Sunday, November 22, 2009

Serotonin and Insulin Secretion

Most of us have heard of serotonin (5-hydroxytryptamine, or 5-HT) as a neurotransmitter. It's the compound that is affected by the SSRI antidepressants.

Nerves use neurotransmitters to transmit messages from one nerve cell to the next. The nerve's signal arrives at the end of one nerve, which then secretes a neurotransmitter. This diffuses across the tiny space between the nerves and is taken up by the next nerve. The neurotransmitter is then reabsorbed by the first nerve and can be used again. The reabsorption also prevents the signal from becoming permanent.

The SSRIs slow down the reuptake of the neurotransmitter so its effects last longer. Serotonin can affect mood, and low levels can cause depression. Hence keeping it around longer by means of the SSRI drugs can reduce depression.

So what does all this have to do with diabetes?

A fascinating new article that appeared in the open-access journal
PLOS recently shows that serotonin in beta cells is required for insulin secretion. A summary of the article appears here.

Apparently it's been known for 30 years that serotonin is synthesized in beta cells and cosecreted from the beta cells along with insulin, but no one knew why, and most textbooks -- even comprehensive ones -- didn't even mention this fact.

But this German research group showed that mice unable to produce serotonin outside the nervous system became diabetic. Infusing them with serotonin corrected the problem.

So all we have to do is take serotonin tabs and all our problems will disappear? Unfortunately, no.

The crucial factor here is whether the serotonin is inside the cell or outside the cell. High serotonin inside the cell stimulates insulin release. High serotonin outside the cell inhibits insulin release. It's the ratio that is important.

So when internal serotonin levels are high, insulin and serotonin are cosecreted. The secreted serotonin then inhibits further insulin release. Gradually the secreted serotonin is taken up again by the beta cells, until there's more inside the cell than outside the cell. Then the cell can secrete more insulin.

The authors postulate that this system is responsible for the well-known insulin pulses that occur in nondiabetic people between meals. This pulsating pattern is lost in people with type 2 diabetes.

This research is also fascinating for a more general reason. Most water-soluble hormones like serotonin, histamine, and the catecholamines were thought to work at the surface of the cell. They bind to a surface receptor in the membrane, causing conformational changes that affect the metabolism inside the cell. This is true of insulin, for example.

Other hormones, the lipid-soluble ones like thyroid hormone and the steroid hormones, get inside the cell and bind receptors in the nucleus, changing the expression of genes.

But this study showed that serotonin works inside the beta cell in a very different way. It doesn't just bind to a receptor. Instead it works by actually forming bonds with other compounds in the cell, called
serotonylation. This action is very different from the way serotonin works as a neurotransmitter.

Serotonylation had previously been found in platelet-forming cells and in smooth muscle cells. Finding it in beta cells suggests that it may turn out to be a general property in many kinds of cells.

This will open the door to a lot more research on how hormones work as well as research to find new drugs that work to control hormone action.

And I hope it results in new treatments for diabetes of all kinds.

Saturday, November 21, 2009

Glitazones and Weight Gain

Many people who take a glitazone drug -- pioglitazone (Actos) or rosiglitazone (Avandia), also known as TZDs (thiazolidinediones) -- find that the drug works well to lower their blood glucose (BG) levels, but it also seems to make them gain weight.

Some doctors will say that the weight gain is simply fluid retention, which is a known side effect of the TZDs. That did happen to me when I was in a short clinical study of Avandia. I put on about 6 pounds during the study, but I lost them without effort when I went off the drug at the end of the study.

But the TZDs are also supposed to trigger the differentiation of precursor cells into new fat cells. The new, small fat cells aren't stuffed with fat like some of the older, large fat cells, and they're more responsive to insulin. Hence they take up more glucose, and this keeps the BG levels down.

Several recent studies have shed more light on the weight gain that occurs with the TZDs.

One study, published in the Journal of Biological Chemistry, showed that in obese mice, at least, rosiglitazone increased the expression of the VLDL receptor gene in fat cells. VLDL is the type of cholesterol particle that carries fats from the liver to the various organs that use it.

With more VLDL receptors on the fat cells, more VLDL would get bound to the fat cells, which would take up more fat. And the mice did, in fact, get fatter than the control mice, although their insulin resistance decreased.

They also showed that in certain mutant mice that couldn't bind VLDL, the effect on insulin resistance was preserved, but the mice didn't gain any weight, meaning it would be possible in theory to separate the effects on BG levels from weight gain.

Another study, in the journal
Clinical Endocrinology and Metabolism, showed that pioglitazone treatment enlarges subcutaneous fat cells in insulin-resistant patients.

This is rather ironic, because obesity-related insulin resistance is associated with large fat cells, and TZD therapy is supposed to result in the birth of smaller fat cells. But in this study, although insulin resistance decreased, the size of the fat cells increased with the TZD treatment.

The TZDs work by stimulating a nuclear transcription factor called
PPAR gamma. A third article described a study in humans in which they separated patients into TZD responders and TZD nonresponders. Previous studies had suggested that about 30% of patients do not respond to the TZDs.

They found that in insulin sensitive people, those without insulin resistance, feeding resulted in the expression of many genes involved with glucose metabolism. This response was blunted in people with insulin resistance.

In the insulin resistant people who responded to a TZD, the drug caused an increase in the genes that were stimulated in the insulin sensitive people. In the insulin resistant nonresponders, the expression of the same genes was not changed.

But they also noted that fat cell gene expression in muscle increased after TZD treatment, especially in those people who responded to the drug, suggesting that the decrease in insulin resistance in the drug responders was caused by more fat cells in the muscle tissue.

