Protein and amino acid metabolism and therapy: what is new and what has been left aside.
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Aging↗
Biomedical subjects
T R Ziegler
Publications and source records attributed to T R Ziegler.
Intestinal adaptation after extensive small bowel resection: differential changes in growth and insulin-like growth factor system messenger ribonucleic acids in jejunum and ileum.
The distal small bowel exhibits greater adaptive growth than proximal segments after partial small intestine resection. To explore this process, we evaluated adaptive cellularity, intestinal insulin-like growth factor (IGF) system messenger RNA (mRNA) transcripts, and effects of recombinant IGF-I treatment in jejunum and ileum of adult rats. Gastrostomy-fed animals underwent 80% jejuno-ileal resection or intestinal transection and reanastomosis without resection, followed by infusion of human recombinant IGF-I (2.4 mg/kgXday) or vehicle. After 7 days, resected rats demonstrated modest adaptive growth in jejunum and marked cell proliferation in ileum. Resection increased IGF-I mRNA in both jejunum (183%) and ileum (249%) and up-regulated IGFBP-4 mRNA levels in both tissues. IGFBP-3 mRNA fell significantly in ileum after resection. IGF-I infusion modestly increased ileal cellularity after resection, but had no effect in jejunum. IGF-I markedly increased IGFBP-3 mRNA levels in jejunum after both transection and resection. These data confirm that bowel resection induces greater adaptive growth in ileum than jejunum. IGF-I administration modestly increases ileal, but not jejunal, growth after resection. Increased levels of intestinal IGF-I and IGFBP-4 mRNA suggest roles for IGF-I and IGFBP-4 in mediating small bowel adaptation. Higher levels of jejunal IGFBP-3 mRNA may be related to limited jejunal vs. ileal growth after extensive jejuno-ileal resection.
Adaptation, Physiological↗
Human growth hormone induces system B transport in short bowel syndrome.
BACKGROUND: After massive enterectomy, remnant intestine undergoes compensatory adaptation. A combination of human growth hormone (hGH) and a glutamine-enriched modified diet induces further adaptation in patients with short bowel syndrome (SBS) on long-term total parenteral nutrition. The specific actions of each component, however, are not well-defined. METHODS: New Zealand White rabbits were randomized to control, sham operation, or SBS (70% midjejunoileal resection) groups and treated with either hGH or saline. Sodium-dependent uptake of glucose, glutamine, alanine, leucine, and arginine into brush border membrane vesicles was quantitated. Serum insulin-like growth factor-I (IGF-I) levels were determined by immunoradiometric assay. Mucosal mRNA expression of IGF-I and IGF binding protein 4 (IGFBP-4) was evaluated by northern blot analysis using rat cDNA probes. RESULTS: Glutamine and leucine transports were 33 and 39% greater, respectively, in the hGH-treated versus saline-treated SBS group (P < 0.05), supporting induction of system B amino acid transport. This upregulation was due, in part, to an 88% increase in glutamine carrier capacity (Vmax) with no change in carrier affinity (Km). Both hGH treatment and SBS increased serum IGF-I levels without direct correlation with increased nutrient transport. IGFBP-4 mRNA expression in small bowel mucosa of saline-treated SBS animals was significantly greater than saline-treated unoperated control values. Mucosal IGFBP-4 mRNA was not significantly altered from control in the other study groups. IGF-I mRNA expression was not detected in mucosa, but weak hybridization was noted in rabbit liver. CONCLUSIONS: Human growth hormone accelerates early adaptation in SBS by upregulation of system B carrier capacity. Serum IGF-I levels and mucosal IGF-I and IGFBP-4 mRNA expression did not directly correlate with this enhanced nutrient transport, suggesting that hGH might exert its adaptive effects by mechanisms that are independent from the IGF system in this model.
Amino Acids↗
Nutrition and the insulin-like growth factor system.
