BACKGROUND: Amelioration of insulin resistance could improve both glycaemic control and cardiovascular risk factors in patients with type 2 diabetes mellitus. Alpha-lipoic acid has been shown to improve insulin action after parenteral administration. OBJECTIVE: the aim of the study was to assess the effect of oral administration of alpha-lipoic acid on insulin sensitivity in patients with type 2 diabetes. DESIGN: twelve patients (mean+/-sD; age 52.9+/-9.9 yrs; body mass index 33.9+/-7.4 kg/m(2)) were treated with oral alpha-lipoic acid, 600 mg twice daily over a period of 4 weeks. twelve subjects with normal glucose tolerance served as a control group in terms of insulin sensitivity (Is). Is was measured by a 2h manual hyperinsulinaemic (insulin infusion rate-40 mU/m(2 )body surface area/min) euglycaemic (blood glucose kept at 5 mmol/l) clamp technique and expressed as a glucose disposal rate (M) and insulin sensitivity index (IsI). RESULTS: At the end of the treatment period, Is of diabetic patients was significantly increased: M from 3.202+/-1.898 to 5.951+/-2.705 mg/kg/min (mean+/-sD), p<0.01; and IsI from 4.706+/-2.666 to 7.673+/-3.559 mg/kg/min per mIU/l x 100 (mean+/-sD), p<0.05. the difference was not statistically significant between the Is of diabetic patients after alpha-lipoic acid therapy and control subjects. CONCLUSION: short-term oral alpha-lipoic acid treatment increases peripheral insulin sensitivity in patients with type 2 diabetes mellitus.