Evidence that multiple defects in lipid regulation occur before hyperglycemia during the prodrome of type-2 diabetes.

Simon G Anderson,Moulinath Banerjee,Royston Goodacre,David I Broadhurst,J Kennedy Cruickshank,Marie Brown,Douglas B Kell,Garth J S Cooper,Warwick B Dunn,Victor Sanchez-Margalet

doi:10.1371/journal.pone.0103217

Abstract

BackgroundBlood-vessel dysfunction arises before overt hyperglycemia in type-2 diabetes (T2DM). We hypothesised that a metabolomic approach might identify metabolites/pathways perturbed in this pre-hyperglycemic phase. To test this hypothesis and for specific metabolite hypothesis generation, serum metabolic profiling was performed in young women at increased, intermediate and low risk of subsequent T2DM.MethodsParticipants were stratified by glucose tolerance during a previous index pregnancy into three risk-groups: overt gestational diabetes (GDM; n = 18); those with glucose values in the upper quartile but below GDM levels (UQ group; n = 45); and controls (n = 43, below the median glucose values). Follow-up serum samples were collected at a mean 22 months postnatally. Samples were analysed in a random order using Ultra Performance Liquid Chromatography coupled to an electrospray hybrid LTQ-Orbitrap mass spectrometer. Statistical analysis included principal component (PCA) and multivariate methods.FindingsSignificant between-group differences were observed at follow-up in waist circumference (86, 95%CI (79–91) vs 80 (76–84) cm for GDM vs controls, p<0.05), adiponectin (about 33% lower in GDM group, p = 0.004), fasting glucose, post-prandial glucose and HbA1c, but the latter 3 all remained within the ‘normal’ range. Substantial differences in metabolite profiles were apparent between the 2 ‘at-risk’ groups and controls, particularly in concentrations of phospholipids (4 metabolites with p≤0.01), acylcarnitines (3 with p≤0.02), short- and long-chain fatty acids (3 with p< = 0.03), and diglycerides (4 with p≤0.05).InterpretationDefects in adipocyte function from excess energy storage as relatively hypoxic visceral and hepatic fat, and impaired mitochondrial fatty acid oxidation may initiate the observed perturbations in lipid metabolism. Together with evidence from the failure of glucose-directed treatments to improve cardiovascular outcomes, these data and those of others indicate that a new, quite different definition of type-2 diabetes is required. This definition would incorporate disturbed lipid metabolism prior to hyperglycemia.

Highlights

The metabolic basis of type 2 diabetes mellitus (T2DM) has traditionally had hyperglycemia as its sine qua non, despite generally being accompanied by a long prior history of obesity together with relative physical inactivity
Significant between-group differences were observed at follow-up in waist circumference, adiponectin, fasting glucose, post-prandial glucose and HbA1c, with means and all ranges are still within the ‘normal’ range, between control and both UQ and gestational diabetes mellitus (GDM) women
In maximum-likelihood multinomial logit models, increasing adiponectin concentrations (60% reduction in risk per mg.L21) was independently associated with a GDM classification compared to control (Relative risk ratios: 0.41 (0.22, 0.78), p = 0.005) in a model including age (1.16 (1.00, 1.37)), BMI (1.03 (0.86, 1.24)), history of smoking (0.75 (0.93, 1.99)), Ln non-esterified free fatty acids (NEFA) (0.85 (0.29, 2.50)), Between-group differences in metabolite concentrations 3,552 metabolomic features were judged suitable for univariate analysis after raw metabolite data and related quality assurance processes had been performed

Summary

Introduction

The metabolic basis of type 2 diabetes mellitus (T2DM) has traditionally had hyperglycemia as its sine qua non, despite generally being accompanied by a long prior history of (central) obesity together with relative physical inactivity. Evidence suggests that blood vessel dysfunction, either overt or inducible, is detectable prior to rises in blood glucose [1,2,3], as occurs in the disease itself [4]. HMG CoA reductase inhibitors with its anti-flammatory and anti-thrombotic effects [13,14], have been used to target successfully total and LDL-cholesterol [15,16] Despite such reductions, intriguingly statin treatment may marginally increase glycemia [17,18,19]. We hypothesised that a metabolomic approach might identify metabolites/pathways perturbed in this pre-hyperglycemic phase To test this hypothesis and for specific metabolite hypothesis generation, serum metabolic profiling was performed in young women at increased, intermediate and low risk of subsequent T2DM

Methods

Results

Conclusion