Circulating ghrelin concentrations are lowered by intravenous glucose or hyperinsulinemic euglycemic conditions in rodents.

Ghrelin is a peptide secreted mainly by gastric parietal cells that may play a role in appetite regulation. Circulating ghrelin is abruptly lowered by food intake, but factors involved in ghrelin regulation remain unclear. The aim of this study was to determine whether intravenous glucose infusion lowers ghrelin, and to determine whether glucose, insulin or some measure of insulin action best predicts the effect of feeding on ghrelin. Rats were infused over 3 h with either A. saline (controls); B. dextrose to steady state blood glucose approximately 16.7 mM, or C. insulin 7.5 mU/kg x min, plus dextrose as needed to clamp to euglycemic basal concentrations. During 3 h of infusion, group B had significantly greater (P<0.01) glucose, 17.4+/-0.3 mM, than groups A (6.6+/-0.3) or C (6.1+/- 0.2). Groups B and C had hyperinsulinemia at the end of the 3 h infusion (894+/-246, 804+/-156 pM) compared with saline-infused (222+/-24 pM, P<0.01). Ghrelin concentrations were reduced (P<0.01) in both hyperinsulinemic groups (B=85+/-2; C=103+/-0.6 pM) versus controls (163+/-9). Ghrelin was strongly correlated with insulin (r=-0.68), glucose infusion rate (r=-0.75) and free fatty acids (r=0.67), when all 3 groups were combined, although only the 2 latter variables were independent predictors of ghrelin. In conclusion, neither a rise in blood glucose nor presence of nutrient in the stomach is required for the effect of feeding on ghrelin. The data suggest that whole body insulin responsiveness plays either a direct or indirect role in meal-related ghrelin inhibition.

Inflammatory mediators in patients receiving long-term home parenteral nutrition.

This study was designed to examine circulating and urine cytokine levels in patients receiving long-term home total parenteral nutrition (TPN) support. Twelve patients who had been receiving home TPN for more than 1 year (range, 1.3-19.5 years) were enrolled for study. To avoid the potential confounding effects of intercurrent infection, patients were studied during periods of clinical stability without clinical evidence of infection. Ten normal healthy volunteers served as controls. Serum levels of albumin and C-reactive protein, temperature, body weight, and blood white cell counts were determined. The levels of soluble tumor necrosis factor receptor II (sTNF-RII) and interleukin 6 (IL-6) were measured in serum and 24-hr urine. The results showed that the concentrations of sTNF-RII and IL-6 in 24-hr urine and serum were significantly higher in patients, indicating that long-term home TPN may be associated with a persistent low-grade inflammatory state.

Physicochemical stability assessments of lipid emulsions of varying oil composition.

BACKGROUND AND AIMS: Intravenous lipid emulsions have been shown to be unstable when the percent fat >5 microm (PFAT >5 microm) exceeds 0.4% by weight of the total fat present. We investigated the physicochemical stability of a standard low amino acid and carbohydrate mixture containing electrolytes when combined with four different commercial intravenous lipid emulsions of varying oil composition. METHODS: The 20% (w/v) lipid emulsions studied were composed of the following oils (by weight): 1) 1 : 1 soybean/safflower (SS); 2) 100% soybean (S); 3) 1 : 1 soybean/MCT (SM) and 4) 4 : 1 olive/soybean (OS). Physicochemical stability was assessed by light obscuration or extinction using a single-particle optical sensing technique to detect growth of fat globules in the large diameter tail (>1 microm) of the droplet size distribution and by visual analyses for evidence of phase separation. RESULTS: The physicochemical stability of SS and S-based all-in-one mixtures significantly deteriorated over time when compared to the mixtures made from SM and OS. In addition, of the four mixtures studied that contained SS (n=2) and S (n=2), only one of each bag studied showed visually obvious destabilization by the presence of free oil from phase separation, despite highly abnormal changes in the globule size distribution of all four preparations. CONCLUSION: The results suggest that all-in-one mixtures composed of either soybean oil alone or in combination with safflower oil are less stable than those mixed with either MCT or olive oil which also contain sodium oleate that can act as co-emulsifying agent.

Comparison of growth and fatty acid metabolism in rats fed diets containing equal levels of gamma-linolenic acid from high gamma-linolenic acid canola oil or borage oil.

