Molecular Mechanism Explains Increased Insulin Resistance in Type II Diabetes

A recent paper outlined the molecular mechanism that makes the p75 neurotrophin receptor (p75NTR) a key regulator of glucose uptake and insulin resistance and suggested a possible new therapeutic approach for the treatment of type II diabetes.

Investigators at the University of California, San Francisco (USA) identified p75NTR as being associated with glucose regulation due to its location in fat and muscle tissue and its participation in many aspects of cell metabolism. To examine more precisely the role of p75NTR they genetically engineered a line of mice to lack the gene that produces this protein.

Results published in the March 28, 2012, online edition of the journal Proceedings of the [US] National Academy of Sciences revealed that compared to normal animals, the p75NTR “knockout” mice demonstrated increased insulin sensitivity on normal chow diet, independent of changes in body weight. Deletion of the p75NTR gene increased the insulin-stimulated glucose disposal rate and suppression of hepatic glucose production.

Other mice were manipulated to overexpress p75NTR in their adipocytes. In these animals, insulin-stimulated glucose transport was decreased. In adipocytes, p75NTR was found to form a complex with the Rab5 family GTPases Rab5 and Rab31 that regulate the activity of the glucose transport protein GLUT4. Rab5 and Rab31 directly interacted with p75NTR primarily via helix 4 of the p75NTR death domain. Adipocytes from p75NTR knockout mice showed increased Rab5 and decreased Rab31 activities, and dominant negative Rab5 rescued the increase in glucose uptake seen in p75NTR knockout adipocytes.

“We identified that p75NTR is a unique player in glucose metabolism,” said senior author Dr. Katerina Akassoglou, associate professor of neurology at the University of California, San Francisco. “Therapies targeted at p75NTR may represent a new therapeutic approach for diabetes, and our studies of p75NTR's unanticipated role in regulating glucose metabolism suggest a new target for drug therapies. Future work is needed to test whether this finding may translate into a potential treatment.”

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