Pancreatic Microexons Regulate Islet Function and Glucose Homeostasis

Overview

Journal Nat Metab

Publisher Springer Nature

Specialty Endocrinology

Date 2023 Feb 9

PMID 36759540

Authors

Jonas Juan-Mateu

Simon Bajew

Marta Miret-Cuesta

Luis P Iniguez

Amaya Lopez-Pascual

Sophie Bonnal

Goutham Atla

Silvia Bonas-Guarch

Jorge Ferrer

Juan Valcarcel

Manuel Irimia

Affiliations

Soon will be listed here.

Abstract

Pancreatic islets control glucose homeostasis by the balanced secretion of insulin and other hormones, and their abnormal function causes diabetes or hypoglycaemia. Here we uncover a conserved programme of alternative microexons included in mRNAs of islet cells, particularly in genes involved in vesicle transport and exocytosis. Islet microexons (IsletMICs) are regulated by the RNA binding protein SRRM3 and represent a subset of the larger neural programme that are particularly sensitive to SRRM3 levels. Both SRRM3 and IsletMICs are induced by elevated glucose levels, and depletion of SRRM3 in human and rat beta cell lines and mouse islets, or repression of particular IsletMICs using antisense oligonucleotides, leads to inappropriate insulin secretion. Consistently, mice harbouring mutations in Srrm3 display defects in islet cell identity and function, leading to hyperinsulinaemic hypoglycaemia. Importantly, human genetic variants that influence SRRM3 expression and IsletMIC inclusion in islets are associated with fasting glucose variation and type 2 diabetes risk. Taken together, our data identify a conserved microexon programme that regulates glucose homeostasis.

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