Pharmacometabolomic Approach to Investigate the Response to Metformin in Patients with Type 2 Diabetes: A Cross-Sectional Study

Abstract

Metformin constitutes the foundation therapy in type 2 diabetes (T2D). Despite its multiple beneficial effects and widespread use, there is considerable inter-individual variability in response to metformin. Our objective is to identify metabolic signatures associated with poor and good responses to metformin, which may improve our ability to predict outcomes for metformin treatment. In this cross-sectional study, clinical and metabolic data for 119 patients with type 2 diabetes taking metformin were collected from the Qatar Biobank. Patients were empirically dichotomized according to their HbA1C levels into good and poor responders. Differences in the level of metabolites between these two groups were compared using orthogonal partial least square discriminate analysis (OPLS-DA) and linear models. Good responders showed increased levels of sphingomyelins, acylcholines, and glutathione metabolites. On the other hand, poor responders showed increased levels of metabolites resulting from glucose metabolism and gut microbiota metabolites. The results of this study have the potential to increase our knowledge of patient response variability to metformin and carry significant implications for enabling personalized medicine.

Fecal Dysosmobacter spp. concentration is linked to plasma lipidome in insulin-resistant individuals with overweight, obesity and metabolic syndrome

“…Despite their presence in circulation, the role of plasma acylcholines in metabolic syndrome remains largely unexplored. In a 2023 Qatari cohort of individuals with T2D treated with metformin, palmitoylcholine and arachidonoylcholine were associated with a better treatment response (36). This is particularly intriguing given that a previous study from our lab demonstrated an increased abundance of Dysosmobacter spp in metformin-treated diabetic individuals.…”

Fecal Dysosmobacter spp. concentration is linked to plasma lipidome in insulin-resistant individuals with overweight, obesity and metabolic syndrome

“…Despite their presence in circulation, the role of plasma acylcholines in metabolic syndrome remains largely unexplored. In a 2023 Qatari cohort of individuals with T2D treated with metformin, palmitoylcholine and arachidonoylcholine were associated with a better treatment response (36). This is particularly intriguing given that a previous study from our lab demonstrated an increased abundance of Dysosmobacter spp in metformin-treated diabetic individuals.…”

Metformin Treatment Potentially Modifies Genetically Driven Metabolite-HbA1c Associations: A Gene–Environment Interaction Mendelian Randomization Study

“…Glycine and glutamine–glutamate metabolism have been shown to consistently and negatively correlate with T2D [ 19 ], as studies have shown that individuals who are insulin resistant or have impaired glucose metabolism have lower levels of circulating glycine and glutamine [ 20 , 21 ] and elevated glutamate levels [ 22 ]. Our previous study also demonstrated that higher glycine and glutamine levels and lower glutamate levels are associated with a good response to metformin among T2D individuals [ 6 ]. In this study, while the genetically influenced glycine shows a protective basal association with HbA1c; however, the interaction term shows a strong positive causal effect among metformin users.…”

“…The metabolites demonstrating significant PRS-metformin interaction effects gather within metabolic pathways that have well-established links to glucose metabolism, insulin sensitivity, and amino acid pathways that are relevant in metformin’s mechanism of action [ 6 ]. Glycine and glutamine–glutamate metabolism have been shown to consistently and negatively correlate with T2D [ 19 ], as studies have shown that individuals who are insulin resistant or have impaired glucose metabolism have lower levels of circulating glycine and glutamine [ 20 , 21 ] and elevated glutamate levels [ 22 ].…”

“…The formula used in this analysis was adopted from a previously published study of MR-G×E [ 16 ]. Our previous study has shown 44 metabolites associated with HbA1c in T2D patients treated with metformin [ 6 ]. The primary focus of this analysis was to investigate the potential causal relationships between SNP-associated metabolites, considering metabolite levels as the exposure and HbA1c as the outcome in metformin users and non-users (binary).…”

Pharmacometabolomics of sulfonylureas in patients with type 2 diabetes: a cross-sectional study

“…Functional enrichment analysis was performed on all nominally significant metabolites using Wilcoxon sum of ranks test and was followed by p -value adjustment using FDR method. Additional details of the statistical analysis has previously been provided [ 17 ].…”

Fecal Dysosmobacter spp. concentration is linked to plasma lipidome in insulin-resistant individuals with overweight, obesity and metabolic syndrome

“…Despite their presence in circulation, the role of plasma acylcholines in metabolic syndrome remains largely unexplored. In a 2023 Qatari cohort of individuals with T2D treated with metformin, palmitoylcholine and arachidonoylcholine were associated with a better treatment response (36). This is particularly intriguing given that a previous study from our lab demonstrated an increased abundance of Dysosmobacter spp in metformin-treated diabetic individuals.…”

