Infectious diseases.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
R G Douglas
Publications and source records attributed to R G Douglas.
Synergistic effect of insulin-like growth factor-I administration on the protein-sparing effects of total parenteral nutrition in fasted lambs.
Using primed constant isotopic infusions, we investigated the effects of recombinant human insulin-like growth factor-I (IGF-I) infusion on protein kinetics in both fasted and parenterally fed (TPN) lambs. Infusion of IGF-I at a dose of 50 micrograms/kg.h in fasted animals increased (P less than 0.005) the mean plasma IGF-I concentration from 77.5 +/- 9.7 to 454.4 +/- 51.4 ng/ml. During IGF-I infusion the rate of net protein catabolism (NPC) was decreased (P less than 0.005) by 17% from 3.5 +/- 0.2 to 2.9 +/- 0.2 g/kg.day, and the rate of appearance (Ra) of leucine in plasma decreased (P less than 0.01) from 5.0 +/- 0.4 to 3.4 +/- 0.4 mumol/kg.min. In addition, the fractional synthetic rate of protein in cardiac and diaphragmatic muscle increased by 100% (P less than 0.05) during the same period. After 3 h of TPN, the rate of NPC was decreased (P less than 0.01) in the TPN animals compared to that in their fasted counterparts (1.89 +/- 2.27 vs. 4.1 +/- 0.2 g/kg.day, respectively). The rate of NPC was further decreased after another 300 min of TPN to 0.76 +/- 0.27 g/kg.day. However, the Ra of leucine was not changed compared to the initial value. Infusion of IGF-I concurrently with TPN reversed (P less than 0.001) the rate of NPC from 1.02 +/- 0.21 g/kg.day after 180 min of TPN alone to a state of net protein gain of 0.14 +/- 0.19 g/kg.day after a further 300 min of combined IGF-I and TPN infusion. The Ra of leucine decreased (P less than 0.01) from 3.9 +/- 0.8 to 2.5 +/- 0.47 mumol/kg.min during IGF-I and TPN infusion. Similarly, the fractional synthetic rates of protein in cardiac muscle, diaphragm, adductor muscle, psoas muscle, and hepatic tissue were increased (P less than 0.05) compared to those in animals that received only TPN. The protein-sparing effects of IGF-I and TPN were synergistic, and the infusion of both agents resulted in the induction of a protein anabolic state within 60 min of commencing IGF-I infusion. In contrast, neither IGF-I nor TPN alone resulted in a state of net protein anabolism, and neither had an effect on protein kinetics until 120 min into the infusion. Consequently, IGF-I shows considerable potential as an anticatabolic agent when used synergistically with nutritional support.
Animals↗
Passive immunization against circulating insulin-like growth factor-I (IGF-I) increases protein catabolism in lambs: evidence for a physiological role for circulating IGF-I.
Primed constant infusions of [14C]urea were used to determine the acute effect of passive immunization against circulating free and protein-bound insulin-like growth factor-I (IGF-I) on the rate of net protein catabolism (NPC) in castrated male lambs fasted for 48 h. Following an intravenous bolus of 50 ml IGF-I antiserum, the rate of NPC increased to a peak 30 min after injection of 1.69 +/- 0.16 g/kg per day from a baseline value of 1.45 +/- 0.22 g/kg per day (P < 0.05, n = 4). In three animals given 50 ml equivalents of the purified immunoglobulin fraction, NPC increased from 1.31 +/- 0.20 to 1.59 +/- 0.16 g/kg per day (P < 0.05). A similar trend was observed in animals given 25 ml antiserum (n = 4). The rate of NPC did not increase following a bolus of non-immune serum in control animals and the rate of NPC in the treated lambs returned to control levels within 60 min of antibody injection. Plasma insulin and glucose concentrations in both the treated and control groups were unchanged throughout the study. These data suggest that circulating IGF-I has a physiological role in regulating whole body protein turnover during starvation and possibly other catabolic states. The effect of immunoneutralization of circulating IGF-I is transient and this suggests that while IGF-I has an endocrine role in the regulation of protein turnover, other regulatory mechanisms are involved.
Animals↗
Infectious diseases.
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Acquired Immunodeficiency Syndrome↗
The circulating molecular weight forms of infused recombinant insulin-like growth factor-I and effects on glucose and fat metabolism in lambs.