We have utilized transgenic technology to develop a new source of gamma-linolenic acid (GLA) using the canola plant as a host. The aim of the present study was to compare the growth and fatty acid metabolism in rats fed equal amounts of GLA obtained from the transgenic canola plant relative to GLA from the borage plant. Young male Sprague-Dawley rats (n = 10/group) were randomized and fed a purified AIN93G diet (10% lipid by weight) containing either a mixture of high GLA canola oil (HGCO) and corn oil or a control diet containing borage oil (BO) for 6 wk. GLA accounted for 23%, of the triglyceride fatty acids in both diets. Growth and diet consumption were monitored every 2-3 d throughout the study. At study termination, the fatty acid composition of the liver and plasma phospholipids was analyzed by gas chromatography. The growth and diet consumption of the HGCO group were similar to the BO group. There were no adverse effects of either diet on the general health or appearance of the rats, or on the morphology of the major organs. There was no significant difference between the diet groups for total percentage of n-6 polyunsaturated fatty acids present in either the total or individual phospholipid fractions of liver or plasma. The relative percentage of GLA and its main metabolite, arachidonic acid, in each phospholipid fraction of liver or plasma were also similar between groups. The percentage of 18:2n-6 in liver phosphatidylethanolamine and phosphatidylinositol/serine was higher (P < 0.05) and 22:5n-6 was lower in the HGCO group than the BO group. This finding could be attributed to the higher 18:3n-3 content in the HGCO diet than the BO diet. Results from this long-term feeding study of rats show for the first time that a diet containing transgenically modified canola oil was well-tolerated, and had similar biological effects, i.e., growth characteristics and hepatic metabolism of n-6 fatty acids, as a diet containing borage oil.

Impact of inflammation on nutrition, iron status, and erythropoietin responsiveness in ESRD patients.

Since many end stage renal disease (ESRD) patients experi inflammation, malnutrition, and anemia, the interplay of these processes should be considered in the approach to patients treated with erythropoietin (EPO). This article reviews the interrelationship between these factors. The systemic inflammatory response caused by exposure to inflammatory stimuli results in anorexia and metabolic disturbances leading to protein calorie malnut tion as well as sequestration of iron and hyporesponsiveness to EPO. The implications of these effects and possible strategies to optimize anemia management in the presence of these conditions are discussed.

Endotoxin-induced inhibition of growth hormone receptor signaling in rat liver in vivo.

The bacterial lipopolysaccharide endotoxin induces a catabolic response characterized by resistance to multiple anabolic hormones. The objective of this study was to determine the effects of endotoxin on the GH signaling pathway in rat liver in vivo. After the iv injection of Escherichia coli endotoxin (1 mg/kg), there was a progressive decrease in liver STAT5 (signal transducer and activator of transcription-5) tyrosine phosphorylation in response to GH (40% decrease 6 h after endotoxin), which occurred in the absence of a change in abundance of the STAT5 protein. Endotoxin resulted in a rapid 40-fold increase in liver Janus family kinase-2 (JAK2) messenger RNA, followed by a 2-fold increase in JAK2 protein abundance. This was associated with a 50% decrease in phosphorylated/total JAK2 after GH stimulation. GH receptor abundance was unchanged, suggesting a postreceptor site of endotoxin-induced GH resistance. Rat complementary DNAs for three members of the suppressor of cytokine signaling gene family were cloned [cytokine-inducible sequence (CIS), suppressor of cytokine signaling-2 (SOCS-2), and SOCS-3] and, using these probes, messenger RNAs for SOCS-3 and CIS were shown to be increased 10- and 4-fold above control values, respectively, 2 h after endotoxin infusion. The finding of endotoxin inhibition of in vivo STAT5 tyrosine phosphorylation in response to a supramaximal dose of GH in the absence of a change in GH receptor abundance or total GH-stimulated JAK2 tyrosine phosphorylation provides the first demonstration of acquired postreceptor GH resistance. We hypothesize that this may occur through a specificity-spillover mechanism involving the induction of SOCS genes by cytokines released in response to endotoxin and subsequent SOCS inhibition of GH signaling.

The systemic inflammatory response and its impact on iron nutriture in end-stage renal disease.

