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Pancreatic microexons regulate islet function and glucose homeostasis

Jonàs Juan-Mateu1, Simon Bajew2, Marta Miret-Cuesta2

  • 1Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain. jonas.juan@crg.eu.

Nature Metabolism
|February 9, 2023
PubMed

Insights

Scientists discovered a new microexon program in pancreatic islet cells that regulates glucose homeostasis. This finding is crucial for understanding diabetes and hypoglycaemia, offering potential therapeutic targets.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Genetics

Background:

  • Pancreatic islets are vital for glucose homeostasis through hormone secretion.
  • Dysfunctional islets lead to diabetes or hypoglycemia.
  • Alternative splicing, including microexons, plays a role in cell function.

Purpose of the Study:

  • To identify and characterize a conserved microexon program in pancreatic islet cells.
  • To investigate the role of the RNA-binding protein SRRM3 in regulating these microexons.
  • To explore the implications of this program in glucose homeostasis and diabetes.

Main Methods:

  • Analysis of alternative microexons in islet cell mRNAs.
  • Investigated the regulation of microexons by SRRM3.
  • Depletion of SRRM3 and repression of microexons in beta cell lines and islets.
  • Studied mice with Srrm3 mutations.
  • Correlated human genetic variants with glucose levels and diabetes risk.

Main Results:

  • Discovered a conserved program of alternative microexons (IsletMICs) in islet cells, particularly in genes related to vesicle transport and exocytosis.
  • SRRM3 regulates IsletMICs, which are induced by high glucose.
  • SRRM3 depletion or IsletMIC repression caused inappropriate insulin secretion.
  • Srrm3 mutations in mice led to impaired islet cell function and hyperinsulinaemic hypoglycemia.
  • Human genetic variants affecting SRRM3 and IsletMICs are linked to fasting glucose variation and type 2 diabetes risk.

Conclusions:

  • Identified a novel, conserved microexon program (IsletMICs) regulated by SRRM3 in pancreatic islets.
  • This program is critical for proper insulin secretion and glucose homeostasis.
  • The findings link microexon regulation to diabetes pathogenesis and offer potential therapeutic targets.

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