Insulin resistance in type 2 diabetes is linked to defects in the insulin receptor in numerous organs, including the liver. The search for better drug targets is an ongoing effort. Narendra Wajapeyee, Ph.D., associate professor of pathology, and Gerald I. Shulman, M.D., Ph.D., the George R. Cowgill Professor of Medicine (Endocrinology) and professor of cellular and molecular physiology, have led a study that identifies a promising protein target.
After a large-scale RNA interference screen of more than 600 proteins that interact with E3 ubiquitin ligase, another protein that is involved in many cellular processes, the team found MARCH1 to be a highly influential protein that degrades the surface of the insulin receptor—thus thwarting the normal function of insulin, which is to keep glucose levels from rising in the bloodstream. To the researchers’ surprise, they found that obese people had noticeably higher levels of MARCH1 expression than non-obese people. Their study was published Aug. 31 in Nature Communications.
According to Wajapeyee, patients need more treatment options because they face a catch-22. “Type 2 diabetes cannot initially be treated with insulin because the glucose signaling is disrupted,” he says. The team now will work to find a small molecule drug to target MARCH1.