Hypothesis: Intensive insulin therapy-induced mortality is due to excessive serotonin autoinhibition and autonomic dysregulation.

ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES (ACCORD), THE ACTION IN DIABETES AND VASCULAR DISEASE: Preterax and Diamicron Modified Release Controlled Evaluation and the Veterans Affairs Diabetes Trial were designed to study whether older patients with type 2 diabetes mellitus could reduce the risk of heart attacks and stroke and thereby prolong their lives by maintaining their blood glucose levels at near-healthy levels but failed to demonstrate the hoped-for benefit. Why the trials failed, though, and why ACCORD saw significantly more deaths due to increased rates of cardiovascular events in the intensive therapy arm of the study are not clear. These data have now been confirmed by the results of the recently concluded NICE-SUGAR Study which again revealed that intensive glucose control increased mortality among adults in intensive care units. I propose that the negative results noted in these trials are due to altered brain serotonin concentrations and autonomic dysregulation in addition to the low-grade systemic inflammation, decreased endothelial nitric oxide and enhanced free radical generation, diminished anti-oxidant defenses and altered metabolism of essential fatty acids present in patients with type 2 diabetes.