The effects of transcription factor 7-like 2 rs7903146 and paired box 4 rs2233580 variants associated with type 2 diabetes on the therapeutic efficacy of hypoglycemic agents.

Aim: This study aims to investigate the effects of the TCF7L2 rs7903146 and PAX4 rs2233580 (R192H) variants associated with T2D on the therapeutic efficacies of various HAs in patients with T2D after follow-up for 3 years. Methods: A total of 526 patients who were followed up at the Diabetic Clinic of Siriraj Hospital during 2016-2019 were enrolled. The variants TCF7L2 rs7903146 and PAX4 rs2233580 (R192H) were genotyped using the RNase H2 enzyme-based amplification (rhAmp) technique and the associations between genotypes and glycemic control after treatments with different combinations HA were evaluated using Generalized Estimating Equations (GEE) analysis. Results: Patients who carried TCF7L2 rs7903146C/T + T/T genotypes when they were treated with biguanide alone had significantly lower fasting plasma glucose (FPG) than those of the patients who carried the C/C genotype (p = 0.01). Patients who carried the PAX4 rs2233580 G/G genotype when they were treated with sulfonylurea alone had significantly lower FPG than those of the patients who carried G/A + A/A genotypes (p = 0.04). Conclusion: Genotypes of TCF7L2 rs7903146 and PAX4 rs2233580 (R192H) variants associated with T2D influence the therapeutic responses to biguanide and sulfonylurea. Different genotypes of these two variants might distinctively affect the therapeutic effects of HAs. This finding provides evidence of pharmacogenetics in the treatment of diabetes.

Investigation of Monogenic Diabetes Genes in Thai Children with Autoantibody Negative Diabetes Requiring Insulin.

Purpose: The objective of this study was to clarify the phenotypic characteristics of monogenic diabetes abnormalities in Thai children with autoantibody-negative insulin. Patients and Methods: Two hundred and thirty-one Thai type 1 diabetes (T1D) patients out of 300 participants with recent-onset diabetes were analyzed for GAD65 and IA2 pancreatic autoantibodies. A total of 30 individuals with T1D patients with negative autoantibody were screened for 32 monogenic diabetes genes by whole-exome sequencing (WES). Results: All participants were ten men and twenty women. The median age to onset of diabetes was 8 years and 3 months. A total of 20 people with monogenic diabetes carried genes related to monogenic diabetes. The PAX4 (rs2233580) in ten patients with monogenic diabetes was found. Seven variants of WFS1 (Val412Ala, Glu737Lys, Gly576Ser, Cys673Tyr, Arg456His, Lys424Glu, and Gly736fs) were investigated in patients in this study. Furthermore, the pathogenic variant, rs115099192 (Pro407Gln) in the GATA4 gene was found. Most patients who carried PAX4 (c.575G>A, rs2233580) did not have a history of DKA. The pathogenic variant GATA4 variant (c.1220C>A, rs115099192) was found in a patient with a history of DKA. Conclusion: This study demonstrated significant genetic overlap between autoantibody-negative diabetes and monogenic diabetes using WES. All candidate variants were considered disease risk with clinically significant variants. WES screening was the first implemented to diagnose monogenic diabetes in Thai children, and fourteen novel variants were identified in this study and need to be investigated in the future.

Immune Response after SARS-CoV-2 Infection with Residual Post-COVID Symptoms.

Many patients develop post-acute COVID syndrome (long COVID (LC)). We compared the immune response of LC and individuals with post-COVID full recovery (HC) during the Omicron pandemic. Two hundred ninety-two patients with confirmed COVID infections from January to May 2022 were enrolled. We observed anti-SARS-CoV-2 receptor-binding domain immunoglobulin G, surrogate virus neutralization test, T cell subsets, and neutralizing antibodies against Wuhan, BA.1, and BA.5 viruses (NeuT). NeuT was markedly reduced against BA.1 and BA.5 in HC and LC groups, while antibodies were more sustained with three doses and an updated booster shot than ≤2-dose vaccinations. The viral neutralization ability declined at >84-days after COVID-19 onset (PC) in both groups. PD1-expressed central and effector memory CD4+ T cells, and central memory CD8+ T cells were reduced in the first months PC in LC. Therefore, booster vaccines may be required sooner after the most recent infection to rescue T cell function for people with symptomatic LC.

