A new study by Columbia researchers has uncovered a previously unknown mechanism that allows insulin-producing cells to function properly. As the only source of insulin in our bodies, the pancreas’s beta cells must accurately sense the levels of glucose in the blood and respond by releasing just the right amount of insulin. Type 2 diabetes ensues when beta cells malfunction and can’t secrete enough insulin to match the body’s increasing needs.
About 100 variants in the human genome have been linked to type 2 diabetes, yet only a few genes associated with those variants have been identified. The causative genes have been difficult to identify because most of the variants occur in regulatory regions far away from genes. In such cases, it can be difficult to determine the gene impacted by the variant.
Using a combination of chromatin immunoprecipitation studies, RNA analysis, and comparison of human and experimental animal data on super-enhancers (chromosomal loci with ability to regulate important cellular processes through hubs of transcription factors), the researchers — led by Taiyi Diana Kuo, PhD and Domenico Accili, MD — identified a previously unknown gene, C2cd4a, which they proceeded to functionally analyze with genetically engineered animal models.
The experiments showed that the C2cd4a gene plays an important role in insulin secretion. When the C2cd4a gene was removed from the beta cells of mice, the cells could not secrete enough insulin to meet the mice’ demands, similar to the way cells behave in people with type 2 diabetes.
C2cd4a impacts insulin secretion by suppressing certain genes that are “disallowed” in normal beta cells. (If these disallowed genes are active, beta cells cannot accurately measure the amount of glucose in the blood and therefore cannot secrete the right amount of insulin).
Since C2cd4a regulates insulin secretion, it may be an attractive new target for diabetes therapies. The techniques that Kuo developed to identify C2cd4a provide a blueprint that other researchers can follow to identify still hidden genes associated with type 2 diabetes and other complex diseases.
