Compensatory Islet Response to Insulin Resistance Revealed by Quantitative Proteomics

Compensatory
islet response is a distinct feature of the prediabetic
insulin-resistant state in humans and rodents. To identify alterations
in the islet proteome that characterize the adaptive response, we
analyzed islets from 5 month old male control, high-fat diet fed (HFD),
or obese ob/ob mice by LC–MS/MS and quantified ∼1100
islet proteins (at least two peptides) with a false discovery rate
< 1%. Significant alterations in abundance were observed for ∼350
proteins among groups. The majority of alterations were common to
both models, and the changes of a subset of ∼40 proteins and
12 proteins were verified by targeted quantification using selected
reaction monitoring and western blots, respectively. The insulin-resistant
islets in both groups exhibited reduced expression of proteins controlling
energy metabolism, oxidative phosphorylation, hormone processing,
and secretory pathways. Conversely, an increased expression of molecules
involved in protein synthesis and folding suggested effects in endoplasmic
reticulum stress response, cell survival, and proliferation in both
insulin-resistant models. In summary, we report a unique comparison
of the islet proteome that is focused on the compensatory response
in two insulin-resistant rodent models that are not overtly diabetic.
These data provide a valuable resource of candidate proteins to the
scientific community to undertake further studies aimed at enhancing
β-cell mass in patients with diabetes. The data are available
via the MassIVE repository, under accession no. MSV000079093.