Alpha to Beta Cells: A Pathway Towards a Diabetes Cure

Abstract

Type 1 Diabetes (T1D) is insulin deficiency and hyperglucagonemia due to auto immune destruction of the insulin-secreting beta cells. A viable strategy to treat T1D is to restore the beta cell mass. Here, our approach focuses upon beta cell replacement from alpha cells, which are closely related to beta cells, but not destroyed in T1D. In rodent models containing specific fluorescent genetic lineage labeling of alpha and beta cells, we identified a group of cells at the islet periphery that appear to be beta cells that are transdifferentiated from alpha cells (AB). Preliminary live cell imaging and electrophysiology studies suggest that these AB cells acquire a typical beta cell glucose response, which suggests that beta cell regeneration from endogenous alpha cell populations may be a viable TID cure approach. In human islets, we also discovered endogenous cells expressing both insulin and glucagon. The dynamics of these bi-hormonal cells in terms of glucose response and hormone (insulin and/or glucagon) secretion are yet to be elucidated. We are performing imaging based islet studies that utilize virally delivered far red fluorescent secretory pathway fluorescent labels to determine the glucose response and inulin/ glucagon secretion dynamics of these bi hormonal cells. Our single cell islet secretion assays will also be used in combination with alpha and beta cell specific RCaMP1h and GCaMP6 Ca2+ response indicators in order to also understand how Ca2+ couples with secretion in these cells types. Findings from this study will advance our understanding in these unique rodent and human cell types. The long term goal study goal is to target these unique cell populations for conversion into functional beta cells.