"Hyperglycemic Memory": Observational Evidence to Experimental Inference.

Several epidemiological studies have appreciated the impact of "duration" and "level" of hyperglycemia on the initiation and development of chronic complications of diabetes. However, glycemic profiles could not fully explain the presence/absence and severity of diabetic complications. Genetic issues and concepts of "hyperglycemic memory" have been introduced as additional influential factors involved in the pathobiology of late complications of diabetes. In the extended phase of significant diabetes randomized, controlled clinical trials, including DCCT/EDIC and UKPDS, studies have concluded that the quality of glycemic or metabolic control at the early time around the diabetes onset could maintain its protective or detrimental impact throughout the following diabetes course. There is no reliable indication of the mechanism by which the transient exposure to a given glucose concentration level could evoke a consistent cellular response at target tissues at the molecular levels. Some biological phenomena, such as the production and the concentration of advanced glycation end products (AGEs), reactive oxygen species (ROS) and protein kinase C (PKC) pathway activations, epigenetic changes, and finally, the miRNAs-mediated pathways, may be accountable for the development of hyperglycemic memory. This work summarizes evidence from previous experiments that may substantiate the hyperglycemic memory soundness by its justification in molecular terms.

Knowledge discovery in genetics of diabetes in Iran, a roadmap for future researches.

PURPOSE: The pathogenesis of diabetes is considered polygenic as a result of complex interactions between genetic/epigenetic and environmental factors. This review intended to evaluate the scientometric and knowledge gap of diabetes genetics researches conducted in Iran as a case of developing countries, and drawn up a roadmap for future studies. METHODS: We searched Scopus and PubMed databases from January 2015 until December 2019 using the keywords: (diabetes OR diabetic) AND (Iran). All publications were reviewed by two experts and after choosing relevant articles, they were categorized based on the subject, level of evidence, study design, publication year, and type of genetic studies. RESULTS: Of 10,540 records, 428 articles were met the inclusion criteria. Generally, the number of researches about diabetes genetics rose since 2015. Case-control/cross-sectional and animal studies were the common types of study design and based on the subject, the most frequent researches were about genetic factors involved in diabetes development (38%). Briefly, the top seven genes that were evaluated for T2DM were TCF7L2, APOAII, FTO, PON1, ADIPOQ, MTHFR, and PPARG respectively, and also, CTL4 for T1DM. miR-21, miR-155, and miR-375 respectively were the most micro-RNAs that were evaluated. Furthermore, there were six studies about lncRNAs. DISCUSSION AND CONCLUSION: Investigation about the genetic of diabetes is progressed although there are some limitations like non-homogenous data from Iran, heterogeneity of ethnicity, and rationale of studies. Compared to the previous analysis in Iran, still, GWAS and large-scale studies are required to achieve better policies for manage and control of diabetes disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-021-00838-8.

Investigating the association of matrix metalloproteinase-2 gene variants with endometriosis in an Iranian population.

OBJECTIVES: matrix metalloproteinases including matrix metalloproteinase-2 play a key role in endometrial extra cellular matrix breakdown in endometriosis. Aberrant expression of matrix metalloproteinase-2 has been reported in eutopic and ectopic endometrial tissue of endometriosis patients so altered expression of matrix metalloproteinase-2 due to polymorphisms may lead to establishment and progression of endometriosis. In this study the association between -735 C/T (rs2285053) and -1575 G/A (rs243866) variants of matrix metalloproteinase-2 gene with presence of endometriosis in an Iranian population were investigated for the first time. STUDY DESIGN: A case-control association study was conducted to investigate the role of MMP-2-735 C/T and _1575 G/A variants in development of endometriosis. Polymerase chain reaction-restriction fragment length polymorphism method was used to determine genotype frequencies of these variants in 100 endometriosis patients and 200 normal samples. Total genomic DNA was extracted from blood samples and single-nucleotide polymorphism flanking regions were amplified using designed specific primers. Enzymatic digestion was performed using Pag I and Hinf I restriction enzymes for rs2285053 and rs243866 variants, respectively. Statistical analysis was ascertained using statistical package for social science version 16 and "SHEsis" software. RESULTS: There were no significant differences in genotype frequencies of rs2285035 (-735C/T) variant between case and control groups (CC + CT vs. TT p = 0.40; OR = 0.50, 95 % CI 0.100-2.551). There were also no significant differences for C allele frequencies in both case and control groups (p = 0.9). For variant rs243866 (-1575 G/A) the differences in genotype frequencies between case and controls group were determined to be significant (GG + GA vs. AA p = 0.041; OR = 6.46, 95 % CI 0.82-50.43). The frequency of G allele was significantly different in case and control groups (p = 0.037). CONCLUSION: In conclusion, existence of rs243866 variant in promoter region of matrix metalloproteinase-2 gene can increase the risk of endometriosis in Iranian women.

