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Myocardial and whole-body glucose metabolism was assessed in 19 insulin-dependent diabetes mellitus (IDDM) patients. A hyperglycemic clamp was performed 1 ) in the absence of insulin at free fatty acid (FFA) levels of 1.0 mmol/l (test 1); 2 ) in the absence of insulin at low FFA levels (0.1 mmol/l) by means of a lipid-lowering drug, acipimox (test 2); 3 ) during insulin infusion to achieve systemic levels of 400 pmol/l and FFA levels of 0.1 mmol/l (test 3); and 4 ) at the insulin levels of test 3 but increasing FFA to 1.0 mmol/l by means of heparin and intralipid infusion (test 4). Myocardial glucose uptake was measured by positron emission tomography (PET) and 2-[ 18 F]fluoro-2-deoxy-D-glucose. Whole-body glucose uptake was measured in the four conditions by the glucose infusion rate during the PET scanning period. Myocardial glucose uptakes were 40.3 ± 18.0, 395.5 ± 139.6, 852.2 ± 99.1, and 1,388.4 ± 199.1 μmol · kg tissue −1 · min −1 (mean ± SD) and whole-body glucose uptakes were 10.1 ± 2.3, 10.1 ± 3.4, 42.8 ± 5.8, and 30.5 ± 5.6 μmol · kg body wt −1 · min −1 during tests 1, 2, 3, and 4, respectively. Thus, in IDDM patients without coronary artery disease under the condition of hyperglycemia, an increase of myocardial glucose uptake was obtained either by lowering of FFA levels during hypoinsulinemia or by an increase in FFA levels during hyperinsulinemia. In both conditions no significant changes of whole-body glucose uptake were demonstrated.