Zmiz1 is required for mature β-cell function and mass expansion upon high fat feeding
Tamadher A. Alghamdi, Nicole A. J. Krentz, Nancy Smith, Aliya F Spigelman, Varsha Rajesh, Alokkumar Jha, Mourad Ferdaoussi, Kunimasa Suzuki, Jing Yang, Jocelyn E. Manning Fox, Han Sun, Zijie Sun, Anna L. Gloyn, Patrick E. MacDonald
Abstract
OBJECTIVE: Identifying the transcripts which mediate genetic association signals for type 2 diabetes (T2D) is critical to understand disease mechanisms. Studies in pancreatic islets support the transcription factor ZMIZ1 as a transcript underlying a T2D GWAS signal, but how it influences T2D risk is unknown. METHODS: mice and their control littermates on chow diet (CD) and high fat diet (HFD). Islet morphology and function were examined by immunohistochemistry and in vitro islet function was assessed by dynamic insulin secretion assay. Transcript and protein expression were assessed by RNA sequencing and Western blotting. In islets isolated from genotyped human donors, we assessed glucose-dependent insulin secretion and islet insulin content by static incubation assay. RESULTS: mice fail to expand β-cell mass and become severely diabetic. Human islets from carriers of the ZMIZ1-linked T2D-risk alleles have reduced islet insulin content and glucose-stimulated insulin secretion. CONCLUSIONS: β-Cell Zmiz1 is required for normal glucose homeostasis. Genetic variation at the ZMIZ1 locus may influence T2D-risk by reducing islet mass expansion upon metabolic stress and the ability to maintain a mature β-cell state.