Even-numbered dicarboxylic acids (DA) have been proposed as an alternative fuel substrate in parenteral nutrition. In particular, dodecanedioic acid (C12) shows a rapid plasma clearance from tissues, a very low urinary excretion compared with other DA and a high oxidation rate. The aim of the present study was to investigate the effect of C12 infusion on insulin-stimulated glucose uptake in patients with non-insulin-dependent diabetes mellitus (NIDDM) compared with healthy volunteers. A primed-constant infusion of C12 (0·39 mmol/min) was administered over 240 min, and at 120 min a 2 h euglycaemic hyperinsulinaemic clamp was performed. Blood specimens were sampled every 30 min and fractioned urines were collected over 24 h. The levels of C12 were measured by HPLC. Indirect calorimetry was performed continuously during the entire session. Body composition was assessed in all subjects studied to obtain fat-free mass (FFM) values. Whole-body glucose uptake decreased significantly during C12 infusion in both groups, although this effect was much more evident (P < 0·01) in NIDDM patients (52·4 (sd 15·8) % decrease compared with saline) than in controls (25·9 (sd 12·1) % decrease). The M value (μmol/kgffm per min) was reduced by C12 to lower levels in NIDDM patients than in normal controls (12·6 (sd 3·9) ν. 25·9 (sd 4·5), P < 0·01). Urinary excretion of C12 over 24 h was significantly lower in NIDDM patients than in controls (4·26 (sd 0·30) mmol ν. 5·43 (sd 0·48), P < 0·01), corresponding to less than 3 % of the administered dose. The infusion of C12 decreased non-protein RQ significantly in both groups of patients. In conclusion, this study shows, for the first time, that C12 significantly reduces glucose uptake in both normal controls and NIDDM patients, although this sparing effect on glucose uptake is much more pronounced in diabetic patients. These data suggest that C12 decreases glucose uptake and oxidation, mainly through a mechanism of substrate competition. Thus, it might be a useful alternative substrate in enteral or parenteral nutrition, sparing glucose utilization and increasing glycogen stores, in those clinical conditions, like NIDDM, where reduced insulin-induced glucose uptake and oxidation are observed.