Insulin sensitivity with respect to changes in blood glucose, lactate, and ketone body concentrations has been studied in normal and streptozotocin-diabetic rats. Insulin was infused at doses ranging from 0.03 to 100 U/kg/hr and dose response curves established. Maximal responsiveness was achieved at 1 U/kg/hr for glucose and 0.3 U/kg/hr for ketone bodies in normal rats. In diabetic rats, responsiveness and sensitivity were directly proportional to pH. When pH was less than 6.9, there was little or no response. Ammonium chloride administration to normal rats or to mildly acidotic diabetic rats caused almost total loss of responsiveness to insulin. The insulin insensitivity found in severely acidemic diabetic rats could be reversed by sodium bicarbonate administration. Liver and muscle metabolite patterns suggested that loss of responsiveness and sensitivity was due both to effects at the insulin receptor and direct effects on glycolysis, presumptively at phosphofructokinase. Reversal of these changes with bicarbonate was associated with a fall in hepatic ATP content. It is suggested that the insulin resistance of severe diabetic ketoacidosis in the rat is secondary to inhibitory effects of hydrogen ion; the exact mechanism remains to be established.