INS and type 1 diabetes mellitus: Although impaired proinsulin conversion with elevated proinsulin secretion is a hallmark of type 2 [73] and type 1 diabetes [74, 75], genetic variants affecting the junction between the C-peptide and the A chain, such as replacement of R89 [50] (Fig. 1), or the proteolytic activities of either PC1/3 [76] or CPE [77] have only been identified in a few individuals with type 2 diabetes or altered glucose metabolism.