Abstract
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder of glucose and lipids and characterized by defect in insulin secretion or action. Oxidative imbalance has also been implicated in the etiology of diabetes. Paraoxonase-1 (PON1) is an esterase and lactonase which is found in the circulation bound to high-density lipoproteins (HDL). Alterations and associations of circulating PON1 levels with a variety of diseases including diabetes encourages us to investigate the possible association between PON1 A/G rs854573 polymorphism and serum PON1 activity with T2DM. The study essentially follows a population based case-control format with 101 diabetic and 102 healthy controls. The findings revealed association of polymorphism with the diseased status (p value 0.0002, OR 3.49, 95% CI 1.77 to 6.9). With significantly higher range of mean serum PON1 Arylesterase (AREase) activity in control (9.99 – 0.96 kU/L) than in diabetic patients (5.25 - 0.508 kU/L) (p value,<0.001), a large difference between common diabetic AA genotype and combined diabetic heterozygous and homozygous genotypes (AG+GG) for risk allele G (assymptometic p value,<0.001), or in between two AA genotypes (Diabetic/Non diabetic, p<0.001), was explored by parametric and non parametric statistical pairwise comparison. Serum PON1 activity was found to be independent of other clinical factors such as plasma glucose levels. Western blot analysis of serum samples detected a significant difference of PON1 proteins in diabetic patients and control subjects (p value 0.008). In conclusion serum PON1 AREase activity which to an extent correlated with PON1 promoter polymorphism might be a good predictor of the disease risk.
Highlights
Diabetes mellitus (DM) is a chronic disorder caused by impaired metabolism of glucose and lipids due to defect in insulin secretion or action and characterized hyperglycemia which eventually leads to microvascular and/or macrovascular pathologies affecting more than 17.5 million deaths worldwide [1]
This study presented a statistical correlation between different clinical parameters relevant to Type 2 diabetes mellitus (T2DM) including body mass index (BMI), fasting and postprandial blood glucose levels with PON1 A>G polymorphism
A significant difference in the level of serum PON1 AREase activity was detected between the healthy control and the diabetic individuals (Mean 3.897 katal unit/L (kU/L) vs 1.54 kU/L, p value 0.00001, Table 1, Figure 1A) and this difference to an extent was found to operate in a genotype dependent manner such as AG and GG genotypes in the T2DM group have lower enzyme activity than that of AA genotype (p value assymptometic
Summary
Diabetes mellitus (DM) is a chronic disorder caused by impaired metabolism of glucose and lipids due to defect in insulin secretion or action and characterized hyperglycemia which eventually leads to microvascular and/or macrovascular pathologies affecting more than 17.5 million deaths worldwide [1]. Growing body of evidence suggests that oxidative stress plays a key role in the pathogenesis of micro- and macrovascular diabetic complications [4]. PON1 is found in the circulation bound to highdensity lipoproteins (HDL) [5]. PON1 degrades oxidized phospholipids in lipoproteins and plays an important role in the maintenance of organism's antioxidant system [6, 7]. Alteration in circulating PON1 level has been found to be associated with a variety of diseases that involves oxidative stress [8]. Following the introduction of the oxidative stress hypothesis in the aetiopathology of atherosclerosis and the discovery of antioxidant effect of HDL [9], PON1 has attracted significant interest as a protein responsible for the most of antioxidant properties of HDL [10]. Purified PON1 protects HDL and low-density lipoprotein (LDL) from oxidation catalyzed by copper ions [11]. Dissociation is promoted by HDL, very-lowdensity lipoprotein (VLDL), and in much lesser extent by protein-free phospholipids particles or ApoA-I protein [14]
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