Compensatory Islet Response to Insulin Resistance Revealed by Quantitative Proteomics

Area of Science:

• Metabolomics and Proteomics
• Endocrinology
• Diabetes Research

Background:

• Compensatory islet response is characteristic of prediabetes and insulin resistance in humans and rodents.
• Understanding islet proteome alterations is crucial for identifying adaptive mechanisms in prediabetes.

Purpose of the Study:

• To identify changes in the islet proteome associated with the compensatory response in insulin-resistant states.
• To compare proteomic alterations in two distinct rodent models of insulin resistance (high-fat diet and ob/ob mice).

Main Methods:

• Proteomic analysis of islets from control, high-fat diet (HFD), and obese ob/ob mice using liquid chromatography-tandem mass spectrometry (LC-MS/MS).
• Quantification of approximately 1100 islet proteins with a false discovery rate < 1%.
• Verification of a subset of protein changes using targeted quantification (selected reaction monitoring and western blots).

Main Results:

• Significant alterations in approximately 350 islet proteins were observed in insulin-resistant models, with most changes common to both models.
• Insulin-resistant islets showed reduced expression of proteins involved in energy metabolism, oxidative phosphorylation, hormone processing, and secretion.
• Increased expression of proteins related to protein synthesis, folding, endoplasmic reticulum stress response, cell survival, and proliferation was noted.

Conclusions:

• This study provides a comprehensive comparison of the islet proteome in two insulin-resistant rodent models that are not overtly diabetic.
• The identified candidate proteins can inform future research aimed at enhancing beta-cell mass for diabetes treatment.
• The proteomic data are publicly available in the MassIVE repository (accession no. MSV000079093).