The Variants in ADIPOQ are Associated with Maternal Circulating Adipokine Profile in Gestational Diabetes Mellitus.

Background: Gestational diabetes mellitus (GDM) is the most common association with hyperglycemia and glucose intolerance during pregnancy. The adipokines play an important to control insulin secretion and glucose. This study aimed to investigate the association between maternal circulating adipokine levels and ADIPOQ gene polymorphism among pregnant women subjects with GDM and normal glucose tolerance (NGT). Methods: Participants including 229 normal pregnant women and 197 GDM pregnant women were enrolled from 2015 to 2018 at Siriraj hospital. Serum adipokine levels including adiponectin, adipsin/factor D, NGAL/Lipocalin-2, total PAI-1, and resistin were measured by immunoassay. ADIPOQ variations were investigated including -11377C/G (rs266729), +45T/G (rs2241766), and +276G/T (rs1501299). Results: Serum adiponectin concentration was also significantly decreased among the GDM who had aged less than 35 years old whereas adipsin levels were significantly lower among the GDM who had aged more than 35 years old. Also, adiponectin and total PAI-1 levels were significantly lower among the GDM who had a BMI of less than 30 kg/m2. The G allele frequency of ADIPOQ +45T/G was significantly different between GDM and controls (p = 0.03). ADIPOQ +45T/G was associated with an increased risk of GDM (odds ratio [OR]: 1.554; 95% confidence interval [CI]: 1.010-2.390; p=0.045). The -11377C/G was affected by the level of adiponectin (p = 0.04). The C allele of -11377C/G SNP declined serum adiponectin levels and may be a risk factor for GDM. Conclusion: This study revealed that genetics play important roles in circulating adipokines among pregnant women. ADIPOQ polymorphisms had significant associations with adiponectin levels in GDM patients.

The genetic polymorphisms and levels of adipokines and adipocytokines that influence the risk of developing gestational diabetes mellitus in Thai pregnant women.

INTRODUCTION: Aberrant immune and inflammatory response is thought to be involved in the pathogenesis of gestational diabetes mellitus (GDM). OBJECTIVE: To investigate the genetic polymorphisms and levels of adipokines/adipocytokines that influence the risk of developing GDM in Thai women. RESEARCH DESIGN & METHODS: This case-control recruited 400 pregnant Thai women. A total of 12 gene polymorphisms at ADIPOQ, adipsin, lipocalin-2, PAI-1, resistin, IL-1ß, IL-4, IL-17A, TGF-ß, IL-10, IL-6, and TNF-α were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay and RNase H2 enzyme-based amplification (rhAmp) SNP assay. Serum levels of adipokines/adipocytokines were evaluated using Luminex assays. RESULTS: Mean age, weight before and during pregnancy, body mass index before and during pregnancy, blood pressure, gestational age at blood collection, and median 50 g glucose challenge test were significantly higher in GDM women than control. Significantly lower adiponectin and higher IL-4 levels were found in GDM compared to controls (p = 0.001 and p = 0.03, respectively). The genotype frequencies of IL-17A (rs3819025) were significantly different between GDM and controls (p = 0.01). Using additive models, IL-17A (rs3819025) and. TNF-α (rs1800629) were found to be independently associated with increased risk of GDM (odds ratio [OR]: 2.867; 95 % confidence interval [CI]: 1.171-7.017; p = 0.021; and OR: 12.163; 95 %CI: 1.368-108.153; p = 0.025, respectively). In GDM with IL-17A (rs3819025), there was a significant negative correlation with lipocalin-2 and PAI-1 levels (p = 0.038 and p = 0.004, respectively). CONCLUSION: The results of this study highlight the need for genetic testing to predict/prevent GDM, and the importance of evaluating adipokine/adipocytokine levels in Thai GDM women.

Prevalence and Characteristics of Prediabetes and Metabolic Syndrome in Seemingly Healthy Persons at a Health Check-Up Clinic.

