Emerging perspectives on essential amino acid metabolism in obesity and the insulin-resistant state - PubMed (original) (raw)

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Emerging perspectives on essential amino acid metabolism in obesity and the insulin-resistant state

Sean H Adams. Adv Nutr. 2011 Nov.

Abstract

Dysregulation of insulin action is most often considered in the context of impaired glucose homeostasis, with the defining feature of diabetes mellitus being elevated blood glucose concentration. Complications arising from the hyperglycemia accompanying frank diabetes are well known and epidemiological studies point to higher risk toward development of metabolic disease in persons with impaired glucose tolerance. Although the central role of proper blood sugar control in maintaining metabolic health is well established, recent developments have begun to shed light on associations between compromised insulin action [obesity, prediabetes, and type 2 diabetes mellitus (T2DM)] and altered intermediary metabolism of fats and amino acids. For amino acids, changes in blood concentrations of select essential amino acids and their derivatives, in particular BCAA, sulfur amino acids, tyrosine, and phenylalanine, are apparent with obesity and insulin resistance, often before the onset of clinically diagnosed T2DM. This review provides an overview of these changes and places recent observations from metabolomics research into the context of historical reports in the areas of biochemistry and nutritional biology. Based on this synthesis, a model is proposed that links the FFA-rich environment of obesity/insulin resistance and T2DM with diminution of BCAA catabolic enzyme activity, changes in methionine oxidation and cysteine/cystine generation, and tissue redox balance (NADH/NAD+).

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Conflict of interest statement

Author disclosures: S. H. Adams, no conflicts of interest.

Figures

Figure 1

Figure 1

A model of perturbations in essential amino acid catabolism in tissues under conditions of impaired insulin action and T2DM. Under the FFA-rich environment of diabetes, intra-mitochondrial matrix redox status is shifted toward increased NADH/NAD+ coupled to FFA-derived acetyl-CoA generation, inhibiting the mitochondrial matrix-associated enzymes BCKD and PDH. Oxidative stress and ROS generation promote catabolism of methionine to form glutathione with concomitant production of cysteine-cystine; cystine acts to inhibit the tyrosine catabolic enzyme TAT. Because BCKD and to some extent PDH catabolize the methionine derivative α-KB, inhibition of these enzymes promotes accumulation of α-KB and its derivative, α-HB. These events would selectively increase tissue and blood concentrations of some essential amino acids and their derivatives (BCAA, methionine/cysteine-cystine, α-KB/α-HB, tyrosine, phenylalanine). Secondary outcomes such as anaplerotic stress, reduced TCA cycle intermediate levels, and ultimately suboptimal TCA cycle function leading to a mismatch between FFA delivery and combustion could result. α-HB, α-hydroxybutyrate; α-KB, α-ketobutyrate; BCKD, branched-chain α-ketoacid dehydrogenase; BCATm, mitochondrial branched chain aminotranserase; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; ROS, reactive oxygen species; TAT, tyrosine aminotransferase; TCA, tricarboxylic acid; T2DM, type 2 diabetes mellitus.

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