Neuronal insulin signal transduction mechanisms in diabetes phenotypes

The hippocampus is an important integration center for learning and memory in the mammalian central nervous system (CNS) and is particularly sensitive and responsive to changes in insulin and glucose concentrations. Insulin administration improves cognitive performance in a variety of physiological and pathophysiological settings, including diabetes phenotypes. Our previous studies demonstrated that hyperglycemia produces behavioral, neuroanatomical and neurochemical changes in the adult rat hippocampus that are indicative of accelerated brain aging. In addition, the trafficking of insulin-sensitive glucose transporters (GLUTs) is impaired in experimental models of diabetes. Such results suggest that insulin receptor (IR) signaling may be disrupted in diabetes phenotypes, although the signaling mechanisms utilized by neurons are not clearly defined. To this end, we have employed in vivo and in vitro approaches to determine the insulin signaling pathways utilized by neurons. These methodologies provide insight into the signaling mechanisms utilized by neuronal IRs and ultimately will allow for determination of the IR signaling deficits that may contribute to accelerated brain aging in the hippocampus of diabetic subjects.