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Department of Nutritional Sciences, University of Wisconsin-Madison, WI 53706;
* Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; and
Departments of Statistics and Plant Pathology, University of Wisconsin-Madison, Madison, WI 53706
2To whom correspondence should be addressed. E-mail: ney{at}nutrisci.wisc.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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CHO) ± Dex and 50% AE with high fat (50%EFAT) ± Dex. There was a significant interaction between energy level and Dex such that the increase in body catabolism due to 50%E from CHO or FAT was reduced by 
50%, although the amount of body weight and nitrogen lost over 7 d was significantly greater with 50%E than with AE. AE+Dex induced a 60% increase in liver mass, whereas 50%E+Dex reduced the increase to 26%. AE+Dex induced a 5-fold increase in serum insulin level, whereas 50%E+Dex normalized the insulin to glucose ratio. Serum IGF-I levels were reduced 14–18% by Dex and 30% by 50%E. Hepatic immunoreactive IGF-I was significantly correlated with serum IGF-I and nitrogen balance. 50%ECHO and 50%EFAT had differential effects on hepatic IGF-I mRNA with a 40% decrease in IGF-I mRNA due to 50%EFAT+Dex. In summary, CHO or FAT hypoenergetic PN with adequate protein had similar effects in normalizing hyperinsulinemia, attenuating hepatomegaly, and reducing the increment, but not the total amount of body protein catabolism, induced by glucocorticoid excess.
KEY WORDS: • glucocorticoids • insulin • nitrogen catabolism • insulin-like growth factor-I
Parenteral nutrition (PN)3 is often required to provide nutritional support for critically ill patients. Provision of adequate energy during catabolic illness can slow the rate of net protein catabolism but cannot prevent the loss of body protein induced by the neurohormonal response to stress (1–3). Thus, it is difficult to define the optimal level of energy for critically ill patients, although it is clear that overfeeding worsens the complications associated with PN (4). Catabolic or critical illness is associated with elevated levels of glucocorticoids (1), which can be replicated in animal models by administration of dexamethasone (Dex). Daily injections of a large dose of Dex induces many of the general features characteristic of the neurohormonal response to stress, including decreased appetite and food intake (5,6), protein catabolism (2,7), suppression of the immune system (8,9), and insulin resistance (7,10). However, Dex treatment does not reflect the spectrum of symptoms observed in a specific type of critical illness such as head injury or burns. In this study, we evaluated the effect of hypoenergetic PN on metabolism and insulin-like growth factor-I (IGF-I) responses in rats with Dex-induced catabolism.
IGF-I is an anabolic hormone whose production is regulated by dietary intake of protein and energy such that changes in IGF-I generally reflect nutritional status (11). Growth hormone (GH) stimulates hepatic production of IGF-I, the major source of circulating IGF-I, and IGF-I mediates many of the anabolic effects of GH (12). A decrease in circulating concentration of IGF-I due to elevated levels of glucocorticoids during critical illness (11) may explain the inability of nutrition to prevent loss of body protein during critical illness. In support of this notion, we demonstrated that whole-body catabolism induced by Dex in parenterally fed rats is associated with downregulation of the hepatic IGF-I endocrine system at the post-transcriptional level when adequate nutrition is provided (2). Moreover, the whole-body protein catabolism and insulin resistance induced by Dex can be reduced by co-infusion of IGF-I with PN solution (2,7). Thus, IGF-I appears to modulate the metabolic response to catabolic illness, possibly by improving insulin sensitivity.
The total amount and source of nonprotein macronutrient energy may be critical for maintaining normal circulating levels of insulin and IGF-I and attenuating loss of body protein during critical illness (3,12). For example, hypoenergetic PN may be beneficial in reducing the stimulus for insulin secretion and the hepatic complications of PN, although few controlled studies have addressed this (4,13). The literature reflects conflicting studies regarding the relative effects of carbohydrate and fat in modulating nitrogen balance and IGF-I levels (12,14–18). Moreover, the mechanisms of nutritional regulation of hepatic IGF-I gene expression are largely undefined in models of energy restriction, other than fasting (19–24). In addition, well-designed dietary controls are lacking in studies in which energy is restricted and feeding patterns are changed. For example, by reducing fat, energy density is reduced and animals are stimulated to eat more (25).
This study sought to better define optimal levels of parenteral energy during catabolic illness by examining metabolic and IGF-I responses in Dex-treated rats administered adequate and hypoenergetic PN. Our objective was to determine whether 50% energy (50%E) restriction due to a specific reduction in either carbohydrate or fat, with provision of adequate protein and micronutrients, ameliorated the detrimental effects of Dex on body protein catabolism, insulin resistance, and serum and hepatic IGF-I responses. The PN rat model provides precise nutritional control that is required to maintain constant energy intake per kilogram of body weight (BW) for our experimental design (2).
