Diabetes Metab J.  2013 Oct;37(5):301-314. 10.4093/dmj.2013.37.5.301.

Regulation of Muscle Pyruvate Dehydrogenase Complex in Insulin Resistance: Effects of Exercise and Dichloroacetate

• Constantin-Teodosiu D

• KMID: 1965976
• DOI: http://doi.org/10.4093/dmj.2013.37.5.301

Abstract

Since the mitochondrial pyruvate dehydrogenase complex (PDC) controls the rate of carbohydrate oxidation, impairment of PDC activity mediated by high-fat intake has been advocated as a causative factor for the skeletal muscle insulin resistance, metabolic syndrome, and the onset of type 2 diabetes (T2D). There are also situations where muscle insulin resistance can occur independently from high-fat dietary intake such as sepsis, inflammation, or drug administration though they all may share the same underlying mechanism, i.e., via activation of forkhead box family of transcription factors, and to a lower extent via peroxisome proliferator-activated receptors. The main feature of T2D is a chronic elevation in blood glucose levels. Chronic systemic hyperglycaemia is toxic and can lead to cellular dysfunction that may become irreversible over time due to deterioration of the pericyte cell's ability to provide vascular stability and control to endothelial proliferation. Therefore, it may not be surprising that T2D's complications are mainly macrovascular and microvascular related, i.e., neuropathy, retinopathy, nephropathy, coronary artery, and peripheral vascular diseases. However, life style intervention such as exercise, which is the most potent physiological activator of muscle PDC, along with pharmacological intervention such as administration of dichloroacetate or L-carnitine can prove to be viable strategies for treating muscle insulin resistance in obesity and T2D as they can potentially restore whole body glucose disposal.

Keyword

Carnitine; Diabetes mellitus, type 2; Dichloroacetate; Diet, high-fat; Exercise; Glucose disposal; Inflammation; Peroxisome proliferator-activated receptors; Statins

MeSH Terms

Blood Glucose
Carnitine
Coronary Vessels
Diabetes Mellitus, Type 2
Dichloroacetic Acid
Diet, High-Fat
Glucose
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Inflammation
Insulin Resistance*
Life Style
Muscle, Skeletal
Muscles
Obesity
Pericytes
Peripheral Vascular Diseases
Peroxisome Proliferator-Activated Receptors
Pyruvate Dehydrogenase Complex*
Sepsis
Transcription Factors
Blood Glucose
Carnitine
Glucose
Insulin
Peroxisome Proliferator-Activated Receptors
Pyruvate Dehydrogenase Complex
Pyruvic Acid
Transcription Factors

Figure

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  Fig. 1 Metabolic inflexibility in type 2 diabetes.

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  Fig. 2 Energy expenditure and fuel selection during cycling exercise at 75% of VO2max. Adapted from van Loon et al. J Physiol 2001;536(Pt 1):295-304 [1]. FFA, free fatty acid.

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  Fig. 3 Physiological factors that control muscle pyruvate dehydrogenase activity. NAD, nicotinamide adenine dinucleotide; CoASH, coenzyme A; NADH, nicotinamide adenine dinucleotide hydrogen; ATP, adenosine triphosphate; ADP, adenosine diphosphate.

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  Fig. 4 The competition between pyruvate dehydrogenase complex (PDC) activity-mediated carbohydrate oxidation and fat oxidation for the cellular coenzyme A (CoASH) and carnitine availability. NAD, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide hydrogen; ATP, adenosine triphosphate; ADP, adenosine diphosphate; CPT, carnitine palmitoyl carnitine; TCA, tricarboxylic acid.

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  Fig. 5 (A) Muscle pyruvate dehydrogenase kinase isoform 4 (PDK4) and (B) pyruvate dehydrogenase phosphatase catalytic subunit 1 (PDP1) are concomitantly up- and down-regulated, respectively, in a lipopolysaccharide (LPS)-inflammation model compared with their corresponding control (saline). Adapted from Crossland et al. J Physiol 2008;586(Pt 22):5589-600 [33]. HMBS, hydroxymethylbilane synthase. aSignificantly different from control; P<0.05.

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  Fig. 6 Muscle pyruvate dehydrogenase complex (PDC) activity at rest and after 30 minutes of electrically evoked submaximal intensity isometric contraction after 6 days of medication with different doses of peroxisome proliferator-activated receptor (PPAR)-δ agonist GW610742 (0 mg [control; empty bar], 5 mg [grey bar], and 100 mg kg-1 body weight [black bar]). Adapted from Constantin-Teodosiu et al. J Physiol 2009;587(Pt 1): 231-9 [37]. a,bSignificantly different from the corresponding control; P<0.05.

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  Fig. 7 Rat skeletal muscle force during 30 minutes of electrically evoked submaximal intensity isometric contraction after 6 days of medication with different doses of peroxisome proliferator-activated receptor (PPAR)-δ agonist GW610742. Adapted from Constantin-Teodosiu et al. J Physiol 2009;587 (Pt 1):231-9 [37]. aSignificantly different from vehicle; P<0.05.

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  Fig. 8 Mechanism of forkhead class O (FOXO) 1 mediated pyruvate dehydrogenase kinase isoform (PDK) 4 up-regulation and thereby pyruvate dehydrogenase complex (PDC)-mediated inhibition of carbohydrate oxidation. GLUT4, glucose transporter isoform 4; IGF, insulin-like growth factor; FFA, free fatty acid; TNF, tumor necrosis factor; PTEN, phosphatase and tensin homolog; PI3K, phosphoinositol 3-kinase; GSK, glycogen synthase; IRS-1, insulin receptor substrate 1.

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  Fig. 9 Human quadriceps muscle pyruvate dehydrogenase complex activity (PDCa) at rest, 10 and 60 minutes of submaximal intensity exercise (75% VO2max) with dichloroacetate (DCA) or saline infusion prior to exercise after 3 days of either a standard diet (CD) or high-fat diet (HFD). Adapted from Constantin-Teodosiu et al. Diabetes 2012;61:1017-24, with permission from American Diabetes Association [2].

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  Fig. 10 Ways to improve muscle glucose disposal in type 2 diabetes patients. PDC, pyruvate dehydrogenase complex.

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