Effect of Intensive Insulin Therapy on Insulin Sensitivity in the Critically Ill

CONTEXT: Hyperglycemia and hyperinsulinemia are common in intensive care unit (ICU) patients and relate to illness severity. Intensive insulin therapy (IIT) to maintain normoglycemia reduces morbidity and mortality. Blood glucose control explains this benefit because a high insulin dose is associated with adverse outcome. Mitogenic insulin effects could theoretically explain this link. OBJECTIVE: To investigate further the association between insulin dose and adverse outcome, we studied the effect of IIT on circulating insulin levels, markers of insulin sensitivity, and the metabolic and mitogenic insulin signaling molecules in key tissues. DESIGN: This is a subanalysis of a large randomized, controlled study. SETTING: The study was performed in a university hospital surgical ICU. PATIENTS: A total of 339 critically ill patients, treated in ICU for at least a week, were included in this subanalysis. INTERVENTION: Strict normoglycemia with IIT compared with conventional insulin therapy was performed. RESULTS: Severalfold higher insulin doses than with conventional insulin therapy were required to maintain normoglycemia with IIT. However, serum insulin levels were only transiently higher with IIT, despite the much lower blood glucose levels. IIT normalized the elevated serum C-peptide levels and increased circulating adiponectin levels. The metabolic insulin signal was increased by IIT in muscle, but not in liver. The mitogenic insulin signal in either tissue was not affected by IIT. CONCLUSIONS: Normoglycemia can be maintained in ICU patients without a sustained further elevation of insulinemia. Together with the increased adiponectin levels, this finding suggests that IIT may improve insulin sensitivity. Skeletal muscle, but not liver, revealed an increased metabolic insulin signal. The therapy did not impose mitogenic risk in these tissues.