RESUMO
Over the past years, type 2 diabetes mellitus (T2DM) has been defined as a disease caused by insulin resistance, as part of the metabolic syndrome. Insulin resistance does exist in T2DM; however, it exists to the same extent in many more persons without diabetes, whether with or without other features of the metabolic syndrome. Therefore, insulin resistance alone can not be the determining pathogenic factor in T2DM.From its earliest stages, including impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), but perhaps even before these measurable changes, at the "prediabetic" period, T2DM shows derangements in the kinetics of insulin release. Its main characteristic is the loss of first-phase insulin response to glucose, with gradual impairment of also second-phase or overall insulin secretion. Loss of first-phase response has metabolic consequences: lack of rapid insulinization of the liver delays the suppression of hepatic glucose output and causes therefore postprandial hyperglycemia. β-Cell mass has been found to be reduced in T2DM in some but not all studies; therefore this necessitates further confirmation. Nevertheless, it is clear that the diabetes-prone β-cell has limited capacity to adapt cell function to increased secretory demand in insulin resistance or caloric load. Furthermore, even mild hyperglycemia dramatically impairs insulin secretion and proinsulin biosynthesis, thus further reducing the availability of insulin for metabolic needs. The transcription factor PDX-1 plays a central role in this context. Therefore, early and effective induction of near-normoglycemia in T2DM is of paramount importance, especially with restoration of first-phase insulin secretion.