Beta cell adaptation mechanisms during caloric restriction and ER stress - Project Summary Type 2 diabetes (T2D) is caused by the collapse of glucose homeostasis mechanisms, and the odds of devel- oping T2D increase during old age. Beta cells make insulin, a major hormone involved in the regulation of glucose homeostasis; these cells modulate insulin release in response to changes in blood glucose levels and/or meta- bolic demands. During T2D and aging, beta cell function and identity become compromised due to activation of stress pathways. Recent studies by us and others show that aging beta cells experience an underlying state of chronic endoplasmic reticulum (ER) stress associated with compromised autophagic flux and reduced expres- sion of beta cell identity markers, while reversal of ER stress rescues beta cell function and identity. It is currently unknown how beta cell heterogeneity is modulated during the adaptation process in response to changes in metabolic demands, and how these aspects are affected by aging and/or ER stress. In addition, the spatial organization of the beta cell epigenome, and its correlation with beta cell gene transcriptional heterogeneity, at the single cell level remains unknown. This project has the overarching goal of investigating how beta cell epi- genetic, transcriptional, functional, and cell longevity landscapes are affected by metabolic modulation intro- duced by changes in diet composition (e.g., calorie restriction (CR), high-fat diet), or during aging and/or ER stress. Moreover, we will investigate fundamental aspects regarding the spatial (in situ) organization of the beta cell (epi)genome in 3D, and how this aspect correlates with heterogeneous gene transcriptional patterns. The experiments in this proposal will leverage single cell multiome transcriptomics, high-resolution light, electron and stable-isotope microscopy, and quantification of in vivo beta cell function to determine the spatial, molecular, and functional landscapes of mouse and human beta cells exposed to different metabolic challenges. It is anticipated that CR will promote beta cell longevity and health by increasing the expression of beta cell identity while reduc- ing ER stress; this feature is expected to enable CR to mitigate the loss of beta cell identity and function observed in aging human beta cells. Understanding how beta cells adapt to changes in metabolic demands and/or ER stress to maintain their long-term function and health can lead to new ways to promote and/or preserve beta cell function in aging patients as well as in those living with T2D.
