Impact of SLC22A1 variants rs622342 and rs72552763 on HbA1c and metformin plasmatic concentration levels in patients with type 2 diabetes mellitus
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SUBMITTER: Ortega-Ayala A
PROVIDER: S-EPMC11209864 | biostudies-literature | 2024 Jun
REPOSITORIES: biostudies-literature
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Project description:BackgroundMetformin is the most widely used oral antidiabetic agent and can reduce insulin resistance (IR) effectively. Organic cation transporter 1 (encoded by SLC22A1) is responsible for the transport of metformin, and ataxia-telangiectasia-mutated (ATM) is a gene relating to the DNA repair and cell cycle control. The aim of this study was to evaluate if the genetic variants in SLC22A1 rs622342 and ATM rs11212617 could be effective predictors of islet function improvement in patients with type 2 diabetes mellitus (T2DM) on metformin treatment.MethodsThis cross-sectional study included 111 patients with T2DM treated with metformin. Genotyping was performed by the dideoxy chain-termination method. The homeostatic indexes of IR (HOMA-IR) and beta-cell function (HOMA-BCF) were determined according to the homeostasis model assessment.ResultsFasting plasma glucose (FPG) levels, HbA1c levels, and HOMA-IR were significantly higher in patients with the rs622342 AA genotype than in those with C allele (P < 0.05). However, these significant differences were not observed between rs11212617 genotype groups. Further data analysis revealed that the association between the rs622342 polymorphism and HOMA-IR was gender related, and so was rs11212617 polymorphism and HOMA-BCF. HOMA-IR was significantly higher in males with rs622342 AA genotype than in those with C allele (P=0.021), and HOMA-BCF value was significantly higher in females carrying rs11212617 CC genotype than in those with A allele (P=0.038). The common logarithm (Lg10) of HOMA-BCF was positively correlated with the reciprocal of HbA1c (r = 0.629, P < 0.001) and negatively associated with Lg10 FPG (r = -0.708, P < 0.001).ConclusionsThe variant of rs622342 could be a predictor of insulin sensitivity in patients with T2DM treated with metformin. The association between the rs622342 polymorphism and HOMA-IR and the association between the rs11212617 polymorphism and HOMA-BCF were both gender related.
| S-EPMC7231067 | biostudies-literature
Project description:Type 2 diabetes mellitus (T2DM) constitutes a major portion of Jordan's disease burden, and incidence rates are rising at a rapid rate. Due to variability in the drug's response between ethnic groups, it is imperative that the pharmacogenetics of metformin be investigated in the Jordanian population. The objective of this study was to investigate the relationship between twenty-one single nucleotide polymorphisms (SNPs) in the SLC22A1, SLC22A2, and SLC22A3 genes and their effects on metformin pharmacogenetics in Jordanian patients diagnosed with type 2 diabetes mellitus. Blood samples were collected from 212 Jordanian diabetics who fulfilled the inclusion criteria, which were then used in SNP genotyping and determination of HbA1c levels. The rs12194182 SNP in the SLC22A3 gene was found to have a significant association (p < 0.05) with lower mean HbA1c levels, and this association more pronounced in patients with the CC genotype (i.e., p-value was significant before correcting for multiple testing). Moreover, the multinomial logistic regression analysis showed that SNP genotypes within the SLC22A1, SLC22A2, and SLC22A3 genes, body mass index (BMI) and age of diagnosis were significantly associated with glycemic control (p < 0.05). The results of this study can be used to predict response to metformin and other classes of T2DM drugs, making treatment more individualized and resulting in better clinical outcomes.
