Aspects of organ protein, amino acid and glucose metabolism in a porcine model of hypermetabolic sepsis

Abstract

Although glucose and protein metabolism have been investigated extensively in experimental models of hypodynamic sepsis, relatively little information is available regarding the compensated stage of sepsis. We investigated interorgan amino acid and glucose metabolism in a porcine model of compensated hyperdynamic sepsis. Fasting catheterized pigs received endotoxin ( Escherichia coli lipopolysaccharide; 3 microg.h(-1).kg(-1); intravenous) or saline (controls) and volume resuscitation over 24 h to reproduce hyperdynamic sepsis. Primed-constant infusions of p -aminohippurate and (3)H-labelled isotopes were used to measure glucose, amino acid and protein metabolism across the portal-drained viscera, liver and hindquarters (to represent muscle) at 0 and 24 h of endotoxaemia. Whole-body protein and glucose flux were increased during hyperdynamic compensated sepsis. In endotoxaemic pigs, visceral protein was conserved, and hindquarter protein breakdown exceeded the increase in liver protein synthesis, resulting in net whole-body protein loss. Endotoxaemia increased hindquarter and visceral glycolysis and branched-chain amino acid transamination. The rate of efflux of glutamine and alanine from the hindquarters was higher than anticipated from protein breakdown, indicating de novo synthesis of these amino acids during endotoxaemia. In addition to the hindquarters, the portal-drained viscera provided substantial gluconeogenic amino acids and lactate to the liver. Although increased liver glutamate release constitutes an important nitrogen-sparing mechanism and carbon skeletons are effectively being cycled in glucose, net body protein is lost through increased ureagenesis during the hyperdynamic stage of sepsis. Specific amino acid requirements may develop in compensated hyperdynamic sepsis that is characterized by maintained organ perfusion and increased substrate utilization at the expense of body protein.

Amino acids augment muscle protein synthesis in neonatal pigs during acute endotoxemia by stimulating mTOR-dependent translation initiation

“…BCAA have been shown to spare protein synthesis during sepsis (27), but their role in counteracting catabolism during sepsis remains controversial (15,57). Plasma BCAA levels decrease in response to endotoxin in swine (4), and in our study the LPSinfused neonatal pigs required higher amino acid infusion rates to maintain baseline fasting plasma BCAA. More specifically, leucine has been shown to play a regulatory role in anabolism in normal conditions (54) and during sepsis (15,32,61).…”

“…During acute inflammation and sepsis, the balance between whole body amino acid uptake and plasma amino acid availability depends on a catabolic response that mobilizes amino acids from muscle for the synthesis of hepatic acute-phase reactants and gluconeogenesis (4,16,25). Some amino acids may retain a specific role during sepsis, such as arginine as a substrate for the synthesis of nitric oxide (44,61), alanine as a gluconeogenic substrate (62), and leucine as a regulator of protein anabolism in muscle (15, 44, 61).…”

“…Derangements in skeletal muscle glucose and amino acid metabolism evoked by sepsis result from the body's attempt to maintain the balance between peripheral substrate stores and the increased metabolic demands required to activate the immune system and the stress response (4,37). These adaptative responses are different from those in the normal fasting person in that the immune response is the drive for the metabolic enhancement (11,59).…”

“…growth; sepsis; mammalian target of rapamycin; eukaryotic initiation factor 4G; ribosomal protein S6 kinase THE SYSTEMIC INFLAMMATORY RESPONSE and sepsis syndromes elicited in the host in response to a bacterial pathogen or its products (35) are associated with hypermetabolism, increased oxygen consumption and energy expenditure, activation of peripheral protein catabolism, and alteration in the flux of metabolic substrates between skeletal muscle and liver (4,39). Derangements in skeletal muscle glucose and amino acid metabolism evoked by sepsis result from the body's attempt to maintain the balance between peripheral substrate stores and the increased metabolic demands required to activate the immune system and the stress response (4,37).…”

Dose-dependent effects of leucine supplementation on preservation of muscle mass in cancer cachectic mice

“…this plasma amino acid decrease after leucine supplementation was dominated by the total non-essential amino acids, of which alanine decreased most. Because alanine is a product of intracellular transamination of free amino acids, which occurs when there is an increase in intracellular free amino acids, during proteolysis, for example (44), the increase in plasma amino acids, particularly alanine, might reflect an increase in the transamination of amino acids released from the muscle during protein breakdown.…”