Prohormone convertase 1 in obesity, gestational diabetes mellitus, and NIDDM: no evidence for a major susceptibility role.

Improved understanding of the primary molecular events underlying NIDDM and obesity is essential if more effective therapies are to be devised. Individual susceptibility to these interrelated conditions is under genetic influence (1), and clues to the identity of the major aetiological genes may come from physiological studies that pinpoint candidate pathways. A characteristic feature of NIDDM and certain prediabetic states, such as gestational diabetes mellitus (GDM), is a marked increase in the proportion of circulating insulin precursor molecules (proinsulin and split proinsulin intermediates) (2,3). Release of disproportionate amounts of these biologically inactive precursors may contribute to the relative insulin deficiency apparent in GDM and NIDDM (2). The processing of proinsulin to mature insulin is catalyzed by prohormone convertase (PC) enzymes active in (3-cell granules. PCI (also named PC3) cleaves intact proinsulin to produce 32,33 split proinsulin. PC2 and carboxypeptidase E (CPE) catalyze subsequent reactions (4). Functional defects in any of these candidate genes could contribute to the NIDDM phenotype. Furthermore, recent studies indicate a role for these loci in the determination of obesity. Mutations in the Cpe gene resulting in absent enzyme activity in islets and pituitary underlie the phenotype of the fat/fat mouse (5). More recently, Jackson et al. (6) reported on a family segregating two distinctPCi mutations. The mother was a compound heterozygote who had presented with childhood obesity, GDM, and a variety of