Moreover, sustained activation of the HIF1α/PFKFB3 stress response pathway and the consequent metabolic remodeling that occurs in response to misfolded protein stress provides a unifying explanation for the early loss of cell function (i.e., β-cell glucose responsiveness) but slow rate of β-cell loss in misfolded protein diseases such as Alzheimer’s disease and T2D. Here, PFKFB3 is linked to type 2 diabetes mellitus.