Thyroxine and T3 induced oxygen consumption and glucose uptake were studied in vitro in mononuclear blood cells isolated from patients with non-insulin-dependent diabetes mellitus (NIDDM) and from non-diabetic control persons. Cellular oxygen consumption and glucose uptake were promptly increased by physiological and supraphysiological concentrations of T3 and T4 in a dose-dependent manner (50-5000 nmol/l), whereas rT3 and T2 had no stimulatory effect. The effect of T3 and T4 was independent of new protein synthesis in that it was not blocked by tunicamycin (1 mg/l) and tiothepa (75 mg/l). Examination of stimulation of cells from control subjects and patients with NIDDM revealed an identical oxygen consumption, whereas the thyroid hormone-induced glucose uptake was significantly increased in cells from patients with NIDDM. T4 (5 mumol/l) stimulation in controls: 1.34 +/- 0.23 mmol.l-1 (mg DNA)-1.h-1, in NIDDM: 3.24 +/- 0.77 mmol.l-1.(mg DNA)-1.h-1, P less than 0.05 (mean +/- SD). These studies indicate that T4 as well as T3 increases cellular oxygen consumption and glucose uptake and that this stimulation is independent of new protein synthesis. Examination of cells from patients with NIDDM revealed an increased thyroid hormone induced glucose uptake, indicating increased thyroid hormone sensitivity. This observation contrasts the well known insulin insensitivity, suggesting separate mechanisms for glucose uptake elicited by insulin and thyroid hormones.