Metabolomics analyses in non-diabetic middle-aged individuals reveal metabolites impacting early glucose disturbances and insulin sensitivity

Maxime M Bos,Raymond Noordam,P Eline Slagboom,Diana Van Heemst,Izabella Surowiec,Dennis O Mook-Kanamori,Marian Beekman,Kate Bennett,Torbjörn Lundstedt,Ko Willems Van Dijk

doi:10.1007/s11306-020-01653-7

Abstract

IntroductionSeveral plasma metabolites have been associated with insulin resistance and type 2 diabetes mellitus.ObjectivesWe aimed to identify plasma metabolites associated with different indices of early disturbances in glucose metabolism and insulin sensitivity.MethodsThis cross-sectional study was conducted in a subsample of the Leiden Longevity Study comprising individuals without a history of diabetes mellitus (n = 233) with a mean age of 63.3 ± 6.7 years of which 48.1% were men. We tested for associations of fasting glucose, fasting insulin, HOMA-IR, Matsuda Index, Insulinogenic Index and glycated hemoglobin with metabolites (Swedish Metabolomics Platform) using linear regression analysis adjusted for age, sex and BMI. Results were validated internally using an independent metabolomics platform (Biocrates platform) and replicated externally in the independent Netherlands Epidemiology of Obesity (NEO) study (Metabolon platform) (n = 545, mean age of 55.8 ± 6.0 years of which 48.6% were men). Moreover, in the NEO study, we replicated our analyses in individuals with diabetes mellitus (cases: n = 36; controls = 561).ResultsOut of the 34 metabolites, a total of 12 plasma metabolites were associated with different indices of disturbances in glucose metabolism and insulin sensitivity in individuals without diabetes mellitus. These findings were validated using a different metabolomics platform as well as in an independent cohort of non-diabetics. Moreover, tyrosine, alanine, valine, tryptophan and alpha-ketoglutaric acid levels were higher in individuals with diabetes mellitus.ConclusionWe found several plasma metabolites that are associated with early disturbances in glucose metabolism and insulin sensitivity of which five were also higher in individuals with diabetes mellitus.

Highlights

Several plasma metabolites have been associated with insulin resistance and type 2 diabetes mellitus
We investigated which metabolites measured by a Gas chromatography-mass spectrometry (GC–mass spectrometry (MS)) assay are associated with early indices of disturbances in glucose metabolism and insulin sensitivity in individuals that do not use glucose lowering drugs and do not have a history of diabetes mellitus
We identified twelve metabolites to be associated with different indices of glucose metabolism and insulin sensitivity, in individuals without diabetes mellitus from the general population

Summary

Introduction

Several plasma metabolites have been associated with insulin resistance and type 2 diabetes mellitus. Results Out of the 34 metabolites, a total of 12 plasma metabolites were associated with different indices of disturbances in glucose metabolism and insulin sensitivity in individuals without diabetes mellitus. The homeostatic model assessments can be used to quantify insulin resistance (HOMA-IR) based on fasting glucose and insulin levels (Retnakaran et al 2008; Singh and Saxena, 2010; Matthews et al 1985; Wallace et al 2004) If both fasting and post-prandial measures are available, indices such as the Matsuda Index or Insulinogenic index can be used to assess insulin resistance and β-cell function r espectively. These and other indices all reflect different yet partly overlapping aspects of glucose tolerance and insulin sensitivity that play a role in T2D onset

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