Metformin Treatment Potentially Modifies Genetically Driven Metabolite-HbA1c Associations: A Gene–Environment Interaction Mendelian Randomization Study

“…Glycine and glutamine–glutamate metabolism have been shown to consistently and negatively correlate with T2D [ 19 ], as studies have shown that individuals who are insulin resistant or have impaired glucose metabolism have lower levels of circulating glycine and glutamine [ 20 , 21 ] and elevated glutamate levels [ 22 ]. Our previous study also demonstrated that higher glycine and glutamine levels and lower glutamate levels are associated with a good response to metformin among T2D individuals [ 6 ]. In this study, while the genetically influenced glycine shows a protective basal association with HbA1c; however, the interaction term shows a strong positive causal effect among metformin users.…”

“…The metabolites demonstrating significant PRS-metformin interaction effects gather within metabolic pathways that have well-established links to glucose metabolism, insulin sensitivity, and amino acid pathways that are relevant in metformin’s mechanism of action [ 6 ]. Glycine and glutamine–glutamate metabolism have been shown to consistently and negatively correlate with T2D [ 19 ], as studies have shown that individuals who are insulin resistant or have impaired glucose metabolism have lower levels of circulating glycine and glutamine [ 20 , 21 ] and elevated glutamate levels [ 22 ].…”

“…The formula used in this analysis was adopted from a previously published study of MR-G×E [ 16 ]. Our previous study has shown 44 metabolites associated with HbA1c in T2D patients treated with metformin [ 6 ]. The primary focus of this analysis was to investigate the potential causal relationships between SNP-associated metabolites, considering metabolite levels as the exposure and HbA1c as the outcome in metformin users and non-users (binary).…”

Pharmacometabolomics of sulfonylureas in patients with type 2 diabetes: a cross-sectional study

“…Functional enrichment analysis was performed on all nominally significant metabolites using Wilcoxon sum of ranks test and was followed by p -value adjustment using FDR method. Additional details of the statistical analysis has previously been provided [ 17 ].…”

Fecal Dysosmobacter spp. concentration is linked to plasma lipidome in insulin-resistant individuals with overweight, obesity and metabolic syndrome

“…Despite their presence in circulation, the role of plasma acylcholines in metabolic syndrome remains largely unexplored. In a 2023 Qatari cohort of individuals with T2D treated with metformin, palmitoylcholine and arachidonoylcholine were associated with a better treatment response (36). This is particularly intriguing given that a previous study from our lab demonstrated an increased abundance of Dysosmobacter spp in metformin-treated diabetic individuals.…”

Metformin Treatment Potentially Modifies Genetically Driven Metabolite-HbA1c Associations: A Gene–Environment Interaction Mendelian Randomization Study

“…Glycine and glutamine–glutamate metabolism have been shown to consistently and negatively correlate with T2D [ 19 ], as studies have shown that individuals who are insulin resistant or have impaired glucose metabolism have lower levels of circulating glycine and glutamine [ 20 , 21 ] and elevated glutamate levels [ 22 ]. Our previous study also demonstrated that higher glycine and glutamine levels and lower glutamate levels are associated with a good response to metformin among T2D individuals [ 6 ]. In this study, while the genetically influenced glycine shows a protective basal association with HbA1c; however, the interaction term shows a strong positive causal effect among metformin users.…”

“…The metabolites demonstrating significant PRS-metformin interaction effects gather within metabolic pathways that have well-established links to glucose metabolism, insulin sensitivity, and amino acid pathways that are relevant in metformin’s mechanism of action [ 6 ]. Glycine and glutamine–glutamate metabolism have been shown to consistently and negatively correlate with T2D [ 19 ], as studies have shown that individuals who are insulin resistant or have impaired glucose metabolism have lower levels of circulating glycine and glutamine [ 20 , 21 ] and elevated glutamate levels [ 22 ].…”

“…The formula used in this analysis was adopted from a previously published study of MR-G×E [ 16 ]. Our previous study has shown 44 metabolites associated with HbA1c in T2D patients treated with metformin [ 6 ]. The primary focus of this analysis was to investigate the potential causal relationships between SNP-associated metabolites, considering metabolite levels as the exposure and HbA1c as the outcome in metformin users and non-users (binary).…”

Pharmacometabolomics of sulfonylureas in patients with type 2 diabetes: a cross-sectional study

“…Functional enrichment analysis was performed on all nominally significant metabolites using Wilcoxon sum of ranks test and was followed by p -value adjustment using FDR method. Additional details of the statistical analysis has previously been provided [ 17 ].…”