A protein in the pancreas is giving researchers at the Stanford University School of Medicine their first chance at cracking the code that determines how diabetes develops during pregnancy, a finding that could lead to new treatments for all forms of diabetes.
The study may help explain why roughly 5 percent of women develop diabetes temporarily while pregnant, a condition called gestational diabetes. That condition is a leading cause of birth defects and can predispose the child to develop diabetes later in life.
"The basis of gestational diabetes has been a black box," said Seung Kim, MD, PhD, associate professor of developmental biology and senior author on the study. The results will be published in the Nov. 2 issue of the journal Science.
The protein Kim and his colleagues studied, called menin, was already known to have a role in preventing cancer in the pancreas and other organs. When menin is present it blocks the growth of pancreatic cells and, in that way, prevents cancer.
However, cells of the hormone-producing part of the pancreas, called the islets, need to grow in pregnant women or when people gain weight as a way of providing enough insulin for the burgeoning supply of cells. The increase in pancreas islet cells provides the additional insulin needed for the cells of the body to take up sugar from the blood. After a pregnant woman delivers her child, the pancreatic islets return to their original size.
According to Kim's work in mice, the pancreas accomplishes that adaptive growth by producing less menin during pregnancy. With less of the brake present, the pancreatic islet cells can divide, and this growth provides the additional insulin. Within a week after delivery the menin levels in the mice were back up to normal and the pancreatic islets began shrinking to their original size.
When Kim and postdoctoral scholar Satyajit Karnik, PhD, first author of the study, created mice that produce too much menin, the islets couldn't grow sufficiently during pregnancy and the mice ended up with gestational diabetes.
"This suggests that there is an internal code for controlling pancreatic islet growth, a code we intend to crack," Kim said. That code appears to be regulated partly by the level of menin.
Kim's group also showed that a natural way of regulating the amount of menin present in the pancreas is through a hormone called prolactin, which is abundant in pregnant women. Other researchers had previously shown that prolactin during pregnancy stimulates the islet cells to start dividing, but how it accomplished this stimulation was unclear.
Kim and Karnik suspected menin might be the link other researchers had been looking for. To test that idea, they gave prolactin to nonpregnant mice. As predicted, menin levels dropped and the pancreas increased in size, mimicking what is seen during pregnancy.
Kim said that although most of this research relates to menin regulation during pregnancy, similar forces may be at work in obese adults with diabetes. He and Karnik found that obese mice have less menin in the pancreas than mice at a normal weight. That finding suggests that menin may have a central role in obesity-related diabetes as well.
Kim said prolactin may be just one way of regulating menin levels and as a result regulating pancreatic growth. Other hormones may be involved in increasing or decreasing menin in nonpregnant adults.
Understanding the mechanisms of regulating menin should lead to new ways of growing islets for transplantation into people with type-1 diabetes and could lead to new treatments for diabetes in pregnant women or obese adults, Kim said.
Gestational diabetes, which is on the rise nationwide, is becoming more recognized as a significant risk to mothers and their babies. Sen. Hillary Rodham Clinton, D-NY, recently cosponsored a bill aimed at devoting more funding to understanding, preventing and treating the disease.
The work was funded by a Kirschstein Postdoctoral Fellowship, the Stanford Regenerative Medicine Training Program, the Stanford Medical Scientist Training Program, the American Diabetes Association and the National Institutes of Health.
Other Stanford researchers involved in the study include postdoctoral scholars Hainan Chen, PhD, and Michael H. Yen, MD, PhD; research associate Graeme W. McLean; MD/PhD student Jeremy Heit; research assistant Xueying Gu; Andrew Zhang, and assistant professor of pathology Magali Fontaine, MD, PhD.
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