful about that.

Surwit: Data do exist on carvedilol’s unique properties, and it has been shown to improve glucose tolerance in people with diabetes being treated for hypertension as well. The problem is that

nobody has taken a look at whether this works particularly well in people with high central adiposity, which is what our hypothesis would suggest. And we don’t suggest using other β-blockers, like metoprolol or propranolol. Carvedilol blocks α-adrenergic receptors as well as β receptors. That prevents the reduction in insulin secretion that occurs when giving another β-blocker. We think this is a promising avenue.

EBDM: It sounds like this approach might be more appropriately categorized as a treatment for the metabolic syndrome than specifically for T2DM.

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