IAPP and Hyperglycemia: As a compensatory mechanism, IAPP may activate HIF-1α/6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) to protect against oligomer toxicity, thus delaying the loss of β cells but at the cost of impairing β cell function.154 However, HIF-1α in islets is decreased in T2D, by hyperglycemia through inhibiting the HIF-1α-HIF-1β dimer formation, and by NEFAs through increasing the proteolysis, leading to inability to initiate hypoxic adaptive responses.155 Depletion of HIF-1α shows impaired GSIS, due to the decreased basal and glucose-stimulated ATP concentration155,156 (Fig. 2h).