| S-EPMC6462993 | biostudies-literature
Project description:Since the treatment outcome with oral anti-diabetics differs between individuals, the objective of this study is to evaluate the significance of rs622342 in SLC22A1, CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910) with regard to the efficacy of metformin/sulfonylurea combination therapy in individuals with type 2 diabetes mellitus (T2DM). Eighty-eight Lebanese individuals with T2DM received metformin/sulfonylurea combination therapy over 3 and 6 months. The clinical and biochemical characteristics were collected. Genotyping of rs622342 in SLC22A1, CYP2C9*2 and CYP2C9*3 was performed using hybridization probes on real-time polymerase chain reaction (PCR) instrument. Statistical analysis was performed using SPSS 22.0. The levels of fasting blood sugar (FBS) and glycated hemoglobin (HbA1c) showed a statistically significant reduction over 3 and 6 months of follow-up (p < 0.001). An interaction between rs622342 in SLC22A1, CYP2C9*2 and CYP2C9*3 (p = 0.035) was found associated with reduced levels of HbA1c levels after 3 and 6 months. A significant difference between the means of HbA1c was observed among the different groups after 3 and 6 months (p = 0.004 and p < 0.001, respectively). The most beneficial group was; AA and AC, *1*3, whereas the individuals that benefited the least were CC, *1*3 at 3 and 6 months. In contrast to HbA1c, no interaction was found between the three polymorphisms to affect FBS (p = 0.581). The combination of metformin/sulfonylurea therapy led to the maximum glycemic control in individuals with T2DM carrying AA or AC genotypes in SLC22A1 and *1*3 in CYP2C9.
| S-EPMC7354490 | biostudies-literature
Project description:Background: The incidence of Type 2 Diabetes Mellitus (T2DM) in Egypt is considered one of the highest in the world. Metformin and Sulfonylureas are usually prescribed together due to their efficacy and their relatively low cost. Organic cation transport 1, encoded by SLC22A1 gene, is the main transporter of metformin into hepatocytes, which is considered metformin site of action. Sulfonylureas enhance insulin release from pancreatic B-cells through binding to sulfonylurea receptor 1, encoded by ABCC8 gene. Single nucleotide polymorphisms in the SLC22A1 and ABCC8 genes might affect the response of each drug. Aims: To investigate the influence of SLC22A1 rs622342 (A>C) and ABCC8 rs757110 (A>C) genetic variants on the efficacy of metformin and glimepiride combination therapy in Egyptian T2DM patients. Methods: Observational cross-sectional study in which patients receiving metformin and glimepiride combination therapy for at least 6 months were included for genotyping and classified into either responders or non-responders, based on their HbA1C level. Results: A total of 127 patients were included and genotyped. They were divided into 93 responders (HbA1C<7%) and 34 non-responders (HbA1C≥7%). Minor allele frequencies for rs622342 and rs757110 were 0.189 and 0.271, respectively. Only SLC22A1 rs622342 variant was found to be associated with the response of combination therapy, in which AA alleles carriers were 2.7-times more responsive to metformin than C allele carriers (Recessive model, odds ratio = 2.718, p = 0.025, 95% CI = 1.112-6.385). Conclusion: Genotyping of rs622342 can be useful in predicting the response to metformin in combination therapy in Egyptian T2DM patients.
| S-EPMC6566583 | biostudies-literature
Project description:Background: In Mexico, 75% of diabetes mellitus type 2 (DMT2) patients are not in glycaemic control criteria (HbA1c<7%); this entails a significantly variable drug response. Amongst the factors influencing such variability, are genetics, more specifically, single nucleotide polymorphisms (SNPs). Three genes implied in metformin pharmacokinetics are SLC22A1, SLC22A2, and SLC22A3, which are polymorphic. While there have been cross-sectional studies on their SNPs impact over drug response, a longitudinal study would contribute valuable information on their effect over time. Methods: SNPs of SLC22A1 (rs72552763, rs622342, rs12208357, rs2282143, rs594709, rs628031, and rs683369), SLC22A2 (rs316019), and SLC22A3 (rs2076828), were determined through PCR-TR. The clinical records of 69 patients undergoing metformin monotherapy were retrospectively assessed. Metformin is the first line treatment against DMT2. A level of HbA1c <7% (time 0) was considered as an inescapable inclusion criterion. The study's cases were those patients