Related Experiment Video

Updated: Sep 12, 2025

Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
14:32

Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates

Published on: February 27, 2016

8.4K

The protein deacetylase SIRT2 exerts metabolic control over adaptive β cell proliferation

Matthew Wortham1,2, Bastian Ramms1, Chun Zeng1

  • 1Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, UCSD, La Jolla, California, USA.

The Journal of Clinical Investigation
|August 5, 2025
PubMed

Insights

Scientists discovered that inhibiting Sirtuin 2 (SIRT2) in pancreatic beta cells promotes controlled beta cell proliferation during hyperglycemia, offering a potential diabetes therapy. This approach preserves feedback control, preventing excessive cell growth.

Area of Science:

  • Endocrinology and Metabolism
  • Cell Biology
  • Molecular Medicine

Background:

  • Therapies for diabetes aim to expand endogenous pancreatic beta cells while maintaining feedback control.
  • Excessive beta cell proliferation must be avoided to prevent complications.
  • Identifying regulators of beta cell proliferation is crucial for developing safe and effective treatments.

Purpose of the Study:

  • To identify regulators of beta cell proliferation that allow for controlled expansion.
  • To investigate the role of Sirtuin 2 (SIRT2) in regulating beta cell mass.
  • To explore a novel therapeutic strategy for increasing beta cell mass in diabetes.

Main Methods:

  • Genetic deletion of Sirt2 in mouse beta cells.
  • Analysis of beta cell proliferation under homeostatic and hyperglycemic conditions.
  • Inhibition of SIRT2 in human islets and analysis of acetylated proteins.
  • Transcriptomic analysis of Sirt2-inactivated beta cells.
  • Systemic administration of GLP1-coupled Sirt2-targeting antisense oligonucleotide in mice.

Main Results:

  • Sirt2 deletion in mouse beta cells increased proliferation during hyperglycemia but not under homeostatic conditions, preserving feedback control.
  • SIRT2 was found to restrain proliferation in human islet beta cells, indicating conserved function.
  • SIRT2 inhibition affected enzymes involved in oxidative phosphorylation and altered the interpretation of hyperglycemia as a stress.
  • Systemic administration of an antisense oligonucleotide successfully inactivated SIRT2 in beta cells, stimulating proliferation during hyperglycemia.

Conclusions:

  • Sirtuin 2 (SIRT2) acts as a key regulator that restrains beta cell proliferation.
  • Inactivating SIRT2 offers a therapeutic strategy to increase beta cell mass in diabetes without disrupting feedback control mechanisms.
  • Further research is needed to validate these findings in human beta cells from diabetic and non-diabetic individuals.
Keywords:
Beta cellsDiabetesEndocrinologyMetabolismMitochondria

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