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TMEM219 regulates the transcription factor expression and proliferation of beta cells

Francesca D'Addio1,2, Emma Assi1, Anna Maestroni1

  • 1International Center for Type 1 Diabetes (T1D), Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Sciences (DIBIC), Università di Milano, Milan, Italy.

Frontiers in Endocrinology
|February 6, 2024
PubMed

Insights

Blocking TMEM219 preserves pancreatic beta cells by inhibiting cell death and promoting proliferation. The microRNA miR-129-2 regulates TMEM219, offering a potential therapeutic target for type 1 diabetes.

Area of Science:

  • Endocrinology and Metabolism
  • Cell Biology
  • Diabetes Research

Background:

  • Pancreatic beta cell replenishment is a key therapeutic strategy for type 1 diabetes.
  • Stimulating endogenous beta cell proliferation is crucial for patients with diminished beta cell mass.
  • TMEM219, a pro-apoptotic receptor, plays a role in regulating beta cell fate.

Purpose of the Study:

  • To investigate the role of TMEM219 in pancreatic beta cell development and survival.
  • To explore the potential of targeting TMEM219 for therapeutic benefit in type 1 diabetes.
  • To identify upstream regulators of TMEM219, specifically microRNAs, involved in beta cell regulation.

Main Methods:

  • Expression analysis of TMEM219 in fetal pancreas and embryonic endocrine progenitors.
  • Pharmacological blockade of TMEM219 in islets and in vitro-derived endocrine progenitors.
  • Investigation of the TMEM219 regulatory network, focusing on microRNA-129-2 (miR-129-2) using mimics and inhibitors.

Main Results:

  • TMEM219 is expressed in early pancreatic development and negatively regulates beta cell precursors via Caspase 8-mediated cell death.
  • TMEM219 blockade enhanced beta cell precursor markers, proliferation, and survival in vitro and in islets.
  • miR-129-2, highly expressed in human islets (especially in type 1 diabetes patients), downregulates TMEM219; conversely, miR-129-2 inhibition increases TMEM219, restoring proliferation and function in insulinoma cells.

Conclusions:

  • TMEM219 acts as a critical negative regulator of beta cell precursor development and survival.
  • Pharmacological inhibition of TMEM219 offers a promising approach for beta cell preservation and potential regeneration in type 1 diabetes.
  • The miR-129-2/TMEM219 axis represents a novel endogenous regulatory pathway controlling beta cell fate and regenerative potential.
Keywords:
IGFBP3TMEM219endocrine progenitorsisletsmature and immature beta cellstype 1 diabetes

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