To assess the mechanism, temporal patterns and magnitudes of the metabolic responses to the K_ATP channel agonist diazoxide, neuroendocrine and metabolic responses to intravenous diazoxide (saline, 1.0 mg/kg and 2.0 mg/kg) and oral diazoxide (placebo, 4.0 mg/kg, and 6.0 mg/kg) were assessed in healthy young adults. Intravenous diazoxide produced rapid, but transient, decrements (P=0.0023) in plasma insulin (e.g., nadirs of 2.8 ± 0.5 and 1.8 ± 0.3 µU/mL compared with 7.0 ± 1.0 µU/mL after saline at 4.0-7.5 minutes) and C-peptide (P=0.0228) associated with dose-related increments in plasma glucose (P=0.0044) and serum nonesterified fatty acids (P<0.0001). Following oral diazoxide plasma insulin appeared to decline, as did C-peptide, again associated with dose-related increments in plasma glucose (P<0.0001) and serum nonesterified fatty acids (P=0.0141). Plasma glucagon, as well as cortisol and growth hormone, was not altered. Plasma epinephrine increased (P=0.0215) slightly only after intravenous diazoxide. There were dose-related increments in plasma norepinephrine (P=0.0038 and P=0.0005 respectively), undoubtedly reflecting a compensatory sympathetic neural response to vasodilation produced by diazoxide, but these would not raise plasma glucose or serum nonesterified fatty acid levels. Thus, selective suppression of insulin secretion, without stimulation of glucagon secretion, raised plasma glucose and serum nonesterified fatty acid concentrations. These findings define the temporal patterns and magnitudes of the metabolic responses to diazoxide and underscore the primacy of regulated insulin secretion in the physiological regulation of postabsorptive carbohydrate and lipid metabolism.