Lars Ekman

Glucose turnover, gluconeogenesis from glycerol, and estimation of net glucose cycling in cancer patients

A double isotope method was used in patients with progressive malignancy and in control patients to measure: glucose turnover, conversion rate of carbon skeleton of glycerol into glucose, and the interorgan cycling of glucose carbons (Cori‐cycle plus alanine‐glucose cycle). [U‐14Clglycerol and [6‐3H]glucose were given intravenously as a single dose injection. The time course of the specific radioactivities of [6‐3H] and [U‐14C]glucose was followed in blood. The pool size and the turnover rate of glucose were increased in the cancer group as compared with the control patients. The net recycling of glucose carbons was not increased in the cancer group, despite the increased turnover of glucose. The alterations in the metabolism of glucose did not correlate with the plasma levels of insulin or thyroid hormones (T4, T3, rT3) neither in the entire cancer group nor in those cancer patients who were repeatedly investigated at different intervals of time. The turnover rate of glucose in the cancer patients correlated inversely to their body weight index. The gluconeogenesis rate, given as the fractional conversion rate of the injected radioactive dose of [14C]glycerol, or as mol glucose · kg body weight−1 · day−1, was increased in the cancer group, but still contributed only 3% of the glucose turnover rate in both cancer and control patients. We conclude that an increased gluconeogenesis from glycerol is not significant in terms of energy expenditure in patients with progressive malignancy, as has previously been concluded for the gluconeogenesis from alanine.15 It seems that increased turnover of glucose may contribute to inappropriately high energy expenditure in cancer patients.

A comparative study of the influence of malignant tumor on host metabolism in mice and man. Evaluation of an experimental model.

Metabolic alterations in skeletal muscles and liver tissue from cancer patients were compared with corresponding alterations in mice (C‐57) with sarcoma (MCG‐101). In tumor‐bearing man and mice similar changes in enzyme activities and in protein turnover were found. Glycolytic and oxidative enzyme activities were decreased in skeletal muscle tissue. Tumor‐associated increase in lysosomal enzyme activities was found in both species. Leucine was incorporated into skeletal muscle proteins at a lower rate and into hepatic proteins at a higher rate in both species with malignant tumor. In tumor‐bearing mice ribosome profiles from skeletal muscle, heart muscle and liver showed a preponderance of slowly sedimenting units of polyribosomes suggesting that initiation of protein synthesis may be a rate limiting step. The metabolic host reactions in tumor‐bearing mice were similar to those in cancer patients implying that experimental tumors are relevant to use for analysis of mechanisms behind the development of cancer cachexia in man.

Utilization of intravenously administered N-acetyl-L-glutamine in humans

L-glutamine is too unstable for inclusion in solutions for parenteral nutrition, but its acetylated analogue, N-acetyl-L-glutamine is not. The purpose of this three-part study was to investigate the utilization of intravenously (IV) administered acetylglutamine in humans. In study 1, nine healthy postabsorptive subjects were given 9.4 g acetylglutamine IV during four hours. In study 2, five healthy subjects were studied on two occasions following an overnight fast. They were given 9.4 g of acetylglutamine or an equivalent amount of glutamine as part of a total parenteral nutrition (TPN) regimen during 7.2 hours. A control group of five subjects was given the same TPN regimen, but without acetylglutamine or glutamine. The nutrient solution included glucose, amino acids, and a fat emulsion, supplying 9.4 g nitrogen and 6,300 kJ in a total volume of 1.8 L. In study 3, four patients were studied the day after major surgery. They were given the same TPN regimen as in study 2, containing 9.4 g acetylglutamine, during 7.2 hours. Plasma concentrations and urinary excretion of acetylglutamine and glutamine were measured in all three studies, and so were splanchnic and renal exchange of acetylglutamine and glutamine in study 1. In study 1, the plasma concentration of glutamine rose from 594 +/- 28 mumol/L to 728 +/- 26 mumol/L (P less than .001), whereas plasma levels of acetylglutamine exceeded 1,000 mumol/L in all subjects at the end of infusion. The eight-hour urinary excretion of acetylglutamine and glutamine corresponded to 18% of the infused amount of acetylglutamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic alterations in liver, skeletal muscle, and fat tissue in response to different tumor burdens in growing sarcoma-bearing rats

