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Insulin sensitivity in vivo and insulin binding in vitro to adipocytes have been studied in streptozotocin diabetic rats with ketoacidosis. Insulin sensitivity in vivo measured as the acute (20 min) fall in blood glucose in response to an insulin infusion of 1 U/kg body weight per hour correlated positively with arterial blood pH (r = 0.92,p < 0.01 : n = 38). At pH < 6.9 there was no fall in blood glucose. For studies of insulin binding to adipocytes ketoacidotic animals were divided into a group with moderate ketoacidosis (pH > 7.0) and a second group with severe ketoacidosis (pH < 6.9). Insulin binding to adipocytes was maximal in cells from both ketoacidotic and from normal rats at pH 7.6-7.8. Total binding was decreased in the diabetic rats (p < 0.01) and this was more marked in the severely diabetic group (p < 0.001) at all pHs studied. At pH 7.4, 125I-insulin binding was decreased in diabetics compared with normal rats (0.89 + 0.14 versus 2.0 + 0.24% with 2 • 105 cells/ml: n = 6;p < 0.01) and also inthe severe compared with the moderate ketoacidotic rats (0.5 + 0.08%/2 • 105 cells; n = 6, p < 0.05). Equilibrium binding studies showed that there was a small decrease in apparent affinity in adipocytes from both groups of diabetics (KD = 2.8 __ 0.2 x 10 ~ mol/1, n = 6 in moderate ketoacidosis; 2.5 + 0.3 • 10 -9 tool/l, n = 6 in severe ketoacidosis) compared with control animals (KD = 1.8 _ 0.15 • l0 -9 mol/1, n = 6). Scatchard analysis revealed that there was also a decrease in receptor concentration which was greater in the severely ketoacidotic group. These findings may explain in part the insulin resistance of severe ketoacidosis.