To assess whether proinsulin levels are elevated in first-degree relatives of insulin-dependent diabetes mellitus (IDDM) patients and whether there is a relationship between proinsulin levels and the occurrence of immunological markers.

Research Design and Methods

Fasting proinsulin concentrations were measured in 85 first-degree relatives (54 siblings, 20 parents, 11 children) of IDDM patients and in 90 age- and weight-matched control subjects with no family history of diabetes mellitus.


Fasting proinsulin levels (median, 25th, and 75th percentiles) were 8 pM (range 3.2–14 pM) in first-degree relatives and 1.7 pM (range 1.7–4 pM) in control subjects (P <0.0001). Proinsulin was significantly elevated in siblings (7.2 pM, range 3.8–15 pM; P <0.0001), parents (9.8 pM, range 6.4–13 pM; P <0.0001), and children (6.6 pM, range 1.8–12 pM, P = 0.04) compared with control subjects but without differences between these groups. Islet cell antibody positive (ICA+) IDDM relatives had significantly higher proinsulin levels than ICA- (16 pM; range 7.2–25 vs. 6.9 pM, range 3.1–12 pM; P = 0.02). There was no difference between individuals with and without insulin autoantibodies. No difference in proinsulin levels was observed if the relatives were subdivided according to HLA-DR sharing with the diabetic proband.


Fasting proinsulin concentrations were raised not only in siblings but also in parents and children of IDDM patients. Because proinsulin is more elevated in ICA+ than in ICA subjects, increased proinsulin levels could reflect minor β-cell damage due to previous immunological attack.

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