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Male Sprague-Dawley rats (220–240g) were acclimated to a 12-h light:dark cycle at 22°C for 3 d; they consumed a modified AIN 93G semipurified diet and water ad libitum (26). Rats were food deprived 18 h before the placement of a catheter into the right jugular vein for a continuous 24 h/d infusion of a PN solution using a swivel infusion device (27). The University of Wisconsin-Madison Animal Care and Use Committee approved the facilities and protocol.
The experiment included 6 parenterally fed groups that were randomized as an incomplete block design (28): adequate energy (AE) ± Dex, 50% AE with high carbohydrate (50%ECHO) ± Dex and 50% AE with high fat (50%EFAT) ± Dex. The first block had the combinations: AE+Dex (n = 4), AE–Dex (n = 4), 50%EFAT+Dex (n = 8), and 50%EFAT–Dex (n = 8). The second block had the combinations: AE+Dex (n = 5), AE–Dex (n = 4), 50%ECHO+Dex (n = 8), and 50%ECHO–Dex (n = 8). The success rate was 90–92% with a final sample size of 8 rats per treatment group, except for the AE+Dex group, which had 9 rats, and a final sample size in total of 49 rats. Rats were administered PN for 7 d and received i.p. injections of 70 µg/d Dex or saline (29). Adequate energy, previously defined by Tao et al. (30) and Lasekan (27), provided 967-1025 nonprotein kJ/(kg BW · d); 50%E provided 485–515 nonprotein kJ/(kg BW · d).
PN solutions. The PN solutions were prepared aseptically using commercial preparations of amino acids plus electrolytes (8.5% Travasol, Baxter), 60% dextrose (Baxter), 20% Intralipid (Baxter), vitamins (Astra USA), and trace elements (Multitrace-4, American Regent Laboratories), Table 1. All solutions contained 43 g amino acids/L and were formulated to be isovolumetric. Gradual infusion of PN solution began postsurgery (20 mL on the day of surgery, 40 mL on d 1) and was increased to deliver treatment energy requirements from d 2 through 7 (60 mL/d).
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CHO) or CHO (50%EFAT) with no change in protein, vitamins, minerals, or volume of the solutions. The 50%ECHO solution provided 107 g/L dextrose and 2 g/L lipid to provide essential fatty acids. The 50%EFAT solution provided 54 g/L dextrose and 20 g/L lipid. These solutions provided a nonprotein energy carbohydrate to fat ratio of 80:20 (AE), 95:5 (50%ECHO), and 49:51 (50%EFAT). The percentage of total energy provided by protein, carbohydrate, and fat for the 3 PN solutions is as follows: AE, 16% protein, 68% carbohydrate, and 16% fat; 50%ECHO, 31% protein, 66% carbohydrate and 3% fat; and 50%EFAT, 31% protein, 34% carbohydrate, and 35% fat.
Because of the dramatic weight loss induced by 50%E and Dex, the PN solutions were reformulated on d 4, 5, and 6 to decrease the amount of energy provided from fat and carbohydrate (29). This was required to maintain a constant energy intake per unit body weight throughout the 7-d study. The solution was reformulated for the 50%ECHO+Dex group as follows (g/L dextrose and lipid, respectively): d 4 and 5, 101 and 2; d 6, 95 and 2. The solution was reformulated for the 50%EFAT+Dex group as follows (g/L dextrose and lipid, respectively): d 4 and 5, 48 and 20; d 6, 42 and 20. The amount of PN solution infused was calculated by determining the differences in weights of the infusion bags over a 24-h period. The AE groups received a mean of 971–996 nonprotein kJ/(kg BW · d) and the 50%E groups received 456–510 nonprotein kJ/(kg BW · d) on d 2 through 7. The variance in the amount of energy infused within a treatment group was <2%.
Body weight, nitrogen analysis and tissue collection.
Body weights were recorded daily. Urine was collected and the volume was recorded daily; boric acid was added to a final concentration of 0.01% and samples were stored at 4°C. Urinary nitrogen was determined by micro-Kjeldahl analysis as previously described (7). Nitrogen balance was determined daily and then summed to determine cumulative N balance over the 7-d study period to reflect the changes in lean body mass that accompanied the net changes in body weight. On d 7, 24h after the last injection of Dex, the rats were exsanguinated between 800 and 1100 h, after i.v. injection of 18 mg ketamine/kg body weight within 5 min of stopping the PN. Blood was collected and partitioned for deproteinized blood or centrifuged at 1700 x g for 15 min to isolate for serum.