Nutritional status is a key regulator of the circulating and tissue insulin-like growth factor (IGF) system. IGF-I mRNA and protein levels decrease in tissues such as liver and intestine with fasting and are restored with refeeding. Additional studies suggest that the level of protein and calorie intake independently regulate plasma IGF-I concentrations in man. The level of nutrition effects the biological actions of recombinant growth hormone (GH) and IGF-I administration in humans. Limited data demonstrate that plasma and tissue levels of the insulin-like growth factor binding proteins (IGFBPs) are also sensitive to nutrient intake. Specific micronutrients, such as potassium, magnesium and zinc also appear to be important for optimal IGF-I synthesis and anabolic effects in animal models. Malnutrition is common in elderly patients, however, the interaction between specific nutrients, general nutritional status and the aging process on the IGF system is incompletely understood. Mechanisms of nutrient-IGF system interactions which may affect the biological actions of IGF-I, IGF-II, and the IGFBPs are increasingly being determined in basic studies. The effects of underlying nutritional status and responses to dietary intake will be important to evaluate in clinical studies of the IGF system and exogenous growth factor therapy.
Aged↗
Tissue-specific effects of chronic dietary protein restriction and gastrostomy on the insulin-like growth factor-I pathway in the liver and colon of adult rats.
Dietary protein restriction decreases plasma concentrations of insulin-like growth factor-I (IGF-I) and reduces IGF-I mRNA levels in the liver. In addition to the actions of systemic IGF-I, locally produced IGF-I is thought to mediate autocrine and paracrine growth effects in the colon. The objectives of the present study were to investigate the IGF-I pathway in the colon and liver of adult rats under conditions of dietary protein restriction, surgical stress, and dietary protein repletion. Two groups of rats were placed on either a 20% or 2% casein diet for 19 days. Two additional groups of rats underwent gastrostomy after a 2% casein diet for 2 weeks, and then were either kept on the 2% casein diet or changed to a 20% casein diet until day 19. Dietary protein restriction reduced plasma concentrations of IGF-I and IGF-binding proteins (IGFBPs) and hepatic IGF-I mRNA content, while increasing colonic IGF-I receptor mRNA. Gastrostomy in protein-depleted animals had no effect on hepatic IGF-I mRNA, but led to a marked increase in colonic IGF-I mRNA levels. Dietary protein repletion resulted in a decrease in colonic IGF-I receptor mRNA. The distinct effects of dietary protein depletion and operative stress on the IGF pathway in the colon as compared with the liver may serve to maintain the level of IGF-I signaling in the colon by autocrine or paracrine mechanisms under these conditions.
Animals↗
Epidermal growth factor and human growth hormone accelerate adaptation after massive enterectomy in an additive, nutrient-dependent, and site-specific fashion.
BACKGROUND: After massive enterectomy (ME), remnant intestine undergoes compensatory adaptation. Epidermal growth factor (EGF) and human growth hormone (hGH) have each been shown to enhance total length small intestine nutrient transport after ME. This study aims to determine the differential effects of EGF and hGH on proximal and distal small intestinal remnants after ME. METHODS: New Zealand white rabbits underwent 70% mid-jejunoileal resection. After 1 week, animals received hGH (0.2 mg/kg/day), EGF (1.5 micrograms/kg/hr), hGH + EGF, or vehicle (equal volume) for 7 days. Sodium-dependent uptake of glucose, glutamine, alanine, leucine, and arginine into brush border membrane vesicles was quantitated. Serum insulin-like growth factor-I concentrations as well as proximal and distal villus and microvillus heights were measured. IGF binding protein-3 and -4 mRNA expression was determined in full-thickness proximal and distal gut remnants. RESULTS: Concomitant hGH and EGF treatment up-regulates glucose (100%), glutamine (80%), and leucine (60%) transport in the proximal remnant; alanine (150%) and arginine (400%) transport in the distal remnant; and microvillus height (25% to 35%) both proximally and distally. Serum IGF-I levels and gross villus heights were not different among groups. CONCLUSIONS: Co-infusion of hGH and EGF accelerates intestinal adaptation after ME in an additive, nutrient-dependent, and site-specific fashion via enhanced nutrient transport as well as microvillus hypertrophy.
Alanine↗
Adjunctive therapies in nutritional support.
