The addition of phenobarbital (PB) to a sulphonylurea regimen improves glucose control in patients with non-insulin dependent diabetes mellitus (NIDDM, Type 2). A change in insulin sensitivity is possibly involved. We hence investigated insulin mediated glucose metabolism before and after a ten day course of PB therapy in healthy, nondiabetic subjects using the euglycemic glucose clamp technique. The glucose disposal rate (M) increased from 5.95 +/- 1.63 mg/kg/min to 8.00 +/- 1.64 mg/kg/min (p less than 0.001), the immunoreactive insulin (IRI) level decreased from 19.1 +/- 2.9 mU/l to 15.2 +/- 4.2 mU/l (p less than 0.02), whereas fasting blood glucose values and body weight remained unchanged. The lactate level remained unaltered, whereas the metabolism of lactate to pyruvate improved with PB therapy. The data demonstrate that PB increases insulin mediated glucose metabolism . This suggests a new approach to influencing insulin sensitivity in man.