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Impaired basal glucose effectiveness but unaltered fasting glucose release and gluconeogenesis during short-term hypercortisolemia in healthy subjects

¹Department of Endocrinology, Aarhus Kommunehospital and Department of Clinical Pharmacology, University of Aarhus, ²Department of Medicine V, Aarhus University Hospital, and ³Department of Surgical Gastroenterology L, Aarhus Kommunehospital, DK-8000 Aarhus, Denmark; ⁴Metabolism and Nutrition Unit, San Raffaele Scientific Institute, 20132 Milan, and ⁵Department of Electronics and Informatics University of Padova, 35128 Padua, Italy; ⁶Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106; and ⁷Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota 55905

Submitted 23 December 2002 ; accepted in final form 8 September 2003

Excess cortisol has been demonstrated to impair hepatic and extrahepatic insulin action. To determine whether glucose effectiveness and, in terms of endogenous glucose release (EGR), gluconeogenesis, also are altered by hypercortisolemia, eight healthy subjects were studied after overnight infusion with hydrocortisone or saline. Glucose effectiveness was assessed by a combined somatostatin and insulin infusion protocol to maintain insulin concentration at basal level in the presence of prandial glucose infusions. Despite elevated insulin concentrations (P < 0.05), hypercortisolemia resulted in higher glucose (P < 0.05) and free fatty acid concentrations (P < 0.05). Furthermore, basal insulin concentrations were higher during hydrocortisone than during saline infusion (P < 0.01), indicating the presence of steroid-induced insulin resistance. Postabsorptive glucose production (P = 0.64) and the fractional contribution of gluconeogenesis to EGR (P = 0.33) did not differ on the two study days. During the prandial glucose infusion, the integrated glycemic response above baseline was higher in the presence of hydrocortisone than during saline infusion (P < 0.05), implying a decrease in net glucose effectiveness (4.42 ± 0.52 vs. 6.65 ± 0.83 ml·kg^-1·min^-1; P < 0.05). To determine whether this defect is attributable to an impaired ability of glucose to suppress glucose production, to stimulate its own uptake, or both, glucose turnover and "hot" (labeled) indexes of glucose effectiveness (GE) were calculated. Hepatic GE was lower during cortisol than during saline infusion (2.39 ± 0.24 vs. 3.82 ± 0.51 ml·kg^-1·min^-1; P < 0.05), indicating a defect in the ability of glucose to restrain its own production. In addition, in the presence of excess cortisol, glucose disappearance was inappropriate for the prevailing glucose concentration, implying a decrease in glucose clearance (P < 0.05). The decrease in glucose clearance was confirmed by the higher increment in [3-³H]glucose during hydrocortisone than during saline infusion (P < 0.05), despite the administration of identical tracer infusion rates. In conclusion, short-term hypercortisolemia in healthy individuals with normal -cell function decreases insulin action but does not alter rates of EGR and gluconeogenesis. In addition, cortisol impairs the ability of glucose to suppress its own production, which due to accumulation of glucose in the glucose space results in impaired peripheral glucose clearance. These results suggest that cortisol excess impairs glucose tolerance by decreasing both insulin action and glucose effectiveness.

insulin action

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