Lack of relationship between 11beta-hydroxysteroid dehydrogenase setpoint and insulin sensitivity in the basal state and after 24h of insulin infusion in healthy subjects and type 2 diabetic patients.

OBJECTIVES: To test whether insulin resistance in type 2 diabetes mellitus is associated with an altered overall setpoint of the 11beta-hydroxysteroid dehydrogenase (11betaHSD) mediated cortisol to cortisone interconversion towards cortisol, and to evaluate whether changes in insulin sensitivity induced by antecedent hyperinsulinaemia are related to changes in the 11betaHSD setpoint. PATIENTS AND MEASUREMENTS: The urinary ratio of (tetrahydrocortisol + allo-tetrahydrocortisol)/tetrahydrocortisone ((THF + allo-THF)/THE) and of free cortisol/free cortisone (UFF/UFE), as well as the plasma cortisol/cortisone ratio were measured in 8 male type 2 diabetic patients and 8 healthy male subjects without and after 24 h of insulin infusion. Insulin was infused at a rate of 30 mU/kg/h with blood glucose being clamped at euglycaemic levels in healthy subjects and at isoglycaemic levels in diabetic patients. Insulin sensitivity was assessed by measurement of whole body glucose uptake (M-value) during a 3-4 h euglycaemic clamp, directly after the 24 h insulin infusion and compared to the M-value on a control day, at least 1 week apart from the 24 h insulin infusion.
RESULTS: Despite impaired insulin sensitivity (M-value, 11.6 +/- 7.7 vs. 28.5 +/- 11.6 micromol/kg/minutes, in type 2 diabetic and healthy subjects, respectively, P < 0.05), urinary (THF + allo-THF)/THE ratio and baseline plasma cortisol/cortisone ratio at 0800 h were similar in type 2 diabetic patients (0.82 +/- 0.07 and 3. 77 +/- 0.70, respectively) and healthy subjects (0.76 +/- 0.14 and 3. 81 +/- 0.88, respectively, ns). Insulin sensitivity was not correlated with urinary (THF + allo-THF)/THE ratio nor with baseline plasma cortisol/ cortisone. In type 2 diabetic patients, insulin sensitivity was further impaired by antecedent hyperinsulinaemia (P < 0.05), but the urinary (THF + allo-THF)/THE ratio (0.80 +/- 0.14, ns) and the plasma cortisol/cortisone at 0800 h (3.66 +/- 0.72, ns) did not change. In healthy subjects, insulin sensitivity did not change significantly (M-value, 22.5 +/- 9.7 micromol/kg/minutes, ns), although the urinary (THF + allo-THF)/THE ratio (0.92 +/- 0.25, P < 0.05) and the plasma cortisol/cortisone (4.59 +/- 0.63, P < 0.05) increased. Insulin did not affect the UFF/UFE ratio in either group.
CONCLUSION: The present study does not support the hypothesis that insulin resistance in type 2 diabetes mellitus is associated with an overall change in the 11betaHSD set point towards cortisol. In view of the stimulatory effects of insulin and cortisol on adipogenesis, long-term stimulation of 11betaHSD reductase activity by insulin could aggravate visceral obesity.