Association of microRNA gene polymorphisms with Type 2 diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a metabolic disorder with growing prevalence and increasing economic burden. Based on the role of genetics and epigenetic factors on T2DM, we aimed to carry a systematic review and meta-analysis for all miRNA gene polymorphisms and risk of T2DM. MATERIALS AND METHODS: A computerized literature search was carried out on PubMed, Web of Science, Scopus, Embase, as well as references of relevant review/meta-analysis. Key search terms were "Diabetes Mellitus, Type 2," "MicroRNAs," and "Polymorphism, Single Nucleotide." All types of observational studies from January 1, 1992, to November 30, 2019, were included, without language restriction. Data analysis was performed using R programming language (3.5.2). Level of heterogeneity was obtained by Cochran's Q test (P < 0.05), and subgroup analysis was performed based on ethnicity. RESULTS: Thirty-two polymorphisms from fifteen articles were included. Meta-analysis was carried out based on minor allele frequencies. Seven studies with 2193 cases and 3963 controls were included for rs2910164 polymorphism. In subgroup analysis, there were significant results in Caucasian population in dominant model (odds ratio [OR] =1.12; 95% confidence interval [CI]: 0.83-1.51), homozygote model (OR = 1.78; 95% CI: 1.06-3.00), heterozygote model (OR = 1.77; 95% CI: 1.03-3.05), and recessive model (OR = 1.78; 95% CI: 1.07-2.96). Four studies with 2085 cases and 1933 controls were included for rs895819 polymorphism. Overall, there was no significant result for association with rs895819, but subgroup analysis revealed that minor allele significantly decreased the risk of T2DM in Caucasians by recessive model (OR = 0.34; 95% CI: 0.18-0.66), dominant model (OR = 0.70; 95% CI: 0.52-0.94), homozygote model (OR = 0.32; 95% CI: 0.16-0.62), heterozygote model (OR = 0.37; 95% CI: 0.19-0.74), allelic model (OR = 0.67; 95% CI: 0.52-0.85). CONCLUSION: The minor allele of rs2910164 may increase the risk of T2DM by leading to lower level of miR-146a. In contrast, minor allele of rs895819 may decrease the risk of T2DM by leading to higher level of miR-27a.

Haplotypes in vitamin D receptor gene encode risk in diabetic nephropathy.

BACKGROUND: Diabetic Nephropathy (DN) is one of the microvascular complications of diabetes and its early diagnosis can improve patient's quality of life. Genetic factors may increase the risk of DN development. This study aimed to evaluate the association of vitamin D receptor (VDR) gene polymorphisms and DN. METHOD: A total of 313 Iranian participants including 104 diabetic patients with nephropathy (DN), 100 diabetic patients without nephropathy (D) and 109 healthy people (HC) were studied. The frequencies of rs7975232, rs731236 and rs4516035 variants of VDR gene were determined and compared between three groups. Estimated haplotype frequencies between polymorphisms in the cases and controls were also calculated. RESULTS: No significant differences were identified for allele /genotype frequencies in HC, D and DN groups. However haplotype analysis showed that haplotype encompassing CCC alleles for rs7975232, rs731236 and rs4516035 variants, respectively was more frequent in DN subjects compared to HC (p-value = 0.01) and also, haplotype comprising TCC alleles was more frequent in DN group compared to both HC and D groups (p-value = 0.004 and 0.007, respectively). CONCLUSION: Our study identified that CCC and TCC VDR haplotypes are risk factors for DN in patients with diabetes type 2.

Association between Trp48Arg polymorphism of the CD11c gene and risk for obesity among Iranian population.

BACKGROUND: Despite assessing the expression of CD11c gene in macrophages in adipose tissues and suggesting association between the gene expressions and predisposing to obesity, the relationship of the changes in CD11c gene and its variants with obesity has not been exclusively evaluated. The present study aimed to assess the relationship between rs2230424 gene polymorphism leading a single amino acid Arginine 48 to Tryptophan interchange in CD11c gene protein chain and obesity in a sample of Iranian population. METHODS: This case-control association study was performed on 247 subjects including obese individuals and a sex- and age-matched healthy non-obese individuals. After DNA extraction, the DNA sequence containing the relevant polymorphic site was amplified by polymerase chain reaction (PCR). Determining different genotypic patterns of the SNP was carried out by restriction fragment length polymorphism (RFLP) analysis. To final draft the suspected genotypes of the SNP, DNA sequencing was performed. RESULTS: The frequency of wild genotype (TT) of Trp48Arg polymorphism of the CD11c gene in obese and non-obese groups was 97.9% and 94.6% and the frequency of heterozygous genotype (TC) was 2.1% and 5.4%, respectively with no significant difference (p = 0.230,). None of the participants had mutant genotypic pattern of the polymorphism. There was no association of the genotypic pattern of Trp48Arg polymorphism with different underlying risk factors as well as mean laboratory parameters. CONCLUSION: The presence of Trp48Arg polymorphism of the CD11c gene is not associated with increased risk for obesity among Iranian population.

