Scientists discover TSG mutation causes islet cell production
after it was discovered that a mutation in a tumour suppressor gene
causes pancreatic islet cells to reproduce.
This discovery could not only further inform basic cancer biology, but also implications for treating Type 1 diabetes, a disease that affects 1 in 20 individuals worldwide.
Researchers from the >University of Pennsylvania School of Medicine, discovered that the loss of the protein, menin causes the production of pancreatic islet cells, which secrete insulin to regulate blood sugar.
Patients who suffer from MEN1 develop benign tumours or hyperplasia (over proliferation of cells) in several endocrine organs, such as parathyroids and pancreatic islet cells.
Normally, the menin protein has a tumour-suppressing or cell-proliferation-suppressing function. Loss of menin can cause proliferation of pancreatic islet cells, but not the adjacent exocrine cells that secrete proteins other than insulin.
In the study, researchers developed an animal model that allowed for precise timing in "cutting" the Men1 gene from the genome of knockout mice.
They showed that within seven days of excising Men1, pancreatic islet cells proliferated in the mice. Previously, other labs could only see proliferating islet cells after months of Men1 excision because they could not precisely time the process.
"Our results show an acute effect of Men1 excision and directly link Men1 to repression of pancreatic islet cell proliferation," said Xianxin Hua, senior author assistant professor of Cancer Biology at Penn's Abramson Family Cancer Research Institute.
The researchers excised Men1, the gene encoding the protein menin, from both islet cells and adjacent exocrine cells in the pancreas, but only in islet cells did they observe cells proliferating.
This is important because Men1 mutations largely cause endocrine hyperplasia or tumours, but not exocrine tumours. "Our results showing preferential effects on islet-cell proliferation could at least in part explain that the loss of menin only leads to endocrine tumours," said Hua.
In type I diabetes, the loss of islet beta cells is the leading reason why a sufficient amount of insulin cannot be produced.
"If we could eventually repress menin function to specifically stimulate beta-cell proliferation, this may facilitate devising new strategies to increase insulin-secreting beta cells and treating diabetes," he added.
"We did not expect the connection between a study about a tumour suppressor and a potential new avenue for treating diabetes," he adds. "By taking advantage of studying a genetically well-characterised tumour syndrome, MEN1, we set out to understand how the first step of benign tumour development is precisely controlled."
Hua added that the more they discovered about menin function, the better they understood the precise role of menin in regulating islet cell proliferation.
This latest finding about the acute and specific role of menin on repressing islet cells, but not adjacent exocrine cells, led to the realisation that manipulating the menin pathway might be a powerful way to stimulate islet cell proliferation to fight type I diabetes.
