Type 2 diabetes has a strong genetic contribution. In most affected persons a battery of poorly understood variations in genes interact with the environment to cause the disease defined by increased blood glucose, a sugar. The best-known genetic culprits for the development of cause poor insulin production caused by defects in pancreatic beta-cell development, survival and function, which leads to elevated blood sugar levels. For the vast majority of the nearly one hundred genetic associations that could contribute to diabetes, how these inherited variations contribute to the disease remains unknown.
Research led by Amnon Schlegel, M.D., Ph.D., assistant professor of internal medicine at the 人妻中出视频 of Utah School of Medicine and an investigator with the 人妻中出视频 of Utah Molecular Medicine Program and Diabetes and Metablism Center, reveals that defects in how the liver metabolizes glucose, caused by changes in the abundance of the FOXN3 protein, can also trigger increased blood sugar levels, and may explain why some individuals with a variation in the FOXN3 gene show signs of being at risk for diabetes.
The first clue for the additional pathway came from genome-wide association studies showing that upon fasting, persons with a specific variation in the FOXN3 gene are more likely to have high blood sugar than those without the change. Schlegel's team examined samples from such patients, and found they also had unusually high levels of FOXN3 protein in the liver, a site at which the body makes and stores glucose. To determine whether changes in FOXN3 cause or simply track with levels of sugar in the blood, the researchers mimicked the human condition by creating transgenic zebrafish in which FOXN3 was elevated at the same site, in the liver.
Like their human counterparts the animals had high fasting blood glucose. Using reporters that glow when genes are turned on, and dim when they are turned off, the researchers were able to see why. Their results indicate that the liver could be churning out more glucose than usual and breaking it down more slowly, as shown by increased expressions of gluconeogenesis genes, and decreased expression of glycolytic genes. "The animal experiment results were a gratifying validation of our hypothesis that excessive FOXN3 protein in the liver drives an increase in fasting blood glucose. Even more satisfying were the results of the gene expression studies in that they revealed a clear and testable pathway through which FOXN3 acts: the 'whole transcriptome' analyses we conducted with Dr. Yost's team were unbiased by design and led us to a mechanistic understanding of FOXN3's role in controlling the genes involved in liver glucose metabolism," said Schlegel.
The transgenic animals had abnormally low levels of a MYC protein that ordinarily turns up glycolytic gene expression, suggesting a molecular mechanism by which FOXN3 may impact their expression. The findings implicate abnormal changes in liver sugar metabolisms as a potential risk factor for diabetes, opening up new avenues for research and treatment. "With further work on how FOXN3 controls liver glucose metabolism, we hope to be in a position to discover new drug targets for type 2 diabetes," said Schlegel.
"" by Santhosh Karanth, Erin K. Zinkhan, Jonathan T. Hill, H. Joseph Yost, and Amnon Schlegel was published online in Cell Reports on June 9, 2016.
The research was supported by the National Institutes of 人妻中出视频, 人妻中出视频 of Utah Diabetes and Metabolism Center, 人妻中出视频 of Utah Molecular Medicine Program, and the Department of Internal Medicine, 人妻中出视频 of Utah School of Medicine.