Metabolomic analysis of healthy human urine following administration of glimepiride using a liquid chromatography-tandem mass spectrometry

Abstract

Glimepiride, a third generation sulfonylurea, is an antihyperglycemic agent widely used to treat type 2 diabetes mellitus. In this study, an untargeted urinary metabolomic analysis was performed to identify endogenous metabolites affected by glimepiride administration. Urine samples of twelve healthy male volunteers were collected before and after administration of 2 mg glimepiride. These samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and then subjected to multivariate data analysis including principal component analysis and orthogonal partial least squares discriminant analysis. Through this metabolomic profiling, we identified several endogenous metabolites such as adenosine 3', 5'-cyclic monophosphate (cAMP), quercetin, tyramine, and urocanic acid, which exhibit significant metabolomic changes between pre-and posturine samples. Among these, cAMP, which is known to be related to insulin secretion, was the most significantly altered metabolite following glimepiride administration. In addition, the pathway analysis showed that purine, tyrosine, and histidine metabolism was affected by pharmacological responses to glimepiride. Together, the results suggest that the pharmacometabolomic approach, based on LC-MS/MS, is useful in understanding the alterations in biochemical pathways associated with glimepiride action.

Understanding glycaemic control and current approaches for screening antidiabetic natural products from evidence-based medicinal plants

“…To date, metabolomics-based approaches have become increasingly applied to all aspects of diabetes research. Recent literature shows that metabolomics has been applied to biomarker and drug discovery, drug assessment [259, 260], toxicology [261, 262], and clinical biochemistry with a particular focus on gestational diabetes mellitus (GDM) [263–270]. Some of the recent metabolomics-aided discoveries in antidiabetic plant research are summarised below.…”

“…An LC–MS n -based profiling of urine samples showed that the sulfonylurea drug glimepiride caused a reduction in the levels of cyclic adenosine monophosphate (cAMP) in urine indicating that glimepiride affects cAMP. cAMP is a secondary messenger important for insulin secretion as well as the metabolism of the amino acids: purine, tyrosine and histidine [259]. This suggested that cAMP can be a potential target for anti-diabetic therapy, and that protein metabolism abnormalities can be expected as a side-effect of glimepiride.…”

Statistical methods and resources for biomarker discovery using metabolomics

“…PLS-DA attempts for optimal break-down of predictor variable X to best explain the response variable Y [73,78,79]. An upgraded version of PLS-DA called OPLS-DA ("orthogonal" PLS-DA) has also gained popularity [80][81][82][83][84]. This model recapitulates the variance into parts that are predictive of the experimental groups and parts that are purely due to noise, also referred to as 'orthogonal' [85][86][87].…”

Analytical tools for urocanic acid determination in human samples: A review

“…Several endogenous metabolites, such as UCA, were found to change between pre‐ and posturine samples. The data suggested that the pharmacometabolomic approach using LC‐MS/MS was useful to understand the biochemical changes caused by glimepiride use [47].…”