The need for new therapeutic approaches to improve the metabolic and clinical efficacy of nutritional therapy has been increasingly emphasized. The field of nutrition support of catabolic, malnourished, or hospitalized patients is rapidly evolving in response to the beneficial effects observed with adjunctive therapies in animal models and in emerging clinical investigations. Enteral nutrition is being increasingly administered, and enteral diets are being tested to improve gut structure and function. Adjunctive therapies in enteral and parenteral nutrition are being actively investigated. These include administration of recombinant growth factors and anabolic steroid hormones (e.g., growth hormone, oxandrolone); conditionally essential amino acids (e.g., arginine, glutamine); novel lipid products (e.g., structured lipids, fish oils); nutrient antioxidants (e.g., vitamins C and E); and combinations of these approaches. It is likely that current methods of enteral and parenteral nutrition support will evolve in response to the results of these research studies.
Amino Acids, Essential↗
Aging, physical activity, insulin-like growth factor I, and body composition in Guatemalan women.
Aging is associated with diminished secretion of growth hormone and the major endogenous mediator of growth hormone action, insulin-like growth factor I (IGF-I). Aging is also associated with decreased physical activity. Alterations in body composition characteristic of the aging process (increased fat mass and decreased lean body mass) may be related to the decline in anabolic effects of IGF-I with aging, decreased physical activity, or both. Guatemalan women often maintain a high level of physical activity during aging. The purpose of this study was to determine whether IGF-I concentrations correlated with physical activity level (determined by standardized scoring of a self-report questionnaire) and body composition (determined by bioelectrical impedance analysis) in elderly Guatemalan women. In 112 women aged 20-87 y, we found a progressively lower serum IGF-I with age (r = -0.732). In subjects > 60 y of age, the self-reported activity level was associated with a lower percentage body fat (P < 0.001) but there was no significant relation between physical activity level and either lean body mass or IGF-I. We conclude that there is a significant age-related decline in serum IGF-I concentrations in Guatemalan women, similar to that observed in both men and women in the United States. An increased level of physical activity in the elderly Guatemalan population was associated with reduced body fat but did not modify the expected reduction in circulating IGF-I concentrations that occurs with aging.
Adult↗
Glutamine supplementation in catabolic illness.
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Amino Acids↗
Gut adaptation and the insulin-like growth factor system: regulation by glutamine and IGF-I administration.
Intestinal adaptation after extensive small bowel resection in rats is augmented by the provision of diets supplemented with the amino acid glutamine (Gln) or by administration of insulin-like growth factor-I (IGF-I). The goal of this study was to investigate potential synergistic effects of Gln and IGF-I on postresection ileal hyperplasia. Rats underwent 80% small bowel resection (SBR) and then were fed low-Gln or L-Gln-enriched diets and subcutaneously given recombinant human IGF-I or vehicle for 7 days. Gln and IGF-I each significantly enhanced adaptive ileal hyperplasia (DNA content) compared with rats receiving vehicle and low-Gln diet. Ileal DNA content was highest when IGF-I was administered together with Gln supplementation. Combined IGF-I plus Gln synergistically increased ileal weight and protein content. This was associated with higher plasma concentrations of IGF-I and Gln than observed when IGF-I or Gln was given individually. Ileal IGF-I mRNA expression rose nearly twofold during gut adaptation after SBR; this response was augmented with IGF-I administration but was unaltered by Gln feeding. In contrast, dietary Gln, but not IGF-I therapy, prevented a decrease in hepatic IGF-I mRNA induced by SBR. We conclude that parenteral IGF-I and enteral Gln have both individual and synergistic effects on ileal adaptation after massive small intestinal resection. These findings support the concept that specific gut-trophic nutrients and growth factors may be combined to enhance intestinal adaptation and possibly reduce the severity of short bowel syndrome after intestinal resection.
Animals↗
Insulin-like growth factor-I improves mucosal structure and function in transplanted rat small intestine.