We assessed the absolute and relative (g/100 g BW) wet weights of selected tissues and organs including liver and kidney as a reflection of increased nitrogen catabolism, thymus as a reflection of immune function, and gastrocnemius muscle as an index of skeletal muscle mass. Tissues, including liver, kidney, right and left gastrocnemius muscle, and thymus, were collected, weighed, and immediately frozen in liquid nitrogen. The mass reported for gastrocnemius muscle is the sum of the mass of the right and left muscles.
Hormone concentrations. Total serum IGF-I concentrations were measured by a double antibody RIA (31) after removal of IGF-I binding proteins by HPLC under acidic conditions. Materials included recombinant human (rh)IGF-I as a standard, 125I-rhIGF-I (Amersham), polyclonal antibody to human IGF-I (National Hormone and Pituitary Program), goat anti-rabbit IgG, and normal rabbit serum (Antibodies). The concentration of immunoreactive IGF-I in liver was measured by RIA after IGF-I was extracted from liver (2). Serum concentrations of insulin and GH were measured using RIA kits (Linco Research and Amersham Pharmacia Biotech, respectively). Concentrations of glucose in deproteinized blood were measured using the glucose oxidase technique (32).
Liver IGF-I RNase protection assay (RPA). Total RNA was extracted from liver (TRIzol Reagent, Gibco BRL Life Technologies) and the integrity confirmed by visualizing ethidium bromide–stained 18S and 28S rRNA on an agarose/formaldehyde gel. RPAs were performed with total liver RNA and nontarget yeast RNA, and saturating amounts of IGF-I Exon-2 and 18S probes. A 464-bp 32P-labeled antisense RNA probe complementary to Exon-2 derived c-DNA template (29,33) was synthesized to detect IGF-I mRNA. A 128-bp 18S ribosomal RNA antisense probe was transcribed from a pTRI RNA 18S antisense control template (Ambion). When hybridized with total liver RNA, Exon 2-containing IGF-I mRNAs protected a doublet at 305 bp and a band at 290 bp, reflecting different Exon 2 transcription start sites, and a band at 238 bp, reflecting total Exon 1-containing IGF-I mRNAs (29,33). The 18S probe protected a closely migrating doublet at 80 bp. All RPAs were performed using the Hybspeed RPA Kit (Ambion). Briefly, 10 µg of total liver RNA or yeast RNA was coprecipitated with saturating amounts of Exon-2 and 18S probes, resuspended in buffer at 95°C, and hybridized at 68°C for 10 min. Samples were digested with RNA A/T1 for 30 min at 37°C and precipitated at –70°C overnight. Pellets were resuspended in gel loading buffer and electrophoresed on 5% acrylamide:8 mol/L urea gel. The gels were vacuum dried and quantitatively analyzed by phosphorimage analysis. Levels of IGF-I mRNA transcript were normalized for 18S ribosomal RNA and expressed as fold increases relative to AE control. RPAs were performed in duplicate gels with 2–3 samples per treatment group on each gel.
Statistical analysis.
Data were analyzed using SAS (version 8.0, SAS Institute) taking into account block x treatment effects. No significant block effects were found; thus, the remaining analyzes were performed using 1-way ANOVA. A series of contrasts were used to examine the following primary treatment effects among the groups (28,29): 1) the main effect of energy, 2) the main effect of Dex, 3) the interaction between energy level and Dex, and 4) the interaction between nonprotein macronutrient composition and Dex during 50%E intake. Hepatic IGF-I mRNA and serum GH were the only variables to show a significant contrast for the interaction between nonprotein macronutrient composition and Dex during 50%E intake. Thus, data are shown as combined CHO and FAT 50%E groups for all variables except IGF-I and GH. Statistics were performed on log-transformed data for serum concentrations of IGF-I because residual plots indicated unequal variance among groups. Data are presented as means ± SE. Means that differed at P < 0.05 were identified by the PLSD test after 1-way ANOVA.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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50%, although the absolute amount of N loss was significantly greater with 50%E compared with AE. The magnitude of the loss in body weight and negative nitrogen balance did not differ with CHO or FAT 50%E (data not shown), suggesting that intake of carbohydrate or fat induces a similar loss of body protein under conditions of 50%E.
