The above discussion illustrating the multitude of variables which influence insulin sensitivity in normal subjects challenges the prevailing view that insulin sensitivity is genetically determined in patients with NIDDM. The lack of accurate quantitation of all determinants of insulin sensitivity in the cross-sectional studies, and the difficulty in distinguishing between insulin secretion and sensitivity in prospective studies implies that the inherited metabolic abnormality in NIDDM still remains to be defined. The methodological difficulties in assessing the fate of glucose in many insulin-resistant states raise the possibility that defects in glycogen synthesis may not be rate-limiting for insulin action. It seems more likely that defects in glucose transport or phosphorylation are rate-limiting for glucose disposal, and thus represent either the primary regulatory steps or the steps via which distal defects signal their influence on glucose uptake. The above considerations should not be interpreted to suggest that insulin resistance is unimportant in the pathogenesis of NIDDM. It clearly increases the risk of developing NIDDM, and more importantly, its early amelioration by lifestyle modification seems sufficient to prevent NIDDM.