INS and Hyperglycemia: When beta-cell are exposed to a high nutrient environment including hyperglycemia and saturated fatty acids, mitochondrial metabolism is enhanced, and cytosolic ATP synthesis is increased, thereby closing ATP-sensitive K+ (K+-ATP) channels, resulting in depolarization of the plasma membrane, Ca2+ influx, and impaired insulin granule exocytosis, which further increases metabolism and oxidative phosphorylation (74).