OBJECTIVE: To determine whether first-degree relatives of individuals with type 2 diabetes, who are at high risk of subsequently developing hyperglycemia, manifest alterations in beta-cell function including an alteration in the co-release of insulin and amylin. RESEARCH DESIGN AND METHODS: In 30 first-degree relatives and 24 matched subjects with no family history of diabetes, beta-cell function was measured as the intravenous glucose-induced acute insulin response (AIR(g)) and acute amylin response (AAR(g)). The insulin sensitivity index (S(I)) was quantified and used to account for the role of insulin sensitivity to modulate beta-cell function (S(I) x beta-cell function). RESULTS: Fasting plasma glucose (5.3 +/- 0.1 vs. 5.1 +/- 0.1 mmol/l; means +/- SEM), immunoreactive insulin (IRI) (68 +/- 7 vs. 57 +/- 6 pmol/l) and amylin-like immunoreactivity (ALI) (5.5 +/- 0.6 vs. 4.7 +/- 0.7 pmol/l) were similar in relatives and control subjects, respectively. Relatives were insulin resistant compared with control subjects (S(I): 4.86 +/- 0.63 vs. 7.20 +/- 0.78 x 10(-5) min(-1). pmol(-1). l(-1), P = 0.01), but their AIR(g) (392 +/- 59 vs. 386 +/- 50 pmol/l) and AAR(g) (5.9 +/- 0.9 vs. 6.1 +/- 0.8 pmol/l) did not differ. When beta-cell function was determined relative to insulin sensitivity, in the first-degree relatives, both AIR(g) (S(I) x AIR(g): 1.60 +/- 0.23 vs. 2.44 +/- 0.31 x 10(-2) min(-1), P < 0.05) and AAR(g) (S(I) x AAR(g): 2.39 +/- 0.35 vs. 4.06 +/- 0.56 x 10(-4) min(-1), P < 0.05) were reduced. The molar proportion of ALI to IRI was not altered in high-risk subjects (1.75 +/- 0.16 vs. 1.71 +/- 0.15%). CONCLUSIONS: First-degree relatives of subjects with type 2 diabetes have diminished beta-cell function at a time when they are not hyperglycemic, and this reduction affects insulin and amylin responses proportionally. Thus, an altered amylin-to-insulin ratio is not likely to identify individuals at high risk of developing type 2 diabetes.