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

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-BasedDiabetes 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 pharmacologictreatments 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 themanagement 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.

Surwit: That could possibly be the case. We’ve been trying to get the National Institutes of Health to fund the study for 6 years now. And people either tell us, “It won’t work” or “Everybody knows it will work.” Meanwhile, we haven’t yet obtained grant support. If the drug had still been on patent, we might have gotten the manufacturer (GlaxoSmithKline) to fund it. There’s no commercial interest now that carvedilol is sold as a generic.

EBDM: Has any research been done on the effect of anti-anxiety drugs to reduce stress in patients with diabetes?

Feinglos: We looked at that ages ago, both in animal models that we developed and in humans. First of all, we can’t put everyone on anti-anxiety drugs.

Surwit: We evaluated the benzodiazepines. The one that we’ve studied most was alprazolam (Xanax). The first problem is that people develop a tolerance to it. The second problem, as Mark alluded to, is that it does produce sedation…

Feinglos: …and it has an addictive potential. It wasn’t really a good idea. We tried to demonstrate that using it would modify stress and affect glucose levels, and it did. Which is very nice, but you can’t use that as treatment long term in large numbers of people.

Some Early Clues to the Relationship Between Fat Intake and Glucose Management

EBDM: Both of you have been evaluating this area for a long time. How did your interest begin?

Surwit: In 1977 or 1978, when I first came to Duke, I was brought in to run the stress management unit of the department of psychiatry. Mark sent me a consult for a patient with type 1 diabetes who was in very poor control, wanting to know if we could do anything to help her. I said I’d never worked with people with diabetes before. We tried stress management techniques, and this

woman’s glycemic control responded very dramatically. Then we tried it with another patient, who also responded dramatically. So we decided we might be on to something here.

Feinglos: In the late 1980s, we decided to look at this effect in animal models, the Black 6 mouse (also called the BL/6J mouse) which, being the strain on which the mutation is based, everybody thought was a control for the ob-ob mouse, a genetic model of obesity and diabetes. We discovered that this mouse in and of itself was susceptible to developing both significant obesity and T2DM if we fed it a diet with American junk food (basically cookie dough, containing lard and sugars). We asked ourselves, how would we make a susceptible mouse diabetic?

We decided to feed it exactly what the American population eats. It worked. We published that in 1988. We learned that other strains of mice were not as responsive. On further study, it was clear that epinephrine was one of the mechanisms involved in this phenomenon, and it interacted with adiposity. Then we tried to identify the genes that were responsible for this particular problem.

Surwit: When we fed the mice pure sugar, it didn’t do a thing to their blood sugar. Fat was the culprit. The idea that sugar causes diabetes at least in rodents is clearly false. It doesn’t happen.

We published a study in 1997 in the American Journal of Clinical Nutrition, which showed that if we fed women trying to lose weight a hypocaloric diet that was 50% sucrose, they didn’t have any

problems either. They lost weight just fine. So we’re not big proponents of the sugar theory of obesity and diabetes. We think fat is really the culprit. And when you have a high fat diet, adding

sugar makes it worse. But in the absence of fat, sugar and other simple carbohydrates are relatively benign. So I think people have really been paying too much attention to sugar and not enough to fat intake.

The data to support the nefarious effects of sugar in the absence of fat are just not there. But it’s trendy.

Feinglos: A couple of large epidemiologic studies looked at the high intake of sugars in the population and found some correlations to cardiovascular mortality. But nobody has ever demonstrated that high sugar intake causes diabetes, despite the common wisdom. In the countries experiencing the worst epidemics of new-onset diabetes, China and India, for example, it is

usually the result of increased affluence and the concurrent change in diet, the addition of more animal proteins and fats. Remember, the residents of those countries have been eating high-carb diets to begin with.

Surwit: As it’s consumed in poorer sections of Asia, rice has a higher glycemic index than sugar. Yet, in clinical studies, rice actually lowers blood glucose in the absence of fat. We have a famous diet program here in Durham—the Rice Program. Patients with diabetes eat nothing but Uncle Ben’s converted rice—no fat, no animal protein. In the first 2 days, we see enormous

drops in blood sugar levels.

Feinglos: The Atkins diet proponents will show you how they get big drops in blood glucose concentrations with a very high fat and high-protein diet but no carbohydrates.

I think the underlying point is that it’s the combination of uncontrolled caloric intake and the nature of the nutrient that really gets you into trouble.

EBDM: It sounds to me as if even more counseling needs to be done for a patient with diabetes. This cannot possibly be accomplished in the 10-minute office visit.

Feinglos: That’s the seminal problem. There’s a huge burden of diabetes in this country as well as others. There aren’t very many endocrinologists, so most people with diabetes have to be treated by family physicians or general internists. These physicians have very limited amounts of time. Some of them don’t have specific diabetes educators associated with their practice. So the care of diabetes, which is very labor intensive and very expensive, is difficult to accomplish.

The Role of Caffeine in Diabetes

EBDM: We’re talking about nutritional factors and their effect on glycemic control and glycemic response. Both of you have done a good deal of research recently on caffeine and caffeine’seffect on diabetes. What have you learned?

Feinglos: One of our colleagues, Jim Lane, has been interested in caffeine’s effect on blood pressure for a very long time. We started talking about the idea that it would be important to take a look at what caffeine might do to blood glucose levels. We know that caffeine sensitizes the body to the action of epinephrine. Many very large epidemiologic studies show that if you drink a lot of coffee, there is a lower risk of developing diabetes.

Those large epidemiologic studies don’t tell you what happens to people who drink caffeine but who already have abnormal glucose levels.

Surwit: They don’t even separate out people drinking decaffeinated from caffeinated coffee. Coffee also contains all kinds of flavonoids, which may have beneficial effects. The work that we’ve done with Dr Lane clearly demonstrated that when you give caffeine pharmacologically, it makes glucose tolerance worse both in healthy people and in those with T2DM. It does so by sensitizing adrenergic receptors to stimulation by adrenalin, as well as by stimulating adrenalin’s release. We’ve been trying to get funding to do large-scale trials on the effect of eliminating caffeine from the diet of patients with diabetes. Again, we’re greeted by comments like, “Everybody drinks coffee; it couldn’t be bad for you.”

Feinglos: Where it’s really important isn’t even necessarily for adults drinking coffee but for kids with a predisposition to T2DM. Many of them drink a liter a day of caffeinated soft drinks.

Surwit: Or even worse than that, the energy drinks, which are just concentrated caffeine.

EBDM: Do you think that the day will come when you have patients with T2DM or younger patients with prediabetic conditions who will be advised to avoid caffeine altogether?

Feinglos: We do that in the clinic now. We always ask them about their caffeine intake. In people with poorly controlled diabetes, the first thing we tell them is to cut back on the caffeine. Very often, we’ll see a significant improvement in glucose levels without taking any other action.

EBDM: What is the range of glucose level improvement that you see with this action alone?

Feinglos: In the studies that we’ve done, fasting glucose levels don’t change very much, but postprandial levels may drop 20% or more. To put that in context, that sort of reduction caused by an investigational drug will ordinarily be enough for the FDA to approve its use.

EBDM: There’s obviously good reason to follow up on this research, despite the opposition of Starbucks!

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