The transplanted small intestine develops significant mucosal atrophy, impaired nutrient and water absorption, and increased bacterial translocation to mesenteric lymph nodes in rats maintained on elemental diets or total parenteral nutrition. This study determined the effects of administration of an peptide growth factor (insulin-like growth factor-I[IGF-I]) on the mucosal structure and barrier function of rat small bowel isografts. Thirty-six adult Lewis rats underwent either resection of the distal 60% of the small bowel and proximal colon followed by a 40-cm orthotopic jejunal isograft or proximal small bowel transection and distal small bowel resection to leave an analogous length of small intestine in control animals. All rats received an isocaloric, isonitrogenous, polymeric diet (200 kcal/kg/day, 2 gN/kg/day) by gastrostomy and were infused with either IGF-I (2.4 mg/kg/day) or vehicle by osmotic pumps subcutaneously. After 10 days of treatment, jejunal crypt cell production, mucosal morphometric indices, glucose and water absorption, body weight, and bacterial translocation to mesenteric lymph nodes (MLN) were measured. Jejunal mRNA content for IGF-I, IGF-I receptor, and IGF-binding proteins 3 and 4 (IGFBP-3,4) were determined by Northern blotting. Crypt cell production, villus height, crypt depth, and villus surface area were significantly increased in control and transplanted jejunum of rats infused with IGF-I when compared to animals given vehicle alone. Additionally, jejunal glucose absorption and water absorption were significantly improved in both IGF-I groups when compared with their respective vehicle controls. IGF-I infusion increased body weight in transplanted and control animals and markedly reduced bacterial translocation to MLN after small bowel transplantation. Jejunal levels of IGF-I mRNA were significantly increased in transplanted animals when compared to transected controls. IGF-I treatment significantly increased IGFBP-3 tissue mRNA levels in both transected and transplanted animals. These results demonstrate that IGF-I administration, after small bowel transplantation, improves mucosal structure and absorptive function and reduces bacterial translocation to MLN. IGF-I may have important effects in transplanted small bowel both as an endogenous and administered growth factor.
Animals↗
A new treatment for patients with short-bowel syndrome. Growth hormone, glutamine, and a modified diet.
OBJECTIVE: The purpose of this study was to initially determine if growth hormone or nutrients, given alone or together, could enhance absorption from the remnant small bowel after massive intestinal resection. If clinical improvement were observed, this therapy would then be used to treat patients with the short-bowel syndrome over the long term. SUMMARY BACKGROUND DATA: Patients who undergo extensive resection of the gastrointestinal tract frequently develop malabsorption and require long-term parenteral nutrition. The authors hypothesized that the administration of growth factors and/or nutrients could enhance further compensation of the remnant intestine and thereby improve absorption. Specifically, animal studies have shown that there is enhanced cellularity with the administration of growth hormone (GH) or glutamine (GLN), or a fiber-containing diet. METHODS: Initially, 17 studies were performed in 15 total parenteral nutrition (TPN)-dependent short-bowel patients over 3 to 4 weeks in the clinical research center; the first week served as a control period, and during the next 1 to 3 weeks, the specific treatment was administered and evaluated. Throughout the study, food of known composition was provided and all stool was collected and analyzed to determine absorption across the remaining bowel. The effect of a high-carbohydrate, low-fat diet (DIET), the amino acid glutamine (GLN) and growth hormone (GH) administered alone or in combination with the other therapies (GH + GLN + DIET) was evaluated. The treatment was expanded to 47 adults (25 men, 22 women) with the short-bowel syndrome, dependent on TPN for 6 +/- 1 years. The average age was 46 +/- 2 years, and the average jejunal-ileal length was 50 +/- 7 cm (median 35 cm) in those with all or a portion of colon and 102 +/- 24 cm (median 102 cm) in those with no colon. After 28 days of therapy, the patients were discharged on only GLN + DIET. RESULTS: The initial balance studies indicated improvement in absorption of protein by 39% accompanied by a 33% decrease in stool output with the GH + GLN + DIET. In the long-term study, 40% of the group remain off TPN and an additional 40% have reduced their TPN requirements, with follow-up averaging a year and the longest being over 5 years. CONCLUSION: GH + GLN + DIET offers a potential method for providing cost-effective rehabilitation of surgical patients who have the short-bowel syndrome or other complex problems of the gastrointestinal tract. This therapeutic combination also may be useful to enhance bowel function in patients with other gastrointestinal diseases and those requiring extensive intestinal operations, including transplantation.
Adult↗
Resection-induced colonic adaptation is augmented by IGF-I and associated with upregulation of colonic IGF-I mRNA.
