In vivo glucose uptake (Rd) occurs via two mechanisms: insulin-mediated glucose uptake (IMGU), which occurs in insulin-sensitive tissues, and noninsulin-mediated glucose uptake (NIMGU), which occurs in both insulin-sensitive and non-insulinsensitive tissues. To determine whether these two pathways for in vivo glucose disposal are regulated independently, we studied the effect of stress levels of cortisol on IMGU and NIMGU in seven normal subjects after an overnight fast. To study NIMGU, somatostatin (SRIF, 600 μg/h) was infused to suppress endogenous insulin secretion and create severe insulinopenia, and glucose turnover was measured isotopically while serum glucose was clamped at ∼200 mg/dl for 240 min. Separate studies were performed during the overnight infusion of saline or hydrocortisone (HCT; 2.0 μg · kg−1 · min1). The final 120 min of each study were used for data analysis. Under these conditions, insulin action is absent, and Rd = NIMGU. NIMGU was 204 ± 11 mg/min and 208 ± 8 mg/dl during saline and HCT, respectively (P NS). Therefore, HCT did not modulate NIMGU. To measure the effect of cortisol on Rd, hyperglycemic (200 mg/dl)-hyperinsulinemic clamp studies (30 mU · m−2 · min1) were performed during the infusion of saline or HCT. The results demonstrate that during saline infusion, steady-state rates of Rd (10.4 ± 0.8 mg · kg−1 · min1) were achieved by 160 min; in contrast, during HCT infusion, Rd never reached steady state but increased from 4.5 ± 0.2 in the 2nd h to 7.6 ± 0.4 mg kg1 min1 in the 4th h, P < .01. In conclusion, 1) cortisol has no measurable modulatory effect on NIMGU, 2) IMGU and NIMGU are independently regulated and functionally distinct, and 3) cortisol causes insulin resistance by causing a decrease in the rate at which insulin activates the glucose uptake system.

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