In most chronic disease conditions, the systemic inflammatory response and its mediators play an essential pathogenic role. Protein calorie malnutrition, a prominent feature of end-stage renal disease (ESRD), also develops, largely as a consequence of the systemic inflammatory response. ESRD (uremia), dialysis, systemic metabolic acidosis, and infections activate the systemic inflammatory response. Elevations in C-reactive protein and depressions of serum albumin below 4 g/dL are found in more than 50% of ESRD patients undergoing dialysis. In many patients receiving dialysis, the impact of this acute-phase response on measures of iron metabolism limits the ability to diagnose iron deficiency. Furthermore, there are risks to iron administration, although data linking iron overload to risk of infection in dialysis patients is suggestive, not definitive. It seems reasonable to hypothesize that the greatest risk of iron administration is in patents who are already infected, and the greater risk would be to raise the serum iron level and transferrin saturation precipitously. The total-dose infusion method, which provides all iron required to correct deficiency in 1 dose, is more likely to produce side effects and rapidly raise serum iron levels and transferrin saturation. The use of low-dose intravenous iron supplementation (10 to 20 mg per dialysis treatment or 100 mg every second week) avoids iron overtreatment and should reduce adverse events. In ESRD patients receiving dialysis, the importance of the systemic inflammatory response in the development of protein calorie malnutrition, the impact of the acute-phase response on iron nutriture, and the response to erythropoietin therapy must be considered to achieve an understanding of the altered responses to nutritional therapy in this setting.

Essential fatty acid deficiencies in patients with chronic liver disease are not reversed by short-term intravenous lipid supplementation.

The purpose of this study was to determine the plasma triglyceride and phospholipid fatty acid (FA) composition of severely malnourished patients with chronic liver disease and to examine the effects of parenteral nutrition with a total nutrient admixture (TNA) on these profiles. Nine consecutive patients with end-stage chronic liver disease were compared with 35 patients admitted for elective surgery of upper gastrointestinal malignancy. Baseline laboratory values and the FA profiles of the plasma triglyceride and phospholipids were analyzed. FA profiles were also performed after infusion of a TNA including 33+/-7 g of lipid/24 hr for 7.9+/-4 days in the patients with chronic liver disease. Compared with control patients, the plasma phospholipid fatty acid analysis results (relative mole percentage) of patients with chronic liver disease were significantly lower in the two essential FA, linoleic acid (15.4+/-3.4% vs. 20.8+/-2.9%, P<0.001) and alpha-linolenic acid (0.02+/-0.05% vs. 0.08+/-0.10%, P<0.001). Similar changes were demonstrated in the FA composition of the triglyceride fraction. Short-term infusion of intravenous lipid resulted in a significant increase in linoleic acid in the triglyceride fraction (9.9+/-2.8% before supplementation vs. 20.7+/-9.4% after supplementation, P<0.01) and a decrease in oleic acid (38.7+/-5.2% before supplementation vs. 29.3+/-7.5 after supplementation, P<0.01). In conclusion, acute and chronic deficiencies of essential FA occurs in patients with chronic liver disease. The clinical significance of these deficiencies is unknown, but they potentially may impact on eicosanoid metabolism. Short-term supplementation with modest amounts of intravenous lipid has only a minimal effect on normalization of longer-chain fatty acids.

Incidence, prognosis, and etiology of end-stage liver disease in patients receiving home total parenteral nutrition.

BACKGROUND: Elevations in liver function tests have been reported in patients receiving total parenteral nutrition (TPN). The clinical aspects of end-stage liver disease (ESLD) associated with the prolonged use of home TPN have not been fully clarified. In previous series patients with duodenocolostomies appeared to be at higher risk than persons with some jejunum or ileum remaining in situ. METHODS: The records of 42 patients treated with home TPN for more than 1 year were examined. This constituted 283 person-years of home TPN. Patients with duodenocolostomies were examined as a separate group on the basis of the literature experience. RESULTS: Six of 42 patients who received chronic home TPN had ESLD with 100% subsequent mortality, at an average of 10.8 +/- 7.1 months after the initial bilirubin elevation. Thirteen of 42 patients had superior mesenteric artery or vein thrombosis (SMT) leading to duodenocolostomy. In 8 of these 13 patients with SMT and underlying inflammatory or malignant disorder, 2 had ESLD. The remaining 5 SMT patients who had only minimal liver enzyme elevation over 13.6 +/- 6.7 (range 3 to 19) years of home TPN were significantly younger (36 +/- 7 years vs 64 +/- 13 years) and did not have underlying inflammation either by clinical diagnosis or as reflected in the high normal serum albumin level (> or = 4.0 g/dL). Despite their extreme short bowel syndrome and long exposure to home TPN, ESLD did not develop. CONCLUSIONS: Approximately 15% of patients who receive prolonged TPN have ESLD with a high rate of morbidity and mortality. The combination of chronic inflammation and the short bowel syndrome appears to be necessary for the development of ESLD with prolonged home TPN.

