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New Protein Identified In Regulating Insulin Resistance

Understanding the role of p75NTR on glucose regulation in mice may lead to a potential therapy for insulin resistance and type 2 diabetes in humans….

Scientists from the Gladstone Institutes in California have discovered the role of a key protein that regulates insulin resistance. The p75 neurotrophin receptor, called p75NTR, could become an important target for the treatment of type 2 diabetes. Usually associated with the functions of neurons, p75NTR has also been found in fat and muscle tissue and has been hypothesized to participate in many important cell functions including glucose regulation.

Gladstone investigator Katerina Akassoglou, PhD stated, "We identified that p75NTR is a unique player in glucose metabolism…Therapies targeted at p75NTR may represent a new therapeutic approach for diabetes."

To better understand the function of p75NTR, researchers studied mice that lacked the genes for p75NTR compared to control mice and the insulin response following a meal. The researchers found that mice lacking p75NTR were more responsive to insulin when fed a normal diet. Secondly, when researchers inhibited the action of the p75NTR protein in fat cells, increased glucose absorption resulted from response to insulin.

The researchers also reported that when fat cells expressed more p75NTR, glucose absorption was reduced. Additionally, the researchers identified Rab5 and Rab 31 proteins that are associated in the role of p75NTR’s impact on metabolism.

Lead author Bernat Baeza-Raja, PhD said, "The results indicate a unique model, whereby p75NTR differentially regulates Rab5 and Rab31 leading to decreased GLUT4 plasma membrane translocation that results in decreased insulin-stimulated glucose uptake."

The authors further clarified the interactions of these proteins: "In adipocytes, loss of p75NTR increases the activity of Rab5, which promotes GLUT4 trafficking, while decreasing the activity of Rab31, which promotes GLUT4 retention, thus resulting in increased plasma membrane translocation of GLUT4 and increased glucose uptake."

Future studies are required in order to understand the implications of regulating this protein in humans as a potential therapeutic target for insulin resistance and type 2 diabetes.

Bernat Baeza-Raja, Pingping Li, Natacha Le Moan et al. p75 neurotrophin receptor regulates glucose homeostasis and insulin sensitivity.Proceedings of the National Academy of Sciences 2012 : 1103638109v1-201103638.