The complex combination of COVID-19 and diabetes: pleiotropic changes in glucose metabolism

PURPOSE: Angiotensin converting enzyme 2 (ACE2) is the door for SARS-CoV-2, expressed in critical metabolic tissues. So, it is rational that the new virus causes pleiotropic alterations in glucose metabolism, resulting in the complication of pre-existing diabetes's pathophysiology or creating new disease mechanisms. However, it seems that less attention has been paid to this issue. This review aimed to highlight the importance of long-term consequences and pleiotropic alterations in glucose metabolism following COVID-19 and emphasize the need for basic and clinical research in metabolism and endocrinology.RESULTS: SARS-CoV-2 shifts cellular metabolism from oxidative phosphorylation to glycolysis, which leads to a decrease in ATP generation. Together with metabolic imbalance, the impaired immune system elevates the susceptibility of patients with diabetes to this deadly virus. SARS-CoV-2-induced metabolic alterations in immune cells can result in hyper inflammation and a cytokine storm. Metabolic dysfunction may affect therapies against SARS-CoV-2 infection. The effective control of metabolic complications could prove useful therapeutic targets for combating COVID-19. It is also necessary to understand the long-term consequences that will affect patients with diabetes who survived COVID-19.CONCLUSIONS: Since the pathophysiology of COVID-19 is still mostly unknown, identifying the metabolic mechanisms contributing to its progression is essential to provide specific ways to prevent and improve this dangerous virus's detrimental effects. The findings show that the new virus may induce new-onset diabetes with uncertain metabolic and clinical features, supporting a potential role of COVID-19 in the development of diabetes

Association between the synonymous variant organic cation transporter 3 (OCT3)-1233G>A and the glycemic response following metformin therapy in patients with type 2 diabetes

Objective(s): Organic cation transporter 3 (OCT3) as a high-capacity transporter contribute to the metabolism of metformin. The present study was conducted to determine the genotype frequencies of the variant OCT3-1233G>A (rs2292334) in patients with newly diagnosed type 2 diabetes (T2D) and its relationship with response to metformin. Materials and Methods: This study included 150 patients with T2D who were classified into two groups following three months of metformin therapy: responders (by more than 1% reduction in HbA1c from baseline) and nonresponders (less than 1% reduction in HbA1c from baseline). PCR-based restriction fragment length polymorphism (RFLP) served to genotype OCT3-564G>A variant. Results: The parameters such as HbA1c (PA variant in our study and different ethnic populations confirm that the variant is a highly polymorphic variant

Paraoxonase-2 variants potentially influence insulin resistance, beta-cell function, and their interrelationships with alanine aminotransferase in type 2 diabetes

Background: The aim of this study was to determine whether insulin resistance, beta-cell function, and their associations with alanine aminotransferase (ALT) are affected by the functional variants of paraoxonase-2 (PON2) as an intracellular antioxidant in patients with type 2 diabetes (T2D). Materials and Methods: Quantitative insulin sensitivity check index (QUICKI) and homeostasis model assessment for beta-cell function (HOMA-BCF) were assessed in T2D patients. Insulin levels were determined using ELISA. The variants PON2-A148G and PON2-S311C were genotyped using polymerase chain reaction-based restriction fragment length polymorphism. Results: According to the PON2-G148A variant, ALT was found to be significantly correlated with QUICKI (r = −0.616, P = 0.005) and HOMA-BCF (r = 0.573, P = 0.01) in the GA + GG group; however, the correlations were not statistically significant in the AA genotypes. Based on the genotypes of PON2-S311C, there was a significant correlation between ALT with QUICKI (r = −0.540, P = 0.031) and HOMA-BCF (r = 0.567, P = 0.022) in the SC + CC group. In the multiple adjusted logistic regression analyses, considering the variants PON2-G148A and PON2-C311S as independent variables and QUICKI and HOMA-BCF as the dependent variables, both variants were significantly associated with the QUICKI (P = 0.019 for PON2-G148A and P = 0.041 for PON2-C311S). Furthermore, PON2-C311S remained significantly associated with HOMA-BCF (P = 0.03). Conclusion: These data implicate a role for the functional variants of PON2 in insulin resistance and beta-cell function as well as underscore the effective role of these variants in the associations between them and ALT. Our data contribute to our understanding of the important physiologic functions of PON2 in glucose metabolism and its related metabolic diseases

Increased oxidized-LDL levels and arylesterase activity/HDL ratio in ESRD patients treated with hemodialysis

Purpose: Investigations, in which oxidized-low density lipoprotein (ox-LDL), serum paraoxonase (PON1) and homocysteine (Hcy) are considered together as important agents involved in the development of oxidative and atherogenic events in non-diabetic hemodialysis (HD) population, are limited. This case-control study was designed to evaluate these parameters in the patients and control subjects and to determine the correlations among the factors. Methods: Forty-nine age- and sex- matched subjects, including 28 non-diabetic HD patients (paired pre-and post-dialysis samples) and 21 control subjects, were enrolled. Ox-LDL and Hcy levels were measured with ELISA and EIA methods, respectively. Arylesterase activity of PON1 was measured by spectrophotometric assay. Results: Compared with the control group, ox-LDL levels were significantly increased both before (p=0.001) and after HD (p=0.036). Arylesterase activity-to-HDL ratio in HD patients was significantly higher than control subjects (p=0.003). Homocysteine levels in the ESRD patients were higher than control subjects both in pre-dialysis and post-dialysis. There was a significant positive correlation (r= 0.25, p= 0.026) between ox-LDL and homocysteine in samples obtained before HD. Logistic regression analysis revealed ox-LDL levels (OR=3.02, p < 0.001) and arylesterase activity/HDL ratio (OR=2.43, p=0.01) to be associated with the increased risk of ESRD. Conclusions: Ox-LDL levels and arylesterase activity/HDL ratio indicated the strongest association with ESRD risk. These factors, especially ox-LDL as an indicator of oxidative stress, may be biomarkers in evaluating the status of non-diabetic ESRD patients. Because of the pathogenic relationship between ox-LDL and homocysteine as nontraditional risk factors of atherosclerosis, therapeutic strategies adopted to reduce them may be useful in decrease of high prevalence of cardiovascular mortality in dialysis patients. In addition, measurement of PON1 activity to HDL ratio is possibly a more valuable biomarker than arylesterase activity alone in non-diabetic ESRD

