Healthy subjects with previously observed low insulin responses to i.v. glucose have been further characterized. A low insulin response was relatively stable over decades. Adaptability to increased demands for insulin secretion was poor. Hence, dexamethasone treatment for 60 h induced insulin resistance but did not enhance insulin responses to glucose or to arginine. Birth weight was not associated with low insulin responses. Data are compatible with major influences of inherent factors on insulin secretion. Low insulin responses in healthy subjects were compared with responses in glucokinase-deficient subjects. Second phase of glucose-induced insulin secretion and glucose-dependent potentiation of arginine-induced secretion were decreased in both groups. However, the first phase response to glucose was higher in glucokinase-deficient subjects. Hence, decreased first phase insulin secretion is not specifically linked to deficiencies in beta-cell metabolism.