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10 Percent of Type 2 Diabetes Patients Have Mutation in Single Gene

A multinational study has identified four mutations in a single key gene as responsible for type 2 diabetes in nearly 10 percent of patients of white European ancestry. The study, which originated in Italy and was validated at the University of California-San Francisco (UCSF) and the University of Reims, found that defects in the HMGA1 gene led to a major drop in the body’s ability to make insulin receptors – the cell’s sensor through which insulin tells the cell to absorb sugar. This drop in insulin receptors leads to insulin resistance and type 2 diabetes, according to the paper, which was published online on March 2 in JAMA. Until now, no mutations in a single gene have been significantly associated with playing a role in type 2 diabetes. The results provide the unique opportunity for a test to predict potential for the disease in patients, as well as the possibility of identifying which of the current diabetes medications work best for people with one of the gene mutations, the authors said. Ultimately, it also could help drive research to find new and improved drugs for those patients. While the study focused on Caucasians, it also lays the groundwork for similar analyses in patients of Asian, African, and Native American descent, who suffer from higher rates of the disease, according to diabetes researcher Dr. Ira Goldfine, a UCSF professor of medicine and of physiology who led the U.S. arm of these studies. “This is a major breakthrough in type 2 diabetes,” said Dr. Goldfine, noting that 26 million Americans have diabetes and an estimated 79 million have pre-diabetes. “Many of our current diabetes drugs are very effective in some patients and not in others. This finding could not only explain why that is, but also could help us target the right drug for the right person, so diabetics can manage their disease better and lead healthier lives.”

The advance originated in 1993, when Dr. Antonio Brunetti –at the time a postdoctoral fellow in Dr. Goldfine’s laboratory–discovered that insulin receptors were turned on in cells by a certain protein, which is now understood to be produced by the HMGA1 gene. Brunetti, the senior author on this paper, continued his research at the University of Catanzaro, in Italy, and ultimately identified this gene mutation in a population of 3,278 Italians with diabetes, matched against a similar number of their compatriots who had neither diabetes nor pre-diabetes.

Brunetti’s current study found at least one mutation in that gene in 9.8 percent of the diabetics in the Italian population, versus only 0.6 percent of the control group.

The UCSF team then ran a genetic analysis on 1,928 similar patients from the Genomic Resource in Arteriosclerosis, a DNA bank in the UCSF Cardiovascular Research Institute, a repository for 30,000 patient samples dating back to 1994. That data generated the same percentages as in the Italian population study, as did a subsequent study of 404 patients at the University of Reims, in France, by Dr. Vincent Durlach.

Dr. Brunetti said future research will include further study of variants within the HMGA1 gene, including studies in people with other racial heritages. [Press release] [JAMA abstract]