Plasma and urine metabolic profiles are reflective of altered beta-oxidation in non-diabetic obese subjects and patients with type 2 diabetes mellitus.

Jesús Zacarías Villarreal-Pérez,Consuelo Ruiz-Herrera,Laura Elia Martínez De Villarreal,Jesús Zacarías Villarreal-Martínez,María Del Rosario Torres-Sepúlveda,Ricardo Martín Cerda-Flores,Fernando Javier Lavalle-González,Erik Rubén Castillo-García,Irám Pablo Rodríguez-Sánchez

doi:10.1186/1758-5996-6-129

Abstract

ObjectivesThe two primary pathophysiological characteristics of patients with type 2 diabetes mellitus (T2DM) are insulin resistance (IR) and beta cell dysfunction. It has been proposed that the development of IR is secondary to the accumulation of triacylglycerols and fatty acids in the muscle and liver, which is in turn thought to be secondary to an enzymatic defect in mitochondrial beta-oxidation. The purpose of the present study was to analyze the molecules of intermediary metabolism to determine if an alteration in mitochondrial function exists in T2DM patients and, if so, to determine whether this alteration is caused by excess nutrients or an enzymatic defect.Design and methodsSeventy-seven subjects were recruited and divided into four groups (21 T2DM patients, 17 non-diabetic overweight/obese subjects, 20 offspring of T2DM patients, and 19 healthy subjects). Anthropometric parameters were determined by air plethysmography, and biochemical and metabolic parameters were measured, including 31 acylcarnitines (ACs) and 13 amino acids quantified by MS/MS and 67 organic acids measured by GC/MS.ResultsPatients with T2DM showed elevation of short-chain ACs (C2, C4), a glycogenic amino acid (valine), a glycogenic and ketogenic amino acid (tyrosine), and a ketogenic amino acid (leucine) as well as altered excretion of dicarboxylic acids. T2DM offspring with abnormal glucose tolerance test GTT showed increased levels of C16. Subjects in the obese group who were dysglycemic also showed altered urinary excretion of dicarboxylic acids and lower levels of a long-chain AC (C14:2).ConclusionsThese results suggest that mitochondrial beta-oxidation is altered in T2DM patients and that the alteration is most likely caused by nutrient overload through a different pathway from that observed in obese subjects.

Highlights

Type 2 diabetes mellitus (T2DM) and obesity are two deleterious metabolic conditions [1] whose incidence has increased worldwide in the last decade [2]
Subjects in the obese group who were dysglycemic showed altered urinary excretion of dicarboxylic acids and lower levels of a long-chain AC (C14:2). These results suggest that mitochondrial beta-oxidation is altered in T2DM patients and that the alteration is most likely caused by nutrient overload through a different pathway from that observed in obese subjects
The molecular pathogenesis of lipotoxicity is not clear, it has been proposed that it occurs secondary to altered mitochondrial function, resulting from a decline in betaoxidation, an excess of non-esterified fatty acids arriving at the mitochondria, or both [7]

Summary

Introduction

Type 2 diabetes mellitus (T2DM) and obesity are two deleterious metabolic conditions [1] whose incidence has increased worldwide in the last decade [2]. Recent studies have suggested that lipid accumulation results from a lower oxidative capacity of the mitochondria [7] or reduced activity of the tricarboxylic acid cycle [6]. Another possible explanation for this reduction in beta-oxidation is an excessive increase in the delivery of fatty acids to the mitochondria [10]

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