β-cell aging markers and functional decline in type 2 Diabetes

This proposal focuses on understanding the beta cell aging process and how this contributes to the development of type 2 diabetes (T2D). T2D is related to aging and is partly characterized by dysfunctional insulin secretion. The direct interaction between age and altered beta cell function remains poorly understood but its importance is illustrated by a continued beta cell functional decline as diabetes progresses coupled with an inability of the beta cell population to regenerate. Such a lack of response to mitogenic stimuli is considered cellular senescence and has been linked to the expression of p16Ink4a. Therefore, a powerful new tool to study the role of aged cells is the INK-ATTAC (p16Ink4a mediated Apoptosis Through Targeted Activation of Caspase) mouse, which can be used to mark p16Ink4a -positive senescent cells with enhanced green fluorescence protein (EGFP) allowing their detection and collection. In addition, this cell population can be selectively cleared in the presence of the synthetic drug AP20187, which induces apoptosis in p16Ink4a-positive cells, both in vitro and in vivo. Our hypothesis is that with age, the senescent population of beta cells accumulates and contributes to the pathophysiology of diabetes. The overall goal of this project is to use INK-ATTAC mouse as a model to study beta cell aging by identifying markers of young and old beta cells, understanding their functional changes and determining how this process influences the progression of T2D.