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Maladaptive Positive Feedback Production of ChREBPβ Drives Glucotoxic β-Cell Failure

ABSTRACT: Purpose: Test the role of ChREBPbeta in pancreatic beta cells using tools that distinguish ChREBPalpha and ChREBPbeta and loss and gain of function experiments, confirming its role in glucose toxicity and finding mitigation strategies. Methods: INS-1 832/13 cells cultured in 2 mM or 11 mM glucose were transduced with adenoviruses expressing GFP as control or ChREBPbeta. After 48 h, RNA was isolated and amplified via the NuGEN Ovation RNA-Seq System V2 prior to RNA sequencing. Human islets from non-diabetic and T2D subjects were transduced with adenovirus ZSGreen and cell sorted. RNA was isolated and subjected to RNAseq. Results: Overexpression of ChREBPbeta led to increased expression of cell cycle and apoptotic genes and a decrease in beta cell maturity genes. T2D human beta cells expressed an increased ratio of ChREBPbeta to ChREBPalpha compared to non-diabetics. Conclusions: ChREBPbeta is necessary for adaptive beta cell expansion, but drives glucose toxicity when overexpressed, mimicking the graded effect of Myc overexpression in beta cells.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE197864 | GEO | 2022/06/02

REPOSITORIES: GEO

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