Metabolomic biomarkers for personalised glucose lowering drugs treatment in type 2 diabetes

Abstract

We aimed to identify metabolites to predict patients’ response to glucose lowering treatment during the first 5 years after detection of type 2 diabetes. Metabolites were measured by GC–MS in baseline samples from 346 screen-detected type 2 diabetes patients in the ADDITION-NL study. The response to treatment with metformin and/or sulphonylurea (SU) was analysed to identify metabolites predictive of 5 year HbA1c change by multiple regression analysis. Baseline glucose and 1,5 anhydro-glucitol were associated with HbA1c decrease in all medication groups. In patients on SU no other metabolite was associated with HbA1c decrease. A larger set of metabolites was associated with HbA1c change in the metformin and the combination therapy (metformin + SU) groups. These metabolites included metabolites related to liver metabolism, such as 2-hydroxybutanoic acid, 3-hydroxybutanoic acid, 2-hydroxypiperidine and 4-oxoproline). Metabolites involved in oxidative stress and insulin resistance were higher when the HbA1c decrease was larger in the metformin/sulphonylurea group. The associations between baseline metabolites and responsiveness to medication are in line with its mode of action. If these results could be replicated in other populations, the most promising predictive candidates might be tested to assess whether they could enhance personalised treatment.

Mechanism by which Metformin Influence Metabolic Changes in Human: A Systematic-Review

“…Glucose reduction (exact percents are not shown) after metformin treatments identified in 3 articles [22][23][24] was significantly associated with glycolysis or gluconeogenesis pathway (p=0.0129) in MetPA homo sapiens group. Metformin lowers blood glucose level by inhibiting glycogenolysis.…”

“…We identified many metabolites according to (1) various disease types (e.g., healthy [22] T2DM [9,[22][23][24][25] [26] (2) diverse number of patients (n=9 to 151); (3) different doses of metformin and its treatment period in the included trials (the shortest treatment period, 12 h and the longest follow-up period, 7 years); and (4) various analytical techniques used to identify metabolites from biological fluids (e.g., gas chromatography mass spectrometry [GC/MS], liquid chromatography mass spectrometry [LC/MS] and nuclear magnetic resonance [NMR]). We evaluated further details in the full-text article and included literature on the "metformin medication" regardless of above all conditions.…”

“…The studies by Henk den Ouden et al [23] and Irving et al [24] examining treatment with metformin alone for 5 years and in combination with pioglitazone for 3 months showed a decrease in the plasma glucose concentration. The results of studies by Henk den Ouden et al [23] Irving et al [24] and Vinaixa et al [26] showed a significant decrease in blood glutamate levels compared to those before treatment.…”

“…The studies by Henk den Ouden et al [23] and Irving et al [24] examining treatment with metformin alone for 5 years and in combination with pioglitazone for 3 months showed a decrease in the plasma glucose concentration. The results of studies by Henk den Ouden et al [23] Irving et al [24] and Vinaixa et al [26] showed a significant decrease in blood glutamate levels compared to those before treatment. Treatment with metformin 850 mg/d, pioglitazone 7.5 mg/d, and flutamide 62.5 mg/d in PCOS showed an approximately 54.0% decrease in glutamate levels [26] and another study indicated a 17.0% decrease [24] in these levels at 3 months follow-up after combination therapy.…”

“…The plasma levels of phenylalanine and tyrosine decreased by 7.76% and 13.0%, respectively [24]. In addition, the results reported by Henk den Ouden et al showed a decrease in the plasma levels of l-phenylalanine [23]. Preiss et al [25] showed that metformin monotherapy in 86 patients with coronary disease for 18 months induced a decrease in the levels of aromatic amino acid metabolites such as tyrosine by 10% and phenylalanine by 4% and an increase in the levels of alanine by approximately 16%.…”