Differential tissue sensitivity to elevated endogenous insulin levels during experimental peritonitis in rats

283

A B S T R A C T A study was undertaken of patients on a regimen of total parenteral nutrition comparing the nitrogen balance, energy substrates, blood amino acids, immunoreactive insulin, and immunoreactive glucagon levels during the sequential infusion of nonprotein calories as either glucose alone (glucose system) or 83% as Intralipid (Pharmacia Fine Chemicals, Montreal, Canada) and 17% glucose (lipid system). These nonprotein calories were administered with a constant background of amino acids (1 g/kg per day), vitamins, and minerals. Each system was infused for a week at a time and the order of infusion randomized. In some patients whole blood arteriovenous (A-V) levels of amino acids were measured across forearm muscle.During the glucose system there was a significantly higher level of pyruvate, lactate, alanine, and immunoreactive insulin, consistent with glucose being the principal source of energy. In contrast, during the lipid system there was a rise in free fatty acids and ketone bodies with a fall in insulin, suggesting that lipid was now the principal source of energy. Despite these two very diverse metabolic situations the nitrogen balance with both systems was positive to a comparable degree after the establishment of equilibrium. Correspondingly, A-V differences of whole blood amino acid nitrogen showed uptake by muscle to an equivalent degree with both systems.Clinical studies indicated that the lipid system as defined herein could be infused by peripheral vein for up to This work was presented in part at the Symposium on

Section: Protocol Imentioning

confidence: 99%

Metabolic studies in total parenteral nutrition with lipid in man. Comparison with glucose.

Hoy¹,

Anderson²,

Nakhooda³

et al. 1976

283

“…Septicemia is characterized by severe muscle wasting with the majority of amino acids being released from skeletal muscle for eventual uptake by the liver for glucogenesis (2) and synthesis of acute phase plasma proteins (3,4). The ability of muscle to utilize glucose, fat, and ketones as energy sources is compromised during septic shock (5)(6)(7)(8)(9)(10). However, total body leucine oxidation was increased by -50% in rats with Pseudomonas aeruginosa bacteremia (1 1).…”

Section: Introductionmentioning

confidence: 99%

“…In some studies rats underwent bilateral adrenalectomy (Adx) [5][6][7] d before endotoxin treatment and were provided with a 1% NaCI solution as well as drinking water to maintain salt balance. Controls underwent sham operations.…”

Section: Introductionmentioning

confidence: 99%

Administration of endotoxin, tumor necrosis factor, or interleukin 1 to rats activates skeletal muscle branched-chain alpha-keto acid dehydrogenase.

Nawabi¹,

Block²,

Chakrabarti³

et al. 1990

111

Protein catabolic states (i.e., sepsis and trauma) are thought to be associated with accelerated oxidation of branched-chain amino acids (BCAA). Branched-chain a-keto acid dehydrogenase (BCKAD), the rate-limiting enzyme for BCAA oxidation by muscle, is regulated by phosphorylation/dephosphorylation. Skeletal muscle BCKAD was only 2-4% active in control rats. Intravenous injection of Salmonella enteritidis endotoxin (0.25-10 mg/kg) did not change total BCKAI) activity, but increased the percent active enzyme in muscle three-to fourfold in 4-6 h. Identical results were observed in adrenalectomized rats pretreated with one dose of a-methylprednisolone (2.5 mg/kg i.p.) 30-60 min before saline or endotoxin injection, indicating that endotoxin's effect was not mediated by hypersecretion of adrenal hormones. Cortisone pretreatment of normal rats (100 mg/kg per d) for 2 d prevented endotoxin-induced activation of muscle BCKAD, suggesting that endogenous secretion products mediated BCKAD activation by endotoxin. Human recombinant tumor necrosis factor-a and/or IL-1ft or a (50 jig/kg) increased muscle BCKAD activation two-to fourfold in normal rats 4-6 h after intravenous injection. We conclude that cytokine-mediated activation of muscle BCKAD may contribute to accelerated BCAA oxidation in

“…This ketonemic adaptation to starvation reduces the need for energy derived from glucose calories, which in turn spares body protein by decreasing the rate of amino acid usage for glucose synthesis. However, there is a general failure of ketonemic adaptation to occur dunrng caloric deprivation associated with severe sepsis in man, monkey, or rodent (2)(3)(4)(5)(6). Because of the lack of alternative fuels during severe sepsis, skeletal muscle breaks down protein and increases the usage of amino acids, especially the branched-chain ones, as a source of energy (7).…”

mentioning

confidence: 99%

“…In turn, the blood concentration of ketone bodies (acetoacetate and /3-hydroxybutyrate) is a function of both the rate of hepatic production and peripheral usage (14,15 (8,16). When rats were made septic by cecal ligation and subjected to a 2-d fast period, plasma free fatty acid concentrations were decreased and fat mobilization appeared to be reduced as compared to measurements made in fasted control rats (5). In contrast, in preliminary studies on perfused livers of infected rats, ketone body production was decreased frQm oleic acid but not from octanoic acid (17).…”

mentioning

confidence: 99%

Role of the Liver in Regulation of Ketone Body Production during Sepsis

Wannemacher¹,

Pace²,

Beall³

et al. 1979

A B S T R A C T During caloric deprivation, the septic host may fail to develop ketonemia as an adaptation to starvation. Because the plasma ketone body concentration is a function of the ratio of hepatic production and peripheral usage, a pneumococcal sepsis model was used in rats to measure the complex metabolic events that could account for this failure, including the effects of infection on lipolysis and esterification in adipose tissue, fatty acid transport in plasma and the rates of hepatic ketogenesis and whole body oxidation of ketones. Some of the studies were repeated with tularemia as the model infection. From these studies, it was concluded that during pneumococcal sepsis, the failure of rats to become ketonemic during caloric deprivation was the result ofreduced ketogenic capacity of the liver and a possibly decreased hepatic supply of fatty acids. The latter appeared to be a secondary consequence of a severe reduction in circulating plasma albumin, the major transport protein for fatty acids, with no effect on the degree of saturation of the albumin with free fatty acids. Also, the infection had no significant effect on the rate of lipolysis or release of fatty acids from adipose tissue. Ketone body usage (oxidation) was either unaffected or reduced during pneumococcal sepsis in rats. Thus, a reduced rate of ketone production in the infected host was primarily responsible for the failure to develop starvation ketonemia under these conditions.