Tuesday, May 12, 2009

Bromocriptine and Hibernation

The Food and Drug Administration recently approved the drug bromocriptine mesylate for use in treating diabetes.

The drug works on dopamine receptors in the brain to produce the same effects as dopamine would produce. For this reason, it's been used in dopamine-deficiency diseases like Parkinson's disease for some time.

In other words, it's not a new drug. It's a new use of an old drug.

But why, you might wonder, would a drug that works on dopamine receptors in the brain do anything for diabetes, which is a disease that causes blood glucose (BG) levels to be too high?

This is because there is some evidence that insulin resistance and obesity are regulated in part by the brain.

One example of this is the phenomenon of hibernation or, in some species, what is called torpor, a shorter period of reduced temperature and slower metabolism. Animals that hibernate typically put on a lot of weight in the late summer and fall. They also have increased insulin resistance.

People who believe that obesity is simply a case of eating too much and not exercising enough, causing obesity that in turn causes insulin resistance, would say this is what is happening in hibernating animals. There's a lot of food in the late summer and fall so the animals pig out and get fat, and the fat causes the insulin resistance, they'd argue.

But here's the interesting part. Ground squirrels normally put on a lot of weight in the fall. They also eat a lot more. But if you keep the squirrels in the laboratory and don't let them eat any more than normal, they'll put on weight anyway, mostly fat.

In other words something, most likely hormonal signals triggered by changes in daylength, are telling the squirrels to store fat. Because they're storing the fat instead of letting it hang around in the blood to be burned for energy, they have an energy deficit, and this makes them hungry.

This is consistent with the theory of weight gain described by Gary Taubes in his book Good Calories, Bad Calories. He says the "energy balance" equation so beloved of dieticians who use it to say that the only thing that matters is calories in and calories out is true, but the cause and effect have been reversed. This equation says:

Change in weight = energy in - energy out.

The dieticians would say if you change the right hand side of the equation, reducing energy in or increasing energy out, your weight will change. To some degree, this is true in extremes or for the short term, when an animal or person has no access to enough food, as in starvation, or has super willpower because of a belief that the latest diet will really work. But when food is available, the drive to eat becomes overpowering and any lost weight will be regained.

Taubes and other argue that some external force, mostly likely hormones or nervous system signals (Taubes argues that it's insulin) affects the left-hand side of the equation. This causes extreme hunger or lethargy, or both, as the body tries to balance the equation.

In other words, the net energy change is not causing the weight change, but the weight change makes the body try to balance the equation by creating an overwhelming desire to eat and aversion to exercise.

When food is available, the animal or person will thus eat more than normal and exercise less. But if you don't let them eat more than normal, they'll still store the fat. They'll just be very hungry and lethargic.

Furthermore, animals are not machines. Energy in from the same food can differ depending on the efficiency of digestion, and energy out can vary with the efficiency of transforming food into forms of energy the body can use. Some people turn excess calories into heat instead of turning them into fat.

So where does bromocriptine come into all this?

Syrian hamsters normally become insulin resistant and gain a lot of weight before they hibernate; these effects are blocked by bromocriptine. Similar effects were seen in obese women: glucose and insulin levels decreased and energy expenditure and fat burning both increased, although body weight did not change in this 8-day experiment. And other researchers
found that bromocriptine helped people with type 2 diabetes.

Some authors see hibernation as a model for insulin resistance, and the more we learn about what triggers the weight gain in hibernating animals, the more we'll know about what triggers insulin resistance and weight gain in obese humans.

They suggest that hibernators have a sliding set point. The con
cept of a set point is that the body has a certain weight that it wants to be, and if you go over or under that weight, you will have a strong urge to eat more if you're under the set point or eat less if you're over the set point. Instead of having one set point, hibernators have different set points depending on the time of year.

There are reasons to believe that bromocriptine might help people who have serious problems with obesity and insulin resistance. The drug has been around for a long time to treat other diseases, so we have a better idea of side effects than we do with brand-new drugs. And there are side effects.

The Mayo Clinic has a good outline of some of these side effects. They note that they're more apt to occur in older people, and can include confusion and hallucinations (the drug is an ergot alkaloid). This is a powerful drug, and I doubt that many physicians would prescribe it as the first choice when someone is diagnosed.

But for a person with a serious weight problem that isn't helped by other measures as well as uncontrolled BG levels, the drug might be worth a try, keeping a close watch to make sure no serious side effects occurred.


  1. It's heartening to see one more person who understands the "energy balance". One day we'll all get there. :-)

  2. It's plausible that not only hibernation but also migration is behind the switching from high insulin fat storage mode to low insulin fat utilisation mode.

    Many birds in northern Europe, Sedge Warblers are a prime example, cross the Sahara to winter in Africa. Before making this journey they may double their body weight. They do this by eating high carb insects - plum reed aphids stuffed full of the sugars from the plant sap, then they use the fat as fuel for the journey.

    That's another reason why Type 2 diabetes might have evolved to be a reversible condition in other species, and in our case the reversal mechanism is stuck. Incretins may be a factor in coupling and decoupling insulin levels with food intake.

    SAD and similar forms of depression may also be a factor in inducing torpor. Bromocriptine has also been used off label as a depression treatment.

