PROINSULIN IMMUNOREACTIVITY IN IDENTICAL-TWINS DISCORDANT FOR NONINSULIN-DEPENDENT DIABETES-MELLITUS

Disproportionate elevation [increased proinsulin/insulin (PI/INS) rati o] of PI immunoreactivity is associated with noninsulin-dependent diab etes mellitus (NIDDM). The nature of this abnormality is not known. To address the question of whether genetic factors contribute to hyperpr oinsulinemia, we measured fasting levels of PI immunoreactivity, intac t INS, and C peptide (CP) in 12 pairs of monozygotic twins discordant for NIDDM for a mean (+/-SEM) period of 9 +/- 3 yr. Thirteen age- and body mass index-matched healthy subjects without any family history of NIDDM acted as controls. The nondiabetic twins had levels of fasting INS, CP, PI, PI/CP, and PI/INS similar to those of control subjects. F asting levels of PI, and PI/CP and PI/INS ratios were significantly 2- to 3-fold elevated in NIDDM twins compared to those in both nondiabet ic twins and control subjects. To investigate whether hyperproinsuline mia in these NIDDM patients was due to a differential elevation of int act PI or conversion intermediates, we analyzed PI profiles in NIDDM t wins and normal subjects by high pressure liquid chromatography. PI wa s heterogeneous and consisted mainly of des(31,32)-PI and intact PI in both NIDDM patients and normal subjects, with no major difference in composition between the groups. Small amounts of des(64,65)-PI (0-11%) were measured in some patients and normal subjects. The results sugge st that hyperproinsulinemia is not a genetically determined trait per se in NIDDM. Disproportionately elevated PI levels seem to be related to the actual disease process. Further conversion of intact PI and des (31,32)-PI may be equally impaired in NIDDM.