Our work is aimed at unraveling the role of the first-phase insulin secretion in the natural history of type 2 diabetes mellitus (T2DM) and its interrelationship with insulin resistance and with β cell function and mass. Starting from pathophysiology, we investigate the impact of impaired secretion on glucose homeostasis and explore postmeal hyperglycemia as the main clinical feature, underlining its relevance in the management of the disease. We also review dietary and pharmacological approaches aimed at improving early secretory defects and restoring residual β cell function. Furthermore, we discuss possible approaches to detect early secretory defects in clinical practice. By providing a journey through human and animal data, we attempt a unification of the recent evidence in an effort to offer a new outlook on β cell secretion.