And Bioenergetics In The Normal Heart

3.1. Carbon Substrate Selection

The primary carbon substrates (Fig. 4) taken up and metabolized by the myocardium are free fatty acids and glucose. The heart readily takes up and metabolizes pyruvate, lactate and ketone bodies, but the generally low blood concentrations of these substrates limit their utilization. However, under certain conditions such as exercise, which can markedly elevate the blood lactate content, or during periods when blood levels of ketone bodies are elevated, utilization of these substrates may be dominant. A detailed discussion of the regulation of blood levels of these substrates exceeds the scope of this chapter, but a few orienting comments are appropriate regarding glucose and free fatty acid availability.

Blood glucose levels are maintained within a narrow range (~5 mM) in nondiabetic subjects. Its homeostasis is maintained by a balance among alimentary uptake of glucose, glucose release from the liver (which can synthesize glucose or release glucose from the glycogen storage pool), and the uptake and metabolism of glucose by the various organ systems. Glucose uptake is strongly influenced by the pancreatic secretion of insulin, a hormone that enhances glucose transport into the cells of many tissues.

The heart has often been labeled as an omnivore because of its capacity to consume virtually any available carbon substrate. Glucose is transported into the cardiomyocyte by a family of sarcolemmal glucose transport proteins, some of which are insulin dependent. Fatty acids enter myocytes via a sarcolem-mal fatty acid transport protein, and pyruvate and lactate enter via a sarcolemmal monocarboxylic acid transporter. Utilization of glucose by the heart is largely regulated by the availability of fatty acids in the blood. Thus, in the fasted state, blood fatty acid levels are high, and fatty acids are the predominant cardiac substrate despite normal blood glucose levels.

In contrast, during vigorous exercise, blood lactate levels can rise markedly and compete strongly with fatty acids and glucose despite substantial blood levels of the latter substrates. After a carbohydrate meal, however, blood glucose levels rise and elicit insulin secretion. Insulin stimulates glucose uptake by the heart and other tissues and causes blood fatty acid levels to decrease. As a result, myocardial glucose consumption increases, and fatty acid consumption decreases. Nevertheless, fatty acids and lactate are the favored cardiac substrates when they are available in sufficient concentrations in the blood.

3.2. Glucose Metabolism

Figure 5 shows a flowchart for glucose metabolism. Glucose enters the cardiomyocyte via the sarcolemmal glucose transport proteins, GLUT1 (which is insulin independent) and GLUT4 (which is insulin dependent). Once in the cell, glucose is phosphorylated to glucose-6-phosphate by the enzyme hexokinase. Because glucose-6-phosphate is membrane impermeable, it is effectively trapped within the cell, where it can enter the glycogen synthesis pathway (glycogen is a macromolecu-lar polymeric storage form of glucose) or undergo molecular rearrangement via the enzyme phosphohexose isomerase to

Fig. 4. A general overview of carbon substrate metabolism in the heart. Ingested food is broken down into usable carbon substrates, primarily glucose and fatty acids. The pathways that convert amino acids and other molecules to glucose are not shown. Glucose and fatty acids are processed (via intermediary metabolic processes) to yield the reducing equivalents nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), which supply the electrons to the ETC that, in turn, powers oxidative phosphorylation. The last processes, which occur in mitochondria in the presence of oxygen, supply almost all of the adenosine triphosphate (ATP) synthesized in the heart. CoA, coenzyme A; ETC, electron transport chain; TCA, tricarboxylic acid.

Fig. 4. A general overview of carbon substrate metabolism in the heart. Ingested food is broken down into usable carbon substrates, primarily glucose and fatty acids. The pathways that convert amino acids and other molecules to glucose are not shown. Glucose and fatty acids are processed (via intermediary metabolic processes) to yield the reducing equivalents nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), which supply the electrons to the ETC that, in turn, powers oxidative phosphorylation. The last processes, which occur in mitochondria in the presence of oxygen, supply almost all of the adenosine triphosphate (ATP) synthesized in the heart. CoA, coenzyme A; ETC, electron transport chain; TCA, tricarboxylic acid.

Fig. 5. A flowchart depicting the cellular uptake of glucose and the pathways through which glucose metabolism proceeds. The red dots indicate reactions which consume ATP and the blue dots designate reactions which produce ATP.See text for discussion. ADP, adenosine diphosphate; ATP, adenosine-triphosphate; ETC, electron transport chain; NAD, NADH, nicotinamide adenine dinucleotide; TCA, tricarboxylic acid.

Fig. 5. A flowchart depicting the cellular uptake of glucose and the pathways through which glucose metabolism proceeds. The red dots indicate reactions which consume ATP and the blue dots designate reactions which produce ATP.See text for discussion. ADP, adenosine diphosphate; ATP, adenosine-triphosphate; ETC, electron transport chain; NAD, NADH, nicotinamide adenine dinucleotide; TCA, tricarboxylic acid.

Phosphoenol-pyruvate

Pyruvate kinase

Pyruvate

[¿date dehydrogenase

Pyruvate

Ox alo-a ceta te

Acetvl Co A

Ox alo-a ceta te

Acetvl Co A

Although under aerobic conditions most pyruvate produced is converted to acetyl CoA, which enters the TCA cycle, a certain amount is car boxy lated to form oxa!«acetate. The latter enters the TCA cycle inter mediate pool. This is an an a pi erotic pathway.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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