The cause of diabetes during pregnancy is directly controlled by serotonin, a chemical produced by the body and normally known as a neurotransmitter, and is influenced by the amount of protein in the mother's diet early in pregnancy, according to new findings of an international team led by researchers at UCSF.
The surprise discovery could lead to simple dietary solutions and possible therapeutics for the disorder known as gestational diabetes, which if untreated, has serious implications for both mother and child. It also offers new insights into possible ways to reverse non-gestational diabetes in its early stages, the researchers say.
The findings will be reported in an upcoming issue of "Nature Medicine" and are available June 27 via Advance Online Publication at http://dx.doi.org/10.1038/nm.2173.
Scientists have puzzled for decades over the fact that the onset of pregnancy causes a woman to double the number of insulin-producing islet cells in her pancreas, according to UCSF Professor Michael German, MD, who is senior author of the paper. While that increase ultimately enables the mother to control the flow of nutrients to the fetus during its final growth spurt in the third trimester, the islet cell production occurs long before those nutrients are actually needed.
Until now, no one has known what caused that change. Clearly, German said, it is not stimulated by the need for nutrients at the time it occurs, so something else had to be causing it. That has made it of great interest to researchers studying gestational diabetes, in which too little insulin is produced, as well as type I diabetes, in which islet cells are killed off. German's team set out to find out why.
Using a genomic analysis of both pregnant and non-pregnant mice, the researchers conducted a broad scan of all of the genes that were turned either on or off in the islet cells during pregnancy. At the top of the list, he said, was tryptophan hydroxylase (Tph1), the enzyme that produces serotonin from the amino acid tryptophan. In the newly pregnant mice, that enzyme rose exponentially.
"This is really novel," said German, who is a member of the UCSF Diabetes Center. "This was not an expected finding and we really stumbled upon it. To see a gene go up 1,000-fold that we didn't know was involved is very rewarding."
Because serotonin is made from tryptophan - an amino acid that comes from high-protein foods such as milk, eggs, meat and fish - this result also provides a clear link between the amount and type of protein consumed by the mother early in pregnancy and the generation of islet cells needed to protect her against gestational diabetes late in pregnancy, when the fetal caloric needs are highest.
Serotonin has been widely studied as a neurotransmitter in the brain for its effects on appetite and mood, especially depression, and has generated numerous pharmaceuticals targeting both the receptors and inhibitors of the protein. Outside the brain, serotonin also is made in the gut and is critical in blood clotting and in liver regeneration.
Due to similarities between the insulin producing cells in the pancreas and certain types of neurons in the brain, German's laboratory had been collaborating for years with two faculty members in the UCSF Department of Psychiatry: John Rubenstein, MD, PhD, who studies fetal brain development, and Laurence H. Tecott, MD, PhD, who focuses on serotonin receptors and was a co-author on this "Nature Medicine" paper. Together, the three laboratories had been studying the developmental and functional similarities between serotonin-producing brain cells and insulin-producing cells.