Foxa2^loxP/loxP;Ins.Cre islets exhibit misregulated hormone secretion in response to glucose and amino acids. (A) Control islets (filled symbols) immediately secrete insulin in response to 25 mM glucose but do not respond to amino acids alone. In contrast, Foxa2^loxP/loxP;Ins.Cre islets (open symbols) secrete insulin in a dose-dependent manner upon exposure to increasing concentrations of a mixture of all 20 amino acids (0.55 mM/min for 30 minutes up to 17 mM) followed by 20 minutes at 17 mM, with no additional response to 25 mM glucose. Data shown are mean ± SEM of 2 identical experiments. Similar responses were seen in 8 additional trials (data not shown). (B) Control islets do not respond to amino acid stimulation, but 300 nM glyburide closes K_ATP channels and leads to insulin secretion. As in A, Foxa2^loxP/loxP;Ins.Cre islets respond to the identical amino acid ramp, but glyburide has no additional effect. Trace shown is representative of 2 similar experiments. (C) Control islets secrete glucagon in response to low concentrations of an amino acid ramp (0.55 mM/min for 30 minutes up to 17 mM), but Foxa2^loxP/loxP;Ins.Cre islets do not. While the amino acid concentration is held constant at 17 mM, additional exposure to 25 mM glucose for 20 minutes has no effect on secretion from either control or mutant islets. Mean ± SEM of two identical experiments is shown. Downward arrows indicate times of reagent administration.