In order to quantify the changes in insulin sensitivity, particularly of endogenous glucose production and fat metabolism, in patients with severe sepsis, a prospective study was conducted in five normal subjects and in five patients with severe sepsis hospitalized in an intensive care unit. The responses of endogenous glucose production, glucose utilization, plasma fatty acids and ketone body concentrations to progressive increase in plasma insulin levels (exogenous insulin infusion rates of 0, 0.5, 1 and 2 m-unitsċmin-1ċkg-1) were measured using the isoglycaemic clamp technique. Total glucose turnover was determined with D-[6,6-2H2]glucose. In each group, plasma glucose was maintained at basal levels (control subjects, 4.32±0.22 mmolċl-1; patients with sepsis, 7.10±2.29 mmolċl-1; P < 0.05). Plasma insulin concentrations were comparable in the two groups at an insulin infusion rate of 0.4 m-unitċmin-1ċkg-1 for controls and 0.5 m-unitċmin-1ċkg-1 for patients with sepsis, but differed following infusion at 2 m-unitċmin-1ċkg-1 (control subjects, 102±13.4 m-unitsċl-1; patients with sepsis, 124.8±19.7 m-unitsċl-1; P < 0.05). Endogenous glucose production was completely suppressed in control subjects by the first insulin infusion (0.4 m-unitċmin-1ċkg-1), but was only suppressed during infusion at 1 m-unitċmin-1ċkg-1 insulin in patients with sepsis. The glucose utilization rate increased significantly with exogenous insulin infusion in control subjects, but did not increase in patients with sepsis. Plasma non-esterified (free) fatty acid and ketone body levels were significantly decreased in both groups by the infusion of exogenous insulin, but the sensitivity of lipolysis was impaired in patients with sepsis. In conclusion, sepsis impaired to a varying extent the action of insulin on endogenous glucose production, glucose utilization, lipolysis and ketogenesis. Whole-body glucose uptake was the most affected, with a total lack of response to the elevated insulin levels obtained in this study. Suppression of endogenous glucose production and lipolysis could only be achieved with higher doses of insulin than those required in normal subjects.

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