The effects of exogenous insulin-like growth factor-I (IGF-I) on colonic adaptation were examined in male Sprague-Dawley rats (n = 60, 225-275 mg) after either a 60% small bowel and cecal resection (RX) or mid-small bowel transection with reanastomosis (TX). Animals received a 7-day treatment with either IGF-I (2.4 mg.kg-1.day-1) or vehicle (V; 0.1 mol/l acetic acid). Body weight decreased significantly after resection (-25.6 +/- 4.0 g; P < 0.05 vs. TX/V). IGF-I treatment significantly reduced weight loss after resection (-12.4 +/- 3.8 g; P < 0.01 vs. RX/V) and induced significant weight gain after transection (15.6 +/- 4.0 g; P < 0.05 vs. TX/V). Plasma IGF-I decreased with resection (526 +/- 41 TX/V vs. 344 +/- 17 ng/ml RX/V; P < 0.01). IGF-I treatment significantly increased plasma IGF-I levels (805 +/- 100 ng/ml TX/IGF, 677 +/- 56 ng/ml RX/IGF). After resection, IGF-I treatment significantly increased colonic mucosal weight, DNA, protein content, and crypt depth when compared with resection alone (P < 0.05). Colonic water absorption, measured by an in vivo [3H]polyethylene glycol assay, was significantly increased by IGF-I treatment in resected animals (399 +/- 23 RX/IGF vs. 306 +/- 32 microliter.cm-1.h-1 RX/V; P < 0.05). Resection resulted in increased steady-state colonic IGF-I mRNA (182% of TX/V; P < 0.01) without significantly affecting IGF-I receptor mRNA expression. Regulation of IGF binding protein (BP)-3 and -4 was discoordinate, with IGFBP-3 mRNA tending to decrease with resection (67% of TX/V; P is not significant) and IGFBP-4 increasing significantly (191% of TX/V; P < 0.05). An important role for IGF-I in colonic adaptation after massive intestinal resection is indicated by 1) significantly enhanced colonic mucosal growth and water absorption with IGF-I treatment and 2) postresection upregulation of colonic IGF-I mRNA and alteration of IGFBP-3 and IGFBP-4 mRNA expression.
Adaptation, Physiological↗
A comparison of rat small intestinal insulin and insulin-like growth factor I receptors during fasting and refeeding.
Insulin-like growth factor I (IGF-I) and insulin may be important regulators of intestinal growth. To investigate small intestinal IGF-I receptors (IGF-IR) and insulin receptors (IR) during intestinal cell atrophy and regeneration, we compared indexes of IGF-IR and IR expression in rat jejunum after 72 h of fasting and 24-72 h of enteral refeeding. Fasting induced intestinal atrophy, reduced plasma insulin and IGF-I concentrations, and markedly decreased jejunal IGF-I messenger RNA (mRNA) levels; these changes were reversed by refeeding. Fasting significantly increased jejunal specific insulin binding, IR content (to 230% of the fed control value), and the 9.6- and 7.4-kilobase IR mRNA transcript levels (to 202% and 218% of control values, respectively). These IR indexes rapidly decreased to control levels with refeeding. Levels of IGF-IR (by Scatchard analysis) and IGF-I-R mRNA were not significantly altered with fasting. The 11-kilobase IGF-IR mRNA transcript increased significantly during the first 24 h of refeeding (to 166% of the control value), and IGF-IR number rose 3-fold. We conclude that rat jejunal IR and IGF-IR are differentially regulated by nutrient availability. Up-regulation of jejunal IGF-I and IGF-IR expression during refeeding suggests a role for the IGF action pathway in gut trophic responses to enteral nutrients.
Animals↗
A cost-evaluation of glutamine-supplemented parenteral nutrition in adult bone marrow transplant patients.
