Association between IL-18 and IL-6 gene polymorphisms and the risk of T1D in Egyptian children.

PURPOSE: To test the involvement between IL-18 and IL-6 genetic polymorphisms and susceptibility to Type 1 diabetes (T1D). METHODS: Single nucleotide polymorphisms (SNPs) at positions -607A/C and - 137G/C in IL-18 promoter region were examined by sequence specific primers-polymerase chain reaction (SSP-PCR) and position -174G/C in promoter region of IL-6 gene which analyzed by Mutagenically Separated PCR (MS-PCR) in 104 T1D participants and 114 controls. RESULTS: IL-18 -137GC and -137CC genotypes and -137C allele were significantly decreased in T1D subjects (P < 0.05), while -137GG genotype was insignificantly increased as compared to controls. A significant decrease was detected in haplotype -137C/-607C frequency in T1D participants compared with controls (OR = 0.04, P < 0.001). There was significant association between IL-18 -607 of (CC, AC and AA genotypes) in age at diagnosis, glycated hemoglobin (HbA1c) and higher body mass index (BMI) (P < 0.05). CONCLUSION: This study demonstrated that IL-18 gene promoter polymorphisms might be associated with susceptibility to T1D in Egyptian children. Individuals carrying CC genotype at position -137 of IL-18 promoter may be at a low risk of T1D progression. Additionally, the susceptible combination of IL-18 and IL-6 cytokine genes associated with T1D highlight their risk toward the disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-021-00763-w.

E-cadherin and periostin in early detection and progression of diabetic nephropathy: epithelial-to-mesenchymal transition.

BACKGROUND: Diabetic nephropathy (DN) is a severe complication of diabetes mellitus (DM). Many mechanisms are involved in its development; one of these mechanisms is epithelial-to-mesenchymal transition (EMT). During EMT, losing of the epithelial biomarkers like E-cadherin and increasing of mesenchymal biomarkers like periostin are very characteristic. METHODS: The study included 19 healthy controls and 71 DN patients categorized according to their urinary albumin-to-creatinine ratio (UACR) into 19 normoalbuminuric (UACR < 30 mg/g), 37 microalbuminuric (UACR 30-300 mg/g), and 15 macroalbuminuric (UACR > 300 mg/g) patients. Fasting plasma glucose (FPG), glycated hemoglobin (HbA1C%), serum creatinine (Cr), and urea were measured. E-cadherin and periostin were measured by ELISA and compared among groups. RESULTS: Concerning E-cadherin levels, in comparison to control group, there were significantly decreased in all groups (0.94, 0.52, and 0.14 ng/mL in normoalbuminuria, microalbuminuria, and macroalbuminuria groups; respectively). For periostin levels, nonsignificant increase in normoalbuminuria (0.32 ng/mL) than control group (0.3 ng/mL) was observed. There was a significant increase in other groups with the highest values in macroalbuminuria group (1.66 ng/mL). E-cadherin and periostin were correlated with each other (r = - 0.353, P < 0.001). UACR was negatively correlated with E-cadherin and positively correlated with periostin. ROC curve analyses showed that the AUC to diagnose established microalbuminuria using E-cadherin was 0.998 (95% CI 0. 932-1), and using periostin was 0.833 (95% CI 0.709-0.919). CONCLUSION: Serum E-cadherin and periostin could be considered as reliable biomarkers involved in DN pathogenesis and linked to its stages.

Epidermal growth factor receptor and podocin predict nephropathy progression in type 2 diabetic patients through interaction with the autophagy influencer ULK-1.

AIMS: Diabetic nephropathy (DN) that progress to end stage renal failure is a serious health problem. Autophagy is involved in DN pathogenesis. Finding renal prognostic biomarkers can help in the future renal status prevision. Therefore, the aim of current study was to evaluate and correlate circulating levels of autophagy regulator protein Unc-51-like kinase 1 (ULK-1) with the widely expressed receptor in mammalian kidney; epidermal growth factor receptor (EGFR); and the key functional podocyte protein podocin (PDCN). METHODS: Serum levels were assessed by ELISA in 72 type 2 diabetic patients classified according to their urinary albumin/creatinine ratio; 19 normoalbuminuric, 37 microalbuminuric and 16 macroalbuminuric patients; age and sex matched with 18 healthy controls. RESULTS: Microalbuminuria and macroalbuminuria patients exhibited decreased ULK-1, EGFR and PDCN levels. Only EGFR showed lower levels in normoalbuminuria compared with controls. ULK-1 and EGFR were significantly higher in normoalbuminuria compared with microalbuminuria and macroalbuminuria patients. ULK-1, EGFR and PDCN were correlated with each other and with some metabolic parameters. CONCLUSIONS: ULK-1 with EGFR can predict early impairment in DN while PDCN can highlight progressive DN risk EGFR and PDCN may interact synergistically with ULK-1 in autophagy dysregulation as a pathogenic mechanism of DN induction and progression.

