Glucose-stimulated insulin secretion is dysregulated in isolated islets of HNF-4α^loxP/loxP; Ins.Cre mice. (A) Isolated islets from HNF-4α mutants (open circles) lack a robust first-phase insulin secretory response to glucose perifusion compared with that of controls (filled squares), and fail to rapidly terminate insulin secretion upon switching to 0 mM glucose (n = 3). (B) ATP levels in isolated islets from HNF-4α^loxP/loxP; Ins.Cre mice (white bars) stimulated with 2, 5, or 10 mM glucose for 60 minutes are virtually indistinguishable from those of control mice (black bars) (n = 2 per group), indicating that glucose metabolism is not adversely affected in HNF-4α–deficient β cells. (C) The intracellular calcium concentration ([Ca²⁺]_i) increases rapidly in response to 16.7 mM glucose (2.9 nM/s), 1 μM glyburide (10.0 nM/s), and 30 mM KCl in control islets. (D) In contrast, the intracellular calcium concentration increases at a slower rate in response to glucose (0.7 nM/s) and glyburide (2.0 nM/s) in HNF-4α^loxP/loxP; Ins.Cre mice. For all calcium-imaging experiments, n = 4 per group. These are representative plots.