DNA chip technology helps with discovery of new type 2 diabetes gene

Using the newest DNA chip technology, scientists at Joslin Diabetes Center have discovered a new gene implicated in the cause of type 2 diabetes.

In a new study appearing in the August 12 issue of the journal Cell, the investigators first identified genes that were altered in their level of expression in islets isolated from people with type 2 diabetes. The researchers then went on to show that when they created a defect in one of these genes called ARNT in mice, the mice developed alterations in insulin secretion that were like those in humans with type 2 diabetes.

The ARNT (aryl hydrocarbon receptor nuclear translocator) gene is a member of a family of transcription factors essential for normal embryonic development and also is involved in response to conditions of hypoxia and certain environmental toxins, such as dioxin. Transcription factors like ARNT control the expression and activity of many other genes in the cell and thus serve as master regulators of cell function. As a component of the response to toxins and hypoxic stress, ARNT is also at a potential site to integrate genetic and environmental insults.

"While previous work suggested defects in other pathways in a small percentage of people with type 2 diabetes, what was unexpected was that the islets (beta cells) from all of the people with type 2 diabetes studied demonstrated a marked down-regulation of the nuclear transcription factor ARNT," said C. Ronald Kahn, M.D., President and Director of Joslin Diabetes Center and the Mary K. Iacocca Professor of Medicine at Harvard Medical School, who led the research team. "These findings provide new insights into the pathogenesis of the most common forms of type 2 diabetes and a possible new target for treatment of this disease," he said.

The investigators, including lead author Jenny Elizabeth Gunton, M.B.B.S., F.R.A.C.P., Ph.D., a C.J. Martin Fellowship recipient from Australia, then went on to demonstrate that reducing the level of the ARNT gene in beta cells in culture also produced defects in glucose-stimulated insulin release and alterations in islet gene expression that mimic those in humans with type 2 diabetes.

"This study represents the first use of DNA chips to study islets of diabetic patients and the first demonstration of an important role for ARNT and altered gene expression in impaired beta-cell function in the pathogenesis of human type 2 diabetes," Dr. Kahn said.

Type 2 diabetes is the most common human metabolic disease, affecting almost 200 million people worldwide, and is increasing at epidemic rates in the U.S. and worldwide. The pathogenesis of type 2 diabetes involves two defects: insulin resistance and impaired functioning of the insulin-producing beta cells in the pancreas. Both of these have some element of genetic programming. In 2 to 5 percent of patients with a form of type 2 diabetes known as maturity onset diabetes of the young (MODY), defects involving genes essential for beta-cell function have been found. However, in the majority of patients with the common variety of type 2 diabetes, the genetic defects of this beta-cell defect remain unknown.

The research was supported by funding from the Mary K. Iacocca Professorship and the Diabetes Genome Anatomy Project (DGAP) of the National Institute of Health's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). It represents the unique synergy of a jointly funded public program, DGAP, and private support for diabetes research from the Iacocca Foundation.

Other researchers who participated in the study included Rohit N. Kulkarni, M.D., Ph.D., Yu-Hua Tseng, Ph.D., Terumasa Okada, Ph.D., all from Joslin; Russell S. Roberson, Ph.D., formerly of Joslin; Frank J. Gonzalez, M.D., and SunHee Yim, Ph.D., of the National Institutes of Health's National Cancer Institute; Camillo Ricordi, M.D., of the University of Miami's Diabetes Research Institute; Phillip J. O'Connell, M.D., and Wayne J. Hawthorne, M.D., of the National Pancreas Transplant Institute of the University of Sydney in Australia.