Evaluation of the presence of Epstein-Barr virus (EBV) in Iranian patients with thyroid papillary carcinoma.

BACKGROUND AND PURPOSE: Papillary thyroid carcinoma (PTC) is the most common thyroid cancer. EBV is one of the most important viruses related to different types of malignancies. This study investigated the relationship between EBV and papillary thyroid carcinoma. MATERIAL AND METHODS: In this study the presence of Epstein-Barr Nuclear Antigen 1 (EBNA1) gene in papillary thyroid carcinoma tissues were examined by nested-PCR method. Paraffin-embedded tissues (N=41) blocks of thyroid cancer were used. DNA was extracted from all samples and then samples were evaluated for the presence of EBV gene. RESULTS: In 41 samples, EBNA1 was detected in 65.8% of patients with papillary thyroid carcinoma which was significantly higher in younger ages. CONCLUSION: The significant presence of EBV genome in papillary thyroid carcinoma suggests that this virus may play a role in this cancer especially in younger ages. As a result, monitoring of patients with EBV latent infection for PTC can be very important.

Effects of extremely low frequency electromagnetic fields on paraoxonase serum activity and lipid peroxidation metabolites in rat.

BACKGROUND: Atherogenic effects of ELF-MF exposure have not been studied well so far. Therefore we have hypothesized that ELF-MF exposure might have atherogenic effect by impairing antioxidant function and increasing lipid peroxidation. This study was therefore undertaken to examine the effects of ELF-MF on paraoxonase (PON) activity, antioxidant capacity and lipid peroxidation metabolites. Effects of time on remodeling of antioxidant system were also investigated in this study. METHODS: Seventy five Wistar rats were randomly allocated into five groups as follows: 1) Sham exposure, 2) Single exposure to 60 Hz, sacrificed immediately after exposure, 3) Single exposure to 60 Hz, sacrificed 72 hours after exposure, 4) Fourteen days of exposure to 60 Hz, sacrificed immediately after exposure, and 5) Fourteen days of exposure to 60 Hz, sacrificed 72 hours after exposure. Blood samples were collected and analyzed. The results were compared using ANOVA and post hoc Tukey HSD for multiple caparisons. RESULTS: Single ELF-MF exposure significantly increased lipid peroxidation (CD and MDA) and increased antioxidant serum activity (HDL, paraoxonase activity, and serum total antioxidant capacity). Chronic ELF-MF exposure increased lipid peroxidation and affected antioxidant system. Free fatty acids levels were significantly increased after both single and two weeks exposure. Chronic exposure led to irreversible changes while acute exposure tended to reversible alterations on above mentioned parameters. CONCLUSIONS: According to the results of this study, ELF-MF exposure could impair oxidant-antioxidant function and might increase oxidative stress and lipid peroxidation. Antioxidant capability was dependent on the duration and continuity of ELF-MF exposure.

A patient with features of albright hereditory osteodystrophy and unusual neuropsychiatric findings without coding Gsalpha mutations.

BACKGROUND: Pseudohypoparathyroidism(PHP) is a heterogeneous group of rare metabolic disorders characterized by hypocalcemia and hyperphosphatemia resulting from PTH resistance. Different forms of PHP have been reported based on biochemical and clinical manifestation and genetic findings. Most of these forms are caused by defects in GNAS, an imprinted gene locus with multiple subunits. We reported a 12- year- old girl with unusual clinical manifestations of Pseudopseudohypoparathyroidism(PPHP). METHODS: After clinical and biochemical evaluations, the patients' genomic DNA was isolated from peripheral blood leukocytes using salting out method. The whole coding sequences of GNAS gene including 13 exons were amplified by PCR. Quantitative PCR reactions were performed too. FINDINGS: We described a 12- year- old girl with Albright Hereditory osteodystrophy (AHO) phenotype, poor school performance, some abnormal movements, TSH resistance with normal serum calcium and phosphorus levels and normal Gsα bioactivity with no mutation in GNAS exons. Unusual neuropsychiatric findings in this patient were compatible with Asperger syndrome. CONCLUSIONS: According to our findings this patient could not be categorized in any of PHP subgroups. Identifying of such individuals may be useful to discover different genetic patterns in pseudohypoparathyroidism and pseudopseudohypoparathyroidism. It is important to identify patients in whom PHP is caused by novel GNAS mutations, as careful investigations of these findings will likely further our knowledge of this complex and this unique disorder. In addition this case presented with unusual neuropsychiatric findings which has not been reported up to now.