l-Arginine: An Ultradian-Regulated Substrate Coupled With Insulin Oscillations in Healthy Volunteers

Abstract

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 Ͻ 0.01). The mean period of L-arginine oscillations was 77.2 Ϯ 6.2 min, and their mean amplitude was 19.9 Ϯ 1.7%, similar to that of glucose (17.0 Ϯ 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. Diabetes Care 26:168 -171, 2003A number of studies have demonstrated that L-arginine triggers insulin release in the presence of D-glucose (1-4). The underlying mechanisms are not fully elucidated. The insulinotropic action of L-arginine has been ascribed to transporter-mediated accumulation of this cationic amino acid inside the ␤-cells, with resulting depolarization of the plasma membrane (2,3). One other putative mechanism is the formation of nitric oxide (NO) from Larginine by the action of NO synthase in pancreatic ␤-cells (4 -7). It has been reported that systemic infusion of Larginine induces vasodilation, inhibits platelet aggregation, and reduces blood viscosity and that these effects are mediated by NO release (8,9). Although there might be a dietary need for L-arginine, it is produced endogenously from the turnover of the urea cycle within the liver and via conversion of citrulline to arginine in the renal proximal tubule (10,11).In normal humans, the insulin secretion rate (ISR) presents an oscillatory pattern characterized by slow ultradian oscillations with a period of 50 -110 min coexisting with rapid small fluctuations of 8 -15 min. These ISR oscillations are closely associated with similar oscillations in plasma glucose and are best seen in situations of insulin stimulation, such as during continuous enteral nutrition (12), after meal ingestion (13), and during intravenous glucose infusion (14). Abnormalities in their pa...

Co‐expression of diurnal and ultradian rhythms in the plasma metabolome of common voles (Microtus arvalis)

“…Ornithine (and arginine, although not deemed ultradian in this study) are directly implicated in the latter steps of the urea cycle, suggesting ultradian rhythms in liver urea formation. While our observations are made in the vole, arginine blood concentrations have also been shown to exhibit ultradian rhythms in healthy human male volunteers, and have been linked to insulin‐mediated glucose homeostasis 52 . Indeed, both insulin and glucose have been shown to exhibit an ultradian pattern in blood concentrations in humans that persists during constant enteral nutrition 53,54 confirming intrinsic, non‐food‐driven ultradian rhythms in glucose homeostasis.…”

“…While our observations are made in the vole, arginine blood concentrations have also been shown to exhibit ultradian rhythms in healthy human male volunteers, and have been linked to insulin-mediated glucose homeostasis. 52 Indeed, both insulin and glucose have been shown to exhibit an ultradian pattern in blood concentrations in humans that persists during constant enteral nutrition 53,54 confirming intrinsic, non-food-driven ultradian rhythms in glucose homeostasis. Recently it has been suggested that other amino acids such as leucine and glutamine may be modulators of pancreatic insulin secretion, 55 and both amino acids exhibit ultradian rhythmicity in our current metabolomics analysis.…”

Evidence for a Coupled Oscillator Model of Endocrine Ultradian Rhythms

“…6-24 M 7-14, Adult or NA NA Goji, 1993;Kimura and Tsai, 1984;Minamitani et al, 1989;Mitsugi and Kimura, 1986;Tannenbaum and Ling, 1984;Tannenbaum and Martin, 1976;Yonezawa et al, Brandenberger et al, 1987;Lefcourt et al, 1999;Polonsky et al, 1988;Schaefer et al, 2003;Scheen et al, 1996;Shapiro et al, 1988;Simon and Brandenberger, 2002;Simon et al, 1987;Sturis et al, 1992 GBA Ghrelin Bagnasco et al, 2002a;Mingrone et al, 2006;Tolle et al, 2002 GBA Bagnasco et al, 2002a;Licinio et al, 1997Licinio et al, , 1998aLicinio et al, , 1998bSaad et al, 1998;…”

“…In addition, 2-to 8-h URs in intestinal activity (Ariga et al, 2007;Code and Marlett, 1975;Deloose et al, 2012Deloose et al, , 2015Fujino et al, 2003;Hoogerwerf, 2010;Husebye et al, 1990;Masuda et al, 2000;Zheng et al, 2009) can be initiated by administration of ghrelin or the related peptide motilin. In rats, plasma ghrelin and leptin and, in humans, glucose and insulin URs occur both in fed and fasted conditions (Bagnasco et al, 2002b;Schaefer et al, 2003;Scheen et al, 1996;Shapiro et al, 1988;Simon et al, 1987;Simon et al, 1998;Simon and Brandenberger, 2002;Sturis et al, 1992), suggesting that these rhythms are not only food entrained but also endogenously maintained. Although interindividual variability makes clear that multiple stable states of varying periodicity exist, the periodicities and phase alignments of GBA components provide compelling evidence for a temporally organized GBA network structure on an ultradian timescale.…”

Changes in arginine are inversely associated with type 2 diabetes: A case‐cohort study in the PREDIMED trial

“…One putative mechanism is the formation of nitric oxide (NO) from l-arginine by NO synthase in pancreatic β cells. 10 Arginine is required for the production of NO via catalysis to citrulline by NO synthase (NOS), 11 and the prevailing hypothesis is that greater arginine bioavailability may stimulate NO production and insulin sensitivity 12,13 ; thus, disturbances in the arginine-NO pathway may underlie both CVD and T2D pathogenesis through similar mechanisms, such as chronic inflammation, mitochondrial dysfunction and oxidative stress. [14][15][16] Nevertheless, a potential role for arginine in the primary prevention of diabetes is still debated.…”