Researchers Suggests Gene Inhibition May Help Normalize Type 2 Diabetes

In research that could lead to new approaches for the treatment of type 2 diabetes, a Yale School of Medicine team has found that suppressing a liver enzyme that induces glucose production helped diminish the symptoms of the disease in a rat model — reducing blood glucose concentrations, decreasing rates of glucose production in the liver, and improving insulin sensitivity.  Decreasing expression of the gene, Sirtuin 1, also lowered total cholesterol levels.

The research appears in the June 15-19 Online Early Edition of the Proceedings of the National Academy of Sciences.

Type 2 diabetes is characterized by high blood glucose concentrations and insulin resistance, which play a major factor in causing the disease. In the U.S., rates of type 2 diabetes have doubled since 1990, and the Centers for Disease Control calls the disease an epidemic. Formerly known as “adult-onset diabetes,” the disorder is increasingly diagnosed in children.

The Yale researchers put the rats on a four-week diet of fructose and high-fat meals to create a metabolic condition that mimics type 2 diabetes. At the same time, they inhibited expression of the Sirtiun 1 gene through injection of an antisense oligonucleotide (short fragments of nucleic acid that inactivate gene expression) specifically targeted to that gene.

“Blood glucose levels in the rats came down close to normal, as did their ability to regulate blood glucose levels with insulin,” said first author Derek Erion, a graduate student in cellular and molecular physiology at Yale.

The authors believe the falling plasma cholesterol levels that also resulted may be attributed to increased cholesterol uptake and export from the liver, due to suppression of key enzymes involved in cholesterol metabolism.

Senior author Gerald Shulman, MD, said the results indicate that inhibiting Sirtuin 1 in the liver may be an attractive approach for the treatment of type 2 diabetes. “With this disorder, diet and exercise only get you so far,” he said. “Many patients may need drug intervention to avoid suffering the debilitating effects of type 2 diabetes.” Shulman is the George R. Cowgill Professor of Physiological Chemistry, Medicine and Cellular and Molecular Physiology at Yale and a Howard Hughes Medical Institute Investigator.

Other authors include: Shin Yonemitsu, Yoshio Nagai and Matthew P. Gillum of the Yale School of Medicine and Howard Hughes Medical Institute; Jennifer J. Hsiao, Takanori Iwasaki, Romana Stark, Dirk Weismann, Varman T. Samuel, Tamas. L. Horvath and Qian Gao of Yale School of Medicine; Xing Xian Yu, Susan F. Murray, Sanjay Bhanot and Brett P. Monia of Isis Pharmaceuticals in Carlsbad, CA.

The work above was funded in part by the Yale Clinical and Translational Science Award (CTSA) grant from the National Center for Research Resources at the National Institutes of Health.

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