Evaluation of the Relationship Between Serum Neuregulin-4 (NRG4) Levels, Obesity Status, and Antidiabetic Treatment Regimens in Patients With Type 2 Diabetes Mellitus: A Prospective Observational Study

Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and progressive pancreatic β-cell dysfunction, resulting in persistent hyperglycemia and an increased risk of both microvascular and macrovascular complications. Obesity is one of the strongest risk factors for the development and progression of T2DM and is associated with chronic low-grade inflammation, dysregulated adipokine secretion, and impaired glucose and lipid metabolism. Despite advances in antidiabetic therapies, identifying novel biomarkers that reflect metabolic status and treatment response remains an important research priority.

Neuregulin-4 (NRG4) is a recently identified adipokine predominantly secreted by brown adipose tissue. Experimental and clinical studies have demonstrated that NRG4 plays an important role in maintaining metabolic homeostasis by regulating glucose metabolism, improving insulin sensitivity, suppressing hepatic lipogenesis, and reducing systemic inflammation. Reduced circulating NRG4 concentrations have been associated with obesity, insulin resistance, non-alcoholic fatty liver disease, metabolic syndrome, and Type 2 Diabetes Mellitus. Lower serum NRG4 levels may therefore represent a potential biomarker of metabolic dysfunction and disease severity.

Although previous studies have investigated the association between serum NRG4 concentrations and obesity or T2DM separately, limited evidence is available regarding the relationship between NRG4 levels, obesity status, and different antidiabetic treatment regimens within the same patient population. In particular, the potential influence of sodium-glucose cotransporter-2 (SGLT2) inhibitors and other commonly used antidiabetic therapies on circulating NRG4 concentrations has not been adequately investigated.

This single-center, prospective observational study aims to evaluate serum NRG4 concentrations in obese and non-obese adults with Type 2 Diabetes Mellitus and to investigate their relationship with different antidiabetic treatment regimens. Participants will be consecutively recruited from the outpatient clinic and classified into five predefined groups according to diabetes status and current treatment regimen: (1) patients receiving SGLT2 inhibitor monotherapy; (2) patients receiving oral antidiabetic therapy without SGLT2 inhibitors; (3) patients receiving combination therapy including SGLT2 inhibitors; (4) newly diagnosed treatment-naïve patients with T2DM; and (5) healthy individuals without diabetes who will serve as the control group.

Clinical and demographic characteristics including age, sex, body mass index (BMI), waist circumference, waist-to-hip ratio, smoking status, and current antidiabetic medications will be recorded. Routine biochemical parameters, including fasting plasma glucose, glycated hemoglobin (HbA1c), and estimated glomerular filtration rate (eGFR), will be obtained from routine clinical evaluations. In addition, one peripheral venous blood sample will be collected from each participant for serum NRG4 measurement. Blood samples will be centrifuged, serum aliquots will be stored at -80°C, and serum NRG4 concentrations will be measured using a validated enzyme-linked immunosorbent assay (ELISA).