Experiments were designed to define the role of glucose in controlling insulin secretion in sheep and to determine if the major products of rumen fermentation, namely, acetic, propionic, and butyric acids have a function in such control. Intravenous injections of glucose (0.56, 1.11, and 1.67 mmoles/kg) into four adult sheep did not increase serum insulin concentrations statistically different from the saline control. Injections of butyrate and propionate produced similar hyperglycemias when administered intravenously (2.5 mmoles/kg). Butyrate, but not propionate, evoked a rapid, sustained elevation of serum insulin not explained by the associated hyperglycemia. Acetate at the same dose did not affect blood glucose or serum insulin. Intravenous butyrate injection (2.5 mmoles/kg) into seven lambs, 2, 6, 12, and 24 weeks of age elevated serum insulin concentrations more than a similar or greater hyperglycemia induced by glucose (1.25 mmoles/-kg). Propionate (2.5 mmoles/kg) evoked insulin release as great and probably greater than glucose, but considerable less than butyrate. As lambs grew older, there appeared to be a reduced sensitivity of the insulin secretory apparatus to stimulation by glucose.