In the original description of the glucose-fatty acid cycle Randle and co-workers (1963) identified that a high circulating concentration of free fatty acids (FFA) was associated with a reduction in insulin sensitivity, primarily due to long chain fatty acids inhibiting muscle glucose uptake. Whether all lengths of fatty acids exert the same metabolic effect is, however, unclear. Acetic acid, a short chain fatty acid, has been shown to decrease glucose appearance in the blood in rats when ingested immediately prior to a glucose load (Ebihara and Nakajima 1988). Additionally sodium acetate administration has been found to enhance insulin secretion in the rat model when glucose was co-infused, resulting in a quicker rate of glucose disappearance (Shah et al. 1977). The current study examined whether sodium acetate ingestion prior to the consumption of a glucose load affects insulin sensitivity and/or the glycaemic and insulinaemic response in humans. Six healthy male subjects volunteered to ingest an equimolar dose (4 mmol/kg body mass) of sodium acetate (NaAc) or sodium bicarbonate (NaHCO3) over a 60 min period followed by the consumption of 75 g of glucose. Trials were completed on two separate occasions 7 days apart. Arterialised-venous blood samples were taken prior to sodium salt ingestion, immediately before consuming the glucose solution and at 15, 30, 60, 90 and 120 min after ingestion of the glucose load. Data were analysed using a 2-way repeated measures ANOVA and where appropriate by post-hoc Wilcoxon matched pairs test. Both sodium salts induced a mild metabolic alkalosis (blood pH ~7.42 vs. 7.48 pre- and post-ingestion in both trials). During the first 15 min of the oral glucose tolerance test there were greater increases in blood glucose (P=0.03) and plasma insulin (P=0.03) in the NaAc compared with the NaHCO3 trial. Although there was no difference in the glycaemic response between trials thereafter, plasma insulin was found to be significantly lower at the end of the NaAc trial (10.6 ± 2.9 μU/ml NaAc; 19.3 ± 3.2 μU/ml NaHCO3, P=0.046). Insulin sensitivity was significantly improved (P < 0.05) following the consumption of sodium acetate when compared with the bicarbonate trial, as determined using the insulin sensitivity index (ISI0,120). In conclusion the ingestion of sodium acetate 60 min prior to a 75 g oral glucose load was found to significantly improve insulin sensitivity when compared to the insulinaemic response following sodium bicarbonate ingestion.