Venn diagram modeling the effect of the interaction between glucose toxicity and lack of insulin on the vulnerable state of critical illness. Complications of type 1 and type 2 diabetes are explained by hyperglycemia and/or lack of insulin effect. Critical illness is also characterized by hyperglycemia and lack of insulin effect, but additional risk factors render both of these effects more acutely toxic, as indicated by the blue shading. These risk factors include the post-hypoxia reperfused state, iNOS-activated NO generation, increased expression of GLUT-1 and GLUT-3 transporters, and cytokine-, neurological-, and hormone-induced alterations in cellular processes. Hence, improved outcome of critical illness with insulin-titrated maintenance of normoglycemia is likely to be explained by the prevention of both direct glucose toxicity and insulin-induced effects that are independent of glucose control.