Gene Linked to Faulty Insulin Production in Down Syndrome and Type 2 Diabetes Identified

Individuals with Down syndrome and those with type 2 diabetes have one thing in common — dysfunctional insulin secretion in pancreatic beta cells. Now researchers have identified a gene, involved in mitochondrial function, controlling this disturbance in both conditions. In addition to explaining the high rates of diabetes in people with Down syndrome, the finding might offer new insights into the development of type 2 diabetes in adults.

Down syndrome — the most common genetic disorder in the world — results when an individual carries three copies of chromosome 21 instead of the usual two. Sometimes the whole chromosome is present as an extra copy, but the presence of parts of it also give rise to Down.

Diabetes in people with Down is common, and scientists have not figured out why, although dysfunctional mitochondria and high levels of oxidative stress in the beta cells accompany the insulin dysfunction — just as they do in type 2 diabetes.

A research team at Flinders University in Australia took on a new approach when trying to figure out if there might be genetic factors linking the two conditions. Starting with four mouse models of Down — two with high blood glucose and two without this feature — the team screened the mice looking for genes on the 21st chromosome that might be involved in producing the insulin deficits. This approach allowed the team to home in on a part of the chromosome.

Armed with the information collected, the researchers turned to data from human beta cells, derived from type 2 diabetics, where the team had previously identified about 5,000 gene expression changes.

The attempt to find a match between mice and humans hit the bull’s eye. Findings, published in the journal PLOS Genetics, revealed the identification of a single gene, RCAN1, present in both the Down syndrome mice and type 2 diabetic human beta cells. The factor was also present in high levels in beta cells of a diabetes mouse model, and when normal mice were exposed to high levels of glucose, RCAN1 protein levels peaked.

Mice overexpressing the gene reacted with lower insulin secretion when stimulated with glucose. Researchers also noted that the cells held dysfunctional mitochondria, observed in both type 2 diabetes and Down syndrome. The mitochondrial dysfunction was also directly linked to lower insulin production.

The study, “A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to β-Cell Mitochondrial Dysfunction in Type 2 Diabetes,” used an approach presenting an enormous advantage compared to blindly investigating thousands of genes. This method could also be used to track down genetic causes of other health conditions affecting individuals with Down.