Abstract
BACKGROUND: Loss of pancreatic β-cell function and increased β-cell death are central to the development of Type 2 diabetes mellitus (T2DM), and understanding the mechanisms behind β-cell failure is crucial for preventing or reversing the disease. While apoptosis and oxidative stress have been implicated in β-cell death, their precise roles remain under investigation. Therefore, the present study aimed to evaluate the serum levels of the apoptotic factor tumor suppressor 53 (p53) and biomarkers of oxidative stress: malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguansine (8-OHdG) in newly diagnosed T2DM, as well as determining the impact of p53, MDA and 8-OHdG and their combined interaction on both diabetic and metabolic syndrome parameters. METHODS: This case-control study included Yemeni male participants aged 30-45 years: 60 were normoglycemic subjects with fasting blood glucose < 100 mg/dL and BMI < 25 kg/m(2) served as controls, and 52 patients with newly diagnosed (≤ 2 months), diet-controlled T2DM (fasting blood glucose > 126 mg/dL). RESULTS: Compared to control subjects, serum levels of p53, MDA, and 8-OHdG were significantly elevated in the newly diagnosed T2DM group (p < 0.001, < 0.001, and 0.002, respectively). Linear regression analysis revealed that β-cell dysfunction was associated with increased MDA (p = 6.3 × 10⁻⁶) and triglycerides (TG) (p = 2 × 10(-4)). Additionally, reduced insulin sensitivity, heightened insulin resistance, and elevated insulin levels were linked to p53 (p = 1.9 × 10(-4), 0.001, 0.006), TG (p = 1.8 × 10(-4), 0.007, 0.025), and BMI (p = 0.004, 3 × 10⁻⁵, 3 × 10(-4)). Fasting blood glucose and HbA1c levels were significantly influenced by MDA (p = 4.5 × 10⁻⁶, 3.6 × 10(-4)), p53 (p = 5 × 10(-5), 2 × 10(-4)), and TG (p = 4.2 × 10⁻¹⁰, 2.7 × 10⁻⁹). The simultaneous interaction of p53, MDA, and 8-OHdG on diabetic traits. revealed synergy: the p53×MDA interaction amplifies insulin resistance, elevated insulin, reduced sensitivity, and higher FBG beyond individual marker contributions, while p53×MDA×8-OHdG elevates HbA1c. CONCLUSION: The results highlight the interplay of apoptosis and oxidative stress in inducing β-cell dysfunction and insulin resistance in newly diagnosed T2DM. Oxidative stress contributes to β-cell dysfunction, while p53 contributes to the development of insulin resistance, possibly by inducing oxidative stress.