Indications for total parenteral nutrition in the hospitalized patient: a prospective review of evolving practice.

The indications for initiating total parenteral nutrition (TPN) were prospectively evaluated in 100 consecutive patients at a tertiary referral hospital with a long-standing Nutritional Support Service to illustrate the reasons why the parenteral route was chosen at this unique institution in terms of patient population. Sixty male and 40 female patients, average age 59 +/- 17 years (range 22-86 years), were classified a priori as to the underlying reasons for initiation of TPN. The study was conducted by a Nutrition Support Service at this hospital without pediatric, trauma, or burn services specializing in the care of patients with diabetes mellitus. Of the 100 patients, 63% were from the surgical service; 24% had diabetes mellitus. Their mean weight (118 +/- 29% of ideal), body mass index (25 +/- 6 kg/m(2)), and serum albumin (2.8 +/- 0.7 g/dL) indicated a reasonable body composition with a moderate systemic inflammatory response. Six patients received preoperative TPN for an average of 5 +/- 3 days with a variety of diagnoses including malignancy, Crohn's disease, bowel obstruction, and gastrointestinal bleeding. The underlying reasons for initiating nutritional support were related to three factors that largely determine the need for involuntary feeding: preexisting protein calorie malnutrition, actual or anticipated semistarvation for a prolonged period, and the presence of a systemic inflammatory response. The choice of TPN was based on anticipated or proven intolerance to full enteral feeding. The duration of time before initiation of TPN postoperatively was 6 +/- 5 days, which reflects our policy that initially well-nourished patients who are experiencing a systemic inflammatory response should not undergo more than 5 to 7 days of inadequate feeding. The duration of TPN overall was 11 +/- 10 days, which primarily illustrates the dramatic reduction in length of hospital stay that has occurred throughout the health care system and the willingness to provide TPN in alternative settings including transitional care units, rehabilitation hospitals, and for short-term care, the patient's home. The most common specific reasons identified for initiating TPN rather than enteral nutrition were ileus (25%), an underlying acid-base or electrolyte/mineral disorder (13%) requiring correction, and the convenience of TPN because a central venous catheter was in place (12%). The usual indication for nutritional support at this tertiary referral and specialty hospital was actual or impending protein calorie malnutrition. TPN was chosen for a variety of reasons related to actual or anticipated tolerance to enteral feeding. This audit demonstrates that our TPN practice has evolved in relation to time of initiation and duration of feeding, which reflect a clearer appreciation of the risks and benefits of TPN.

Nutrition support for patients after cardiopulmonary bypass: required modifications of the TPN solution.

OBJECTIVE: This study was designed to identify the unique metabolic characteristics of patients undergoing cardiopulmonary bypass (CPB) surgery who require postoperative parenteral nutrition. SUMMARY BACKGROUND DATA: Patients undergoing CPB surgery occasionally develop postoperative complications that result in the need for nutrition support. Although enteral nutrition is generally the preferred feeding route, symptomatic hyperlipasemia has been described in critically ill CPB patients receiving enteral nutrition proximal to the ligament of Treitz. In such instances, enteral feeding must be temporarily discontinued or severely curtailed, thereby necessitating the initiation of parenteral nutrition for full or partial support. METHODS: The period from 1988 through 1993 during which time 4091 CPB procedures were performed was reviewed. Data were retrospectively collected on 208 (5%) of the patients who underwent CPB who developed postoperative complications that necessitated the initiation of parenteral nutrition (PN) support. A random sample of 79 patients who underwent CPB who did not require PN were selected as controls. RESULTS: Patients requiring PN after CPB were significantly older and had a higher prevalence of diabetes and metabolic complications, specifically volume overload, hyponatremia, metabolic alkalosis, uremia, and hyperglycemia, than those patients who did not require PN after CPB. In addition, patients requiring PN after CPB were significantly more hypotensive and required more vasopressive drugs during the first 24 to 48 hours after surgery than control patients. CONCLUSIONS: In patients with postoperative complications after CPB, PN is often necessary to correct the metabolic characteristics of overhydration, hyponatremia, uremia, hyperglycemia, and alkalosis.

