Zmiz1 is required for mature β-cell function and mass expansion upon high fat feeding

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: β-Cell-specific Zmiz1 knockout (Zmiz1(βKO)) mice were generated and phenotypically characterised. Glucose homeostasis was assessed in Zmiz1(βKO) 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: Male and female Zmiz1(βKO) mice were glucose intolerant with impaired insulin secretion, compared with control littermates. Transcriptomic profiling of Zmiz1(βKO) islets identified over 500 differentially expressed genes including those involved in β-cell function and maturity, which we confirmed at the protein level. Upon HFD, Zmiz1(βKO) 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.