Desensitization refers to a temporary physiological state of cellular refractoriness to glucose stimulation induced by repeated or prolonged exposure to high glucose concentrations. Desensitization is reversed in a time-dependent manner, usually minutes after restoration of normal glucose concentrations, and implies involvement of an intrinsic and reversible alteration in stimulus-secretion coupling. β-Cell exhaustion refers to a physical depletion of β-cell insulin stores secondary to prolonged, chronic stimulation with glucose or nonglucose secretatgogues, so that insulin secretion is not possible, even if the β-cell were to become resensitized to glucose. An important distinction between β-cell exhaustion and glucose toxicity is that the exhausted islet has no defects in insulin synthesis, and therefore cell function fully recovers as it rests. Glucose toxicity, on the other hand, implies the gradual, time-dependent establishment of irreversible damage to cellular components of insulin production and, therefore, to insulin content and secretion.