Role of glucose metabolism in aggressive phenotype of fibroblast-like synoviocytes: Latest evidence and therapeutic approaches in rheumatoid arthritis.

Glucose metabolism is considerably increased in inflamed joints of rheumatoid arthritis (RA) patients at early stages. Fibroblast-like synoviocytes (FLSs) activation and subsequent joint damage are linked with metabolic alterations, especially glucose metabolism. It has been shown that glucose metabolism is elevated in aggressive phenotype of FLS cells. In this regard, glycolytic blockers are able to reduce aggressiveness of the FLS cells resulting in decreased joint damage in various arthritis models. Besides, metabolic changes in immune and non-immune cells such as FLS can provide important targets for therapeutic intervention. Glycolytic enzymes such as hexokinase 2 (HK2), phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB), and phosphoglycerate kinase (PGK) play essential roles in aggressive behavior of FLS cells. It has been documented that the HK2 enzyme is significantly upregulated in RA FLS cells, compared with osteoarthritis (OA) FLS cells. The HK2 is expressed in a few tissues and upregulated in the inflamed synovium of RA patients that makes it a potential target for RA treatment. Furthermore, HK2 has different roles in each cellular compartment, which offers another level of specificity and provides a specific target to reduce deleterious effects of inhibiting the enzyme in RA without affecting glycolysis in normal cells. Thus, targeting the HK2 enzyme might be an attractive potential selective target for arthritis therapy and safer than global glycolysis inhibition. Therefore, this review was aimed to summarize the current knowledge about glucose metabolism of FLS cells and suggest novel biomarkers, which are potential candidates for RA treatment.

Optimal Glycated Hemoglobin Cutoff Point for Diagnosis of Type 2 Diabetes in Iranian Adults.

OBJECTIVES: The aim of this study was to evaluate the capability of glycated hemoglobin (A1C) levels to be a tool for identifying Iranian adults with diabetes and prediabetes. METHODS: In a cross-sectional population-based study, 1,813 adults, men and women 35 to 75 years of age and without a history of diabetes and hemoglobinopathies, were included. Fasting blood glucose and A1C levels were obtained. According to the criteria of the American Diabetes Association, participants were categorized into 3 groups: newly diagnosed diabetes, prediabetes and healthy subjects. The optimal cutoff point for A1C in diabetes and prediabetes diagnosis was determined by studying the sensitivity and specificity of different cutoff points for A1C, while using different levels of fasting blood glucose as the gold standard. RESULTS: Participants with newly diagnosed diabetes were significantly older than subjects with prediabetes and healthy subjects (mean [± SD] 47.3±12.9, 44.6±13.0 and 39.2±14.1 years, respectively) and also had higher body mass indexes. As expected, the levels of fasting blood glucose (8.79±2.24, 6.01±0.38 and 4.97±0.4 mmol/L) and A1C (6.55±1.4%, 5.61±0.61% and 5.28±0.59%) were significantly different in the groups (p<0.001). The optimal cutoff point for A1C to predict prediabetes was 5.5% (sensitivity of 60.5% and specificity of 63.1%) and for diabetes was 5.9% (sensitivity of 66.7% and specificity of 81.2%). ADA cutoff points for prediabetes and diabetes detection yielded a sensitivity of 45.2% and 39.8%, respectively. CONCLUSIONS: The findings suggest the necessity of determining the A1C cutoffs for detecting diabetes or prediabetes in each region's population. They also suggest that the combination of these A1C cutoffs with fasting blood glucose levels are required to determine diabetes and prediabetes more accurately.

Association between apolipoprotein E polymorphism and nephropathy in Iranian diabetic patients.

Approximately one-third of diabetic patients develop evidence of nephropathy. Pathogenesis of diabetic nephropathy (DN) remains unclear; however, some genetic and metabolic risk factors have been determined for the development and progression of DN. In the recent genetic studies, polymorphism of apolipoprotein E (ApoE) gene has been reported as a risk factor for the development of DN; however, the results are inconsistent. The aim of the present study was to evaluate the association between ApoE polymorphism and nephropathy in Iranian patient with type 2 diabetes. A total of 197 patients with type 2 diabetes in two groups with and without nephropathy (n = 99 and n = 98, respectively) participated in this case-control study. ApoE genotype was determined by restriction fragment length polymorphism analysis. Biochemical factors of all patients were measured. The frequency of Apo ε4 allele was significantly (P <0.05) lower in DN patients (10.6%) than in diabetic patients without nephropathy (20.4%). No significant difference was observed between the groups regarding Apo ε2 and Apo ε3 allele frequencies. Serum level of total and low-density lipoprotein cholesterol in Apo ε2 carriers was lower than Apo ε3 and Apo ε4 carriers, but this difference was not statistically significant. Frequency of Apo ε4 allele is higher in diabetic patients without nephropathy than DN participants. Given to the result, it seems that Apo ε4 has a protective effect in diabetic patients against nephropathy.

Association between ELMO1 gene polymorphisms and diabetic nephropathy in an Iranian population.

BACKGROUND: Diabetic nephropathy (DN) is one of the leading causes of death in patients with type 2 diabetes mellitus (T2DM). Several genome-wide association studies have introduced Engulfment and Cell Motility 1 (ELMO1) as a candidate gene which is associated with DN. This study assessed the association of ELMO1 gene polymorphisms with DN in order to investigate the effects of ELMO1 gene on susceptibility to DN in an Iranian population. METHODS: In the present study, 100 patients with T2DM, 100 patients with DN and 100 healthy subjects who were matched for sex were selected. Allele and genotype frequencies were determined by Tetra-ARMS PCR technique. In all groups, levels of FBS, creatinine, urea, HbA1C, urine levels of albumin creatinine ratio and glomerular filtration rate were measured. RESULTS: A statistically significant association was shown between G allele of rs741301 (odds ratio (OR) = 1.7 [95 % CI 1.17-2.63]; p value = 0.005), and GG genotypes of rs741301 (OR = 2.5 [95 % CI 1.2-5.4]; p value = 0.01) and DN. A significant association was not detected between allelic and genotypic frequencies of rs1345365 and DN. Linkage Disequilibrium (LD) between two variants was weak (D' = 0.11, r2 = 0.008). rs1345365A/rs741301A haplotypes were more frequent in patients with T2DM as compared to DN (OR = 0.5 [95 % CI 0.3-0.7]; p value = 0.0006). Also, genotypes of variant rs741301 in all subjects had significant difference with respect to the mean of ACR (p Value < 0.05). CONCLUSION: This study first investigated the association of ELMO1 gene polymorphisms (rs741301) with DN in an Iranian population, supporting its key role as a candidate gene in the susceptibility to DN.