OBJECTIVE: This study assessed insulin and glucagon secretion in relation to insulin sensitivity in Caucasian women who develop impaired glucose tolerance (IGT) versus those who maintain normal glucose tolerance (NGT) over a 12-year period. RESEARCH DESIGN AND METHODS: At baseline and after 3, 8, and 12 years, glucose tolerance (75-g oral glucose tolerance test), insulin sensitivity (euglycemic-hyperinsulinemic clamp), and insulin and glucagon secretion (2- to 5-min responses to 5 g arginine i.v. at fasting, 14 and >25 mmol/l glucose) were determined in 53 healthy Caucasian women (aged 58 years at baseline) who all had NGT at baseline. RESULTS: During the 12-year period, 26 subjects developed IGT, whereas the remaining 27 subjects maintained NGT throughout the 12-year period. Subjects developing IGT had lower insulin sensitivity than those maintaining NGT in the tests preceding diagnosis of IGT (P < or = 0.05). When judged in relation to insulin sensitivity, beta-cell glucose sensitivity and maximal insulin secretion were lower in those who later developed IGT than in those maintaining NGT at all tests (P < or = 0.05). Furthermore, subjects who developed IGT had defective suppression of glucagon secretion by glucose in the test preceding diagnosis of IGT when they still had NGT (P < or = 0.05). CONCLUSIONS: Beta- and alpha-cell dysfunction are evident several years before diagnosis of IGT, and islet dysfunction is manifested as impaired glucose sensitivity of the beta- and alpha-cells and reduced maximal insulin secretion.