Pyruvate dehydrogenase (PDH) is poorly active in circulating lymphocytes of NIDDM patients; in vitro, it is unresponsive to insulin at 5 microU/ml and activated at 50 microU/ml, instead of activated and inhibited as in healthy controls. This study examines whether healthy offspring of NIDDM patients with a family history for this disease have these alterations. Twenty seven healthy offspring (23+/-10 yr, median 18 yr) and their parents (13 diabetic with a family history for NIDDM and 11 healthy without this history) were enrolled. Twenty healthy individuals without the history and matched for age and gender with the offspring served as controls. Minimum levels for enzyme activity before and after cell stimulation with insulin at 5 microU/ml were computed for a 95% CI with no more than 5% of the controls excluded. Increased or unvaried enzyme activity in response to insulin at 50 microU/ml was defined as abnormal. All NIDDM parents and 11/27 offspring had below normal enzyme activity and defective and reversed enzyme response to insulin at 5 and 50 microU/ml; three offspring had altered enzyme response to insulin at both concentrations, four to insulin at 5 microU/ml, three to insulin at 50 microU/ml and six, together with the healthy parents, had no alterations. We conclude that in healthy individuals a family history for NIDDM is frequently signaled, irrespective of age, by molecular derangements, with an apparent genetic background, in their circulating lymphocytes.