The effect of metabolic alkalosis and acidosis on insulin response to glucose tolerance tests was determined for cows fed a high cation diet to induce a state of metabolic acidosis. The anion diet to induce a state of metabolic acidosis. The glucose tolerance test (500 mg of glucose/kg of BW infused i.v. over 10 min) caused a rapid increase in plasma glucose and insulin concentrations. Plasma glucose concentrations were highest, and plasma insulin concentrations were lowest, during metabolic acidosis. These results suggest that insulin secretion is impaired during metabolic acidosis, which may reduce tissue uptake of glucose. Correction of metabolic acidosis by oral administration of sodium bicarbonate prior to glucose tolerance testing increased blood pH and bicarbonate concentrations and partially restored insulin response to the glucose tolerance test. Interestingly, sodium bicarbonate also caused an elevation in plasma cortisol concentrations. We concluded that glucose utilization is altered in cows with metabolic acidosis. The correction of acidosis associated with diseases such as diarrhea and ketosis may improve the therapeutic benefit of glucose infusions used to treat these diseases.