LAUSR

We combine liquid chromatography coupled with ion mobility spectrometry-mass spectrometry to elucidate how short exposure to corticosterone (Cort) alters the output of mouse pancreatic islet hormones. The workflow enables the robust separation of mouse insulin 1 (Ins1) and insulin 2 (Ins2) and the detection of major islet hormones in a homogenate equivalent to 100-150 islet cells. We show that Ins2 has a unique structure and is degraded much faster than Ins1. Further investigation indicates that Ins2 may populate both T and R states, whereas Ins1 may not. The assemblies of Ins1's B-chain also introduce more structural heterogeneity than Ins2. Collectively, these features account for their unique degradation profiles, the diabetes risk associated with Ins1, and the protective effect of Ins2. In the same experiments, we observe that the ratio of amylin to Ins1 increased significantly in Cort-treated mice (15:1) compared to the control mice (42:1), correlating well with β-cell proliferation observed in immunoassays on the same animal model. We observe no increase in intact full-length insulin levels but more of the truncated forms, indicating that enzymatic activity is accelerated. Our data provide a molecular basis for reduced insulin action induced by Cort and connections between insulin turnover and insulin resistance.