Insulin resistance of skeletal muscle glucose uptake is a prominent feature of Type II diabetes (NIDDM); therefore, pharmacological intervention should aim to improve insulin sensitivity. Thioctic acid (TA), a naturally occurring compound, was shown to enhance glucose utilization in various experimental models after acute and chronic administration. It also increased insulin-stimulated glucose disposal in patients with NIDDM after acute administration. This pilot study was initiated to see whether this compound also augments glucose disposal in humans after repeated treatment. Twenty patients with NIDDM received TA (500 mg/ 500 ml NaCl, 0.9%) as daily infusions over a period of ten days. A hyperinsulinaemic, isoglycaemic glucose-clamp was done on day 0 and day 11. Parenteral administration of TA resulted in a significant increase of insulin-stimulated glucose-disposal by about 30% (metabolic clearance rate for glucose, 2.5 +/- 0.3 vs. 3.2 +/- 0.4 ml/kg/min and insulin-sensitivity-index: 3.5 +/- 0.5 vs. 4.7 +/- 0.4 mg/kg/microU/ml; p < 0.05, Wilcoxon-Rank-Sum-Test). There were no changes in fasting plasma levels for glucose or insulin; this can be explained, however, by the short period of treatment and observation. This is the first clinical study to show that a ten day administration of TA is able to improve resistance of insulin-stimulated glucose disposal in NIDDM. Experimental data suggest several mechanisms in the mode of action. As the present investigation was an uncontrolled pilot trial, the encouraging results call for controlled studies to further elucidate the clinical relevance of the findings and the mode of action of this compound.