Role of CTRP3, CTRP9 and MCP-1 for the evaluation of T2DM associated coronary artery disease in Egyptian postmenopausal females.

C1q complement/tumor necrosis factor (TNF)-related protein (CTRP) family comprises of 15 proteins that posses important implications in energy homeostasis, infection and inflammation. However, their roles in diabetes mellitus (DM) and its vascular complications have not been completely assessed. This works aims to study the association of two CTRPs; 3 and 9, with pro-inflammatory cytokine monocyte chemoattractant protein-1 (MCP-1), and biochemical parameters of type 2 diabetes (T2D), dyslipidemia and coronary artery disease (CAD). METHODS: Biochemical markers and serum levels of CTRPs and MCP-1 were measured in 86 postmenopausal females. Subjects were divided over four groups; 13 apparent healthy subjects as control (group I), 29 patients with CAD (group II), 29 patients with T2D ≥5 years (group III) and 15 patients with CAD secondary to T2D (group IV). Serum CTRP3, CTRP9, MCP-1 and insulin were measured by ELISA. RESULTS: Serum CTRP3 levels were found to be significantly higher in group III and IV, whereas, it was significantly lower in group II on comparing to group I. While, CTRP9 levels were significantly decreased in group II, III and IV on comparing to group I. MCP-1 levels were found to be significantly increased in groups II, III and IV on comparison with group I. Both CTRPs were significantly negatively correlated with each other. While MCP-1 was significantly correlated negatively to CTRP9. CONCLUSION: This study associates the possible role of CTRP3, CTRP9 and MCP-1/CCL2 in the diagnosis/prognosis of CAD complication in T2D postmenopausal females.

Serum Vitamin D and Its Upregulated Protein, Thioredoxin Interacting Protein, Are Associated With Beta-Cell Dysfunction in Adult Patients With Type 1 and Type 2 Diabetes.

OBJECTIVES: Diabetes mellitus is characterized by either complete deficiency of insulin secretion, as in type 1 diabetes, or decompensation of the pancreatic beta cells in type 2 diabetes. Both vitamin D (vitD) and thioredoxin interacting protein (TXNIP) have been shown to be involved in beta-cell dysfunction. Therefore, this study was designed to examine vitD and TXNIP serum levels in patients with diabetes and to correlate these levels with beta-cell function markers in both types of diabetes. METHODS: The routine biochemical parameters and the serum levels of vitD and TXNIP were measured in 20 patients with type 1 diabetes and 20 patients with type 2 diabetes. The levels were then compared to those of 15 healthy control volunteers. Insulin, C-peptide and proinsulin (PI), vitD and TXNIP were measured by ELISA. Beta-cell dysfunction was assessed by homeostatic model assessment (HOMA-beta), proinsulin-to-C-peptide (PI/C) and proinsulin-to-insulin (PI/I) ratios. Correlations among various parameters were studied. RESULTS: Patients with type 1 diabetes had significantly lower HOMA-beta, vitD and TXNIP levels; however, they had higher PI/C levels than the control group. Meanwhile, patients with type 2 diabetes had significantly higher C-peptide, proinsulin, PI/C, HOMA-insulin resistance (HOMA-IR) and lower HOMA-beta and vitD levels, with no significant difference in TXNIP levels as compared to the control group. In addition, vitD was significantly correlated positively with HOMA-beta and TXNIP and negatively with PI, PI/C, PI/I and HOMA-IR. TXNIP correlated positively with HOMA-beta and negatively with PI/C. CONCLUSIONS: Our data showed that vitD and TXNIP were associated with different beta-cell dysfunction markers, indicating their potential abilities to predict the beta-cell status in people with diabetes.

Coxsackievirus B4 as a Causative Agent of Diabetes Mellitus Type 1: Is There a Role of Inefficiently Treated Drinking Water and Sewage in Virus Spreading?

