Yale Researchers Demonstrate Specific Gene Can Cause Type I Diabetes

Yale researchers, for the first time, have shown that a particular gene can cause insulin-dependent, or Type I, diabetes.

The discovery was made when the researchers induced spontaneous diabetes by injecting an animal model with DQ8, a human gene long suspected to be a culprit in insulin-dependent diabetes.

The results were published Monday in the Journal of Experimental Medicine and clearly point to DQ8 as a starting place for studies into Type 1 diabetes prevention, said Li Wen, M.D., assistant professor of internal medicine with a specialty in endocrinology.

“This is the first time it has been shown in a living organism that HLA-DQ8 causes Type I diabetes,” said Wen, although scientists have known for two decades that there is a close association between HLA-DQ8 and insulin-dependent diabetes.

“Not only can we now study DQ8 in more detail in a living organism, this is also very important for work in preventing diabetes,” said Li, whose co-authors on the study were associate research scientist F. Susan Wong in the Department of Immunobiology, research assistants Jie Tang, Ning-Yuan Chen, Martha Altieri in the Department of Internal Medicine, as well as Richard Flavell, M.D., chairman of the Department of Immunobiology, and Robert Sherwin, M.D., director of the Yale Diabetes Endocrinology Research Center.

Type I diabetes is an autoimmune disease, which means it results from an immune reaction produced by an individual’s T- lymphocytes acting against the body’s own tissues. In this case, the pancreas is attacked and cannot produce insulin so the person must take insulin to compensate.

“Immunologists have found certain diseases, in particular, auto immune disorders, have a strong association with a particular MHC (major histocompatability complex),” which is one of the three main components in the immune system along with T- lymphocytes and antigens, Wen said. “DQ8 type of HLA (MHC in humans) is the particular MHC in Type I diabetes.”

The experiment conducted by her group used a transgenic mouse expressing the HLA-DQ8 gene together with another molecule, B7, which by itself does not cause diabetes. The mice spontaneously developed all of the classic signs of Type I diabetes - elevated sugar in their urine; abnormally high blood glucose results; increased thirst and obvious weight loss.

The researchers also studied mice with the HLA-DQ6 gene, a gene associate with resistance to diabetes in humans. These mice showed no sign of diabetes. The question that now can be investigated, said Wen, is whether DQ6 has a role in preventing diabetes from developing, a hypothesis that scientists also have proposed in the past.

“The ultimate goal is to find more effective interventions for the disease,” she said.