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FAT 50%E treatments both reduced Dex-induced hyperinsulinemia to a similar extent. In this model in which glucose was continuously infused, 50%E restriction reduced blood glucose concentrations from 6.0 ± 0.2 mmol/L in the AE+Dex group to 4.8 ± 0.2 mmol/L in the 50%E±Dex groups (P = 0.007). The ratio of insulin to glucose was significantly increased by Dex and significantly reduced by 50%E restriction. There was significant interaction between energy level and Dex (P < 0.0004) due to a greater incremental decrease in the insulin to glucose ratio with 50%E restriction in rats treated with Dex compared with rats not treated with Dex.
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CHO or FAT feeding with no significant interaction between Dex, energy level, and nonprotein energy source. Thus, unlike serum insulin levels and changes in body weight and N balance, 50%E did not diminish the effect of Dex on serum IGF-I level.
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2-fold in association with reduced serum IGF-I levels in rats given adequate or 50%E. In Dex-treated rats, 50%ECHO resulted in a significantly higher serum GH level than was observed with 50%EFAT. Restriction to 50%E without Dex treatment did not alter serum GH levels in association with the 30% decrease in serum IGF-I levels. Liver IGF-I axis: IGF-I mRNA and immunoreactive IGF-I. There were no significant alterations in steady-state liver IGF-I mRNA abundance due to Dex administration or energy restriction, Figure 3. There was a significant interaction of Dex and nonprotein macronutrient source in the 50%E rats (P = 0.0075). These data show that in the presence of Dex, a high-CHO solution maintains IGF-I mRNA compared with a high-fat solution, which decreased IGF-I mRNA by 40%.
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40% (P = 0.0001) independently of energy level and nonprotein macronutrient composition (Fig. 3). Liver IGF-I levels were not correlated with liver IGF-I mRNA, but were correlated with serum IGF-I concentrations (r = 0.54, P = 0.0001) and nitrogen balance (r = 0.61, P = 0.0002). These data support the notion that Dex regulates IGF-I gene expression at a translational or post-translational level (2). Moreover, 50%E does not significantly alter steady-state IGF-I mRNA abundance or hepatic immunoreactive IGF-I in our PN model of continuous infusion, although serum concentration of IGF-I was reduced 30%.
Organ weights.
Dex administration had a greater effect than 50%E restriction on changes in relative organ weights, Table 3. Administration of Dex significantly increased the relative mass of liver; however, there was an interaction between energy level and Dex (P < 0.0001) such that 50%E significantly attenuated the hepatomegaly induced by Dex. More specifically, in rats treated with Dex compared with AE without Dex treatment, relative liver weight was increased by 60% with AE compared with a 26% increase with 50%E from CHO or FAT (P = 0.0001). Relative kidney mass was significantly increased by both Dex and 50%E without a significant interaction between Dex and energy level. Consistent with suppression of immunity, the relative mass of thymus was significantly decreased by both Dex and 50%E without significant interaction between Dex and energy level.
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CHO was associated with a significantly greater relative muscle mass compared with 50%EFAT (1.16 ± 0.03 vs. 0.89 ± 0.05 g/100 g BW, P = 0.0012). These data suggest that under conditions of energy restriction without Dex treatment, CHO spares gastrocnemius muscle mass to a greater degree than does FAT; however, this effect was not observed using the same contrast comparison in body weight change (P = 0.15) or nitrogen balance (P = 0.47). |
DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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To further understand energy needs during critical illness associated with glucocorticoid excess, we investigated how hypoenergetic PN modulates metabolism and IGF-I responses in rats treated with a catabolic dose of Dex. This study reports the benefits of 50%E restriction during PN due to a specific reduction in carbohydrate or fat, with provision of adequate micronutrients and protein, on the detrimental effects of Dex on body protein catabolism, hyperinsulinemia, and serum and hepatic IGF-I system responses. We conclude that hypoenergetic PN improved two aspects associated with Dex-induced catabolism, i.e., hyperinsulinemia and hepatomegaly. Whole-body catabolism was worsened because loss of lean body mass was significantly greater with 50%E than with AE. However, the increment in body catabolism induced by Dex was reduced by 50% in rats given 50%E, suggesting some protection from the catabolic effects of Dex. The reduction in Dex-induced hepatomegaly with 50%E suggests that hypoenergetic PN reduced the potential for hepatic dysfunction.
Dex induces insulin resistance at the level of impaired glucose uptake via a postinsulin receptor mechanism (10). This was apparent in the current study from the dramatic 5-fold increase in insulin levels in Dex-treated rats given AE. Strikingly, 50%E normalized circulating levels of insulin and glucose in Dex-treated rats such that the ratio of insulin to glucose was not significantly different compared with rats given AE or 50%E without Dex. We speculate that the reduction in hepatomegaly and the diminished increment in catabolic response to Dex with 50%E reflects normalization of insulin levels (4,36). These data show that energy level is a key determinant of circulating glucose and insulin concentrations during glucocorticoid excess. Avoidance of hyperglycemia is an important factor in defining an optimal energy level for critically ill patients, especially for overweight and obese individuals with insulin resistance (37).