Purpose: This study investigated the prevalence and characteristics of prediabetes (PreDM) and metabolic syndrome (MetS) in seemingly healthy persons attending a health check-up clinic at a tertiary care hospital. Patients and Methods: This was a cross-sectional study that enrolled 1213 subjects (339 male, 874 female) who underwent an annual health check-up at Siriraj Hospital, Bangkok, Thailand from 2009 to 2019. Factors that independently related to PreDM were analyzed using unconditional logistic regression analysis with adjustments for age, BMI, and gender. Results: The prevalence of PreDM and MetS was 54.3% and 19.7% respectively. Participants with impaired fasting glucose (IFG) and glycated hemoglobin (HbA1c) 38.8-46.4 mmol/mol had significantly higher waist circumference (WC) and blood pressure (BP) compared to those with IFG or HbA1c 38.8-46.4 mmol/mol alone (P < 0.05). Among three PreDM subgroups, the average age was lowest in the HbA1c 38.8-46.4 mmol/mol subgroup (P < 0.001). PreDM participants with MetS were older (p = 0.03), had higher WC, BP, fasting plasma glucose and serum triglyceride level (all P < 0.001) but had lower serum high-density lipoprotein (HDL) cholesterol level (P < 0.001). Multivariate analysis revealed high MetS score, obesity, and low serum HDL cholesterol level to be independently associated with PreDM with odds ratios of 9.02 (95% confidence interval [CI]: 4.03-20.18), 1.8 (95% CI: 1.07-3.04), and 1.42 (95% CI: 1.02-1.96), respectively. Conclusion: The prevalence of PreDM and MetS was relatively high in seemingly healthy persons. Distinct PreDM subgroups with or without MetS exhibited diverse clinical and biochemical features suggesting dissimilar pathogenesis.

Vitamin D pathway gene polymorphisms, vitamin D level, and cytokines in children with type 1 diabetes.

AIMS: The study aimed to examine genetic polymorphism of vitamin D-related genes and association between those genes and vitamin D and cytokines levels in children with type 1 diabetes (T1D). MATERIALS AND METHODS: This study was conducted among 100 T1D children and 100 controls at Division of Endocrinology and Metabolism, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, during 2016 to 2018. Vitamin D metabolite levels were measured by liquid chromatography-tandem mass spectrometry method, serum cytokine levels of IFN- É£, IL-10, IL-13, IL-17α, IL-2, IL-4, IL-6, and TNF-α by immunoassay, and genetic variations at VDR, CYP2R1, CYP27B1, GC, DHCR7, and CYP24A1 by polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: A relationship between studied single nucleotide polymorphisms and T1D was found in CYP2R1 (rs10741657) (GA, OR: 1.83, 95% CI: 1.01-3.31; p = 0.04). VDR haplotypes were also remarkably different between T1D patients and controls. Controls had higher frequency of haplotype TACT than T1D patients (p = 0.02). Vitamin D and all cytokine levels, except for IL-17α, were significantly increased in T1D compared to controls. The polymorphism of DHCR7 (rs12785878) was positively associated with 25OHD3 and 3epi25OHD3 levels and was negatively associated with 25OHD2 level. On the other hand, polymorphism of CYP27B1 (rs4646536) was negatively associated with 3epi25OHD3 level. Polymorphisms of CYP27B1 (rs4646536) and GC (rs2282679) were positively associated with TNF-α levels. VDR variation of rs1544410, rs731236, and rs7975232 also showed negative association with IL-10 levels. In contrast, the level of IL-10 was positively associated with DHCR7 (rs12785878). CONCLUSION: Relationships between T1D and CYP2R1 polymorphism and VDR haplotype were found. Vitamin D gene-related variations were associated with vitamin D and circulating cytokine levels in children with T1D.

Interleukin-34 overexpression mediated through tumor necrosis factor-alpha reflects severity of synovitis in knee osteoarthritis.

