Previous work has suggested that impaired islet glucose recognition occurs in patients with adult onset diabetes, as acute insulin release is absent after iv glucose but present after β adrenergic stimulation with isoproterenol (Iso). However, insulin responses to Iso were variably reduced as compared to normal in the diabetics. In order to evaluate the importance of the so dose, dose-response studies were performed in 9 iabetics (fasting plasma glucose >150 mg/dl) and 10 age-matched controls. In both control subjects and diabetics, 0.5 fig Iso produced no insulin response; 2 fig Iso produced an intermediate response; and 8 and 12 jug Iso produced a higher response. The insulin responses to the larger doses of Iso were lower in diabetics than control subjects (8 µg, 20 ± 5 vs. 39 ± 6 (P < 0.025); 12 fig, 21 ± 6 vs. 37 ± 4 (P < 0.05); x ± SEM, µU/ml). Of 16 diabetics who received 12 µg Iso, 5 had insulin responses >2 SD below the control mean, while others had responses that spanned the entire range of normal. Seven diabetics also were given iv secretin (150 U). Their insulin responses to secretin correlated with the responses to Iso (r = 0.83, P < 0.02). Thus, patients with subnormal responses to Iso also had low secretin responses. The abnormalities of acute insulin secretion in diabetics can be explained by a lesion variably affecting islet membrane receptors; some patients may have glucose receptor damage, but intact responses to other stimuli, and others may have more widespread damage affecting β-adrenergic and secretin responses as well. Alternatively, there may be heterogeneity in adult onset diabetes, as patients with low responses to all stimuli could have a qualitatively different lesion affecting insulin secretory capacity rather than membrane receptors.