OBJECTIVE - To evaluate proinsulin secretion in different types of NIDDM. RESEARCH DESIGN AND METHODS - Proinsulin and insulin were evaluated at diagnosis of diabetes and 3 years later (fasting and after stimulation with intravenous glucose and glucagon) in 10 NIDDM patients without islet cell antibodies (ICAs) at diagnosis (age 52 +/- 4 years), 11 NIDDM patients with ICAs at diagnosis (age 50 +/- 5 years), and 21 healthy control subjects (age 53 +/- 4 years). RESULTS - At diagnosis, lasting proinsulin was higher in NIDDM patients without ICAs than in control subjects (39.6 +/- 10.0 vs. 12.8 +/- 1.6 pmol/l, P < 0.01). Proinsulin response to intravenous glucose decreased in NIDDM patients with ICAs (from 35.6 +/- 6.2 to 13.5 +/- 5.4 pmol/l, P < 0.05), but remained unchanged in those without ICAs. At 3 years after diagnosis, fasting proinsulin (10.0 +/- 3.7 vs. 59.1 +/- 17.0 pmol/l) and proinsulin responses to intravenous glucose (13.5 +/- 5.4 vs. 103.9 +/- 35.1 pmol/l) and to intravenous glucagon (7.4 +/- 3.9 vs. 36.0 +/- 7.7 pmol/l) were much lower (P < 0.01) in NIDDM patients with ICAs than in those without ICAs. CONCLUSIONS - After diagnosis of diabetes, proinsulin secretion decreases significantly in NIDDM patients with ICAs and remains constant in those without.