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The T allele at rs7903146 in TCF7L2 increases the rate of conversion from prediabetes to type 2 diabetes. This has been associated with impaired β-cell function and with defective suppression of α-cell secretion by glucose. However, the temporal relationship of these abnormalities is uncertain. To study the longitudinal changes in islet function, we recruited 128 subjects, with 67 homozygous for the diabetes-associated allele (TT) at rs7903146 and 61 homozygous for the protective allele. Subjects were studied on two occasions, 3 years apart, using an oral 75-g glucose challenge. The oral minimal model was used to quantitate β-cell function; the glucagon secretion rate was estimated from deconvolution of glucagon concentrations. Glucose tolerance worsened in subjects with the TT genotype. This was accompanied by impaired postchallenge glucagon suppression but appropriate β-cell responsivity to rising glucose concentrations. These data suggest that α-cell abnormalities associated with the TT genotype (rs7903146) occur early and may precede β-cell dysfunction in people as they develop glucose intolerance and type 2 diabetes. Article Highlights: Diabetes-associated variation in TCF7L2 alters both α- and β-cell function, but the order in which these occur is uncertain. This study assessed whether α-cell dysfunction precedes β-cell dysfunction in people with diabetes-associated variation in TCF7L2. People with the diabetes-associated allele in TCF7L2 (rs7903146) developed increased postchallenge glucose concentrations, which were accompanied by an appropriate β-cell response to hyperglycemia and impaired glucagon suppression. The findings show that α-cell dysfunction occurs early in people with diabetes-associated variation in TCF7L2. [ABSTRACT FROM AUTHOR]