Changes in intracellular calcium levels are involved in the regulation of myriad cell processes, and study of the many proteins involved in calcium shuttling is an extensive and important field. This work discusses the inositol 1,4,5-trisphosphate receptor (InsP3R), a major calcium transport protein of mammalian cells, and focuses on the role of extracellular sugars in mediating calcium signaling. Hyperglycemia is shown to induce intracellular calcium oscillations in pancreatic β cells dependent on both calcium influx from the extracellular space and release of calcium from intracellular stores. In neuronal cells, chronic exposure to solution containing a high concentration of glucose or N-acetylglucosamine (GlcNAc) is shown to inhibit InsP₃ R-dependent calcium signaling, and this is shown to be due to several effects of these sugars on the InsP₃R. Exposure to high concentrations of these extracellular sugars leads to increased O-linked GlcNAc glycosylation of the InsP₃R. It is demonstrated that this modification functionally inhibits InsP₃R calcium flux at the single channel level. In addition, the spatial mobility of the InsP₃R is restricted, suggesting multiple mechanisms by which chronic sugar exposure inhibits whole cell calcium signaling.