This study proposed to detect the enterovirus (EV) infection in children with type 1 diabetes mellitus (T1D) and to assess the role of insufficiently treated water and sewage as sources of viral spreading. Three hundred and eighty-two serum specimens of children with T1D, one hundred serum specimens of children who did not suffer from T1D as control, and forty-eight water and sewage samples were screened for EV RNA using nested RT-PCR. The number of genome copies and infectious units of EVs in raw and treated sewage and water samples were investigated using real-time (RT)-PCR and plaque assay, respectively. T1D markers [Fasting blood glucose (FBG), HbA1c, and C-peptide], in addition to anti-Coxsackie A & B viruses (CVs A & B) IgG, were measured in control, T1D-negative EV (T1D-EV-), and T1D-positive EV (T1D-EV+) children specimens. The prevalence of EV genome was significantly higher in diabetic children (26.2%, 100 out of 382) than the control children (0%, 0 out of 100). FBG and HbA1c in T1D-EV- and T1D-EV+ children specimens were significantly higher than those in the control group, while c-peptide in T1D-EV- and T1D-EV+ children specimens was significantly lower than that in the control (n = 100; p < 0.001). Positivity of anti-CVs A & B IgG was 70.7, 6.7, and 22.9% in T1D-EV+, T1D-EV-, and control children specimens, respectively. The prevalence of EV genome in drinking water and treated sewage samples was 25 and 33.3%, respectively. The prevalence of EV infectious units in drinking water and treated sewage samples was 8.5 and 25%, respectively. Quantification assays were performed to assess the capabilities of both wastewater treatment plants (WWTPs) and water treatment plants (WTPs) to remove EV. The reduction of EV genome in Zenin WWTP ranged from 2 to 4 log10, while the reduction of EV infectious units ranged from 1 to 4 log10. The reduction of EV genome in El-Giza WTP ranged from 1 to 3 log10, while the reduction of EV infectious units ranged from 1 to 2 log10. This capability of reduction did not prevent the appearance of infectious EV in treated sewage and drinking water. Plaque purification was performed for isolation of separate EV isolates from treated and untreated water and sewage samples. Characterization of the EV amplicons by RT-PCR followed by sequencing of these isolates revealed high homology (97%) with human coxsackievirus B4 (CV B4) in 60% of the isolates, while the rest of the isolates belonged to poliovirus type 1 and type 2 vaccine strains. On the other hand, characterization of the EV amplicons by RT-PCR followed by sequencing for T1D-EV+ children specimens indicated that all samples contained CV B4 with the same sequence characterized in the environmental samples. CV B4-contaminated drinking water or treated sewage may play a role as a causative agent of T1D in children.

Autoimmune Thyroiditis: A Case Control Study on a Sample of Egyptian Type I Diabetic Patients.

Type 1 diabetic patients are vulnerable for autoimmune thyroid disease. The incidence of type I Diabetes in Egypt is 8/100000. Undiagnosed thyroid dysfunction impairs metabolic status and increase cardiovascular risks in diabetic patients. Objectives of the study were to underscore autoimmune thyroiditis and thyroid dysfunction on a sample of Egyptian type I diabetes mellitus. One hundred type 1 diabetic subjects without previously known thyroid diseases and 50 controls were included. Physical examination, HbA1c, thyroid profile (TSH, free T3 and free T4), thyroid ultrasound anti-peroxidase and anti-thyroglobulin antibodies were assessed. Autoimmune thyroiditis was detected in 27 % of the patients, and significantly associated with parental consanguinity, familial autoimmune disease and goiter. It is concluded that autoimmune thyroiditis is evident on laboratory assessment of type 1 diabetic patients who were apparently euthyroid. Screening of type I diabetics for thyroid diseases should be done even in absence of clinical evidence for better glycemic control and to improve long term outcome.

Association of serum pancreatic derived factor (PANDER) with beta-cell dysfunction in type 2 diabetes mellitus.

AIM: Beta-cell dysfunction is the critical determinant for type 2 diabetes. The novel PANcreatic DERived factor (PANDER) has been identified as interesting islet-secreted cytokine that might be involved in beta-cell dysfunction, a role that has n"ot been clinically elucidated yet. Therefore, this study was designed to study the potential clinical association of this cytokine with beta-cell dysfunction in type 2 diabetes. METHODS: Anthropometric parameters, routine biochemical markers and serum levels of PANDER were measured in 63 diabetic subjects including; recently diagnosed type 2 diabetic patients with duration of diabetes ≤6months and long-standing type 2 diabetic patients with duration of diabetes ≥5years then compared to 16 healthy control volunteers. Proinsulin, C-peptide, insulin and PANDER were measured by ELISA. Beta-cell dysfunction was assessed by HOMA2-%ß, proinsulin, proinsulin-to-insulin (PI/I) ratio and proinsulin-to-C-peptide (PI/C-pep) ratio. Relations among various parameters were studied using simple and multiple linear regressions. RESULTS: Serum PANDER levels were found to be significantly elevated in long-standing diabetics as compared to recently diagnosed diabetics and controls. In addition, PANDER was found to be significantly correlated negatively to HOMA2-%ß, as well as positively to proinsulin, PI/I and PI/C-pep ratios. CONCLUSION: PANDER is associated with beta-cell dysfunction in diabetic patients.

CTX Correlation to Disease Duration and Adiponectin in Egyptian Children with T1DM.

