N‐lactoyl amino acids (Lac‐AA) form an emerging class of metabolites that have gained significant attention in recent years due to their ubiquitous presence in different biological systems and potential roles in various biochemical processes. This narrative review aims to provide a comprehensive overview of the current understanding of Lac‐AA, emphasising their biosynthesis, physiological roles, and potential implications in various diseases. We discuss the discovery of Lac‐AA as signalling molecules, and their involvement in exercise‐induced appetite suppression, energy metabolism, and other pathways. This review explores the complex relationship between Lac‐AA and various pathological conditions, including mitochondrial disorders, type 2 diabetes, phenylketonuria, cancer, and rosacea. We also examine the interplay between Lac‐AA and the gut microbiota, as well as their association with metformin treatment. Furthermore, we address the ongoing debate regarding whether Lac‐AA are merely reflections of lactate and amino acid levels or independent signalling molecules. This review synthesises the latest research findings, highlights the significance of Lac‐AA in metabolic research, and identifies promising avenues for future investigation in this rapidly evolving field.

N-lactoyl amino acids (Lac-AAs) are key players that regulate appetite and body weight. The most prominent and well-studied member is N-lactoyl phenylalanine (Lac-Phe), which can be induced by food intake, exercise and metformin treatment. However, its broader metabolic impact remains insufficiently characterized. This study investigates the effects of Lac-Phe on insulin signaling, inflammation, and mitochondrial respiration using HepG2 and differentiated C2C12 cell models, as well as isolated rat brain mitochondria and synaptosomes. Our results demonstrate that Lac-Phe significantly impairs insulin-stimulated phosphorylation of key proteins in the insulin signaling pathway, particularly in skeletal muscle cells, indicating disrupted insulin signaling. Additionally, Lac-Phe exposure increases the secretion of pro-inflammatory cytokines in C2C12 skeletal muscle cells and markedly impairs mitochondrial respiration in HepG2 liver cells and rat brain-derived synaptosomes, but not in isolated mitochondria. These findings highlight potential adverse metabolic effects of Lac-Phe, especially when administered at high concentrations, and underscore the necessity of conducting a comprehensive risk assessment and dose optimization before considering Lac-Phe or related Lac-AAs as therapeutic agents. Our work provides important insights into the molecular liabilities associated with Lac-Phe and calls for further studies to balance its therapeutic promise against possible metabolic risks.

Obesity plays a crucial role in the progression of insulin resistance and type 2 diabetes which are related to inflammation and liver disease. GATA-3 is a transcription factor that is involved in adipogenesis and inflammation. Therefore, it could be a potential therapeutic target for obesity-associated metabolic disorders. This study aimed to examine the effects of GATA-3 suppression on body weight, fat depot redistribution, liver histopathology, and inflammatory markers in transgenic db/db obese mice. Male db/db mice received subcutaneous injections of GATA-3-specific DNAzyme (hgd40; 10 or 100 µg/mL), pioglitazone (as a positive control), or vehicle only (as a negative control), twice weekly for two weeks. Body weight, organ weights, liver histopathology, mRNA expression of selected genes and serum cytokine levels were assessed. GATA-3 expression was not region specific, and its suppression did not significantly affect fat depot distribution or organ weights. However, the low dose of hgd40 accelerated body weight gain transiently. It also increased Il10 mRNA expression in the liver and significantly increased IL-10 protein concentration in the serum. In addition, a high dose of hgd40 resulted in a marked decrease in hepatocyte ballooning degeneration. These findings suggest that GATA-3 suppression may modulate inflammation and liver injury in obesity, warranting further investigation into its therapeutic potential for obesity-related metabolic disorders.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective agents for type 2 diabetes (T2D) management, yet interindividual variability in response mechanisms remains unclear. This study examined genetic interactions influencing clinical and biochemical outcomes among SGLT2i treated patients. Data from 13,808 Qatar Biobank participants were analyzed, including 207 propensity score–matched T2D patients stratified into three groups: SGLT2i-treated, metformin monotherapy, and drug-naïve. Significant clinical traits across groups were further assessed for genotype effects within SGLT2i treated patients. Compared with both comparators, SGLT2i-treated individuals showed elevated serum urea (FDR < 0.05). Genetic analysis identified an association between the WFS1 rs10010131 A allele and higher urea levels exclusively in SGLT2i treated patients (β = +0.63 mmol/L per A allele, 95% CI [0.14–1.11], p = 0.012). This variant showed strong linkage disequilibrium (r² = 0.95, D′ = 0.99) with rs6446482 in WFS1. Kidney-specific eQTL data revealed reduced WFS1 expression in A-allele carriers. These findings suggest a novel pharmacogenetic interaction between WFS1 rs10010131 and urea regulation under SGLT2i therapy. The observed effect could likely reflect a genotype-related renal adaptive response rather than dysfunction, emphasizing the potential of pharmacogenomic profiling to enhance precision treatment for T2D.

Cardiac rehabilitation (CR) aims to enhance cardiovascular health and quality of life, as well as survival through structured exercise training, lifestyle education, cardiovascular risk factor management, and psychosocial support. Despite growing evidence linking sleep disorders, poor sleep health, and circadian rhythm disruption to impaired cardiac recovery, reduced exercise adherence, and increased adverse cardiovascular events, systematic assessment and management of sleep and circadian health remain underutilized in CR programs. In this narrative review, we aim to explore and characterize the gap and address the potential benefits of incorporating sleep and circadian rhythm assessment into CR practice. Sleep disorders commonly encountered in patients undergoing CR, including obstructive sleep apnea, central sleep apnea, and insomnia, may adversely affect CR participation, functional recovery, and cardiovascular prognosis. Practical strategies include routine sleep screening with validated assessment tools, selective use of objective sleep assessments, sleep hygiene education, chronotype-informed exercise scheduling, and referral pathways to sleep medicine specialists. Integrating sleep-circadian considerations into CR may enhance cardiac recovery, improve exercise tolerance and adherence, and support more comprehensive, personalized secondary prevention strategies. Artificial intelligence may further support early detection of sleep disturbances, individualized exercise prescription, remote monitoring, and precision CR approaches integrating sleep and circadian health.