New research reveals how preventing the suppression of a common protein complex called hypoxia-inducible factor-1 (HIF-1) may prevent tissue damage as a complication associated with diabetes. The research was published February 15, 2022, in the open-access eLife journal.

Coauthor and Senior Laboratory Manager at Karolinska Institutet in Stockholm, Sweden, Xiao-Wei Zheng and colleagues Cheng Xu and Sampath Narayanan explored the impact of excessive production of mitochondrial reactive oxygen species (ROS) in development of diabetes complications. The team hypothesized that impaired response and recovery from hypoxia caused ROS overproduction and that suppression of HIF-1 protein complex may contribute—if not entirely be responsible for—that overproduction. Hyperglycemia, the hallmark pathologic consequence of diabetes, has been recognized as a central mechanism for causing the inhibition of the HIF-1 protein complex.

"Hypoxia, a condition where oxygen levels drop in our tissues, has also recently been identified as a harmful player in diabetes," explained Dr. Zheng. "In our study, we wanted to find out if the overproduction of cellular ROS in diabetes is caused by impaired responses to hypoxia due to the inhibition of HIF-1 by high blood sugar levels."

The study methods included exposing healthy subjects with type 1 diabetes to hypoxic conditions and then analyzing the ROS levels in the blood. The relation between the production of ROS production, HIF-1 and glucose levels, and the physiologic consequences were examined in renal cells and in kidneys of diabetic mouse models.

According to Sergiu Catrina, one of the senior authors of the study and a senior physician at Karolinska Institutet, "We've shown that the repression of HIF-1 plays a central role in ROS overproduction and tissue damage in diabetes, and is therefore a potential treatment target for these complications." Dr. Catrina elaborated further, saying, "These results are timely, since the first PHD inhibitor that can activate HIF-1 has recently been approved for clinical use in patients with chronic kidney diseases. If our findings are verified by future studies, then similar inhibitors could be tested as potential new therapies for diabetes."

The authors concluded, "The repression of HIF-1 plays a central role in mitochondrial ROS overproduction in diabetes and is a potential therapeutic target for diabetic complications. These findings are timely since the first PHD inhibitor that can activate HIF-1 has been newly approved for clinical use."

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