Proposal and confirmation of N-(2-carboxyethyl)proline as a human endogenous metabolite.

Rationale: Malondialdehyde, one of the peroxidation products of polyunsaturated fatty acids, has been widely reported as an oxidative stress biomarker in many diseases. However, malondialdehyde is inherently unstable in biological matrices, which renders its measurement unreliable with all the reported analytical methods. To find an alternative oxidative stress biomarker, we envisioned that N-(2-carboxyethyl)proline, a modified conjugate of malondialdehyde and proline, could be a stable candidate for this purpose.

LC-MS/MS method with chemical derivatization for quantitation of L-threonate in human plasma.

An LC-MS/MS-based bioanalytical method has been developed to measure the concentration of L-threonate at its endogenous level in human plasma. Following isotope dilution and protein precipitation, the samples were acetylated and chromatographed under reversed-phase conditions for baseline separation of the derivatized L-threonate and its stereoisomer D-erythronate. The method was assessed by a fit-for-purpose validation with a calibration range from 100 to 10,000 ng/mL.

A novel insulin resistance index to monitor changes in insulin sensitivity and glucose tolerance: the ACT NOW study.

Objective: The objective was to test the clinical utility of Quantose M(Q) to monitor changes in insulin sensitivity after pioglitazone therapy in prediabetic subjects. Quantose M(Q) is derived from fasting measurements of insulin, α-hydroxybutyrate, linoleoyl-glycerophosphocholine, and oleate, three nonglucose metabolites shown to correlate with insulin-stimulated glucose disposal.

Research Design And Methods: Participants were 428 of the total of 602 ACT NOW impaired glucose tolerance (IGT) subjects randomized to pioglitazone (45 mg/d) or placebo and followed for 2.

A novel test for IGT utilizing metabolite markers of glucose tolerance.

The oral glucose tolerance test (OGTT) is the only method to diagnose patients having impaired glucose tolerance (IGT), but its use has diminished considerably in recent years. Metabolomic profiling studies have identified a number of metabolites whose fasting levels are associated with dysglycemia and type 2 diabetes. These metabolites may serve as the basis of an alternative test for IGT.

Cysteine catabolism: a novel metabolic pathway contributing to glioblastoma growth.

The relevance of cysteine metabolism in cancer has gained considerable interest in recent years, largely focusing on its role in generating the antioxidant glutathione. Through metabolomic profiling using a combination of high-throughput liquid and gas chromatography-based mass spectrometry on a total of 69 patient-derived glioma specimens, this report documents the discovery of a parallel pathway involving cysteine catabolism that results in the accumulation of cysteine sulfinic acid (CSA) in glioblastoma. These studies identified CSA to rank as one of the top metabolites differentiating glioblastoma from low-grade glioma.

Metabolomic signatures of aggressive prostate cancer.

Background: Current diagnostic techniques have increased the detection of prostate cancer; however, these tools inadequately stratify patients to minimize mortality. Recent studies have identified a biochemical signature of prostate cancer metastasis, including increased sarcosine abundance. This study examined the association of tissue metabolites with other clinically significant findings.

A novel fasting blood test for insulin resistance and prediabetes.

Background: Insulin resistance (IR) can precede the dysglycemic states of prediabetes and type 2 diabetes mellitus (T2DM) by a number of years and is an early marker of risk for metabolic and cardiovascular disease. There is an unmet need for a simple method to measure IR that can be used for routine screening, prospective study, risk assessment, and therapeutic monitoring. We have reported several metabolites whose fasting plasma levels correlated with insulin sensitivity.

Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes.

Circulating metabolites associated with insulin sensitivity may represent useful biomarkers, but their causal role in insulin sensitivity and diabetes is less certain. We previously identified novel metabolites correlated with insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. The top-ranking metabolites were in the glutathione and glycine biosynthesis pathways.

Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats.