Abstract Metabolic alterations in growing sarcoma-bearing rats were studied and are presented in relationship to a small and moderate tumor burden (5 and 10% dry tumor weight of dry carcass weight). Sarcoma-bearing rats with a small tumor burden had decreased plasma concentration of glucose, significantly changed hepatic protein metabolism, increased lipolysis in fat tissue, but not significantly changed protein metabolism in skeletal muscles. Tumor-bearing rats with a moderate tumor burden had altered hepatic protein metabolism and plasma glucose in a manner similar to rats with a small tumor and similar to that previously reported for nongrowing sarcoma-bearing mice with a large tumor. This was also similar to findings in cancer patients. (K. Lundholm, S. Edstrom, I. Karlberg, L. Ekman, and T. Schersten, Cancer Res. 40 : 2516–2522, 1980; K. Lundholm, S. Edstrom, L. Ekman, I. Karlberg, A-C. Bylund, and T. Schersten, Cancer 42 , 453–461, 1978). In contrast to sarcomabearing mice and man, these rats with a “moderate tumor” still had unchanged nitrogen balance in skeletal muscle. We conclude that metabolic alterations in the liver precede catabolic reactions in peripheral tissues and that initiating factors for increased lipolysis are earlier than those factors initiating wasting of skeletal muscles in growing sarcoma-bearing rats.

Protein synthesis in skeletal muscle of rats following starvation and refeeding

Determination of protein synthesis in individual tissues is important to understand the changes in protein metabolism during catabolic states. Three methods based on different underlying assumptions were compared in assessing muscle protein synthesis during nutritional manipulation. Rats were nonstarved, starved for 1 or 3 days, or refed for 2 days after 3 days of starvation. The extensor digitorum longus (EDL) muscles from the two hindlegs were used for analysis. In one EDL muscle the concentration and size distribution of ribosomes as well as the incorporation of [14C]leucine into protein in a cell-free system were determined. The other EDL muscle was incubated as such and the incorporation of [14C]phenylalanine into protein was measured. The total ribosome concentration per milligram of DNA decreased to 65% on the third day of starvation and remained low after refeeding. The amount of polyribosomes in the percentage of total ribosomes fell to 90% on the first day of starvation, regained the initial level on the third day, and reached 110% upon refeeding. During refeeding amino acid incorporation into protein in a cell-free system decreased to 40% and that in intact muscle to 64% of the prestarvation level. Upon refeeding, the activity increased to or above the original values. The use of several different techniques in parallel to assess protein synthesis in skeletal muscle is recommended since it gives information about the factors involved in regulation of the translational process in intact mammalian tissues.

N-acetyl-L-tyrosine as a source of tyrosine in intravenous nutrition an experimental study in the rat

Abstract The utilization of N-acetyl-L-tyrosine (NAT) in amino acid solutionsgiven intravenously was evaluated in the rat. Prior to the i.v. experiment an enteral study was performed to determine the dietary phenylalanine level at which a tyrosine supplement would give a maximum response with respect to weight gain. In the enteral study young growing rats were given diets with differentcontents of phenylalanine and tyrosine for seven days. Animals fed diets with a content of phenylalanine below 0.3% and no tyrosine lost weight. A dietary level of 0.3% phenylalanine and 0.4% tyrosine resulted in an approximately normal weight gain. In the TPN study the four amino acid solutions were deficient with regard to phenylalanine and contained either no tyrosine, maximum dissolvable tyrosine, an equivalent amount of NAT, or NAT calculated to meet the requirement of tyrosine. The group given no supplemental tyrosine showed signs of malnutritionafter the ten day infusion period. The addition of tyrosine or equivalent amount of NAT resulted in increased nitrogen retention and thymus weight. Higher amounts of NAT in the solution increased weight gain and plasma-free tyrosine level significantly. The results indicate that NAT is readily utilized as a source of tyrosine in the growing rat when supplied intravenously.

Metabolic effects of nutritional support to cancer patients

An adequate understanding of the utilization of administered nitrogen and energy sources as well as the regulation of whole body energy expenditure are important factors for maintaining body weight and body composition. The efficacy and metabolic consequences of adjunct nutritional support to cachectic cancer patients has recently been investigated in a number of studies. This review examines some recent investigations in this area. Depleted cancer patients seem to have a slightly higher resting energy expenditure but a normal metabolic and energetic response to administration of energy substrates. Studies of protein metabolism suggest that depleted cancer patients have a disturbed metabolic response of protein anabolism compared with depleted controls. This could be due to differences in peripheral versus visceral tissues. Adjunct nutritional support plays an important role in restoring the depleted cancer patients although clear correlation to functional parameters is still lacking.