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

Abstract

Genome-wide association studies have identified hundreds of signals for type 2 diabetes (T2D), most of which confer risk through effects on gene expression. We previously identified the transcription factor ZMIZ1 as a probable effector transcript in human islets, but how altered ZMIZ1 expression impacts T2D risk is unknown. We now show that islets from carriers of the T2D-risk alleles have reduced islet insulin content and glucose-stimulated insulin secretion. To elucidate the mechanism for islet-cell dysfunction, we generated {beta}-cell-specific Zmiz1 knockout (Zmiz1{beta}KO) mice. Male and female Zmiz1{beta}KO mice were glucose intolerant with impaired insulin secretion, compared with control littermates. Transcriptomic profiling of Zmiz1{beta}KO islets identified over 500 differentially expressed genes including those involved in {beta}-cell function and maturity which we confirmed at the protein level. After high fat feeding, Zmiz1{beta}KO mice fail to expand {beta}-cell mass and become severely diabetic. Thus, Zmiz1 is required for normal glucose homeostasis and may contribute to T2D risk by maintaining a mature {beta}-cell state and allowing islet mass expansion upon metabolic stress.