To assess the interaction of arterial PO2 (PaO2) and glucose metabolism, conscious 18-h-fasted dogs with chronically implanted sampling catheters (carotid artery, iliac vein) and flow probe (external iliac artery) were studied during inspiration of air containing 21 (n = 9), 14 (n = 6), 11 (n = 4), or 8% (n = 5) O2. Isotopic and arteriovenous methods were used to assess carbohydrate metabolism. PaO2 was 103 +/- 3, 64 +/- 4, 45 +/- 4, and 30 +/- 1 mmHg with decreased inspired O2. Although limb O2 delivery was reduced (51 +/- 6, 42 +/- 8, 39 +/- 7, and 34 +/- 5 ml/min), limb O2 uptake was not compromised. Plasma insulin was 9 +/- 1, 8 +/- 2, 14 +/- 2, and 16 +/- 3 microU/ml, and glucagon was 53 +/- 3, 49 +/- 3, 64 +/- 5, and 101 +/- 7 pg/ml with decreasing O2. Plasma epinephrine and cortisol were increased whereas norepinephrine was unaffected. Glycemia was unaffected by reduced O2, whereas hepatic glucose output (14 +/- 1, 19 +/- 3, 21 +/- 1, and 22 +/- 1 mumol.kg-1.min-1) and glucose disappearance (14 +/- 2, 18 +/- 3, 20 +/- 1, and 22 +/- 2 mumol.kg-1.min-1) rose similarly. Limb glucose uptake (LGU) rose (21.5 +/- 4.7, 21.2 +/- 5.6, 30.6 +/- 4.7, and 45.3 +/- 9.7 mumol/min) with decreasing O2 because of greater fractional extraction (0.023 +/- 0.005, 0.024 +/- 0.005, 0.031 +/- 0.004, and 0.043 +/- 0.004). Of the increased LGU, approximately 33 and 67% were metabolized oxidatively and nonoxidatively.(ABSTRACT TRUNCATED AT 250 WORDS)