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DZD Researchers Decipher Mechanism of Diabetes Development

Scientists at the German Diabetes Center, a partner in the DZD, have elucidated a previously unknown mechanism in the pathogenesis of the metabolic disease diabetes. The findings enable researchers for the first time to identify risk patients and to support them with a personalized therapy.

Scientists at the German Diabetes Center, a partner in the DZD, have elucidated a previously unknown mechanism in the pathogenesis of the metabolic disease diabetes. The findings enable researchers for the first time to identify risk patients and to support them with a personalized therapy.Type 2 diabetes is the most common metabolic disease and currently affects more than six million people in Germany. In metabolically healthy individuals, the insulin released by the body enables the glucose derived from food intake to be absorbed into muscle and fat cells. This process is impaired in diabetes. A team led by the DZD scientist Prof. Dr. Hadi Al-Hasani, director of the Institute of Clinical Biochemistry and Pathobiochemistry at the German Diabetes Center (DDZ), has now elucidated an important mechanism of insulin-dependent glucose uptake in muscle and fat cells. The results have been published in the journal Diabetes (doi: 10.2337/db14-0368).
In a mouse model, the researchers showed that two related genes, TBC1D1 and TBC1D4, play a crucial role in glucose uptake in fat and muscle cells. Defects in one of these genes lead to a progressive loss of insulin sensitivity. If both genes are defective, insulin-dependent glucose uptake can no longer be detected in muscle and fat tissue, and the diabetes risk is greatly increased. As a consequence, the metabolism no longer utilizes carbohydrates as energy source but instead utilizes fat. This increased fat burning protects against obesity, but does not prevent elevated blood glucose levels. “The findings show that the glucose uptake is regulated by multi-layered security mechanisms similar to double security systems,” said Dr. Alexandra Chadt, deputy group leader at the Institute of Clinical Biochemistry and Pathobiochemistry, DDZ.
Only recently, scientists from Denmark identified one of the described genes (TBC1D4) as a major diabetes risk gene in Inuits of Greenland. The findings in the mouse model now help to better understand the mechanism of diabetes pathogenesis and to develop new strategies for diabetes prevention. “For the first time it is possible to identify affected risk patients and to support them with a personalized therapy,” said Prof. Dr. Al-Hasani.

Original publication
Alexandra Chadt et al.: Deletion of Both Rab-GTPase-Activating Proteins TBC1D1 and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport. Diabetes published ahead of print September 23, 2014 1939-327X