Sex Difference Impacts on the Relationship between Paraoxonase-1 (PON1) and Type 2 Diabetes

Abstract

Type-2 diabetes (T2D) and its cardiovascular complications are related to sex. Increasing evidence suggests that paraoxonase 1 (PON1) activity, an antioxidant enzyme bound to high-density lipoproteins (HDL), is implicated in the onset and clinical progression of T2D. Since we previously showed that PON1 is a sexual dimorphic protein, we now investigated whether sex might impact the relationship between PON1 and this chronic disease. To address this aim, we assessed PON1 activity in the sera of 778 patients, including controls (women, n = 383; men, n = 198) and diabetics (women, n = 79; men = 118). PON1 activity decreased in both women and men with T2D compared with controls (p < 0.05 and p > 0.001, respectively), but the change was 50% larger in the female cohort. In line with this result, the enzyme activity was associated with serum glucose level only in women (r = −0.160, p = 0.002). Notably, only within this gender category, lower PON1 activity was independently associated with increased odds of being diabetic (odds ratio (95% Confidence interval: 2.162 (1.075–5.678)). In conclusion, our study suggests that PON1-deficiency in T2D is a gender-specific phenomenon, with women being more affected than men. This could contribute to the partial loss of female cardiovascular advantage associated with T2D.

Oxidative Stress: Pathogenetic Role in Diabetes Mellitus and Its Complications and Therapeutic Approaches to Correction

“…At the same time, in DM complicated by cardiovascular diseases patients, activities of SOD, GPx, and GR significantly decreased, and men had lower activity of SOD and GPx in comparison with women [31,45]. New data also indicate a relationship between paraoxanase 1 (PON1) and hemoxygenase 1 (HO1) in the serum of patients with DM2 and its complications, and a recent meta-analysis showed that PON1 is significantly associated with susceptibility to DM2and the development of macro-and microangiopathies [87].…”

Gestational Diabetes Mellitus: The Genetic Susceptibility Behind the Disease

“…The human paraoxonase 1 (PON1) protein is coded by the PON1 gene located on the long arm of chromosome 7 (7q21.3), and most common polymorphisms are localized to the coding region: a leucine (L) to methionine (M) substitution at position 55 (L55M, rs854560), and a glutamine (Q) to arginine (R) substitution at position 192 (Q192R, rs662) [84]. PON1 is a serum/plasma high-density lipoprotein-binding enzyme primarily expressed in the liver that protects HDL, low-density lipoprotein (LDL), endothelial cells, and intimal macrophages from oxidative damage by catalyzing the hydrolysis of organic phosphates and lipid peroxides [85][86][87]. Lipoprotein oxidation is the key to the development of diabetic macrovascular (atherosclerosis) and microvascular disease, and the tox-…”

“…icity of oxidized lipoprotein to retinal capillary endothelial cells and perivascular cells is significant [87]. Zhou et al found that lactonase activity and PON1 levels were both increased in female Chinese participants with GDM, and that women with the PON1 Q192R RR genotype exhibited lower PON1 lactonase activities and normalized lactonase activity relative to other genotypes [88].…”

Paraoxonase in women with hypertension of different reproductive age. Relationship with cardio-metabolic risk factors

“…В роботі E. Dounousi на АГ з добовим профілем АТ "нон-діпер" реєструється суттєво менша концентрація параоксонази в крові, ніж у осіб з більш сприятливим профілем "діпер" [25]. Відомо, що активність параоксонази характеризується статевим диморфізмом і у чоловіків реєструється менша як арілестеразна, так і лактоназна активність ферменту, ніж у жінок [19,23]. Не виключено, що до регуляції активності цього ензиму причетні статеві гормони.…”