In this connection, Peter Arvan and colleagues recently showed that aberrantly disulfide-bonded proinsulin dimers and higher ladder complexes (trimer, tetramer, pentamer, ---) exist in rat pancreatic β-cell-derived INS1E cells as well as in mouse and human islets, and that the levels of these misfolded forms of proinsulin were markedly increased and instead the level of insulin was markedly decreased in islets of leptin receptor mutant LepRdb/db mice, a mouse model of diabetes, compared with islets of wild-type mice, before the onset of diabetes. Here, INS is linked to diabetes mellitus.