Hence they suggested that the fat infiltration often seen in the muscles of insulin resistant persons may not, in fact, be causing the insulin resistance. Rather, they suggest, the fat cells are absorbing extra calories from overeating and are attempting to reduce the insulin resistance.

All these studies -- and I'm sure there are many more -- are consistent in suggesting that the TZDs
do work by increasing the amount of fat in the body, both subcutaneous fat and fat in muscle tissue, and perhaps elsewhere as well.

They are consistent in suggesting that the TZDs work by stimulating this increased amount of fat while at the same time reducing insulin resistance. If you're taking one of these drugs and you gain weight, don't let your doctor tell you that you're not watching your portion sizes. The drug is probably causing the weight gain.

However, the one study suggested that these two effects could be separated, although no one knows how yet.

The last study also notes the difference between drug responders and nonresponders. The TZDs don't work for everyone.

Most drugs can have both good and bad effects. For example, it turns out that the fat cell precursor cells that the TZDs stimulate to differentiate into baby fat cells are the same ones that can be turned into bone-forming cells. When you produce more fat cells, you produce fewer bone-producing cells. Hence the TZDs can contribute to bone loss, or osteoporosis.

As with all drugs, we need to weigh the pros and cons of the TZDs in light of our own particular situation. First, do they work to reduce BG levels when we take them? Or are we nonresponders? No point in risking side effects if the drug isn't working for us.

Second, are we unhappy with the amount of weight gain that results from the drugs?

Third, are we at high risk for osteoporosis so even a small loss of bone-producing cells might have terrible consequences?

Diabetes is complicated, and there are no simple answers. But the more we understand about how these drugs work, the better the decisions we can make about which drug or drugs work best for our own particular physiology.

Friday, November 20, 2009

On the Popular Press

Does the popular science press help us all by spreading the word about new research? Or is it causing harm by distorting the facts?

I spent 8 years as a reporter/editor working for a small daily newspaper in Vermont, and I'm familiar with the stock complaints about the press. We heard them every day.

"You're blowing it out of proportion." Or "You just want to sell papers." Or "You misquoted me." I was once accused of misquoting a politician because I reported only what he said at a meeting and not what he had intended to say!

So I hate to jump on the "tar the press" bandwagon myself. But sometimes things really go too far.

One thing that has angered me lately is the tendency of the popular science press to blame everything on fast-food gluttony. Whenever there's an article about overeating, for example, they illustrate it with a gargantuan cheeseburger accompanied by a bucketful of French fries. Don't they know it's possible to overeat on chicken and tofu as well?

A recent Science Daily article here really went too far. This one concerned a study showing that a high-calorie diet may accelerate age-related disease. The article was illustrated by a man with a huge plate of french fries. He was eating with his hands, which were covered in catsup. There was also catsup on his face, as if he'd been grabbing the fries and stuffing them in so fast that he got catsup all over everything.

Apparently I wasn't the only person who was fed up with this sort of thing. I see that the current iteration of the story illustrates the other extreme: a plate with very little food: one shrimp, a third of a spear of asparagus, and a mushroom.

And it's not just the popular press that blames everything on fast-food gluttony. Scientists themselves tend to single out those factors.

This Science Daily story was about a study showing that people in their 60s today have more disabilities than previous generations. What do the researchers blame this situation on? Immigrants and fat people, of course.

They say that "disabilities may be linked with the changing racial and ethnic makeup of the group that recently reached or will soon be reaching its 60s, with the most rapid growth projected to be among African Americans and Hispanics -- groups with significantly higher rates of obesity and lower socioeconomic status, both of which are associated with higher risk for functional limitations and disabilities.

It's true that very extreme obesity would be likely to make people less likely to walk a quarter of a mile or climb steps. But a lot of people in the "obese" category of BMI are as fit as their thinner counterparts. Maybe the real change is that no one, thin or fat, tends to walk anywhere these days when most people have cars.

And finally, popular science writers obviously don't do any fact checking of science press releases at all. A currently hot topic in the popular press is a recent study in which some researchers did MRI on some mummies and found evidence of heart disease, as reported here. The reporters were agog.

As one said, this new study challenged "longstanding assumptions that cardiovascular disease is mainly a malady of modern societies." But low-carb author Michael Eades discussed the evidence for cardiovascular disease among ancient Egyptians in his book Protein Power, first published in 1996. And apparently the first report of aortic calcification in ancient Egyptians occurred in 1852, as a result of a study by a scientist named Czermack, as discussed in the book Mummies, Disease, and Ancient Cultures.

Let's see. That's only about 150 years ago, but scientists continued to believe that cardiovascular disease is "often attributed to urbanization, fast-food diets, smoking and sedentary lifestyles characteristic of Western societies," according to the Wall Street Journal article. Notice the reference to fast-food diets again. The assumption of the reporter is that all of society's ills are caused by fast food.

Because the Egyptians didn't have fast food, as far as we know, however, they then blame it on the fact that the upper classes (and of course the lower classes, who ate mostly bread and onions, weren't mummified) ate meat "from cattle, ducks, and geese." Again, the bias is that the only healthy diet is one devoid of meat.

I'm quite aware that the reporters who write these popular science article are most likely under tight deadlines. Maybe they have to produce X number of stories per day in order to keep their jobs, so they don't have time to do even quick Internet research on the topic, and they simply print the press releases that flood in every day.

Nevertheless, the biases that are so obvious not just among the science reporters but among the scientists as well (surely they knew that finding evidence of cardiovascular disease in mummies was nothing new; what was new was the technique they used to find it) makes the rest of us sceptical about anything we read.

I think the science reporters and even the scientists who do the research are shooting themselves in the foot.