Glycemic and nonglycemic effects of insulin: how do they contribute to a better outcome of critical illness?

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Abstract
This review gives an overview of the clinical outcome benefits associated with intensive insulin therapy administered to critically ill patients and of the progress in the unraveling of the mechanisms underlying these positive effects. In a large, prospective, randomized, controlled study, strict blood glucose control with intensive insulin therapy strongly reduced mortality and morbidity of surgical intensive care patients. These results were recently confirmed in a more heterogeneous patient population admitted to a mixed medical-surgical intensive care unit. Most of the clinical benefits of intensive insulin therapy appear to be related to prevention of hyperglycemia, which has been demonstrated to adversely affect outcome. Part of the improvement is related to protection of the mitochondrial compartment and innate immunity from glucose toxicity. Also, direct insulin effects contribute to the improved outcome. The beneficial nonglycemic metabolic actions of insulin include a partial correction of the abnormal serum lipid profile and counteraction of the catabolic state evoked by critical illness. The prevention of excessive inflammation and myocardial protection illustrate other nonmetabolic direct anti-inflammatory and anti-apoptotic properties of insulin, although lowering of glucose levels may have played a role in these events as well. Substantial progress has been made in the understanding of the mechanisms underlying the improved survival and reduced morbidity with intensive insulin therapy in critical illness. More studies, however, are needed to further elucidate the exact pathways involved and the relative contribution of prevention of glucose toxicity and direct nonglycemic effects of insulin.