Nutritional management of PKU with glycomacropeptide from cheese whey.

Individuals with phenylketonuria (PKU) must follow a lifelong low-phenylalanine (Phe) diet to prevent neurological impairment. Compliance with the low-Phe diet is often poor owing to restriction in natural foods and the requirement for consumption of a Phe-free amino acid formula or medical food. Glycomacropeptide (GMP), a natural protein produced during cheese-making, is uniquely suited to a low-Phe diet because when isolated from cheese whey it contains minimal Phe (2.5-5 mg Phe/g protein). This paper reviews progress in evaluating the safety, acceptability and efficacy of GMP in the nutritional management of PKU. A variety of foods and beverages can be made with GMP to improve the taste, variety and convenience of the PKU diet. Sensory studies in individuals with PKU demonstrate that GMP foods are acceptable alternatives to amino acid medical foods. Studies in the PKU mouse model demonstrate that GMP supplemented with limiting indispensable amino acids provides a nutritionally adequate source of protein and improves the metabolic phenotype by reducing concentrations of Phe in plasma and brain. A case report in an adult with classical PKU who followed the GMP diet for 10 weeks at home indicates safety, acceptability of GMP food products, a 13-14% reduction in blood Phe levels (p<0.05) and improved distribution of dietary protein throughout the day compared with the amino acid diet. In summary, food products made with GMP that is supplemented with limiting indispensable amino acids provide a palatable alternative source of protein that may improve dietary compliance and metabolic control of PKU.

Disfunção muscular esquelética e composição corporal no hipertireoidismo / Skeletal muscle dysfunction and body composition in hyperthyroidism

O objetivo deste artigo é revisar os aspectos da disfunção muscular esquelética e composição corporal no hipertireoidismo. O hipertireoidismo está associado a uma fraqueza muscular generalizada que é parte da manifestação clínica inicial de cerca de 80 por cento dos pacientes, comprometendo a realização de tarefas cotidianas e a qualidade de vida. Um fator que contribui para a redução da força é a atrofia muscular, que tende a afetar mais comumente os grupos musculares proximais. Além disso, o hipertireoidismo é acompanhado de perda ponderal associada à depleção de massa muscular e tecido adiposo. Estudos demonstram que o tratamento medicamentoso é capaz de recuperar a força e mais lentamente a resistência, definida como a capacidade de sustentar cargas submáximas por períodos prolongados, e que o treinamento contra resistência associado ao tratamento medicamentoso, é capaz de promover um maior ganho de força e de resistência muscular nestes pacientes. Embora não tenha sido estabelecido um padrão de composição corporal na recuperação do peso após o tratamento da doença, sabe-se que pacientes submetidos ao treinamento de força apresentam recuperação de peso acompanhado principalmente de ganho de massa muscular.

Dexamethasone decreases serum and liver IGF-I and maintains liver IGF-I mRNA in parenterally fed rats.

Insulin-like growth factor-I (IGF-I) gene expression is regulated by nutritional and hormonal factors. High-dose glucocorticoids decrease food intake, and this confounds studies addressing glucocorticoid effects on IGF-I gene regulation. We investigated alterations in the hepatic IGF-I endocrine system induced by a catabolic dose of dexamethasone (Dex) in rats given adequate nutrition by continuous infusion of total parenteral nutrition (TPN) solution with or without IGF-I administration. The four TPN groups included control, +Dex, +IGF-I, and +IGF-I + Dex (n = 9-11/group). Dex induced a 12% loss of body weight in association with a 50% decrease in hepatic immunoreactive IGF-I, a 10% decrease in serum IGF-I, and no change in steady-state liver IGF-I mRNA or growth hormone (GH) receptor binding. Exogenous IGF-I increased serum IGF-I, attenuated Dex-induced catabolism, and did not reduce hepatic levels of IGF-I and IGF-I mRNA despite decreased serum GH. These data suggest that Dex-induced catabolism is associated with downregulation of the hepatic IGF-I endocrine system at the translational or posttranslational level when adequate nutrition is provided.

Resection upregulates the IGF-I system of parenterally fed rats with jejunocolic anastomosis.

