TY - JOUR
T1 - Metformin-mediated modulation of epigenetic regulators in type 2 diabetes
T2 - A study on differential expression of DNMT1, TET1, OGG1, and AID genes
AU - Moeez, Sadaf
AU - Riaz, Syeda Kiran
AU - Qaiser, Tanveer Ahmed
AU - Sarfraz, Juneda
AU - Naseer, Asif
AU - Haque, Shafiul
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025.
PY - 2025
Y1 - 2025
N2 - Type 2 diabetes mellitus (T2DM) is a widespread medical condition characterized by high blood glucose and inadequate insulin action, ultimately leading to insulin resistance. Genetic, epigenetic, and non-genetic factors are known to influence the pathogenesis of T2DM. Epigenetic alterations, principally DNA methylation and demethylation dynamics, play an important role, yet, their molecular mechanisms remain poorly understood. The present study aimed to study the expression patterns of DNMT1, TET1, OGG1, and AID genes involved in epigenetic regulation and insulin resistance in T2DM patients, along with in vitro validation using HepG2 insulin–resistant cell models. Blood samples were collected from 160 T2DM patients, categorized as metformin responders and non-responders, along with 40 healthy controls. Insulin resistance was induced in HepG2 cells, which were then treated with metformin and sulfonylureas at various concentrations and time intervals. qPCR was performed to study the differential expression of DNMT1, TET1, OGG1, and AID genes, using GAPDH as an internal control. Statistical analysis was done using SPSS software. Our results indicate that the expression of DNMT1, TET1, OGG1, and AID was significantly higher in T2DM metformin non-responders compared to T2DM metformin responders (P < 0.0001). Furthermore, we found that metformin treatment led to the down-expression of these genes in insulin-resistant HepG2 cells thus proving their in the regulation of the epigenetics state. This study highlights the contribution of epigenetic mechanisms in the pathogenesis of T2DM and underscores the therapeutic role of metformin in modulating key epigenetic regulators, precisely by altering DNA methylation/demethylation pathways through the regulation of key gene. These findings suggest that DNMT1, TET1, OGG1, and AID may serve as potential biomarkers and therapeutic targets for the management of T2DM.
AB - Type 2 diabetes mellitus (T2DM) is a widespread medical condition characterized by high blood glucose and inadequate insulin action, ultimately leading to insulin resistance. Genetic, epigenetic, and non-genetic factors are known to influence the pathogenesis of T2DM. Epigenetic alterations, principally DNA methylation and demethylation dynamics, play an important role, yet, their molecular mechanisms remain poorly understood. The present study aimed to study the expression patterns of DNMT1, TET1, OGG1, and AID genes involved in epigenetic regulation and insulin resistance in T2DM patients, along with in vitro validation using HepG2 insulin–resistant cell models. Blood samples were collected from 160 T2DM patients, categorized as metformin responders and non-responders, along with 40 healthy controls. Insulin resistance was induced in HepG2 cells, which were then treated with metformin and sulfonylureas at various concentrations and time intervals. qPCR was performed to study the differential expression of DNMT1, TET1, OGG1, and AID genes, using GAPDH as an internal control. Statistical analysis was done using SPSS software. Our results indicate that the expression of DNMT1, TET1, OGG1, and AID was significantly higher in T2DM metformin non-responders compared to T2DM metformin responders (P < 0.0001). Furthermore, we found that metformin treatment led to the down-expression of these genes in insulin-resistant HepG2 cells thus proving their in the regulation of the epigenetics state. This study highlights the contribution of epigenetic mechanisms in the pathogenesis of T2DM and underscores the therapeutic role of metformin in modulating key epigenetic regulators, precisely by altering DNA methylation/demethylation pathways through the regulation of key gene. These findings suggest that DNMT1, TET1, OGG1, and AID may serve as potential biomarkers and therapeutic targets for the management of T2DM.
KW - AID
KW - DNMT1
KW - Epigenetics
KW - OGG1
KW - T2DM
KW - TET1
UR - https://www.scopus.com/pages/publications/105018765082
U2 - 10.1007/s00210-025-04700-z
DO - 10.1007/s00210-025-04700-z
M3 - Artículo
C2 - 41087712
AN - SCOPUS:105018765082
SN - 0028-1298
JO - Naunyn-Schmiedeberg's Archives of Pharmacology
JF - Naunyn-Schmiedeberg's Archives of Pharmacology
ER -
