Sleep Loss and Circadian Misalignment - Mechanisms of Insulin Resistance

Cortisol will be clamped with oral administration of Metyrapone, which blocks endogenous cortisol biosynthesis. A loading dose of 3,000mg will be given at 10:00 on day 2. Every 4 hours throughout the sleep restriction and sleep deprivation phases, 500mg will be administered beginning at 14:00 on day 2 and ending with a dose at 18:00 on day 5. Using a subcutaneous pump, hydrocortisone is administered here as physiological replacement, with pulses every 3 hours beginning at 10:00 on day 2. Participants will receive 3 tiers of doses: low (0.5mg), moderate (2.3mg) and high (4.0mg), the timing of which is specified by their condition assignment. For all participants, an oral 25mg dose of hydrocortisone will be given at the end of the constant routine period to prevent any future hypocortisolemia associated with the hormone clamp.

The frequently sampled intravenous glucose tolerance test is performed before and after sleep restriction, and is widely used and validated. This procedure requires intravenous administration of dextrose, 300 mg/kg as a bolus at time zero. Insulin (0.03 units/kg/min) will be slowly infused intravenously over a 5 minute period from 20 to 25 minutes. Few side effects are anticipated as both doses of glucose and insulin should result in a high, but physiological peak. Administration of insulin as 5-min infusion for clinical studies (rather than bolus) reduces the max concentrations achieved. It is not uncommon for glucose to dip below fasting glycemia at some point after the insulin administration. The concentration at the nadir depends on the subject's insulin sensitivity. Return to fasting level is a function of the waning of the insulin effect (incorporated into the minimal model) as well as counterregulation (which depends on the concentration at the nadir). This can be addressed,

The frequently sampled intravenous glucose tolerance test is performed before and after sleep restriction, and is widely used and validated. This procedure requires intravenous administration of dextrose, 300 mg/kg as a bolus at time zero. Insulin (0.03 units/kg/min) will be slowly infused intravenously over a 5 minute period from 20 to 25 minutes. Few side effects are anticipated as both doses of glucose and insulin should result in a high, but physiological peak. Administration of insulin as 5-min infusion for clinical studies (rather than bolus) reduces the max concentrations achieved. It is not uncommon for glucose to dip below fasting glycemia at some point after the insulin administration. The concentration at the nadir depends on the subject's insulin sensitivity. Return to fasting level is a function of the waning of the insulin effect (incorporated into the minimal model) as well as counterregulation (which depends on the concentration at the nadir). This can be addressed,