who reported HbA1c ≥ 7% (time1) after time 0 (t0). Kaplan-Meier curves including a Log-Rank test and a Cox multivariate analysis of proportional risks were performed. Aim: Determining clinical, biochemical, and genetic variables which may affect non-control (HbA1c ≥ 7%) survival time spans amongst DMT2 Mexican-Mestizo patients undergoing metformin monotherapy at Hospital Regional de Alta Especialidad de Ixtapaluca (HRAEI) between October 2013 and December 2023. Results: All 69 patients were monitored over a median period of 642 days (273-1,134). A comparison between time 0 and time 1 (t1) revealed differences in weight (p = 0.036), metformin dose mg/kg/day (p = 0.003), plasmatic glucose mg/dL (p = 0.048), and HbA1c (p < 0.001). The median non-control survival rate was different across the 3 genotypes of rs62552763 in SLC22A1 (p = 0.0034) and the dominant genotypic model GAT/GAT vs. GAT/del + del/del (p = 0.009). There were differences between rs622342 genotypes as well (p = 0.041). In GAT/GAT the Cox model found HR = 0.407 (IC95%: 0.202-0.818, p = 0.011) in the univariate analysis and HR = 0.418 (IC95%: 0.204-0.856, p = 0.034) in the multivariate analysis, adjusted by initial metformin dose (mg/kg/day), initial weight (kg), and final metformin dose (mg/kg/day). Genotype A/A of rs622342 in SLC22A1, reported HR = 0.392 (IC95%: 0.169-0.910, p = 0.029) in the multivariate analysis as well. Conclusion: Among DMT2 Mexican-Mestizo patients undergoing metformin monotherapy the minor allele del in rs72552763 and the minor allele C in rs622342 reported a significantly shorter survival median respect to the wild type variant. Patients carrying del in rs72552763 or C in rs622342, both in SLC22A1, will reach non-control in less time with respect to other patients. Therefore these genotypes may constitute a therapeutic response biomarker for this population.
| S-EPMC11471661 | biostudies-literature
Project description:IntroductionAlu hypomethylation is a common epigenetic process that promotes genomic instability with aging phenotypes, which leads to type 2 diabetes mellitus (type 2 DM). Previously, our results showed significantly decreased Alu methylation levels in type 2 DM patients. In this study, we aimed to investigate the longitudinal changes in Alu methylation levels in these patients.ResultsWe observed significantly decreased Alu methylation levels in type 2 DM patients compared with normal (p = 0.0462). Moreover, our findings demonstrated changes in Alu hypomethylation over a follow-up period within the same individuals (p < 0.0001). A reduction in Alu methylation was found in patients with increasing HbA1c levels (p = 0.0013) and directly correlated with increased HbA1c levels in type 2 DM patients (r = -0.2273, p = 0.0387).ConclusionsAlu methylation in type 2 DM patients progressively decreases with increasing HbA1c levels. This observation suggests a potential association between Alu hypomethylation and the underlying molecular mechanisms of elevated blood glucose. Furthermore, monitoring Alu methylation levels may serve as a valuable biomarker for assessing the clinical outcomes of type 2 DM.
| S-EPMC10623537 | biostudies-literature
Project description:OBJECTIVES: To investigate whether younger patients with type 2 diabetes mellitus have higher glycated hemoglobin A1c (HbA1c) levels compared to older patients, and to determine the factors associated with higher HbA1c levels. METHODS: Data from 1,266 patients from all over Oman were used to obtain the mean HbA1c level, odds ratios (OR), and 95% confidence intervals (CI) from multiple logistic regression models with age groups, sex, duration of diabetes, diabetes treatment, body mass index, estimated glomerular filtration rate (eGFR), tobacco use, and healthcare index as predictors of good (HbA1c <7%) vs. poor (≥7%) glycemic control. RESULTS: Mean HbA1c levels were 8.9, 8.3, and 7.8 in the age groups 20-39, 40-59 and 60+ years, respectively. After controlling for all other covariates, the OR of good glycemic control increased with age, 40-59 years old (OR=1.7; 95% CI 1.1 to 2.6) and 60+ year (OR=2.5; 95% CI 1.6 to 4.0), female gender (OR=1.5; 95% CI 1.2 to 2.0) and in patients with eGFR ≥60 mL/min/1.73 m(2) (OR=1.9; 95% CI 1.1 to 3.3). Longer duration of diabetes (≥5 years) and treatment with oral agents or insulin were inversely related to good glycemic control. CONCLUSION: Younger Omani adults exhibit worse glycemic levels compared to older adults posing a formidable challenge to diabetes care teams.
