P4‐299: Gamma‐secretase/notch signaling in insulin resistance

Abstract

Type 2 diabetes (T2D) is a risk factor for Alzheimer's disease, most likely linked to an impairment of insulin signaling in the brain. Insulin receptors (IR) are desensitized in the brains of AD patients. The impairment of insulin signaling in the brain could play a role in the development of neurodegenerative disorders. Insulin regulates glucose intake from the blood to the liver, muscle, and brain through IR-mediated signal transduction. When insulin signaling is disturbed by insulin resistance, the secretion of insulin into the blood is increased in order to transmit insulin signals to nuclei, resulting in hyperinsulinemia. Soluble Aβ oligomer interferes with insulin-induced autophosphorylation through its binding to IR. The expression of insulin-degrading enzyme is stimulated by insulin signaling in order to degrade Aβ. Insulin also regulates Aβ levels by modulating Aβ production via their actions on BACE1 and/or γ-secretase, as well as by modulating Aβ degradation via Aβ-degrading enzymes, such as insulin-degrading enzyme. In this study we will determine whether gamma-secretase/notch signaling regulates insulin resistance and/or secretion. Glucose and insulin tolerance tests Insulin tolerance tests Induce insulin resistance Insulin-sensitizing effects of γ-secretase inhibitors(GSI) Metabolic characterization of Notch antisense mice and wild type mice NAS and WT mice show similar effects in glucose tolerance test and the insulin tolerance test Four month old NAS and WT mice show different effects in glucose tolerance test and the insulin tolerance test Seven month old NAS and WT mice show different effects in glucose tolerance test and the insulin tolerance test than four month Fasting effects on plasma level of diabetes markers This study shows that in a db/db mice and high fat diet model of insulin resistance, Notch expression was increased in liver and muscle of db/db mice. And also NAS mice increased glucose tolerance and insulin sensitivity.