Paraoxonase 1 activity is associated with interleukin-6 levels in type 2 diabetes: Effects of age and gender

Background: A further understanding of the mechanisms linking inflammation to T2D and related complications can help prevent or control this silent but dangerous disease. This study was conducted to determine the association between paraoxonase 1 (PON1) activity and interleukin-6 (IL-6) in type 2 diabetes (T2D). Furthermore, we have evaluated the role of age and gender in the relationship between the PON1 activity and IL-6. Methods: A total of 105 people with T2D were enrolled in this study. IL-6 levels were determined using ELISA. For the PON1 activity assay, the hydrolysis rate of the substrate phenylacetate was spectrophotometrically assayed in serum at 270 nm. The determined velocities were the initial velocities of substrate hydrolysis. Results: PON1 activity was negatively correlated with IL-6 in total data (r = −0.34, P = 0.001). In both groups with age ≥50 and <50 years, PON1 activity was negatively correlated with IL-6, but the correlation was significant in patients aged 50 years and above (r = −0.358, P = 0.005) compared with patients with age <50 years. In both women and men, PON1 activity was negatively correlated with IL-6, but the correlation was significant in women (r = −0.318, P = 0.006) in comparison with men. Conclusions: Inverse association between PON1 activity and IL-6 in T2D may represent the oxidative–inflammatory interaction in this disease. Our findings highlight that at older ages and in women, the associations between lower PON1 activity and higher IL-6 concentrations are more evident, and this should be considered in patients with T2D

Determination of serum paraoxonase phenotype distribution by double-substrate method in patients with coronary artery disease

Introduction: Considering the high incidence of patients with coronary artery disease (CAD) in the Iranian population and a preventive role of serum paraoxonase (PON1) in development of CAD, the present study was designed to determine the distribution of PON1 phenotypes in patients with CAD. Materials and Methods: A total of 61 patients with coronary stenosis of <50% and 63 patients with coronary stenosis of >70% were included in this study. Paraoxonase and arylesterase activities were measured using paraoxon and phenylacetate as substrate, respectively. Phenotyping of the PON1 Q192R polymorphism was determined by calculating the ratio of salt-stimulated paraoxonase activity to arylesterase activity (double-substrate method). Results: Patients with stenosis of <50 % were separated into three distinct phenotypes at ratios of 2.14 and 5.99 and the population with stenosis of >70% at ratios of 2.42 and 5.91. In patients with stenosis of <50%, PON1 phenotype frequencies were 41% (Q phenotype), 46% (QR phenotype) and 13% (R phenotype). Frequencies of Q, QR and R phenotypes in patients with stenosis of >70% were 48%, 41% and 11%, respectively. Conclusions: Based on his study and other studies conducted in Iran, it can be concluded that in the Iranian population there is no statistically difference in phenotype distribution of PON1 between patients with CAD (with severe stenosis or mild stenosis) and healthy individuals

Differences between baseline parameter levels and levels after three months of treatment, according to metformin response and treatment group.

<p>Differences between baseline parameter levels and levels after three months of treatment, according to metformin response and treatment group.</p

Paraoxonase and Arylesterase activities of human serum paraoxonase in coronary artery disease

Introduction: Considering the importance of serum paraoxonase (PON1) in preventing fromproduction of oxidized low-density lipoprotein (LDL), and consequently, its role in prohibiting fromdevelopment of atherosclerosis, we investigated paraoxonase and arylesterase activities of PON1 inpatients with coronary artery disease (CAD) and with different coronary stenosis.Materials and Methods: In the present study, 120 patients with CAD were examined and theirstenosis documented by coronary angiography. Then, the patients were divided into two groups: 60patients with less than 50% of stenosis and 60 patients with more than 70% of stenosis. Paraoxonaseand arylesterase activity was measured with substrates of paraoxon and phenylacetate, respectively.The effects of eight drugs, which are prescribed in cardiovascular diseases, were assayed onparaoxonase activity.Results: There were no significant differences in LDL-C, total cholesterol and triglyceride levelsbetween two groups, but HDL levels in patients with >70% of stenosis were significantly decreased ascompared with those of patients who had <50% of stenosis (P<0.03). Both paraoxonase andarylesterase activity in patients with >70% of stenosis were significantly lower (P<0.05) than patientswith<50% of stenosis.Conclusion: Paraoxonase and arylesterase activities of PON1 and HDL levels in patients with>70% of stenosis were lower than patients with <50% of stenosis. In other words, the PON1 activitiesand HDL levels decrease with progression of atheroma. Therefore, the study might support theimportant role of HDL-bound PON1 in preventing from formation of ox-LDL and its anti-atherogenicactivity

Change in the study parameters from baseline to three months of metformin therapy in all the three treatment groups.

<p>Change in the study parameters from baseline to three months of metformin therapy in all the three treatment groups.</p

Change in the study parameters from baseline to three months of metformin therapy in responders and non-responders receiving atorvastatin.

<p>Change in the study parameters from baseline to three months of metformin therapy in responders and non-responders receiving atorvastatin.</p