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

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          Abstract

          Objectives

          The 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 methods

          Seventy-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.

          Results

          Patients 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).

          Conclusions

          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.

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          Most cited references 26

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          Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity.

          Dysregulation of fatty acid oxidation (FAO) is recognized as important in the pathophysiology of obesity and insulin resistance (IR). However, demonstrating FAO defects in vivo in humans has entailed complex and invasive methodologies. Recently, the identification of genetic blocks in FAO has been vastly simplified by using tandem mass spectrometry (MS/MS) of dried bloodspots to specify acylcarnitine (AcylCN) alterations characteristic for each disorder. This technology has recently been applied to examine FAO alterations in human and animal models of obesity and type 2 diabetes mellitus (T2DM). This study focused on characterizing AcylCN profiles in human plasma from individuals with obesity and T2DM during fasting and insulin-stimulated conditions. Following an overnight fast, plasma was obtained from lean (n = 12), obese nondiabetic (n = 14), and T2DM (n = 10) participants and analyzed for AcylCN using MS/MS. Plasma samples were also obtained at the end of a 4-h insulin-stimulated euglycemic clamp. In obesity and T2DM, long-chain AcylCNs were similarly significantly increased in the fasted state; free-CN levels were also elevated. Additionally, T2DM subjects of comparable BMI had increased short- and medium-chain AcylCNs, both saturated and hydroxy, as well as increased C(4)-dicarboxylcarnitine (C(4)DC-CN) that correlated with an index of poor glycemic control (HbA(1c); r = 0.74; P < 0.0001). Insulin infusion reduced all species of plasma AcylCN but this reduction was blunted in T2DM. Plasma long-chain AcylCN species are increased in obesity and T2DM, suggesting that more fatty acids can enter mitochondria. In T2DM, many shorter species accumulate, suggesting that they have a generalized complex oxidation defect.
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            Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease.

            The worldwide epidemic of obesity and insulin resistance favors nonalcoholic fatty liver disease (NAFLD). Insulin resistance (IR) in the adipose tissue increases lipolysis and the entry of nonesterified fatty acids (NEFAs) in the liver, whereas IR-associated hyperinsulinemia promotes hepatic de novo lipogenesis. However, several hormonal and metabolic adaptations are set up in order to restrain hepatic fat accumulation, such as increased mitochondrial fatty acid oxidation (mtFAO). Unfortunately, these adaptations are usually not sufficient to reduce fat accumulation in liver. Furthermore, enhanced mtFAO without concomitant up-regulation of the mitochondrial respiratory chain (MRC) activity induces reactive oxygen species (ROS) overproduction within different MRC components upstream of cytochrome c oxidase. This event seems to play a significant role in the initiation of oxidative stress and subsequent development of nonalcoholic steatohepatitis (NASH) in some individuals. Experimental investigations also pointed to a progressive reduction of MRC activity during NAFLD, which could impair energy output and aggravate ROS overproduction by the damaged MRC. Hence, developing drugs that further increase mtFAO and restore MRC activity in a coordinated manner could ameliorate steatosis, but also necroinflammation and fibrosis by reducing oxidative stress. In contrast, physicians should be aware that numerous drugs in the current pharmacopoeia are able to induce mitochondrial dysfunction, which could aggravate NAFLD in some patients. Copyright © 2013 American Association for the Study of Liver Diseases.
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              Relationships Between Circulating Metabolic Intermediates and Insulin Action in Overweight to Obese, Inactive Men and Women

              OBJECTIVE To determine whether circulating metabolic intermediates are related to insulin resistance and β-cell dysfunction in individuals at risk for type 2 diabetes. RESEARCH DESIGN AND METHODS In 73 sedentary, overweight to obese, dyslipidemic individuals, insulin action was derived from a frequently sampled intravenous glucose tolerance test. Plasma concentrations of 75 amino acids, acylcarnitines, free fatty acids, and conventional metabolites were measured with a targeted, mass spectrometry–based platform. Principal components analysis followed by backward stepwise linear regression was used to explore relationships between measures of insulin action and metabolic intermediates. RESULTS The 75 metabolic intermediates clustered into 19 factors comprising biologically related intermediates. A factor containing large neutral amino acids was inversely related to insulin sensitivity (S I) (R 2 = 0.26). A factor containing fatty acids was inversely related to the acute insulin response to glucose (R 2 = 0.12). Both of these factors, age, and a factor containing medium-chain acylcarnitines and glucose were inversely and independently related to the disposition index (DI) (R 2 = 0.39). Sex differences were found for metabolic predictors of S I and DI. CONCLUSIONS In addition to the well-recognized risks for insulin resistance, elevated concentrations of large, neutral amino acids were independently associated with insulin resistance. Fatty acids were inversely related to the pancreatic response to glucose. Both large neutral amino acids and fatty acids were related to an appropriate pancreatic response, suggesting that these metabolic intermediates might play a role in the progression to type 2 diabetes, one by contributing to insulin resistance and the other to pancreatic failure. These intermediates might exert sex-specific effects on insulin action.
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                Author and article information

                Contributors
                zacvilla@yahoo.com.mx
                chuyzacarias@hotmail.com
                drfernandolavalle@hotmail.com
                qcbrtorres@live.com.mx
                c_ruiz99@yahoo.com.mx
                ricardocerda_mx@yahoo.com.mx
                qcberick_gen@hotmail.com
                iramrodriguez@gmail.com
                laelmar@yahoo.com.mx
                Journal
                Diabetol Metab Syndr
                Diabetol Metab Syndr
                Diabetology & Metabolic Syndrome
                BioMed Central (London )
                1758-5996
                27 November 2014
                27 November 2014
                2014
                : 6
                Affiliations
                [ ]Universidad Autónoma de Nuevo León, Hospital Universitario, “Dr. José Eleuterio González”, Servicio de Endocrinología, Monterrey, Nuevo León, 64460 México
                [ ]Departamento de Medicina Interna, Universidad Autónoma de Nuevo León, Hospital Universitario, “Dr. José Eleuterio González”, Monterrey, Nuevo León 64460 México
                [ ]Departamento de Genética, Universidad Autónoma de Nuevo León, Hospital Universitario, “Dr. José Eleuterio González”, Av. Gonzalitos s/n, Colonia Mitras Centro, Monterrey, Nuevo León 64460 México
                [ ]Universidad Autónoma de Nuevo León, Facultad de Enfermería, Avenida Gonzalitos, 1500 Norte, Col. Mitras Centro, Monterrey, NL México
                Article
                420
                10.1186/1758-5996-6-129
                4416397
                © Villarreal-Pérez et al.; licensee BioMed Central. 2014

                This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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