Neuromedin U (NMU) is a neuropeptide involved in gut-brain axis, energy balance and immune response. We aimed at analysing the association between NMU epigenetic variability and metabolic indices and the potential mediating role of low-grade inflammation in a general population of Italian adults. NMU Blood DNA methylation levels at two CpG islands (NMU76 and NMU32) were analysed using pyrosequencing in a randomly selected sub-cohort of 1,160 subjects from the Moli-sani study (≥35years; 49.20% men). Multivariable regressions adjusted for age, sex, smoking, alcohol and vegetable consumption were performed to estimate the associations between methylation and metabolic phenotypes (BMI, waist-to-hip ratio, blood pressure, glucose, HOMA-IR, lipids, lipoprotein(a) and apolipoproteins). Mediation analysis was performed to identify the influence of low-grade inflammation in the association using a composite index based on C reactive protein, granulocyte-to-lymphocyte ratio (GLR), platelet and white blood cell counts (INFLA-score). Using principal component analysis four methylation factors were identified: NMU76-F1, NMU76-F2, NMU32-F1 and NMU32-F2. NMU76-F1 was FDR significantly associated with total cholesterol (for 1 SD increase: β = 4.5 ± 1.4 mg/dL of, R² = 10.8%, p = 0.001), ApoB (0.03 ± 0.01 g/L, 12.2%, p = 0.0004), with INFLA-score (1.05 ± 0.22, p = 2.7E-6) and GLR (-0.27 ± 0.03, 30.4%, p = 1.3E-20). GLR and lymphocyte numbers mediate the association of NMU76-F1 with cholesterol (24.0% of total effect, Sobel p = 0.013) and ApoB (42.6%, p = 9E-7), respectively. These findings suggest that NMU promoter methylation patterns could mark a pathway linking lipids with haematopoiesis and systemic inflammation.

Background/Objectives: Neuromedin U (NMU) is a highly conserved gene encoding a neuropeptide involved in the regulation of feeding behavior and energy homeostasis. We aimed to analyze the association between NMU genetic and epigenetic variations and cardio-metabolic parameters in an Italian population to identify the role of these variants in cardio-metabolic risk. Methods: A total of 4028 subjects were randomly selected from the Moli-sani study cohort. NMU haplotypes were estimated using seven SNPs located in the gene body and in the promoter region; DNA methylation levels in the promoter region, previously associated with lipid-related variables in the same population, were also used. Results: Among the haplotypes inferred, the haplotype carrying the highest number of minor variants (frequency 16.6%), when compared with the most frequent haplotype, was positively associated with insulin levels, HOMA-IR, and diastolic blood pressure, and negatively with HDL-cholesterol. The multivariable analysis that considered methylation levels along with their interactions with SNPs showed that increased methylation levels in two close CpG sites were associated with higher levels of lipid-related variables. Conclusions: This study supports a role for NMU as a regulator of human metabolism. This finding suggests that NMU could be a potential target for preventive interventions against coronary and cerebrovascular diseases, and that NMU genetic and epigenetic variability may serve as a biomarker for cardio-metabolic risk.

Aims: Sodium–glucose cotransporter 2 inhibitors (SGLT2i) increase haematocrit and may cause erythrocytosis, creating uncertainty in type 2 diabetes management. Most available data derive from administrative registries or mixed, non-diabetic and/or non-European population. This study aimed to assess the onset, clinical characteristics and management outcomes of people with type 2 diabetes developing SGLT2i-associated erythrocytosis in a routine clinical setting. Methods: This retrospective, single-centre cohort study included adults with type 2 diabetes who developed at least one episode of erythrocytosis (haematocrit ≥ 48% in women, ≥ 49% in men) during the first year after initiation of SGLT2i therapy. Haemoglobin and haematocrit were collected at baseline, at erythrocytosis onset, and at 6 and 12 months with the first erythrocytosis episode defined as the “index date”. No time effect or effect modification across predictive variables was observed. Management included no intervention in 84.1%, SGLT2i discontinuation in 5.3%, and phlebotomy in 4.5%. JAK2 V617F testing was performed in 19 cases, yielding negative results. Results: Erythrocytosis was detected in 3.4% of subjects ( n = 132 out of 3,848). The cohort was predominantly male (87.9%), with a median age of 68.4 years and diabetes duration of 10.5 years. Cardiovascular comorbidities were common. The median time from SGLT2i initiation to erythrocytosis was 11.9 months. Over 12 months, haematocrit and haemoglobin levels remained stable, with no thrombotic events. Conclusions: SGLT2i-associated erythrocytosis is an uncommon, stable, and seemingly low-risk phenomenon. However, it may trigger unnecessary interventions, including treatment discontinuation. These findings highlight a gap between the benign nature of this effect and real-world practice, supporting the need for evidence-based, multidisciplinary guidelines to preserve SGLT2i cardiorenal benefits and optimise patient management.