Research Resource: A Dual Proteomic Approach Identifies Regulated Islet Proteins During β-Cell Mass Expansion In Vivo

Area of Science:

• Endocrinology
• Proteomics
• Cell Biology

Background:

• Diabetes mellitus is marked by insufficient insulin due to reduced functional beta-cell mass.
• Therapeutic strategies aim to increase beta-cell mass in situ.
• Pregnancy physiologically induces significant beta-cell mass expansion, but underlying mechanisms remain unclear.

Purpose of the Study:

• To characterize pregnancy-induced changes in the islet proteome at the peak of beta-cell proliferation in mice.
• To identify novel proteins and regulatory pathways involved in pregnancy-associated beta-cell expansion.

Main Methods:

• Comparative proteomic analysis of islets from pregnant and nonpregnant mice using in vivo stable isotope labeling and ex vivo dimethyl labeling.
• Proteomic strategies monitored de novo protein synthesis and protein abundance at gestational day 14.5.
• Bioinformatic analyses predicted upstream transcription factors and enriched biological functions.

Main Results:

• 170 islet proteins were upregulated in response to pregnancy.
• Identified novel proteins (CLIC1, STMN1, MCM6, PPIB, NEDD4, HLTF) and known proteins (CHGB, IGFBP5, MATN2, EHHADH, IVD, BMP1) associated with islet expansion.
• Bioinformatics revealed enrichment of 'protein synthesis' and 'proliferation' pathways, with predicted upstream regulators including HNF4α, MYC, and E2F1.

Conclusions:

• This study provides the first characterization of the islet proteome during pregnancy.
• Novel insights into the mechanisms driving pregnancy-induced beta-cell mass expansion and function were uncovered.
• Findings may inform therapeutic approaches for diabetes by elucidating beta-cell regeneration pathways.