Insulin resistance and hyperinsulinemia are closely associated (1). It is widely recognized that a dynamic relationship exists between insulin secretion and insulin resistance in which worsening insulin action (ie, insulin resistance) triggers an increase in insulin secretion, and the hyperinsulinemia compensates for the defect in insulin action. Based on this relationship between insulin secretion and insulin resistance, the prevailing paradigm of the natural history of type 2 diabetes mellitus (T2DM) was formulated that insulin resistance is the primary defect in individuals destined to develop T2DM, and compensatory hyperinsulinemia ensues to offset the diminished efficacy in insulin action. Hyperglycemia develops only when the β-cell fails to augment its insulin secretion and compensate for insulin resistance (1). Indeed, severe insulin resistance preceding or accompanied by hyperinsulinemia can be detected long before the development of T2DM (2). However, the coexistence of insulin resistance and hyperinsulinemia does not establish a causal relationship between the two, nor does it define which defect, insulin resistance or increased insulin, precedes the other. Using data obtained in Pima Indians with the euglycemic insulin clamp and oral glucose tolerance test (OGTT), we pointed out in 1997 (1) that the results were consistent with β-cell hypersecretion of insulin as the primary defect followed by the development of insulin resistance secondary to the resultant hyperinsulinemia (3).

In the past several years, other studies (reviewed in [4]) have challenged this “central dogma” of the natural history of T2DM, and suggested that hyperinsulinemia is the primary defect that precedes insulin resistance and triggers the events responsible for the development of T2DM. This discussion about the “egg and chicken” relationship between hyperinsulinemia and insulin resistance has important clinical implications. If hyperinsulinemia is a compensatory response to insulin resistance, then further elevation of plasma insulin concentration becomes a good strategy to overcome insulin resistance to achieve optimal glycemic control, although the hyperinsulinemia may result in other undesired metabolic effects. Conversely, if insulin hypersecretion and hyperinsulinemia is the primary defect that triggers insulin resistance, therapeutic efforts should focus on strategies to reduce plasma insulin concentration to achieve optimal metabolic control in T2DM patients. In the present issue of the journal, Armiyaw and colleagues (5) provide evidence that challenges the prevailing view of the natural history of T2DM, in which insulin resistance precedes and is the causative factor responsible for the increased insulin secretion. They compared insulin secretion and insulin sensitivity in 2 groups of middle-age patients of African American and non-Hispanic white ethnicity. Insulin sensitivity was measured with the euglycemic hyperinsulinemic clamp and insulin secretion was measured with intravenous glucose tolerance test (IVGTT). The 2 groups had comparable body structure as measured