Rats maintained with parenteral nutrition following 60% jejunoileal resection plus cecectomy exhibit minimal adaptive growth in the residual jejunum but a dramatic adaptive growth in the residual colon. Coinfusion of insulin-like growth factor I (IGF-I) with parenteral nutrition induces jejunal growth but has minimal effects in the colon. Our objective was to study the role of the endogenous IGF-I system in the differential responses of jejunum and colon to resection and/or IGF-I during parenteral nutrition. We measured concentrations of immunoreactive IGF-I in plasma, jejunum, and colon, IGF-I receptor binding, and levels of IGF receptor, IGF-I, IGF binding protein (IGFBP)-3 and IGFBP-5 mRNA in residual jejunum and colon 7 days after resection and/or IGF-I treatment. IGF-I receptor number was increased (74-99%) in jejunum and colon due to resection; IGF-I mRNA was increased 5-fold in jejunum and 15-fold in colon due to resection. Resection increased circulating IGFBPs but did not alter plasma IGF-I concentration. Resection induced colonic growth in association with significantly greater colonic IGFBP-5 mRNA and significantly lower colonic immunoreactive IGF-I. IGF-I treatment had no significant effect on IGF-I mRNA or IGF-I receptor number. Concentrations of plasma and jejunal immunoreactive IGF-I were significantly increased in rats given IGF-I in association with jejunal growth. IGF-I treatment significantly increased IGFBP-5 mRNA in the jejunum, which also correlated with jejunal growth. Thus resection upregulated IGF-I receptor number and IGF-I mRNA in residual jejunum and colon, but differential adaptation of these segments correlated with differential regulation of IGFBP-5 mRNA.

A comparison of two opioid analgesics for relief of visceral pain induced by intestinal resection in rats.

While developing a rat model for human short bowel syndrome, we noted that untreated rats as well as rats administered buprenorphine after intestinal resection exhibited behavior and appearance consistent with visceral pain and distress. To provide appropriate analgesics, we developed criteria to assess pain-related behavioral changes and conducted an experiment to evaluate the effectiveness of buprenorphine versus oxymorphone to alleviate the pain induced by intestinal resection. Rats underwent either small-bowel resection or transection surgery; in addition, animals received jugular catheterization for the delivery of total parenteral nutrition (TPN). Rats treated with buprenorphine received 0.5 mg/kg every 6 h subcutaneously, and rats treated with oxymorphone received 0.03 mg/kg hourly for 32 h via continuous intravenous (i.v.) infusion with TPN solution. Rats treated with buprenorphine exhibited behavior and appearance consistent with pain and distress for as long as 32 h postoperatively, whereas animals treated with oxymorphone exhibited behavior and appearance similar to their preoperative state. Thus, oxymorphone alleviated the pain-related behavioral changes after intestinal resection far better than did buprenorphine. Of interest, we observed that the buprenorphine was associated with a decrease in the volume of urine collected, whereas oxymorphone was associated with urine volumes similar to those of nonresected rats maintained with TPN. Because oxymorphone appeared to be a superior analgesic, we also evaluated three routes for administering this drug. Pain-related behavior changes were alleviated by the administration of oxymorphone by either Alzet mini-pump, bolus i.v. injection, or continuous i.v. infusion. We conclude that compared with buprenorphine, oxymorphone is a superior analgesic for the alleviation of visceral pain due to intestinal resection.

Enterotrophic effect of insulin-like growth factor-I but not growth hormone and localized expression of insulin-like growth factor-I, insulin-like growth factor binding protein-3 and -5 mRNAs in jejunum of parenterally fed rats.