The IGF-I system generally reflects the metabolic and nutritional state such that inadequate intake of energy or protein decreases serum concentration of IGF-I and downregulates hepatic IGF-I production (11,12). In the current study, IGF-I responses reflected nutritional status because increased whole-body catabolism was significantly correlated with decreased serum and liver IGF-I concentrations. We confirm that Dex-induced downregulation of hepatic IGF-I production occurred at a translational or post-translational level with AE (2), extending our understanding of how Dex regulates hepatic IGF-I expression under conditions of 50%E due to restriction of either fat or carbohydrate. Interestingly, in the presence of Dex, 50%ECHO maintained IGF-I mRNA compared with 50%EFAT, which decreased IGF-I mRNA by 40%. These data suggest that Dex induced a different mechanism of regulation, possibly involving decreased transcription, inhibited transcriptional processing, or decreased IGF-I mRNA stability when 50% energy restriction was achieved by a reduction in carbohydrate. Transcription of the IGF-I gene may be induced by carbohydrate similarly to the presence of glucose-response elements for the L-pyruvate kinase, acetyl-coenzyme A carboxylase, and S14 genes (38). Goya et al. (39) reported that glucose increased IGF-I and IGF-II mRNA and mature peptide secretion in fetal rat hepatocytes.
Energy restriction reduces growth and liver IGF-I expression. Straus et al. (40) showed that rats fed a diet with adequate dietary protein with total energy restricted to 70, 60, or 50% of ad libitum consumption for 10 d, due to a reduction in dietary carbohydrate, had similar fold decreases in serum IGF-I and hepatic IGF-I mRNA levels, suggesting downregulation of hepatic IGF-I production at the transcriptional level with energy restriction. In contrast, our model showed a significant 30% reduction in serum IGF-I and no significant differences in steady-state liver IGF-I mRNA abundance (P = 0.71) or in liver immunoreactive IGF-I (P = 0.27) in rats fed 50%E compared with AE. One explanation is that the decrease in serum IGF-I with energy restriction may be due to increased clearance of IGF-I from serum because of continuous parenteral infusion of nutrient solutions with a dextrose concentration of 4–10%. Alternatively, a consistent elevation in serum glucose level due to continuous glucose infusion with hypoenergetic PN, compared with lower mean daily serum glucose levels in meal-fed rats who tend to consume most of their daily food in 1 or 2 meals when energy intake is restricted (7), may also explain the maintenance of liver IGF-I mRNA levels in our model (40).
In conclusion, CHO or FAT hypoenergetic PN normalized hyperinsulinemia, attenuated hepatomegaly, and diminished the increment, but not the total amount of body protein catabolism induced by Dex treatment. These data also suggest that carbohydrate and fat may differentially regulate hepatic IGF-I gene expression during glucocorticoid excess because 50%ECHO maintained the level of IGF-I mRNA, whereas 50%EFAT decreased hepatic IGF-I mRNA by 40% during Dex treatment. From a clinical perspective, these data suggest that hypoenergetic PN may reduce the hepatic complications associated with PN and improve insulin metabolism. These results provide experimental evidence to support the American Gastroenterological Association Technical Review on Parenteral Nutrition which suggests that "it is better to err on the side of giving too few than too many calories to patients, because it is likely that infectious and metabolic complications are increased by overfeeding" (4).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: AE, adequate energy; BW, body weight; CHO, carbohydrate; Dex, dexamethasone; 50%E, 50% of adequate energy; GH, growth hormone; IGF-I, insulin-like growth factor-I; PLSD, protected least significant difference; PN, parenteral nutrition; rh, recombinant human; RPA, RNase protection assay.
Manuscript received 10 August 2004. Initial review completed 20 October 2004. Revision accepted 23 November 2004.
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represents the Exon 2 derived IGF-I riboprobe and * represents the 18S riboprobe. (B) Liver IGF-I mRNA band intensities, gathered by phosphor image analysis, are expressed as a ratio to the 18S control and relative to the AE control (n = 5–7/group). Gels were performed in duplicate. (C) Liver immunoreactive IGF-I. Values are means ± SE; AE+Dex, n = 9, all other groups, n = 8. Means without a common letter differ, P < 0.05.