NMR metabolomics identifies over 60 biomarkers associated with Type II Diabetes impairment in db/db mice

Abstract

Introduction The rapid expansion of Type 2 Diabetes (T2D), that currently affects 90% of people suffering from diabetes, urges us to develop a better understanding of the metabolic processes involved in the disease process in order to develop better therapies. The most commonly used model for T2D research is the db/db (BKS.Cg-Dock7 < m > +/+ Lepr < db >/J) mouse model. Yet, a systematic 1 H NMR based metabolomics characterisation of most tissues in this animal model has not been published. Here, we provide a systematic organ-specific metabolomics analysis of this widely employed model using NMR spectroscopy. Objectives The aim of this study was to characterise the metabolic modulations associated with T2D in db/db mice in 18 relevant biological matrices. Methods High-resolution 1 H-NMR and 2D-NMR spectroscopy were applied to 18 biological matrices of 12 db/db mice (WT control n = 6, db/db = 6) aged 22 weeks, when diabetes is fully established. Results 61 metabolites associated with T2D were identified. Kidney, spleen, eye and plasma were the biological matrices carrying the largest metabolomics modulations observed in established T2D, based on the total number of metabolites that showed a statistical difference between the diabetic and control group in each tissue (16 in each case) and the strength of the O-PLS DA model for each tissue. Glucose and glutamate were the most commonly associated metabolites found significantly increased in nine biological matrices. Investigated sections where no increase of glucose was associated with T2D include all intestinal segments (i.e. duodenum, jejunum, ileum and colon). Microbial co-metabolites such as acetate and butyrate, used as carbon sources by the host, were identified in excess in the colonic tissues of diabetic individuals. Conclusions The metabolic biomarkers identified using 1 H NMR-based metabolomics will represent a useful resource to explore metabolic pathways involved in T2D in the db/db mouse model. Electronic supplementary material The online version of this article (10.1007/s11306-019-1548-8) contains supplementary material, which is available to authorized users.

A comparison of high-throughput plasma NMR protocols for comparative untargeted metabolomics

“…The technique has inherent quantitative capabilities (Nagana Gowda et al 2018), high reproducibility, requires minimal sample preparation, is non-destructive for samples and offers the possibility for compound identification by structure elucidation, all essential characteristics for biomarker discovery (Gowda et al 2008). Although NMR spectroscopy is limited by low sensitivity compared to mass spectrometry (Gowda et al 2008) as well as signal overlap in spectra, it continues to find widespread applications (Cheng et al 2019;Mora-Ortiz et al 2019;Turkoglu et al 2019;Yousf et al 2019). When applied to plasma, a number of considerations should be made in regard to its performance in metabolome profiling with respect to optimal sample group separation that can be explained by a solid biochemical background.…”

Dietary obesity in mice is associated with lipid deposition and metabolic shifts in the lungs sharing features with the liver

“…This question was raised by Mora-Ortiz et al . who examined db/db mice organs 25 , a natural genetic model of obesity and also reported a decrease of 1C related metabolite in many organs (a glycine decrease in kidneys and distal colon; a homoserine decrease in liver and plasma; a serine decrease in brain, kidney and spleen). Unfortunately, they did not include lung in their study.…”

Detection of Early Disease Risk Factors Associated with Metabolic Syndrome: A New Era with the NMR Metabolomics Assessment

“…In a project characterizing biomarkers associated with T2D in eighteen biological matrices in db/db mouse model, allantoin was elevated in urine and plasma [26]. In other study characterizing the urine metabolome between lean and overweight dogs during a feed-challenge, overweight dogs had higher postprandial allantoin concentrations compared with lean dogs [76]. However, there is a need for more studies in humans and NMR approaches, because the evidence of the association in several animal studies should be confirmed with clinical studies.…”