Role of cytokines in AIDS wasting.

There is now a large literature implicating cytokines in the development of wasting and cachexia commonly observed in a variety of pathophysiologic conditions. In the acquired immunodeficiency syndrome (AIDS), cytokines elicited by primary and secondary infections seem to exert subtle and sustained effects on behavioral, hormonal, and metabolic axes, and their combined effects on appetite and metabolism have been postulated to drive wasting. However, correlations of increased blood levels of a particular cytokine with wasting in AIDS have not been consistent observations, perhaps because cytokines act principally as paracrine and autocrine hormones, as well as indirectly by activating other systems. A better understanding of the mechanisms underlying the catabolic effects of cytokines in clearly needed if more efficacious strategies are to be developed for the prevention and treatment of wasting in AIDS. In this review we first examine the interacting factors contributing to the AIDS wasting syndrome. We then analyze the complex and overlapping role of cytokines in the pathophysiology of this condition, and put forward a number of hypotheses to explain some of the most important features of this syndrome.

Role of arachidonic acid in the regulation of the inflammatory response in TNF-alpha-treated rats.

BACKGROUND: This study examined whether adding arachidonic acid (AA) to a fish oil diet would alter certain of the anti-inflammatory effects of fish oil in response to tumor necrosis factor (TNF) infusion in rats. METHODS: AA was given at 0.08 wt% of diet for 6 weeks. The total fat in each diet provided 20% of dietary energy. Four groups were pair-fed sunflower oil (S), S+AA, fish oil (F), or F+AA for 6 weeks. At the end of feeding, each animal received TNF-alpha (20 microg/kg) infusion for 3 hours. After 1 hour of TNF infusion, a euglycemic and hyperinsulinemic clamp (10 mU/min per kilogram of insulin) was used to determine the actions of insulin. The insulin-stimulated glucose utilization in liver, muscle, and fat was determined by using 14C-deoxyglucose. The plasma glucose, insulin, and corticosterone levels were determined at basal, 60 minutes, and the end of the experiment (180 minutes). The fatty acid composition of plasma phospholipids also was determined. RESULTS: Fish oil significantly increased omega-3 fatty acids in phospholipids in both F and F+AA and decreased AA in F, compared with S. AA significantly restored the level of AA and reduced the increase of omega-3 fatty acids in phospholipids in F+AA compared with F, but had no impact on fatty acid composition when added to S. Corticosterone level was significantly lower with fish oil feeding but higher in both F and S containing AA compared with F and S, respectively. The highest glucose uptake in tissues was in F, followed by F+AA, and then S and S+AA. CONCLUSIONS: These results suggest that fish oil is anti-inflammatory principally through a reduction in the AA content of phospholipids.

Appropriate nutritional support in acute and complicated Crohn's disease.

Crohn's disease is frequently complicated by protein-calorie malnutrition. Four common clinical presentations of Crohn's disease include acute exacerbations or flares of disease, intestinal obstruction, fistulizing disease, and perianal disease. In this review, we examine the role of nutritional support in these clinical scenarios. Nutritional support is important for maintaining functional status and preventing loss of lean tissue. Determinants of lean-tissue loss include severity of underlying injury, baseline nutritional status, and duration of inadequate nutrition. One of the clinically useful measures of nutritional status is the nutritional risk index (NRI) defined on the basis of the serum albumin and weight loss. Nutritional support is important in severely malnourished patients (NRI < 83). Enteral nutrition is the route of choice, provided there are no contraindications to using the gastrointestinal tract. In acute exacerbations of Crohn's disease, enteral nutrition also has a role in the primary management of disease although it is not as effective as corticosteroids in inducing remission. The mechanisms are poorly understood and the most effective enteral formulation needs to be determined. Total parenteral nutrition is justified in severely malnourished Crohn's disease patients who are unable to tolerate enteral feeding or in whom enteral feeding is contraindicated. More clinical studies are needed on the assessment of malnutrition in Crohn's disease, the effects of nutritional management on functional status, and the timing of nutritional intervention.

