OBJECTIVE: Coupled oscillations of 50-110 min in insulin and glucose have been found previously in healthy men under continuous enteral nutrition. Because L-arginine induces insulin release as glucose does, we tested the hypothesis that L-arginine can also display such an ultradian rhythm. RESEARCH DESIGN AND METHODS: Seven healthy male subjects participated in one experimental night during which blood was sampled every 10 min from 2300 to 0700. Plasma glucose, C-peptide, and L-arginine levels were measured simultaneously. The insulin secretion rate (ISR) was calculated from plasma C-peptide levels by a deconvolution procedure. RESULTS: Plasma glucose followed the recognizable profiles, with oscillations closely linked to similar changes in the ISR. Pulse analysis of L-arginine profiles revealed significant oscillations linked to glucose and ISR oscillations, with the highest cross-correlation coefficients at time lag 0 ranging from 0.380 to 0.680 for glucose and L-arginine and from 0.444 to 0.726 for ISR and L-arginine (P < 0.01). The mean period of L-arginine oscillations was 77.2 +/- 6.2 min, and their mean amplitude was 19.9 +/- 1.7%, similar to that of glucose (17.0 +/- 1.9%), when expressed as the percentage of mean overnight levels. CONCLUSIONS: This newly discovered ultradian rhythm of L-arginine and its coupling with glucose and ISR oscillations sheds new light on the regulation of L-arginine, the substrate of numerous metabolic pathways, including nitric oxide synthesis. These oscillations may be of significance in conditions of hyperinsulinemia or abnormal glucose tolerance.