2102-LB: Dysregulation of Cholesterol Homeostasis Is an Early Signal of Beta-Cell Proteotoxicity Characteristic of Type 2 Diabetes

Type 2 diabetes (T2D) is a common metabolic disease due to insufficient insulin secretion by pancreatic beta cells in the context of insulin resistance. Islet molecular pathology reveals a role for protein misfolding in beta cell dysfunction and loss with islet amyloid derived from islet amyloid polypeptide (IAPP), a protein co-expressed and co-secreted with insulin. The most toxic form of misfolded IAPP is intracellular membrane disruptive toxic oligomers present in beta cells in T2D and in beta cells of mice transgenic for human IAPP (hIAPP). Prior work revealed a high degree of overlap of transcriptional changes in islets from T2D and pre-diabetic 9-10-week-old mice transgenic for hIAPP with most changes being pro-survival adaptations and therefore of limited therapeutic guidance. The aim of the study was to investigate islets from hIAPP transgenic mice at an earlier age (6 weeks) to screen for potential mediators of hIAPP toxicity that precede predominance of pro-survival signaling. Islets from 6-week-old hIAPP mice and wild-type mice were subjected to bulk RNA sequencing analysis followed by differential expression analysis, and then compared to prediabetic 9-10 weeks-old mouse islets. Analysis of intracellular lipid distribution in islets was performed in pancreas sections and isolated islets. hIAPP misfolding induced early suppression of cholesterol synthesis and trafficking along with aberrant intra-beta cell cholesterol and lipid deposits. The abnormality in lipid homeostasis mediated by hIAPP misfolding align with comparable lipid deposits present in beta cells in T2D and increased vulnerability to develop T2D in individuals taking medications that suppress cholesterol synthesis. Disclosure T. Gurlo: None. R. Liu: None. X. Yang: None. M. Blencowe: None. P.C. Butler: Consultant; Vertex Pharmaceuticals Incorporated. Funding Larry L. Hillblom Foundation (2014-D-001-NET, 2021-D-004-SUP)