  3. GK, I'm afraid I'm sort of pessimistic about the chances of everyone understanding the energy balance equation. It's counterintuitive, and the distinction between relation and cause is so difficult for so many to understand.

  4. Trinkwasser, I think IR evolved for many reasons. One is to allow some tissues access to glucose and others not, for example, denying the muscles easy access to glucose when it's in short supply so the brain can get what it needs.

    The reversible IR that seems to be involved with hibernation and migration is another.

    But I don't think type 2 diabetes (pathological BG levels) was ever an "intentional" (evolution is never really intentional; hence the quotes) result but a normal process that got out of kilter and then became irreversible.

    Remember that in type 2 diabetes, many beta cells are destroyed. Like cancer, that's not something any organism wants.

  5. I think we're on the same page, just facing in opposite directions! Yes it remains reversible in other species (remember those diabetic mice who seem able to grow new beta cells?) but we didn't inherit the full gene set and once the BG goes up and stays up for long enough the process turns into a chain reaction of destruction rather than just a temporary switch off/downregulation

  6. Trinkwasser, humans are also apparently growing new beta cells. They're just being destroyed faster than they're growing.

    That's the basis of Dr. Kaufman's research into curing type 1. She's hoping to turn off the destruction to allow the new beta cells to grow. It seems to work in mice, as do so many things.

    As for inheriting "the full gene set" I'm not sure what you mean. We undoubtedly inherited a mutated gene or two.

  7. Isn't it annoying when you go looking for something and by the time you find it you forgot what you wanted it for?

    Thia paper


    is hard going but worthwhile, they go into the complexities of the various mechanisms involved in Metabolic Syndrome, and what they appear to be saying is that a lot of these mechanisms have a U curve or J curve, where up to a point they are adaptive but when you exceed that point they cause crash and burn.

    If you hit the brakes hard you can stop really quickly. If you hit the brakes harder than that you skid, lose traction and steering and after that anything can happen.

    Our current environment is pushing these genes beyond the parameters where their actions are beneficial into the area where the same mechanisms become destructive.

  8. Very interesting discussion. The primary findings of the large clinical safety and cardiovascular trial are now available online at Diabetes Care.

    You are correct that all vertebrate (migratory, hibernating, over winter or not) species have the capacity to transition from summer lean to winter obese condition (insulin sensitive vs. insulin resistant) - only humans figured out a way to keep us locked in what was supposed to be a transient state long enough so that we destroy our insulin making capability and damage our body.

    A single musician in an orchestra can completely ruin the music of a symphony if he is out of synchrony with the other players. Likewise, if the body’s millions of complex chemical reactions are not in synchrony with each other then disharmony ensues. In humans, it is the important role of the neuroendocrine system to synchronize these many cellular reactions into a circadian, or 24-hour, rhythm so that the entire body is temporally organized internally with its cyclic environment. As the conductor is to the orchestra, the suprachiasmatic nuclei (SCN) of the hypothalamus are the seat of the biological clock that regulates neuroendocrine control of physiology for the entire body. The SCN naturally have the ability to generate either a circadian neuroendocrine organization that produces the normal-insulin sensitive state or one that produces the diabetic-like insulin resistant state. Which of these states results depends upon the biochemical information the hypothalamus receives from the body or from external factors including photoperiod, stress, and diet. In nature, the shift to and away from the diabetic condition is synchronized to the seasons of year when food availability is low and high respectively. In humans the “western lifestyle” provides a milieu for neuroendocrine signals that promote the insulin resistant state. A key brain modulator of the insulin sensitive/insulin resistant condition is dopamine. In the insulin resistant state, dopaminergic activity within the hypothalamus, particularly the normal daily circadian peak within the suprachiasmatic nuclei, is diminished. This diminished dopaminergic tone is coupled with several alterations in hypothalamic neural activities that result in the diabetic state. Time-pulsed administration of the dopamine D2 receptor agonist, Cycloset™, to patients with type 2 diabetes increases hypothalamic dopaminergic tone at the appropriate time of day. This “neuroendocrine resetting” therapy approximates the insulin sensitive neuroendocrine state, which in turn improves insulin resistance and glucose intolerance as well as a host of other cardiometabolic risk factors (i.e. blood pressure and lipids).

  9. Anonymous: Do you have a link for the Diabetes Care article?

    You seem to know a lot about this. Do you have a name? You can e-mail me privately if you don't want to go public.

  10. http://care.diabetesjournals.org/content/early/2010/03/20/dc09-2009.abstract?abspop=1&patientinform-links=yes&legid=diacare;dc09-2009v1

    I am the senior author on the paper.

  11. hello, the points you make about animals' bodies changing in response to hibernation (presumably in response to daylight hours) are interesting.

    what are your thoughts on this interview (http://fatnews.com/index.php/weblog/comments/4135/) where the good doctor suggests that quick-release (ergoset) causes weight loss while slow-releasing (parlodel) doesn't

    also on the same web: bromo caused weight GAIN in lean people (http://fatnews.com/index.php/weblog/comments/4407)
    it seems very, very sketchy and drug doses as well as participants' calorie intakes are not provided.
    have you come across any similar studies to back this up?

  12. Anonymous: I somehow missed your comment in 2013. But note that the Diabetes Care study used bromocriptine-QR, meaning quick release.