OBJECTIVE: In a randomized, double-blind, prospective clinical trial, we evaluated the metabolic effects of glutamine-supplemented parenteral nutrition in patients with bone marrow transplants. We compared hospital charge and cost data for the two groups of patients in the trial. DESIGN: Retrospective review. SETTING: Bone Marrow Transplant Unit, Brigham and Women's Hospital, Boston, Mass. SUBJECTS: Forty-three patients admitted to the Bone Marrow Transplant Unit were assigned randomly to receive either standard parenteral nutrition or an isocaloric, isonitrogenous parenteral nutrition solution containing glutamine starting on day 1 after bone marrow transplant. The two groups were well matched for diagnosis, antineoplastic treatment, and sex. MEASURES: The primary clinical end points evaluated were nitrogen balance, length of hospitalization, incidence of infection, and results of microbial culture. After completion of the study, we compared the hospital charges for the categories of room and board, surgery, laboratory, pharmacy, radiology, ancillary, and miscellaneous between the two groups of patients. STATISTICAL ANALYSIS PERFORMED: The two groups were compared using the unpaired t test or Mann-Whitney test for nonparametric measurements. A P value of < .05 was considered significant. RESULTS: Nitrogen balance improved in the glutamine-supplemented group compared with control subjects (-1.4 +/- 0.5 g/day vs 4.2 +/- 1.2 g/day, respectively; P = .002). Length of hospitalization was significantly shorter in the glutamine-supplemented group than in the control group (29 +/- 1 day vs 36 +/- 2 days, respectively; P = .017). The incidence of positive microbial cultures and clinical infection was also significantly lower with glutamine supplementation. Hospital charges were $21,095 per patient less in the glutamine-supplemented group compared with charges for patients who received standard therapy. Room and board charges were significantly different: $51,484 +/- 2,647 for the glutamine-supplemented group vs $61,591 +/- 3,588 in the control group (P = .02). CONCLUSION: This intervention study using a new therapy demonstrated clinical and nutritional benefits to patients and cost savings to the hospital.
Adult↗
Strategies for attenuating protein-catabolic responses in the critically ill.
Specialized enteral and parenteral nutrition are now a standard components of care in critically ill patients. This adjunctive therapy corrects and prevents nutrient deficiencies, attenuates the loss of body protein, and improves clinical outcomes in malnourished patients. Several novel strategies designed to improve the metabolic and clinical effects of specialized nutrition are under vigorous clinical investigation. These new approaches include increased emphasis on enteral feeding to maintain intestinal absorptive, immune, and barrier function; administration of conditionally essential amino acids (glutamine, arginine); use of specialized lipid products and antioxidants; and administration of growth factors such as human growth hormone. Randomized, controlled clinical trials will define the clinical and metabolic efficacy and cost-effectiveness of these therapies in specialized nutrition support.
Arginine↗
Adjunctive human growth hormone therapy in nutrition support: potential to limit septic complications in intensive care unit patients.
A large number of studies suggest that growth hormone (GH) modulates immune cell number and function. For example, GH administration in vitro or in animal models enhances antibody synthesis, increases T-lymphocyte proliferation, augments cytotoxic activity of natural killer cells, up-regulates priming of peritoneal and alveolar macrophages, and increases survival rates after infectious challenge. Similar effects on immune cells have been observed with insulinlike growth factor I (IGF-I), a major mediator of GH's anabolic actions. In critically ill patients, the administration of recombinant human GH improves nitrogen and mineral retention, enhances protein synthesis, and reduces urea generation. However, only limited data are available on the modulation of immune function and infection rates with GH treatment in catabolic patients. Limited studies in burn patients have shown improved wound healing and shortened hospital stay with GH therapy. Growth hormone was recently shown to improve cell-mediated immune responses and to maintain serum immunoglobulin concentrations after abdominal surgery in clinically stable patients. The immunomodulatory effects of GH administration may potentially limit septic complications in the intensive care unit setting. However, controlled studies in well-defined patient groups are needed to evaluate the potential beneficial effects of GH on immune function and infection risk in critically ill patients.
Animals↗
Growth hormone administration during nutritional support: what is to be gained?
Studies over the past three decades have documented the protein-anabolic effects of human growth hormone (GH) administration in malnourished or critically ill patients. The availability of recombinant GH has facilitated clinical investigation on the metabolic and clinical effects of this peptide in ICU settings. These studies demonstrate that GH improves nutrient utilization efficiency in critically ill patients. Recent randomized, controlled trials document improved wound healing with GH therapy in both adult and pediatric burn patients and reduced length of hospital stay in pediatric burn injury. However, little data have been published on functional or clinical outcome variables in other groups of catabolic patients treated with GH. Administration of growth factors in combination with specialized nutrition represents a novel strategy that may improve outcomes in critically ill patients. Additional clinical studies are needed to further define the safety, functional benefits, cost-effectiveness, and clinical utility of GH use in catabolic patients.
Adult↗