Dietary Nucleotides as Potential Modulators of Inflammatory and Metabolic Pathways with Implications for Insulin Resistance.

Dietary nucleotides and nucleic-acid-derived compounds are considered bioactive nutrients, but their metabolic relevance remains uncertain. This narrative review, supported by a structured literature search, evaluates intestinal handling and evidence on glucose and lipid metabolism, redox homeostasis, immune function, gut barrier regulation, and microbiota. Direct supplementation studies are distinguished from nucleoside/nucleobase evidence, dietary nucleic acids or purine-rich foods, and endogenous extracellular purinergic signaling. Preclinical studies suggest defined nucleotide preparations may modulate AMP-activated protein kinase (AMPK), insulin receptor substrate 1 (IRS-1)/protein kinase B (AKT)/forkhead box protein O1 (FOXO1) signaling, lipid accumulation, and mitochondrial/redox-related endpoints. In contrast, extracellular adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine 5'-monophosphate (AMP) studies provide mechanistic context but do not show that oral supplementation modifies purinergic signaling in humans. Human intervention evidence is sparse and derived from older adults not selected for insulin resistance, type 2 diabetes, or metabolic-dysfunction-associated steatotic liver disease (MASLD). Reductions in homeostatic model assessment of insulin resistance (HOMA-IR) should be interpreted as changes in a surrogate estimate, not proof of therapeutic efficacy. The supplemental doses evaluated in available human intervention studies appear generally well-tolerated, whereas short-term high nucleotide intake can raise circulating uric acid. Dietary nucleotides therefore remain candidate, not established, metabolic or immune therapies.