BACKGROUND: Administration of insulin-like growth factor (IGF)-I, but not growth hormone (GH), stimulates mucosal hyperplasia in surgically stressed rats with intestinal atrophy induced by hypocaloric total parenteral nutrition (TPN). Our aim was to characterize the basis for this disparity in enterotrophic action by assessing the relationships between stimulation of intestinal growth, nutritional adequacy, and localization of expression of IGF-I, insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-5 mRNAs in jejunum. METHODS: Rats were maintained with TPN for 8 days and treated with IGF-I or GH and adequate nutrition for 5 days after recovery from surgery. Jejunal mass, morphology, and sucrase activity were assessed. Localization of expression of IGF-I, IGFBP-3, and IGFBP-5 mRNAs in jejunum was accomplished by in situ hybridization. RESULTS: Serum IGF-I and body weight gain were significantly increased by IGF-I or GH. Jejunal mucosal dry mass, morphology, and sucrase activity were improved with IGF-I but not GH. There were no differences in IGF-I mRNA. IGFBP-3 mRNA was localized in the lamina propria of the villi. IGF-I or GH stimulated IGFBP-3 expression. IGF-I strongly stimulated IGFBP-5 expression in the lamina propria and the muscularis and induced a twofold increase in IGFBP-5 mRNA based on RNase protection assay of intact jejunum total RNA. GH induced a modest increase in IGFBP-5 expression in the muscularis with no effect on intact jejunum total RNA. CONCLUSIONS: The GH resistance observed in the jejunal mucosa of TPN rats cannot be fully explained by inadequate nutrition. The expression of IGFBP-5 in the lamina propria suggests it may modulate the enterotrophic action of exogeneous IGF-I.

Differential jejunal and colonic adaptation due to resection and IGF-I in parenterally fed rats.

Patients with severe short-bowel syndrome (SBS) often require long-term total parenteral nutrition (TPN) to maintain their nutritional status because of limited intestinal adaptation. Growth factors, including insulin-like growth factor I (IGF-I), are under investigation to promote intestinal adaptation and tolerance to oral feeding. We investigated structural and functional adaptation of the jejunum and colon in four groups of rats maintained with TPN for 7 days after a 60% jejunoileal resection and cecectomy or sham surgery and treatment with IGF-I or vehicle. Resection alone did not stimulate jejunal growth. IGF-I significantly increased jejunal mucosal mass, enterocyte proliferation, and migration rates. IGF-I decreased jejunal sucrase specific activity and reduced active ion transport and ionic permeability; resection alone had no effect. In contrast, resection significantly increased colonic mass and crypt depth but had no effect on active ion transport or ionic permeability. IGF-I had minimal effects on colonic structure. IGF-I but not resection stimulates jejunal adaptation, whereas resection but not IGF-I stimulates colonic growth in rats subjected to a model for human SBS. IGF-I treatment may improve intestinal adaptation in humans with SBS.

Growth hormone, insulin-like growth factor-1, and the insulin-like growth factor binding proteins in rats maintaining reduced body protein following lesions of the lateral hypothalamus.

Rats with lesions of the lateral hypothalamus (LH) maintain a reduced body protein mass that they effectively defend when challenged by under- or over-nutrition. The two studies reported here evaluate the potential contributions of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and the insulin-like growth factor-binding (IGFBP) to this persistent maintenance of a reduced body protein mass by LH rats. At 18 weeks postlesion, it was found that the serum levels of GH, IGF-1, total IGFBP, and IGFBP-3 of LH rats maintaining reduced body protein were not different from those of age-matched controls. However, closer to the time of surgery, at which time the lesion-induced body protein adjustments are known to occur, altered hormone and binding protein levels were observed. Specifically, at 3 weeks after lesioning, the IGF-binding proteins of LH rats were significantly elevated, whereas their GH levels were lower than those of controls. Because the GH, IGF-1, and IGF-binding proteins of LH rats were comparable to those of controls at 18 weeks after lesioning, none apparently underlie the chronically reduced body protein mass that LH rats display. Closer to the time of lesioning, however, altered GH and IGF binding protein levels may contribute to the postlesion adjustments by which the body protein mass of LH rats is lowered to its reduced level.

Greater potency of IGF-I than IGF-I/BP-3 complex in catabolic parenterally fed rats.

