Background: Sleep restriction is associated with development of metabolic ill-health, and hormonal mechanisms may underlie these effects. The aim of this study was to determine the impact of short term sleep restriction on male health, particularly glucose metabolism, by examining adrenocorticotropic hormone (ACTH), cortisol, glucose, insulin, triglycerides, leptin, testosterone, and sex hormone binding globulin (SHBG). Methodology/Principal Findings: N = 14 healthy men (aged 27.4±3.8, BMI 23.5±2.9) underwent a laboratory-based sleep restriction protocol consisting of 2 baseline nights of 10 h time in bed (TIB) (B1, B2; 22:00-08:00), followed by 5 nights of 4 h TIB (SR1-SR5; 04:00-08:00) and a recovery night of 10 h TIB (R1; 22:00-08:00). Subjects were allowed to move freely inside the laboratory; no strenuous activity was permitted during the study. Food intake was controlled, with subjects consuming an average 2000 kcal/day. Blood was sampled through an indwelling catheter on B1 and SR5, at 09:00 (fasting) and then every 2 hours from 10:00-20:00. On SR5 relative to B1, glucose (F1,168 = 25.3, p<0.001) and insulin (F1,168 = 12.2, p<0.001) were increased, triglycerides (F1,168 = 7.5, p = 0.007) fell and there was no significant change in fasting homeostatic model assessment (HOMA) determined insulin resistance (F1,168 = 1.3, p = 0.18). Also, cortisol (F1,168 = 10.2, p = 0.002) and leptin (F1,168 = 10.7, p = 0.001) increased, sex hormone binding globulin (F1,167 = 12.1, p<0.001) fell and there were no significant changes in ACTH (F1,168 = 0.3, p = 0.59) or total testosterone (F1,168 = 2.8, p = 0.089). Conclusions/Significance: Sleep restriction impaired glucose, but improved lipid metabolism. This was associated with an increase in afternoon cortisol, without significant changes in ACTH, suggesting enhanced adrenal reactivity. Increased cortisol and reduced sex hormone binding globulin (SHBG) are both consistent with development of insulin resistance, although hepatic insulin resistance calculated from fasting HOMA did not change significantly. Short term sleep curtailment leads to changes in glucose metabolism and adrenal reactivity, which when experienced repeatedly may increase the risk for type 2 diabetes.