This study aimed to investigate whether interleukin-34 (IL-34) mRNA expression is aberrant and modulated by tumor necrosis factor-alpha (TNF-α) in knee osteoarthritis (OA) fibroblast-like synoviocytes (FLS) and determine associations of IL-34 mRNA and protein in the systemic and local joint environments with severity of knee OA synovitis. Transcriptional and translational IL-34 levels in FLS, synovium, synovial fluid, and plasma of knee OA were determined using real-time polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay. Relative mRNA expressions of NF-κB signaling molecules were further measured. In knee OA FLS stimulated with TNF-α, IL-34 mRNA expression was significantly up-regulated in a time-dependent manner. In knee OA synovium with severe synovitis, increased IL-34 mRNA expression was directly associated with IL-6, IκB, NF-κB, and MMP-13, in addition to knee OA FLS. Immunostaining score of IL-34 was considerably greater in knee OA synovium with severe synovitis than that in those with mild and no synovitis. Increments in joint fluid and plasma IL-34 levels in knee OA patients with severe synovitis were closely related to its mRNA and protein expressions in knee OA synovium. Transcriptional and translational expressions of IL-34 were positively correlated with synovitis severity. Collectively, IL-34 overexpression would reflect synovitis severity in knee OA.

HNF1A mutation in a Thai patient with maturity-onset diabetes of the young: A case report.

BACKGROUND: Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes. The disease is transmitted in autosomal dominant mode and diabetes is usually diagnosed before age 25 year. MODY 3 is caused by mutation of hepatocyte nuclear factor (HNF) 1A genes and is the most common MODY subtype. Diagnosis of MODY 3 is crucial since glycemic control can be accomplished by very low dose of sulfonylurea. In this report we described a Thai MODY 3 patient who had excellence plasma glucose control by treating with glicazide 20 mg per day and insulin therapy can be discontinued. CASE SUMMARY: A 31-year-old woman was diagnosed diabetes mellitus at 14 years old. The disease was transmitted from her grandmother and mother compatible with autosomal dominant inheritance. Sanger sequencing of proband's DNA identified mutation of HNF1A at codon 203 which changed amino acid from arginine to cysteine (R203C). This mutation was carried only by family members who have diabetes. The patient has been treated effectively with a combination of oral hypoglycemic agents and must include a very low dose of glicazide (20 mg/d). Insulin therapy was successfully discontinued. CONCLUSION: We demonstrated a first case of pharmacogenetics in Thai MODY 3 patient. Our findings underscore the essential role of molecular genetics in diagnosis and guidance of appropriate treatment of diabetes mellitus in particular patient.

Blood leukocyte LINE-1 hypomethylation and oxidative stress in knee osteoarthritis.

AIM: Joints inflammation is one of the most pathologic processes leading to the development of osteoarthritis (OA), possibly leading to genomic instability. LINE-1 is transposable elements, and alterations in LINE-1 methylation induced by 8-hydroxy-2'-deoxyguanosine (8-OHdG) can cause genomic instability contributing to OA development. Herein, the present study examined associations between LINE-1 methylation, 8-OHdG, and knee OA severity. METHODS: LINE-1 methylation levels were measured in 104 knee OA patients and 96 healthy controls by quantitative combined bisulfite restriction analysis. 8-OHdG was investigated by ELISA. The knee OA severity was appraised by questionnaires (VAS, WOMAC, KOOS, and lequesne index) and radiological severity based on the grading of Kellgren and Lawrence (KL) standard criteria. KEY FINDINGS: Blood leukocyte LINE-1 methylation levels were significantly lower in knee OA patients than in healthy controls. Interestingly, individuals with LINE-1 hypomethylation were significantly associated with an elevated risk of knee OA. Linear regression analysis revealed that LINE-1 methylation was independently associated with KL grading of knee OA. Furthermore, plasma 8-OHdG levels in OA cases were not significantly different from those in healthy volunteers, whereas synovial fluid 8-OHdG values were considerably higher than in paired plasma specimens of the OA subjects. SIGNIFICANCE: This study demonstrated that LINE-1 hypomethylation in blood leukocytes was associated with increased risk and radiographic severity of knee OA, and increased synovial fluid 8-OHdG levels were observed in knee OA patients. Collectively, LINE-1 hypomethylation and elevated 8-OHdG could emerge as biomarkers indicating the severity of knee OA and may take a possible part in the pathological process of knee OA.