Epigenetic markers associated with metformin response and intolerance in drug-naïve patients with type 2 diabetes

Abstract

Metformin is the first-line pharmacotherapy for managing type 2 diabetes (T2D). However, many patients with T2D do not respond to or tolerate metformin well. Currently, there are no phenotypes that successfully predict glycemic response to, or tolerance of, metformin. We explored whether blood-based epigenetic markers could discriminate metformin response and tolerance by analyzing genome-wide DNA methylation in drug-naïve patients with T2D at the time of their diagnosis. DNA methylation of 11 and 4 sites differed between glycemic responders/nonresponders and metformin-tolerant/intolerant patients, respectively, in discovery and replication cohorts. Greater methylation at these sites associated with a higher risk of not responding to or not tolerating metformin with odds ratios between 1.43 and 3.09 per 1-SD methylation increase. Methylation risk scores (MRSs) of the 11 identified sites differed between glycemic responders and nonresponders with areas under the curve (AUCs) of 0.80 to 0.98. MRSs of the 4 sites associated with future metformin intolerance generated AUCs of 0.85 to 0.93. Some of these blood-based methylation markers mirrored the epigenetic pattern in adipose tissue, a key tissue in diabetes pathogenesis, and genes to which these markers were annotated to had biological functions in hepatocytes that altered metformin-related phenotypes. Overall, we could discriminate between glycemic responders/nonresponders and participants tolerant/intolerant to metformin at diagnosis by measuring blood-based epigenetic markers in drug-naïve patients with T2D. This epigenetics-based tool may be further developed to help patients with T2D receive optimal therapy.

DNA Methylation and Type 2 Diabetes: Novel Biomarkers for Risk Assessment?

“…These biomarkers are only useful after the disease onset. In addition, CpG methylation markers may represent a powerful tool for the early detection of T2D complications [68,69] and for the stratification of drug-naïve patients with T2D in responders/non-responders to glycemic-lowering mediations [122,123].…”

“…In 2020, García-Calzón et al investigated the hypothesis that blood-based epigenetic markers may discriminate response and tolerance to metformin therapy in T2D patients [122]. In this effort, genome-wide DNA methylation was analyzed in three different cohorts of drug-naïve patients with T2D at the time of diagnosis.…”

Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area

“…The authors remarked that the methylation pattern of these sites in blood met the methylation pattern in adipose tissue, suggesting that the identified epigenetic changes might also regard metabolically relevant tissues for type 2 diabetes. Finally, the authors showed that silencing five genes annotated to the identified sites significantly altered the expression of metformin transporter genes and genes coding for gluconeogenetic enzymes in cultured hepatocytes, further supporting a link to the pharmacology of metformin [ 122 ].…”

“…Apart from directly targeting a number of metabolic enzymes and transporters, such as glucose transporters GLUT1 and GLUT4, glycogen synthase (GS), acetyl-CoA carboxylase (ACC), and hydroxymethylglutaryl-CoA reductase (HMGCR), AMPK also regulates cell metabolism at the transcriptional level by phosphorylating sterol regulatory element-binding protein 1 (SREBP1), ChREBP, PGC-1α, and transcription factor forkhead box O3 (FOXO3) [ 7 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , …”

From Pharmacogenetics to Gene Expression: Implications for Precision Medicine in Diabetes

“…The A/A genotype carriers had lower methylation (83.6 AE 2.3%) compared to carriers of the G/G (85.3 AE 1.9%, P = 0.002) and G/A (85 AE 1.8%, P = 0.006) genotypes in 132 participants from the discovery and replication cohorts. Lower methylation of this CpG site was associated with a better glycemic response to metformin (Table 2) [129]. In previous work from the same group, they assessed the DNA methylation in OCT1 encoded by SLC22A1, OCT3 encoded by SLC22A3, and MATE1 encoded by SLC47A1 liver biopsies from gastric bypass surgery.…”