Both the insulin response to glucose and the sensitivity to insulin show large variation in the normal population. Many subjects have either a markedly low insulin response or low sensitivity to insulin, with nevertheless normal glucose tolerance. For such subjects to become diabetic, insulin secretion or insulin action must further deteriorate with time, or other factors are added which tip the balance towards diabetes. Most evidence to date indicates that reduced beta-cell responsiveness and reduced insulin sensitivity co-exist in subjects prior to developing NIDDM. Both insulin secretion and insulin action are genetically controlled and influenced by intrauterine and neonatal factors. Insulin secretion and insulin action vary inversely in a closely linked manner; inability to fully compensate for changes in one variable may generate a functional deficit in glucose homeostasis. Subjects combining low functions would run a proportionately larger risk of decompensating the glucose tolerance and be more vulnerable, in terms of diabetes susceptibility, to factors that further reduce insulin output or insulin action. Careful analysis of existing data prompts us to ascribe a dominating role to the impairment of insulin secretion in the pathogenesis of IGT and NIDDM. Patients with NIDDM also exhibit increased proportions of proinsulin and proinsulin conversion intermediates. We used hyperinsulinaemic diabetic and non-diabetic Psammomys obesus to study the possible relationship between steady-state pancreatic insulin stores and the proportion of proinsulin-related peptides in the plasma and the pancreas. A marked increase in these peptides was associated with 90% reduction in insulin stores of the pancreas. After food deprivation, the depletion of pancreatic insulin in the diabetic animals was partially corrected, and the proinsulin/insulin ratio normalized. In contrast, non-diabetic psammomys showed only 50% reduction in pancreatic insulin stores under non-fasting conditions, with no change in proinsulin/insulin ratio. These findings suggest that in the diabetic Psammomys obesus, pancreatic capacity for storage/production of insulin is limited; the metabolic consequences of this limitation are amplified by increased secretory demand secondary to insulin resistance, thus facilitating the establishment of hyperglycaemia, which may in itself further exacerbate the pancreatic dysfunction.