We compared the anabolic effects of recombinant human insulin-like growth factor I (rhIGF-I, 2.5 mg/kg) and equimolar amounts of rhIGF-I prebound to rhIGF binding protein-3 (rhIGF-I/BP-3) coinfused continuously with total parenteral nutrition (TPN) solution in dexamethasone (Dex, 70 microg/day ip)-treated male rats for 6 days. The four TPN groups included control, Dex, Dex + IGF-I, and Dex+IGF-I/BP-3. Pharmacokinetic analysis indicated reduced clearance of IGF-I when infused as IGF-I/BP-3 compared with free IGF-I (0.91 +/- 0.09 vs. 2.01 +/- 0.19 ml serum/min, P < 0.001) and this was associated with significantly greater serum IGF-I concentrations in the Dex+IGF-I/BP-3 group. Despite greater total serum IGF-I levels, infusion of free IGF-I produced greater anabolic responses than IGF-I/BP-3 based on body weight, nitrogen balance, and jejunal cellularity. Treatment with free IGF-I, but not IGF-I/BP-3, significantly reduced serum insulin and glucose levels that were elevated due to Dex. There were no significant differences in liver IGF-I mRNA levels between groups. Serum IGFBP-3 levels were elevated with infusion of IGF-I/BP-3 compared with IGF-I. These results indicate greater anabolic potency of IGF-I compared with IGF-I/BP-3 when administered by continuous parenteral infusion with TPN solution in catabolic rats.

Effects of insulin-like growth factor-I and growth hormone in models of parenteral nutrition.

BACKGROUND: Administration of growth factors such as growth hormone (GH) and insulin-like growth factor-I (IGF-I) is being investigated as a strategy to promote nitrogen accretion in catabolic patients who may require total parenteral nutrition (TPN). IGF-I has advantages compared with GH because IGF-I enhances insulin sensitivity, is effective in conditions of GH resistance, and selectively stimulates the gastrointestinal and immune systems. METHODS: Experiments were conducted to evaluate the anabolic and metabolic effects associated with administration of recombinant human GH or IGF-I in rats subjected to clinically relevant stress and maintained with TPN. RESULTS: Administration of IGF-I, but not GH, attenuates dexamethasone-induced protein catabolism and increases insulin sensitivity. Simultaneous treatment with GH and IGF-I additively increases the serum concentration of IGF-I, whole-body anabolism, and lipid oxidation. GH or IGF-I when given alone produces similar increases in the serum concentration of IGF-I. However, GH selectively increases skeletal muscle mass whereas IGF-I selectively attenuates the intestinal atrophy and abnormal intestinal ion transport induced by TPN. These tissue-selective anabolic effects of GH and IGF-I are associated with differential increases in protein synthesis in skeletal muscle and jejunum, respectively. CONCLUSIONS: Simultaneous treatment with GH and IGF-I may offer the greatest clinical efficacy because of improved nitrogen retention in association with enhanced lipid oxidation and stimulation of protein synthesis in multiple tissue types.

Investigation of insulin-like growth factor (IGF)-I and insulin receptor binding and expression in jejunum of parenterally fed rats treated with IGF-I or growth hormone.

To investigate the ability of insulin-like growth factor-I (IGF-I), but not GH, to stimulate jejunal growth, we compared indices of IGF-I and insulin receptor expression in jejunal membranes from rats maintained with total parenteral nutrition (TPN) and treated with rhIGF-I and/or rhGH. TPN without growth factor treatment (TPN control) induced jejunal atrophy, reduced serum IGF-I, increased serum insulin concentrations, and increased IGF-I receptor number, IGF-I receptor messenger RNA, and insulin-specific binding to 133% to 170% of the orally fed reference values, P < 0.01. Compared with TPN control, IGF-I or IGF-I + GH stimulated jejunal mucosal hyperplasia; IGF-I treatment increased serum IGF-I by 2- to 3-fold and decreased serum insulin concentrations by 60%, decreased IGF-I receptor number by 50% (P < 0.001), and increased insulin receptor affinity and insulin receptor protein content. Treatment with GH alone increased serum IGF-I concentration, did not alter TPN-induced jejunal atrophy, and decreased insulin-specific binding and insulin receptor protein content (39% and 59%, respectively, of the TPN control values, P < 0.01). We conclude that: 1) jejunal IGF-I receptor content reflects circulating concentration of ligand and is not limiting for jejunal growth; and 2) increased circulating concentration of IGF-I may promote jejunal growth via interaction with jejunal insulin or IGF-I receptors.

Dietary conjugated linoleic acids alter serum IGF-I and IGF binding protein concentrations and reduce bone formation in rats fed (n-6) or (n-3) fatty acids.

