Impaired arginine, citrulline, and glutamine metabolism in type 2 diabetes: insights from a stable isotope study

CONTEXT: Arginine (Arg) is an important amino acid in T2D as a potent insulin secretagogue and precursor for nitric oxide (NO). Citrulline (Cit), the substrate for de novo Arg synthesis, is mostly produced from glutamine (Gln). OBJECTIVE: We aimed to investigate their metabolism in T2D using a novel stable isotope tracer approach. METHODS: We studied 42 individuals (21 with T2D, 21 controls). After overnight fasting, blood samples were collected following pulse administration of stable amino acid tracers. Plasma concentrations and isotopic enrichments were measured by LC-MS/MS, and compartmental analyses were performed to calculate their whole-body production (WBP) rates and kinetics. RESULTS: The cohort was 59.5% female, with a mean age of 64.4 (7.5) years and a BMI of 33.0 (4.3) kg/m2 (all P > .05). After adjusting for sex and age, the T2D group had lower plasma concentrations of Arg (P = .007), Cit (P = .002), and Gln (P = .002) than the control group. In T2D, WBP was lower for Cit (P = .004) but higher for Gln (P = .037) and glutamate (P = .017) after controlling for age, sex, and lean soft tissue mass. The T2D group also had lower Cit intracellular production, but higher Gln clearance and intracellular pool size, and a trend toward higher Arg clearance. CONCLUSION: Significant dysregulation exists in Arg-Cit-Gln metabolism in T2D. Our findings suggest a working model in which increased Gln turnover stimulates gluconeogenesis, increases Gln consumption, and reduces Cit availability for Arg and NO synthesis, thereby contributing to metabolic dysregulation in T2D. Interventions targeting Gln-driven gluconeogenesis while increasing Cit availability may benefit T2D management.