BACKGROUND: In this study, we investigated the relationship of adiponectin with bone marker changes in Egyptian children and adolescents with T1DM and the effect of disease duration on these markers, as well as the possible correlations between adiponectin and bone markers in these patients. METHODS: Sixty Egyptian children and adolescent patients with T1DM were studied. Serum adiponectin and collagen breakdown products (cross-linked C-terminal telopeptide of collagen type l ¼CTX«) were measured and compared to the results of 20 age-matched healthy controls. RESULTS: After adjustment for age, BMI, Tanner stage and gender; (total) adiponectin was significantly higher in all T1DM patients. Serum level of CTX and 25(OH)D showed a marked decrease in diabetics with disease duration > 5 years. Serum level of (total) calcium and inorganic phosphorus (Pi) did not show significant difference from control. CTX was inversely correlated to FBG and T1DM duration. Pi was inversely, while 25(OH)D was directly correlated to FBG. Total calcium showed an inverse correlation with HbA1c. FBG, TC, TAG, LDL-C were independent predictors of CTX in T1DM. CONCLUSIONS: Adiponectin showed no correlation with either CTX or bone homeostatic indices. FBG, TC, TAG, LDL-C were independent predictors of CTX in T1DM. We recommend further investigation of adiponectin isoforms in a population-based study, to establish a good age- and sex-related reference.

Fenofibrate reduces inflammation in obese patients with or without type 2 diabetes mellitus via sirtuin 1/fetuin A axis.

AIMS: The aim of the current study is to investigate the effect of fenofibrate alone and in combination with pioglitazone on serum sirtuin 1 and fetuin A of obese patients with Type 2 Diabetes Mellitus (T2DM). METHODS: Intervention effect on inflammatory parameters was assessed before and after treatment. The study was conducted on 60 postmenopausal females of whom, only 44 patients completed the study. They were distributed as follows; obese patients without T2DM (n=15) who administered fenofibrate (160 mg/day) once for 8 weeks, obese patients with T2DM (n=15) who administered fenofibrate (160 mg/day) once for 8 weeks, obese patients with T2DM (n=14) who administered fenofibrate (160 mg/day) and pioglitazone (15 mg/day) combination once for 8 weeks. We measured fasting plasma glucose, glycated hemoglobin (HbA1c), serum lipids. Inflammatory markers (high sensitivity C-reactive protein "hs-CRP", interleukin-6 "IL-6", fetuin A, and sirtuin 1) of patients were measured in serum using enzyme-linked immunoassay (ELISA) kits. RESULTS: Sirtuin 1 levels in obese patients with T2DM were significantly lower than its levels in obese patients while fetuin A levels were significantly higher (P<0.001). Fenofibrate, alone and in combination with pioglitazone, significantly decreased triacylglycerol, hs-CRP, IL-6, fetuin A and increased sirtuin 1 levels (P<0.001) which suggests that it can be used to delay the complications of obesity and T2DM. There is a strong correlation between fetuin A, sirtuin 1, IL-6 and hs-CRP levels suggesting a shared common pathway. CONCLUSIONS: Fenofibrate was shown to increase serum sirtuin 1 and decrease serum fetuin A levels in obese patients. TRIAL NUMBER: PACTR201407000856135.

Metabolic effects of honey in type 1 diabetes mellitus: a randomized crossover pilot study.

The aim of this study was to evaluate the metabolic effects of 12-week honey consumption on patients suffering from type 1 diabetes mellitus (DM). This was a randomized crossover clinical trial done in the National Institute for Diabetes and Endocrinology, Cairo, Egypt. Twenty patients of both sexes aged 4-18 years with type 1 DM and HbA1C<10% participated in the study. They were randomized into two equal groups (intervention to control and control to intervention). The dietary intervention was 12-week honey consumption in a dose of 0.5 mL/kg body weight per day. The main outcome measures were serum glucose, lipids, and C-peptide, and anthropometric measurements. None of participants were lost in follow-up. The intervention resulted in significant decreases in subscapular skin fold thickness (SSFT; P=.002), fasting serum glucose (FSG; P=.001), total cholesterol (P=.0001), serum triglycerides (TG; P=.0001), and low-density lipoprotein (P=.0009), and significant increases in fasting C-peptide (FCP; P=.0004) and 2-h postprandial C-peptide (PCP; P=.002). As possible long-term effects of honey after its withdrawal, statistically significant reductions in midarm circumference (P=.000), triceps skin fold thickness (P=.006), SSFT (P=.003), FSG (P=.005), 2-h postprandial serum glucose (P=.000), TG (P=.003), and HbA1C (P=.043), and significant increases in FCP (P=.002) and PCP (P=.003) were observed. This small clinical trial suggests that long-term consumption of honey might have positive effects on the metabolic derangements of type 1 DM.