A study was designed to examine the effects of dietary conjugated linoleic acid (CLA) on serum concentrations of insulin-like growth factor-I (IGF-I) and IGF binding proteins (IGFBP) and the relationship of these factors to bone metabolism. Weanling male rats were fed AIN-93G diet containing 70 g/kg of added fat for 42 days. Treatments included 0 g/kg or 10 g/kg of CLA and soybean oil (SBO) or menhaden oil + safflower oil (MSO) following a 2 x 2 factorial design. Serum IGFBP was influenced by dietary polyunsaturated fatty acid (PUFA) type ((n-6) and (n-3)) and CLA (p = 0.01 for 38-43 kDa bands corresponding to IGFBP-3). CLA increased IGFBP level in rats fed SBO (p = 0.05) but reduced it in those fed MSO (p = 0.01). Rats fed MSO had the highest serum IGFBP-3 level. Both (n-3) fatty acids and CLA lowered ex vivo prostaglandin E2 production in bone organ culture. In tibia, rats given CLA had reduced mineral apposition rate (3.69 vs. 2.79 microm/day) and bone formation rate (BFR) (0.96 vs. 0.65 microm3/microm2/day); however, the BFR tended to be higher with MSO. Dietary lipid treatments did not affect serum intact osteocalcin or bone mineral content. These results showed that dietary PUFA type and CLA modulate local factors that regulate bone metabolism.

Gastric digestion modifies absorption of butterfat into lymph chylomicrons in rats.

Our objective was to characterize the time course of mesenteric lymph output, lipid composition and size of lymph chylomicrons in rats given gastric infusion of lipid emulsions containing defined fractions of butterfat, palm oil or corn oil. The concentrations of cholesterol, triacylglycerol (TAG) and phospholipid in lymph obtained before lipid infusion were 1.4-2.5-fold greater in rats chronically fed palm oil or solid butterfat compared with corn oil or liquid butterfat (P = 0.02). Total lymph chylomicron TAG output (mg/24 h) stimulated by gastric lipid infusion was 21% greater with corn oil compared with all saturated fats (P = 0.02). Total lymph chylomicron cholesterol output was 1.3-8.6-fold greater than the amount infused in all groups (P = 0.03) and was independent of the amount of cholesterol infused. The size distribution as well as the mean, median and modal diameters of lymph chylomicrons isolated during peak lymphatic TAG output were not significantly different among treatments. The fatty acid and TAG profiles of lymph chylomicrons obtained from rats infused with corn or palm oil did not differ significantly from that of the emulsion infused. In contrast, gastric lipolysis of butterfat significantly modified the lipid composition of lymph chylomicrons. We observed progressive disappearance of short- and medium-chain fatty acids in gastric contents and an absence of detectable short-chain fatty acids with concurrent proportionate increases in long-chain fatty acids and large TAG molecules in lymph chylomicrons compared with butterfat emulsions. These studies demonstrate that gastric digestion is an important modifier of lipid absorption.

Medium-chain compared with long-chain triacylglycerol emulsions enhance macrophage response and increase mucosal mass in parenterally fed rats.

We tested whether infusion of medium-chain triacylglycerols (MCTs) during total parenteral nutrition (TPN) enhanced macrophage response and reduced intestinal atrophy compared with long-chain triacylglycerols (LCTs). Male Sprague-Dawley rats (230-240 g) were maintained with TPN providing 16% or 48% of nonprotein energy from MCTs plus LCTs or LCTs alone or 100% of nonprotein energy from dextrose for 6 or 12 d. Body weight gain was not significantly different among groups. Serum concentrations of beta-hydroxybutyrate were greater with MCTs plus LCTs than with LCTs alone after 6 d (P < 0.05, main effect). Triacylglycerol concentrations in liver were greater with LCTs than with MCTs plus LCTs after 6 or 12 d (P < 0.05, main effect). MCTs plus LCTs increased by 50% the percentage (P < 0.0005) and number of splenic macrophages compared with LCTs alone in conjunction with decreased triacylglycerol concentrations in spleen after 6 d (P < 0.05, main effect). In vitro tumor necrosis factor alpha secretion by splenic or circulating macrophages in response to lipopolysaccharide was increased by MCTs plus LCTs compared with LCTs alone, twofold after 6 and sevenfold after 12 d (P < 0.05, main effect). Jejunal mucosal mass was 30% greater with MCTs plus LCTs than with LCTs alone after 6 or 12 d (P < 0.01); villus height was also significantly greater after 6 d (main effect). The incidence of bacterial translocation to the mesenteric lymph nodes was not significantly different among groups. Compared with LCTs, MCTs enhanced macrophage response and decreased intestinal atrophy.

