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.