We have investigated the relationship between the plasma distribution of infused recombinant insulin-like growth factor-I across the insulin-like growth factor binding proteins and the resultant effects on glucose and fat metabolism. The studies were performed in 24-h fasted ram lambs which received primed constant infusions of 3H labelled glucose tracer. When isotopic equilibrium had been reached, the animals received 90-min infusions of human insulin-like growth factor-I at various doses (2.5, 20, 40 and 120 micrograms.kg-1.h-1, n = 3 for each dose). Total plasma insulin-like growth factor-I was significantly elevated by infusion at a rate of 40 micrograms.kg-1.h-1 (from 185 +/- 14 micrograms/l to 442 +/- 41 micrograms/l, p less than 0.05) and 120 micrograms.kg-1.h-1 (from 181 +/- 2 micrograms/l to 953 +/- 39 micrograms/l, p less than 0.005). The plasma concentrations of insulin-like growth factor-I not associated with binding proteins remained undetectable (less than 15 micrograms/l) at the end of the 2.5 and 20 micrograms.kg-1.h-1 doses, but were significantly elevated at the end of the 40 and 120 micrograms.kg-1.h-1 infusions (to 71 +/- 14 micrograms/l, p less than 0.05 and 176 +/- 55 micrograms/l, p less than 0.01 respectively). The infused insulin-like growth factor-I associated primarily with 35-60 kilodalton binding proteins. Glucose kinetics were significantly altered only by the highest dose infusion, during which there was a fall in plasma glucose concentration from 3.5 +/- 0.2 mmol/l to 1.9 +/- 0.2 mmol/l (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The endocrine role of insulin-like growth factor I.
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Animals↗
Effects of recombinant IGF-I on protein and glucose metabolism in rTNF-infused lambs.
Achieving nitrogen accretion in patients with critical surgical illness or cancer cachexia is often not possible by the simple provision of calories and nitrogen. Cachexia may result from the metabolic derangements caused by release of inflammatory mediators such as tumor necrosis factor (TNF). We wished to determine whether recombinant human insulin-like growth factor I (rhIGF-I) preserves its protein-sparing effects in the face of high plasma TNF concentrations. Primed constant infusions of [15N]urea and [6-3H]glucose tracers were used to measure protein and glucose kinetics in fasted lambs. The lambs were divided into four groups: two groups received normal saline infusions of 480 min, and two groups received recombinant TNF (rTNF) infusions of 1 microgram.kg-1.h-1. During the last 300 min, one of the normal saline and one of the rTNF-infused groups were infused with rhIGF-I at a dose of 50 micrograms.kg-1.h-1. rTNF infusion resulted in the lambs becoming febrile and significantly increased plasma cortisol, glucagon, and insulin levels. rhIGF-I infusion in the control animals reduced the rate of loss of protein by 15% (P less than 0.01) and increased the rate of peripheral glucose clearance by 55% (P less than 0.01). rhIGF-I infusion in the rTNF-treated animals reduced the rate of net protein loss by 15% (P less than 0.01) and caused similar changes in glucose kinetics, as were observed in the control animals. We conclude that as rhIGF-I preserves its protein anabolic action in the face of high rTNF levels, further investigation into a possible clinical role for rhIGF-I in severe surgical illness is warranted.
Animals↗
The effects of infusion of insulinlike growth factor (IGF) I, IGF-II, and insulin on glucose and protein metabolism in fasted lambs.
In vivo effects of 300-min infusions of recombinant insulinlike growth factor I (IGF-I) and IGF-II on glucose and protein metabolism have been investigated in awake, fasted lambs. Two doses of recombinant human (rh) IGF-I were infused: 6.7 nmol/kg.h, which induced hypoglycemia, and 2.0 nmol/kg.h, which did not. The effects were compared with an insulin infusion (0.17 nmol/kg.h) that had the same hypoglycemic potential as the high dose rhIGF-I infusion. rhIGF-II was infused at a rate of 6.7 nmol/kg.h. Primed constant infusions of isotopically labeled glucose, urea and leucine tracers were used to determine glucose and protein kinetics. rhIGF-I lowered blood glucose by increasing the rate of glucose clearance (P less than 0.01), in contrast to insulin, which both increased clearance and reduced glucose production. Net protein loss was reduced after infusion of low and high dose rhIGF-I and insulin by 11% (P less than 0.05), 15% (P less than 0.01), and 12% (P less than 0.05), respectively. rhIGF-II infusion did not alter the rate of net protein loss. In contrast to insulin, high dose rhIGF-I infusion increased the rate of protein synthesis in skeletal (P less than 0.05) and cardiac muscle (P less than 0.01) and in hepatic tissue (P less than 0.05). We conclude that (a) protein metabolism is more sensitive than glucose metabolism to rhIGF-I infusion, as protein loss was reduced by an rhIGF-I infusion that did not alter glucose kinetics; (b) protein synthesis is increased by rhIGF-I infusion but not by insulin infusion; and (c) rhIGF-II is a less effective anabolic agent than rhIGF-I. We speculate that the effects of rhIGF-I on protein metabolism are not mediated by insulin receptors.