Early postoperative glucose control predicts nosocomial infection rate in diabetic patients.

OBJECTIVES: To determined the relationship between perioperative glucose control and postoperative nosocomial infection rate is 100 consecutive diabetic patients undergoing elective surgery. DESIGN AND PATIENTS: One hundred initially uninfected diabetic patients undergoing elective surgery were prospectively monitored for perioperative glucose control and postoperative nosocomial infection rate. Glucose control was determined by the attending surgeon or diabetologist. SETTING: A large tertiary care hospital that serves as the in-patient facility for a local diabetes center. MAIN OUTCOME MEASURES: All patients were screened for infection preoperatively. Only initially uninfected patients were enrolled, and all patients received perioperative antibiotic coverage. Perioperative glucose control and postoperative nosocomial infection rate were monitored prospectively. APACHE II scores were determined on all patients. Patients were stratified into two groups: those with relatively "good" perioperative glucose control (all values < or = 220 mg/dL) and those with "poor" control (at least one value > 220 mg/dL). Contingency tables were generated, comparing nosocomial infection rates vs perioperative glucose control. Correlation coefficients between APACHE II score and maximum and mean glucose values were also determined. RESULTS: A serum glucose > 220 mg/dL on postoperative day one (POD 1) was a sensitive (87.5%) but relatively nonspecific (33.3%) predictor of the later development of postoperative nosocomial infection. In patients with hyperglycemia (> 220 mg/dL) on POD 1, the infection rate was 2.7 times that observed (31.3% vs 11.5%) in diabetic patients with all serum glucose values < 220 mg/dL. When minor infection of the urinary tract was excluded, the relative risk for "serious" postoperative infection increased to 5.7 when any POD 1 blood glucose level was > 220 mg/dL. On the basis of correlation coefficients between serum glucose values and APACHE II score, only 18% of the variance in the highest serum glucose could be explained by disease severity alone. CONCLUSIONS: We conclude that diabetic patients undergoing major cardiovascular or abdominal surgery have an increased risk of infection that is further exacerbated by early postoperative hyperglycemia. The high rate of nosocomial infection observed in diabetic patients with poor glucose control suggests that hyperglycemia itself may be an independent risk factor for the development of infection. Efforts to improve perioperative glucose homeostasis in diabetic patients may reduce the incidence of nosocomial infection and thereby improve outcome.

Effects of dietary protein and tumor necrosis factor on components of the insulin-like growth factor-I pathway in the colon and small intestine in protein-depleted rats.

Intestinal cell growth is markedly affected by nutrient intake and the presence of cytokines. Since insulin-like growth factor-I (IGF-I) is an important hormone regulator of intestinal proliferation, this study examined the effects of dietary protein content and tumor necrosis factor (TNF) on mRNA levels of IGF-I, IGF-I receptor, IGF binding protein-3 (IGFBP-3), and IGFBP-4 and on the histology of the colon, jejunum, and ileum in protein-malnourished rats. After 2 weeks of feeding a 2% casein diet, rats continued on the 2% casein diet or were refed with a 20% casein diet and received daily intraperitoneal injections of either TNF (50 microg/kg) or saline for 4 days. The abundance of mRNA in the intestine was determined by RNA dot-blot analysis, and morphology measurements were performed by light microscopy. Simultaneous refeeding with the 20% casein diet and administration of TNF led to a modest increase in IGF-I and IGFBP-4 mRNA abundance in the colon. However, in the jejunum and ileum, refeeding had no effect but TNF caused a decrease in IGF-I and IGFBP-3 mRNA levels in malnourished rats. Refeeding with the 20% casein diet resulted in relatively modest histologic changes, which were greater in the colon versus the small intestine. The decreased magnitude of histologic changes in the order of the colon, ileum, and jejunum may reflect a response to a gradient of amino acid availability from intraluminal nutrients. These data demonstrate that TNF has distinct effects on colon and small intestine mRNA, but these mild changes had only a slight impact in the colon and did not translate into identifiable histologic changes in the small intestine. Combined protein restriction and TNF administration had only a modest effect on intestinal mRNA levels and mucosal histology.