TrkA and Insulin Receptor in Streptozotocin Induced Diabetes Rat Brain

Abstract

Abnormal blood glucose homeostasis and subsequent hyperglycemia, due to insufficient insulin production, is characteristic of type 1 diabetes mellitus. Neuronal cells are classified as insulin insensitive, thereby insulin is incapable of increasing glucose uptake in neurons. Tropomyosin receptor kinase A (TrkA) is a transmembrane receptor for nerve growth factor (NGF), which is responsible for regulating neuronal survival and differentiation. We have previously shown in our lab that NGF or insulin elicits TrkA to complex with insulin receptor (IR) and insulin receptor substrate -1 (IRS-1), and phosphorylation of these proteins requires a functional TrkA kinase in PC12 cells. It was also shown that a functional TrkA kinase is necessary for Akt activation in PC12 cells. Following these findings, investigation into the activity of TrkA in the diabetic rat brain, created by streptozotocin (STZ) administration, have shown a decrease in its phosphorylation and increase in nitrosylation as compared to control rat brain samples. Further experimentation showed the interaction of TrkA with IR and IRS-1 as well as the tyrosine phosphorylation of these signaling proteins is decreased in STZ rat brain samples. Lastly, STZ rat brain samples had decreased phosphorylation of Akt as compared to control rat brain samples. Therefore, functional TrkA is necessary for proper functioning of the insulin signaling proteins IR, IRS-1, and Akt in neuronal cells, and disruption of its functioning can be seen in neuronal cells of the type 1 diabetic rat model.