| S-EPMC3515045 | biostudies-other
Project description:Diabetes mellitus and metabolic syndrome are closely linked with visceral body composition, but clinical assessment is limited to external measurements and laboratory values including hemoglobin A1c (HbA1c). Modern deep learning and AI algorithms allow automated extraction of biomarkers for organ size, density, and body composition from routine computed tomography (CT) exams. Comparing visceral CT biomarkers across groups with differing glycemic control revealed significant, progressive CT biomarker changes with increasing HbA1c. For example, in the unenhanced female cohort, mean changes between normal and poorly-controlled diabetes showed: 53% increase in visceral adipose tissue area, 22% increase in kidney volume, 24% increase in liver volume, 6% decrease in liver density (hepatic steatosis), 16% increase in skeletal muscle area, and 21% decrease in skeletal muscle density (myosteatosis) (all p < 0.001). The multisystem changes of metabolic syndrome can be objectively and retrospectively measured using automated CT biomarkers, with implications for diabetes, metabolic syndrome, and GLP-1 agonists.
| S-EPMC11413398 | biostudies-literature
Project description:AimsTo investigate the effect of serotonin transporter (5-HTT) polymorphisms on change in HbA1c levels six months after metformin initiation in type 2 diabetes patients.Materials and methodsParticipants of PROVALID (PROspective cohort study in patients with type 2 diabetes mellitus for VALidation of biomarkers) within the GIANTT (Groningen Initiative to ANalyse Type 2 Diabetes Treatment) cohort who initiated metformin were genotyped for combined 5-HTTLPR/rs25531 (L∗L∗, L∗S∗, and S∗S∗) and 5-HTT VNTR (STin 2.12, 12/-, and 10/-) polymorphisms, respectively. Multiple linear regression was applied to determine the change in HbA1c level from baseline date to six months across 5-HTTLPR/VNTR genotype groups, adjusted for baseline HbA1c, age, gender, triglyceride level, low-density lipoprotein level, and serum creatinine.Results157 participants were included, of which 56.2% were male. The average age was 59.3 ± 9.23 years, and the mean baseline HbA1c was 7.49% ± 1.21%. 5-HTTLPR was characterized in 46 patients as L∗L∗, 70 patients as L∗S∗, and 41 patients as S∗S∗ genotypes. No significant association was found between 5-HTTLPR and 5-HTT VNTR genotypes and change in HbA1c after adjustments.Conclusions5-HTT polymorphisms did not affect HbA1c levels six months after the start of metformin. Further long-term studies in large samples would be relevant to determine which polymorphisms can explain the variation in response to metformin treatment.
| S-EPMC10824573 | biostudies-literature
Project description:BackgroundThe rapid increase in prevalence of diabetes mellitus over the last decades warrants more attention to the effects of environmental and occupational exposures on glucose metabolism. Our study aimed to assess the association between the plasma levels of various congeners of polychlorinated biphenyls (PCBs) and the serum concentration of glycated haemoglobin (HbA1c).MethodsOur study population consisted of 140 Iranian adults from seven different occupational groups and a group of non-occupationally exposed female participants. The plasma concentration of PCBs were determined at the laboratory of occupational toxicology at RWTH Aachen University, Germany. We considered an HbA1c concentration of 5.7% and more as indicating a disturbed glucose metabolism. Logistic regression was used to assess the association between quartiles of concentrations of PCB congeners and serum HbA1c.ResultsParticipants with an increased HbA1c value had higher plasma levels of PCB 138, 153, 180 and the PCB sum, although this association was statistically not significant. There was no significant difference between the levels of PCB 138, 153, 180, the sum of these congeners, and PCB 118 in their quartiles when comparing with HbA1c concentrations.ConclusionsFor our cohort, we could not demonstrate a significant association between PCB and HbA1c concentrations indicating a disturbance of glucose metabolism.
| S-EPMC5984357 | biostudies-literature