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Glucose Transporters in Cardiac Metabolism and Hypertrophy

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The heart is adapted to utilize all classes of substrates to meet the high‐energy demand, and it tightly regulates its substrate utilization in response to environmental changes. Although fatty acids are known as the predominant fuel for the adult heart at resting stage, the heart switches its substrate preference toward glucose during stress conditions such as ischemia and pathological hypertrophy. Notably, increasing evidence suggests that the loss of metabolic flexibility associated with increased reliance on glucose utilization contribute to the development of cardiac dysfunction. The changes in glucose metabolism in hypertrophied hearts include altered glucose transport and increased glycolysis. Despite the role of glucose as an energy source, changes in other nonenergy producing pathways related to glucose metabolism, such as hexosamine biosynthetic pathway and pentose phosphate pathway, are also observed in the diseased hearts. This article summarizes the current knowledge regarding the regulation of glucose transporter expression and translocation in the heart during physiological and pathological conditions. It also discusses the signaling mechanisms governing glucose uptake in cardiomyocytes, as well as the changes of cardiac glucose metabolism under disease conditions. © 2016 American Physiological Society. Compr Physiol 6:331‐351, 2016.

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Figure 1. Figure 1. Schematic model of GLUTs in the plasma membrane with 12 membrane‐spanning domains and 6 exofacial loops. The proposed substrate or cytochalasin B‐binding site, and the N‐linked glycosylation site are indicated.
Figure 2. Figure 2. Major signaling mechanisms mediating GLUT4 translocation in muscle and/or adipose tissues: insulin (red and green), ischemia/exercise or contraction (blue) stimulated GLUT4 translocation. For insulin signaling cascade, PI3‐kinase‐dependent (green) and independent (red) pathways are described. APS, adapter protein with Pleckstrin homology and Src homology 2 domains; CAP, c‐Cbl‐associated protein; Cbl, Casitas B‐lineage Lymphoma; Crk, v‐crk avian sarcoma virus CT10 oncogene homolog; IRS1, Insulin receptor substrate 1; PI3K, phosphoinositide 3‐kinase; PIP2, phosphatidylinositol 4,5‐bisphosphate; PIP3, phosphatidylinositol 3,4,5‐triphosphate; PDK1, 3‐phosphoinositide dependent protein kinase‐1; Protein kinase B, Akt; AS160, Akt substrate of 160 kDa; aPKC, atypical protein kinase C; LKB1, liver kinase B1; CaMKK, calcium/calmodulin‐dependent protein kinase kinase; AMPK, 5' AMP‐activated protein kinase; PKD, protein kinase D; NOS, nitric oxide synthase; NO, nitric oxide.
Figure 3. Figure 3. Glucose metabolism pathways in the heart. Changes in the levels of metabolites, key enzymes, or fluxes during pathological cardiac hypertrophy are shown in red (increased) or green (unaltered). G6PD, glucose‐6‐phosphate dehydrogenase; 6‐PGL, 6‐phosphogluconolactone; 6‐PG, 6‐phosphogluconate; NADP+, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; X‐5‐P, xylose‐5‐phosphate; R‐5‐P, ribose‐5‐phosphate; AR, aldose reductase; SDH, sorbitol dehydrogenase; NAD+, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; HK, hexokinase; G‐6‐P, glucose‐6‐phosphate; F‐6‐P, fructose‐6‐phosphate; PFK‐1, phosphofructokinase‐1; F‐1,6‐BP, fructose‐1,6‐bisphosphate; G‐3‐P, glyceraldehyde 3‐phosphate; 1, 3‐BPG, 1,3‐diphosphoglycerate; GAPDH, glyceraldehyde‐3‐phosphate dehydrogenase; PEP, phosphoenolpyruvate; PK, pyruvate kinase; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; acetyl‐coA, acetyl coenzyme A; PC, pyruvate carboxylase; ME, malic enzyme; TCA, tricarboxylic acid; ETC, electron transport chain; GFAT, glutamine fructose‐6‐phosphate aminotransferase; UDP‐GlcNAc, uridine diphosphate‐N‐acetylglucosamine; OGT, O‐GlcNAc transferase.

Figure 1. Schematic model of GLUTs in the plasma membrane with 12 membrane‐spanning domains and 6 exofacial loops. The proposed substrate or cytochalasin B‐binding site, and the N‐linked glycosylation site are indicated.

Figure 2. Major signaling mechanisms mediating GLUT4 translocation in muscle and/or adipose tissues: insulin (red and green), ischemia/exercise or contraction (blue) stimulated GLUT4 translocation. For insulin signaling cascade, PI3‐kinase‐dependent (green) and independent (red) pathways are described. APS, adapter protein with Pleckstrin homology and Src homology 2 domains; CAP, c‐Cbl‐associated protein; Cbl, Casitas B‐lineage Lymphoma; Crk, v‐crk avian sarcoma virus CT10 oncogene homolog; IRS1, Insulin receptor substrate 1; PI3K, phosphoinositide 3‐kinase; PIP2, phosphatidylinositol 4,5‐bisphosphate; PIP3, phosphatidylinositol 3,4,5‐triphosphate; PDK1, 3‐phosphoinositide dependent protein kinase‐1; Protein kinase B, Akt; AS160, Akt substrate of 160 kDa; aPKC, atypical protein kinase C; LKB1, liver kinase B1; CaMKK, calcium/calmodulin‐dependent protein kinase kinase; AMPK, 5' AMP‐activated protein kinase; PKD, protein kinase D; NOS, nitric oxide synthase; NO, nitric oxide.

Figure 3. Glucose metabolism pathways in the heart. Changes in the levels of metabolites, key enzymes, or fluxes during pathological cardiac hypertrophy are shown in red (increased) or green (unaltered). G6PD, glucose‐6‐phosphate dehydrogenase; 6‐PGL, 6‐phosphogluconolactone; 6‐PG, 6‐phosphogluconate; NADP+, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; X‐5‐P, xylose‐5‐phosphate; R‐5‐P, ribose‐5‐phosphate; AR, aldose reductase; SDH, sorbitol dehydrogenase; NAD+, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; HK, hexokinase; G‐6‐P, glucose‐6‐phosphate; F‐6‐P, fructose‐6‐phosphate; PFK‐1, phosphofructokinase‐1; F‐1,6‐BP, fructose‐1,6‐bisphosphate; G‐3‐P, glyceraldehyde 3‐phosphate; 1, 3‐BPG, 1,3‐diphosphoglycerate; GAPDH, glyceraldehyde‐3‐phosphate dehydrogenase; PEP, phosphoenolpyruvate; PK, pyruvate kinase; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; acetyl‐coA, acetyl coenzyme A; PC, pyruvate carboxylase; ME, malic enzyme; TCA, tricarboxylic acid; ETC, electron transport chain; GFAT, glutamine fructose‐6‐phosphate aminotransferase; UDP‐GlcNAc, uridine diphosphate‐N‐acetylglucosamine; OGT, O‐GlcNAc transferase.
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Dan Shao, Rong Tian. Glucose Transporters in Cardiac Metabolism and Hypertrophy. Compr Physiol 2015, 6: 331-351. doi: 10.1002/cphy.c150016