Diabetes Research Center

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Project Summary/Abstract This administrative supplement is for a pilot and feasibility study with Elizabeth Rhea as the Principal Investigator. Impairments in the regulation of central nervous system (CNS) insulin are clearly associated not only with metabolic syndrome and diabetes mellitus but also with Alzheimer's disease (AD), age-related cognitive decline, and mild cognitive impairment (MCI). Peripheral insulin resistance commonly associated with type II diabetes (T2D) increases the risk for developing AD by 56%. Evidence exists for both decreased brain insulin levels and impaired brain insulin signaling (i.e., insulin resistance) as causes for this decreased insulin action. While peripheral insulin resistance and central insulin resistance are two different conditions, the consequences are the same: loss of or reduced response to insulin. Insulin therapy can improve cognition in both healthy subjects as well as those suffering from cognitive impairments, suggesting that with increased CNS levels, CNS insulin resistance can be partially overcome. While much of the focus in this area has been placed on overcoming CNS insulin resistance at the molecular level, we believe the impairment could lie at the blood-brain barrier (BBB). T2D has multiple detrimental effects on the BBB and the link between T2D and late-onset AD is partly due to cerebrovascular pathologies. CNS insulin is derived from the blood and crosses the BBB in a saturable transport system. Therefore, the insulin resistance observed in the CNS in these diseases could be a consequence of insulin deficiency and inadequate insulin BBB transport. Peripheral modulators of insulin transport (serum insulin/triglyceride levels and inflammation) have been extensively studied, with the direct role of the CNS often ignored. Astrocytes are the primary cell type that surround brain endothelial cells. Therefore, the goal of this study is to investigate the role the astrocyte insulin receptor has in regulating CNS insulin levels. SA1 will determine whether loss of the astrocytic insulin receptor alters insulin BBB transport. SA2 will investigate whether the loss of the astrocytic insulin receptor has a direct effect on the BBB. Based on the therapeutic benefit of CNS insulin in AD, we believe the BBB is a regulatory structure that could be targeted for pharmaceutical interventions on the development of CNS insulin resistance due to T2D.