The acute insulin responses to intravenous glucose and tolbutamide were studied serially in middle aged subjects with a wide spectrum of glucose tolerance. Eighty were of normal weight, 102 frankly obese. In normal weight patients, insulin response to glucose, subnormal in chemical diabetes, was almost absent when fasting blood glucose was elevated. Tolbutamide evoked a normal response provided that the fasting blood glucose was lower than 125 mg/100 ml. The response decreased dramatically thereafter. In the obese the response decreased dramatically thereafter. In the obese the response to glucose was decreased in chemical diabetics compared to non-diabetics, but failed completely only when the fasting glycemia exceeded 200 mg/100 ml. The response to tolbutamide decreased only with fasting glycemia in excess of 200 mg/100 ml. When insulin responses were expressed relative to basal insulin values the differences between non diabetic obese and normal weight subjects disappeared but this was not true of the other categories. These findings demonstrate that the B-cell responses differ not only quantitatively but also in kind between normal weight and obese diabetics. Six cases of incipient juvenile diabetes (100 less than fasting blood glucose less than 125 mg/100 ml) showed no insulin response to glucose nor to tolbutamide in contrast to the comparable weight group of maturity onset diabetics.