Animals↗
Leucine kinetics in patients with benign disease, non-weight-losing cancer, and cancer cachexia: studies at the whole-body and tissue level and the response to nutritional support.
We have performed intraoperative isotopic infusions of carbon 14-labeled leucine in 65 patients to define the abnormalities in protein metabolism at both the whole-body and tissue level in patients with weight-losing and non-weight-losing cancer. Eighteen patients had benign disease, 26 had non-weight-losing cancer, and 21 had cancer cachexia. Samples of plasma and expired breath were taken to determine rates of whole-body protein synthesis (WBPS), whole-body protein catabolism (WBPC), net protein catabolism, and albumin fractional synthetic rates. Tissue samples were taken to determine the fractional synthetic rates (FSR) of protein in muscle, liver, cancer, and the tissue in which the cancer arose. In addition, in 14 patients the effect of nutritional support on protein metabolism was assessed. In all parameters examined we were unable to detect any significant differences between patients with no cancer and the patients with non-weight-losing cancer. In contrast, patients with cancer cachexia had a significant elevation (p less than 0.005) in WBPC compared with the other two groups. WBPS was also elevated (to a lesser extent) in the patients with cancer cachexia, and the rate of net protein catabolism was increased significantly (p less than 0.05). Patients with cancer cachexia also had significantly higher values of FSR of protein in muscle (p less than 0.05), liver (p less than 0.05), and albumin (p less than 0.01) compared with the other two groups. In addition, the protein FSR in the cancer rose progressively when the values for the primary cancer were compared with those for nodal and systemic metastases. Further, although nutritional support resulted in an increase in host muscle protein synthesis (p less than 0.04), there was no promotion of FSR of protein in cancer. We conclude that patients with cancer cachexia are actively losing protein as a result of an increase in WBPC that is only partially compensated for by an increase in WBPS. There are compensatory increases in protein synthesis in muscle and liver, but these increases in host protein synthesis are insufficient to keep pace with the combined effect of the accelerated rate of protein synthesis in the cancer per se and the accelerated rate of net protein catabolism at the whole-body level. In response to nutritional support, there is a significant increase in the muscle protein synthesis, but we could not demonstrate any increase in cancer protein synthesis.
Adult↗
Infectious diseases.
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Acquired Immunodeficiency Syndrome↗
Prophylaxis and treatment of influenza.
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Amantadine↗
Metabolic effects of cancer.
The potential causes of deranged metabolism in cancer are discussed with emphasis on changes in energy metabolism of glucose, fat and protein. The implications of these changes for the treatment of cachexia are then considered.
Cachexia↗
Metabolic effects of recombinant human growth hormone: isotopic studies in the postabsorptive state and during total parenteral nutrition.
We have performed a series of isotopic studies in 25 adult patients with sepsis and/or trauma in order to determine the metabolic effects of recombinant human growth hormone (rHGH) administration. Twelve of the patients were receiving total parenteral nutrition, and 13 were eating a normal ward diet and were studied postabsorption. Energy and protein kinetics were quantified isotopically before rHGH administration and following a 3-day course of rHGH (20 units subcutaneously daily). In the total parenteral nutrition group the rate of net loss of protein decreased from 0.82(0.17) g kg-1 day-1 to 0.43(0.20) g kg-1 day-1 (P less than 0.02) following the administration of rHGH. The rate of appearance of leucine was not altered, suggesting that the improvement in nitrogen balance following rHGH was because of an increased rate of protein synthesis rather than reduced catabolism. In the postabsorptive group, rHGH treatment significantly increased the rate of appearance of free fatty acids (from 7.4(2.2) mumol kg-1 min-1 to 11.1(2.6) mumol kg-1 min-1, P less than 0.03) and free fatty oxidation (from 1.3(0.4) mumol kg-1 min-1 to 1.7(0.4) mumol kg-1 min-1, P less than 0.06), while the rate of leucine oxidation was reduced (from 0.44(0.05) mumol kg-1 min-1 to 0.26(0.03) mumol kg-1 min-1, P less than 0.005). Glucose appearance and oxidation remained unchanged. These results suggest that fat was being oxidized in preference to protein, which resulted in a reduction in the net rate of loss of protein of 0.3 g kg-1 day-1 (P less than 0.05). We conclude that rHGH administration is capable of significantly reducing net protein loss in septic or injured surgical patients. Recombinant HGH may be clinically useful in supporting critically ill surgical patients who require intensive nutritional support.
Adult↗
Erosive arthritis, atypical psoriasis, and Pneumocystis carinii pneumonia in an HIV-positive man.
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Adult↗
Bell Commission requirements: doctors or factory workers?
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Hospitals, Teaching↗
Infectious diseases.
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Acquired Immunodeficiency Syndrome↗