**Background:** D-ribose is a pentose sugar essential for RNA and nucleotide synthesis, but its role in disease is controversial. While it can provide energy to myocardium and skeletal muscles, recent studies suggest elevated D-ribose levels may be associated with diabetes and cognitive dysfunction. This narrative review synthesizes current knowledge on D-ribose absorption, metabolism, cellular effects, and its link to diabetes mellitus.
**Methods:** The authors conducted a narrative review of the literature, collecting references on D-ribose metabolism, transport, and its effects in diabetes. They analyzed studies on D-ribose absorption, distribution, transmembrane transport, intracellular metabolic pathways, and both cytoprotective and cytotoxic effects. The review also covers clinical evidence linking D-ribose to diabetes complications, including diabetic nephropathy and encephalopathy.
**Key Results:** D-ribose is rapidly absorbed (87.8–99.8%) via the intestinal tract, with plasma concentrations in healthy adults of 0.02–0.1 mM, much lower than glucose (3.9–6.1 mM). In diabetic patients, urine and serum D-ribose levels are significantly elevated. D-ribose exhibits strong nonenzymatic glycation ability, glycating 59.9% of protein residues in BSA after 14 days, and shows higher glycation capacity than glucose, mannose, galactose, xylose, fructose, and arabinose. D-ribose glycation of serum proteins is more pronounced and faster than D-glucose. Ribosylated products generate autoantibodies (e.g., anti-ribosylated Hb, anti-ribosylated LDL) that are elevated in type 2 diabetes. In vitro, elevated D-ribose concentrations are cytotoxic to various cell types, including peripheral blood mononuclear cells, neuroblastoma SY5Y cells, glomerular interstitial cells, and mesangial cells. The toxicity is mediated through AGEs/RAGE signaling, activating MAPK/ERK, TGF-β, JNK, and NF-κB pathways, leading to oxidative stress and inflammation. In diabetic nephropathy, D-ribose triggers NLRP3 inflammasome activation in podocytes and promotes mesangial cell apoptosis via upregulation of Bax and downregulation of Bcl-2. In diabetic encephalopathy, D-ribose contributes to cognitive impairment, Tau protein hyperphosphorylation, and increased AGE accumulation in the hippocampus. Benfotiamine, a transketolase activator, reduces D-ribose levels and AGE accumulation in diabetic rat brains.
**Clinical Implications:** The review underscores that D-ribose metabolism is dysregulated in diabetes, with elevated levels correlating with HbA1c and glycated serum protein. D-ribose's potent glycation activity may accelerate diabetic complications, particularly nephropathy and encephalopathy. Autoantibodies against ribosylated proteins could serve as biomarkers for diabetes and its complications. However, the optimal dose and safety threshold for D-ribose supplementation remain unclear, as it may be beneficial for energy supply in certain tissues but harmful due to glycation. Further research is needed on D-ribose transmembrane transport, tissue-specific metabolism, and its role in disease pathogenesis to guide clinical use.