Most incidence studies indicate that baseline plasma glucose, either fasting or post-glucose load, is the best predictor of progression to non-insulin-dependent diabetes mellitus (NIDDM)--the higher the level, the higher the risk. Elevated serum insulin concentrations in the presence of normal fasting plasma glucose levels reflect the presence of insulin resistance and they have also been shown to predict deterioration to NIDDM in a number of populations. Hyperinsulinaemia is a notable characteristic of populations with a high prevalence of NIDDM such as Micronesian Nauruans, American Pima Indians, Mexican-Americans and Asian Indians. In Nauruans and Pima subjects with normal glucose tolerance, those with higher post-load (2-hour) serum insulin at baseline were more likely to progress to either impaired glucose tolerance (IGT) or NIDDM. Conversely, amongst subjects with IGT, progression to NIDDM was predicted by lower (but still high relative to normal) baseline insulin responsiveness. Similar results for subjects with IGT have been described in Japanese. It appears from longitudinal studies that baseline insulin and glucose levels explain much of the association of obesity with risk of NIDDM. It remains to be resolved whether obesity itself may be a manifestation of an underlying defect (such as primary hyperinsulinaemia) which leads to both obesity and NIDDM. The possible sequence of events for the development of NIDDM includes a genetic defect resulting in hyperinsulinaemia and/or insulin resistance and leading ultimately to secondary pancreatic exhaustion with an insulin secretory defect which may also be genetically determined or the result of glucotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)