Researchers Studying Diabetes Find a Possible Cause of Infertility
For about one in 10 couples that cannot conceive a child, their reproductive
problem falls under the broad category of “idiopathic infertility,” meaning the
cause remains to be determined. But these idiopathic problems are gradually giving
way to discovery and, in the February issue of the journal Endocrinology, scientists
at the National Institutes of Health and colleagues report that in the course
of animal studies to understand diabetes, they may have uncovered a previously
unknown cause of infertility in women.
The scientists report that some female reproductive problems might involve the
so-called dense core vesicles, the protein packaging that encases insulin and
other secreted hormones. Whereas researchers traditionally have been most interested
in the hormonal content of the vesicles, the team discovered the structural components
of the vesicles play a subtle and until now overlooked role in the secretion
of reproductive hormones from the pituitary gland that stimulate the release
of eggs from the ovaries, or ovulation.
The researchers said this finding is potentially important because, when they
deleted genes that encode two major proteins in the protective outer membrane
of these vesicles, female mice were born infertile. “What’s particularly interesting
is the deleted proteins, called IA-2 and IA-2 beta, also are structurally important
for dense core vesicles in people,” said Dr. Abner Notkins, a scientist at NIH’s
National Institute of Dental and Craniofacial Research (NIDCR) and senior author
on the paper. “That’s why it’s very likely that alterations in these and possibly
other genes that are needed to produce well functioning dense core vesicles would
have similar effects in people.”
Dense core vesicles are key components of our neuroendocrine cells, or cells
that secrete hormones and other signaling proteins into the bloodstream. Under
a laboratory microscope, these hormone-containing vesicles look like tiny granular
specks that shuttle from the cytoplasm to the cell membrane. There, the vesicles
aggregate until the appropriate signal arrives to stimulate the release of their
hormone content into the circulation. The release of hormones from these vesicles
marks an important, tightly controlled event in regulating a variety of biological
processes, including blood glucose and reproductive cycles.
This month’s finding is a classic case of an experiment taking an unexpected
scientific twist. According to Notkins, his laboratory has a longstanding research
interest in the IA-2 and IA-2 beta proteins. In the mid 1990s, his group first
reported that increased levels of autoantibodies against IA-2 in particular are
strongly associated with an increased risk for Type I diabetes. Today, research
laboratories around the world use the measurement of autoantibobies, including
those to IA-2, to predict a person’s likelihood of developing Type I diabetes.
However, the precise function of these proteins has remained unclear. To solve
this issue, Notkins and colleagues created “knockout” mice, a standard laboratory
strategy in which a specific gene of choice is inactivated. In this case, they
created litters of mice that lacked the IA-2 gene, IA-2 beta gene, or both. The
hope was the mice would have some obvious visual manifestation of what happens
when the gene is lacking, offering a clue into each gene’s normal function in
the body.
“When knockout mice are born, we routinely examine them for a variety of biological
features, including fertility,” said Dr. Atsutaka Kubosaki, an NIDCR scientist
and lead author on the paper. “We found most of the female mice that lacked both
the 1A-2 and IA-2 beta genes not only had some characteristics of disordered
glucose metabolism, they failed to ovulate and were essentially infertile. That’s
when we decided to halt some of our other studies and try to find out why the
knockout mice produced so few offspring.”
In collaboration with Drs. Anne Clark and John Morris, scientists at Oxford
University in England and authors on the paper, the NIH researchers found these
mice had totally abnormal reproductive cycles and could not ovulate. This raised
the possibility that changes in the dense core vesicle caused the pituitary gland
to secrete insufficient luteinizing hormone to trigger ovulation. They soon found
this was the case and, when they treated the knockout mice with luteinizing hormone,
ovulation did occur.
“Although we need to define further the roles of IA-2 and IA-2 beta in the secretion
of dense core vesicles in the pituitary gland, our results do suggest an important
role for these proteins in the control of ovulation, which should be considered
in women with an unsolved reproductive problem” said Dr. John Morris.
The National Institute of Dental and Craniofacial Research is the nation's
leading funder of research on oral, dental, and craniofacial health.
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