Epidemiological studies suggest that alcohol consumption is an independent risk factor for the development of non-insulin-dependent diabetes mellitus (NIDDM). Alcoholism is known to be associated with increased plasma levels of two novel diols, 2,3-butanediol and 1,2-propanediol, metabolites known to impair insulin action in isolated adipocytes. This study examines whether 2,3-butanediol and 1,2-propanediol have the capacity to impair insulin action acutely in vivo in the rat. Using the euglycemic-hyperinsulinemic clamp, it is shown that the two diols reduce whole-body glucose utilization (by approximately 30%), with the onset of insulin resistance in vivo occurring at plasma concentrations of 2,3-butanediol (33 micromol/L) at least one order of magnitude (P < .001) lower than 1,2-propanediol (432 micromol/L). Tracer methodologies using [U-14C]glucose and 2-deoxy[1-(3)H]glucose indicate that the reduction in whole-body glucose utilization is accompanied by a reduction in glucose uptake and glycogen synthesis in the skeletal muscle and heart. The association between elevated plasma diol levels and insulin resistance demonstrated in this report raises the question of whether there is a link between the high plasma diol levels in alcohol abusers and their increased susceptibility to NIDDM.