A universal finding in hyperglycemic patients with type II (non-insulin-dependent) diabetes mellitus is that all share a common defect in glucose recognition resulting in abnormal insulin secretion by pancreatic islet β-cells. This defect is 1) specific for glucose signals rather than global, 2) related to chronic hyperglycemia, and 3) partially reversible after brief treatment with insulin to induce normoglycemia and through use of other pharmacological agents without normalizing glucose levels. My perspective is that an essential component of this defect is secondary and may represent a state of homologous desensitization of the β-cell secretory apparatus to glucose. Elucidation of the biochemical mechanism(s) of defective recognition of glucose signals by β-cells— or glucose “non-sense”—in these patients will provide key insights into the pathogenesis of type II diabetes mellitus.