Drug-induced liver injury (DILI) is a significant consideration for drug development. Current preclinical DILI assessment relying on histopathology and clinical chemistry has limitations in sensitivity and discordance with human. To gain insights on DILI pathogenesis and identify potential biomarkers for improved DILI detection, we performed untargeted metabolomic analyses on rats treated with thirteen known hepatotoxins causing various types of DILI: necrosis (acetaminophen, bendazac, cyclosporine A, carbon tetrachloride, ethionine), cholestasis (methapyrilene and naphthylisothiocyanate), steatosis (tetracycline and ticlopidine), and idiosyncratic (carbamazepine, chlorzoxasone, flutamide, and nimesulide) at two doses and two time points.

Early metabolic markers of the development of dysglycemia and type 2 diabetes and their physiological significance.

Metabolomic screening of fasting plasma from nondiabetic subjects identified α-hydroxybutyrate (α-HB) and linoleoyl-glycerophosphocholine (L-GPC) as joint markers of insulin resistance (IR) and glucose intolerance. To test the predictivity of α-HB and L-GPC for incident dysglycemia, α-HB and L-GPC measurements were obtained in two observational cohorts, comprising 1,261 nondiabetic participants from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) study and 2,580 from the Botnia Prospective Study, with 3-year and 9.5-year follow-up data, respectively.

Ethylene glycol monomethyl ether-induced toxicity is mediated through the inhibition of flavoprotein dehydrogenase enzyme family.

Ethylene glycol monomethyl ether (EGME) is a widely used industrial solvent known to cause adverse effects to human and other mammals. Organs with high metabolism and rapid cell division, such as testes, are especially sensitive to its actions. In order to gain mechanistic understanding of EGME-induced toxicity, an untargeted metabolomic analysis was performed in rats.

alpha-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population.

Background: Insulin resistance is a risk factor for type 2 diabetes and cardiovascular disease progression. Current diagnostic tests, such as glycemic indicators, have limitations in the early detection of insulin resistant individuals. We searched for novel biomarkers identifying these at-risk subjects.

Biosynthesis of the irregular monoterpene artemisia ketone, the sesquiterpene germacrene D and other isoprenoids in Tanacetum vulgare L. (Asteraceae).

The incorporation of [1-13C]-labeled glucose into the irregular monoterpene artemisia ketone, the regular monoterpenes camphor and beta-thujone, the sesquiterpene germacrene D, the diterpene trans-phytol and beta-sitosterol and isofucosterol has been studied in axenic cultures of Tanacetum vulgare L. (Asteraceae). Quantitative 13C NMR spectroscopic analysis of the resulting labeling patterns showed that the isoprene units of the monoterpenes and the diterpene are formed via the methylerythritol phosphate (MEP) pathway, whereas the isoprene building blocks of the sesquiterpene and the sterols originate from the mevalonic acid (MVA) pathway.

Biosynthesis of the sesquiterpene germacrene D in Solidago canadensis: 13C and (2)H labeling studies.

The biogenetic origin of the isoprenoid building blocks of the sesquiterpene germacrene D was studied in Solidago canadensis. Feeding experiments were carried out with 1-[5,5-D(2)]deoxy-D-xylulose-5-phosphate (D(2)-DOXP), [5-13C]mevalonolactone (13C-MVL) and [1-13C]-D-glucose. The hydrodistillate of a cut shoot fed with D(2)-DOXP was investigated by enantio-MDGC-MS and the volatile fraction of a shoot supplied with 13C-MVL was examined by GC-C-IRMS.

Incorporation of [1-(13)C]1-deoxy-D-xylulose into isoprenoids of the liverwort Conocephalum conicum.

The incorporation of (13)C labeled 1-deoxy-D-xylulose into the monoterpene bornyl acetate, the sesquiterpene cubebanol, and the diterpene phytol has been studied in axenic cultures of the liverwort Conocephalum conicum. Quantitative (13)C NMR spectroscopic analysis of the labeling patterns of the sesquiterpene indicated a possible degradation of 1-deoxy-D-xylulose to acetate and subsequent incorporation via the mevalonic acid pathway. In bornyl acetate, the labeling occurred only in the acetate moiety whereas the isoprene units remained unlabelled.