Exercise training down-regulates hepatic lipogenic enzymes in meal-fed rats: fructose versus complex-carbohydrate diets.

The maximal activity and mRNA abundance of hepatic fatty acid synthase (FAS) and other lipogenic enzymes were investigated in rats meal-fed either a high fructose (F) or a high cornstarch (C) diet. The diet contained 50% F or C (g/100 g), casein (20%), cornstarch (16.13%), corn oil (5%), minerals (5.37%), vitamins (1%) and Solka-floc (2%). Female Sprague-Dawley rats (n = 44) were randomly divided into C or F groups that were meal-fed for 3 h/d; each group was subdivided into exercise-trained (T) and untrained (U) groups. Treadmill training was performed 4 h after the initiation of the meal at 25 m/min, 10% grade for 2 h/d, 5 d/wk, for 10 wk. Rats were killed 9 h after the meal and 27 h after the last training session. F-fed rats had significantly higher activities of all lipogenic enzymes assayed and mRNA abundance of FAS and acetyl-coenzyme A carboxylase (ACC) than C rats (P < 0.05). Concentrations of plasma insulin and glucose and liver pyruvate were not altered by F feeding. Proportions of the fatty acids 18:2 and 20:4 were lower, whereas those of 16:0 and 16:1 were higher, in livers of F than of C rats (P < 0.05). Training decreased FAS activity by 50% (P < 0.05), without affecting FAS mRNA level in C rats; this down-regulation was absent in the F rats. ACC mRNA abundance tended to be lower in CT than in CU rats (P < 0.075). L-Type pyruvate kinase activity was lower in FT than in FU rats (P < 0.05), whereas other lipogenic enzyme activities did not differ between T and U rats of each diet group. We conclude that hepatic lipogenic enzyme induction by high carbohydrate meal feeding may be inhibited by exercise training and that a fructose-rich diet may attenuate this training-induced down-regulation.

IGF-I alters lymphocyte survival and regeneration in thymus and spleen after dexamethasone treatment.

Insulin-like growth factor I (IGF-I) is a growth factor for the immune system, increasing lymphocyte number and function via greater lymphocyte generation and/or survival. We investigated the effects of IGF-I on lymphocyte survival and regeneration in the thymus and spleen after dexamethasone (Dex) treatment in rats maintained with parenteral nutrition and given recombinant human IGF-I (800 micrograms/day) for 12 h, 48 h, and 5 days. IGF-I did not prevent Dex-induced apoptosis of thymocytes but reduced cell death in the spleen at 12 and 48 h. IGF-I exerted a modest protective effect (10-15% reduction in cell loss) on all splenic T and B cell subsets examined by flow cytometry. IGF-I enhanced recovery of CD4+8+ immature T cells in the thymus and decreased the proportion of CD8+ (cytotoxic/suppressor) T cells in the spleen. In rats not treated with Dex, IGF-I significantly increased total lymphocyte number and the number of CD4+8+ T cells in thymus and spleen. Our results suggest that IGF-I may alter homeostasis in the immune system by modulating lymphocyte generation and survival.

Stimulation of intestinal growth is associated with increased insulin-like growth factor-binding protein 5 mRNA in the jejunal mucosa of insulin-like growth factor-I-treated parenterally fed rats.

