A paper in the Nov. 2, 2007, issue of Science reported that the tumor suppressor menin acts as a regulator under happier growth conditions as well. Researchers at Stanford University show that menin regulates islet cell expansion during pregnancy.
Pregnancy is a well-known emotional roller coaster, but it's also a metabolic one. The body copes with a combination of rapid weight gain and reduced sensitivity to insulin by expanding its supply of pancreatic beta cells. In about 5 percent of pregnancies, though, it does not cope well enough, and gestational diabetes results.
Mutations in menin are known to be a cause of endocrine tumors, and this led the authors of the Science paper to hypothesize, as they wrote in their paper, that "physiological changes in [menin] expression might regulate facultative maternal beta-cell growth in pregnancy" as well.
The researchers first checked menin levels in pregnant mice, and found that menin was reduced during pregnancy; mice engineered to continue producing high levels of menin during pregnancy developed gestational diabetes.
They found that while islet cells from menin-overexpressing pregnant females were quite capable of secreting insulin, there were fewer of such islet cells around to secrete insulin in the first place.
Mechanistically, menin appears to work, in a complex with other proteins to methylate a specific histone, which ultimately controls the levels of two other regulatory proteins, p18 and p27. "I think of menin as the brake pedal and p27 and p18 as the brake pads," senior author Seung Kim, associate professor of developmental biology at Stanford University, told BioWorld Today.
Finally, the researchers found that obese mice have lower levels of menin than normal-weight mice, suggesting that menin could be involved in Type II diabetes as well as gestational diabetes.
Gestational diabetes, though it resolves after delivery in most cases, also is a predictor of regular diabetes later in life. Kim said that the results may explain why. "Even if people resolve . . . you still have this inherent capacity to respond, or not, to stresses," Kim said. And when other such stresses come along - be they too much Halloween candy, or plain old aging - diabetes can again result.
Kim said there are "two broad ways" in which the results could find therapeutic applications. First, menin levels could be used to identify people at risk for gestational diabetes, and perhaps prevent it.
Second, the findings might help researchers figure out how to grow human islet cells for transplant. Islet cells divide when they are stimulated by prolactin, another pregnancy hormone. But from a clinical perspective, the production of functional islet cells "has failed miserably, in part, because we don't know the natural processes underlying islet expansion," Kim said.
Actually, islet cell expansion hits a particularly frustrating snag. Kim's colorful explanation is that "they lose their mind." In other words, islet cells divide in response to growth factors, but "they forget who they [are] and stop producing insulin."
In their paper, when Kim and his colleagues gave prolactin to nonpregnant mice, menin levels dropped and the pancreas increased in size, mimicking what is seen during pregnancy and suggesting that manipulating menin could help produce functional islet cells for transplant.
As a first step toward any therapeutic use, Kim thinks his paper could help change the attitude about targeting the protein, which is currently pretty skeptical. "Menin is not only a tumor suppressor, but a natural regulator of growth," he explained. "Before, people have had a kind of knee-jerk reaction to the idea of reducing [menin]. But in a couple of settings, reducing it is a natural outcome."