INS and Insulin resistance: In the presence of insulin resistance and under glucolipotoxic conditions, various extracellular signals from other organs modulate cellular responses, such as those involved in fuel metabolism, ER, and oxidative stress, as well as activating proinflammatory cascades and, in turn, constituting a vicious feed-forward cycle that promotes impaired insulin secretion, apoptosis, and perhaps dedifferentiation [93].