Surgically stressed rats maintained with total parenteral nutrition (TPN) exhibit jejunal atrophy, which can be attenuated by insulin-like growth factor-I (IGF-I) but not by growth hormone (GH) treatment. In order to understand the basis for the selective action of IGF-I, the levels of mRNAs encoding IGF-I, IGF-binding proteins (IGFBPs), IGF-I receptor, and GH receptor/binding protein (GHR/GHBP) were determined in rats given TPN and treated with GH, IGF-I, or GH + IGF-I. GH treatment significantly stimulated hepatic IGF-I mRNA. IGF-I treatment did not alter liver IGF-I mRNA, nor was there any evidence for interaction between GH and IGF-I. Jejunal mucosa IGF-I mRNA was extremely low and was not altered by TPN or by any of the hormonal treatments. The inability of GH to stimulate jejunal growth was not associated with a deficiency in GHR/GHBP mRNA. In jejunal mucosa, IGF-I and GH treatment independently and synergistically stimulated IGFBP-3 mRNA. IGF-I stimulated jejunal IGFBP-5 mRNA, but GH had no effect on IGFBP-5 mRNA. The levels of IGF-I receptor and IGFBP-1, 2, 4, and 6 mRNAs were extremely low and/or were not altered by any of the treatments. These results suggest that the ability of exogenous IGF-I, but not GH, to induce IGFBP-5 mRNA in jejunal mucosa may lead to the selective growth-promoting effect of IGF-I. Jejunal mucosa IGFBP-3 mRNA levels were not correlated with altered growth. We postulate that IGFBP-5 positively modulates the anabolic effects induced by exogenous IGF-I in the jejunum.

GH elevates serum IGF-I levels but does not alter mucosal atrophy in parenterally fed rats.

Growth hormone (GH) action is primarily mediated by insulin-like growth factor I (IGF-I), although both growth factors show tissue-selective effects. We investigated the effects of GH, IGF-I, and GH plus IGF-I on jejunal growth and function in rats maintained with total parenteral nutrition (TPN) and given recombinant human GH (rhGH) (400 micrograms/day sc, twice daily) and/or rhIGF-I (800 micrograms/day in TPN solution) for 5 days. Administration of GH or IGF-I alone produced similar increases in serum IGF-I levels and body weight; GH plus IGF-I further increased these parameters. TPN reduced mucosal mass, protein and DNA content, villus height, crypt depth, and enterocyte migration rate. IGF-I or GH plus IGF-I produced equivalent increases in all intestinal growth parameters; GH alone had no effect. GH, IGF-I, or GH plus IGF-I reduced TPN-induced increases in sucrase-specific activity. IGF-I, but not GH, attenuated TPN-induced increases in tissue conductance and carbachol-stimulated ion secretion. In contrast to IGF-I, GH does not stimulate intestinal growth during TPN and has less effect on normalizing TPN-induced changes in epithelial function.

Growth hormone or insulin-like growth factor I increases fat oxidation and decreases protein oxidation without altering energy expenditure in parenterally fed rats.

We assessed whether the increased growth in parenterally fed rats treated with growth hormone (GH) or insulin-like growth factor I (IGF-I) or both is associated with alterations in energy expenditure or macronutrient oxidation or both. Surgically stressed male rats (approximately 235 g) were given total parenteral nutrition (TPN) and treated with recombinant human GH (rhGH) (800 micrograms/d), rhIGF-I (800 micrograms/d), rhGH+rhIGF-I (800 micrograms/d of each), or TPN alone for 3 d. Treatment with GH or IGF-I or both resulted in significantly greater body weight gain, nitrogen retention, and serum total IGF-I concentrations compared with TPN alone (P < 0.0001). Assessment of respiratory gas exchange and motor activity for 23 h on day 3 indicated no significant differences between groups in either total or activity-related rates of energy expenditures (kJ/kg0.75). Estimates based on the nitrogen-free respiratory quotient (RQ) revealed fat oxidation to be significantly increased by GH (P < 0.001) and IGF-I (P < 0.03), whereas protein oxidation was significantly reduced (P < 0.0001) by these growth factors. GH and IGF-I combined further enhanced fat oxidation while reducing protein catabolism. Serum insulin concentrations were significantly increased by GH but decreased by IGF-I. GH significantly decreased serum total triiodothyronine concentrations and IGF-I significantly decreased serum corticosterone concentrations. These results suggest that treatment with GH or IGF-I can increase fat oxidation and spare protein for growth without altering energy expenditure in surgically stressed rats maintained with TPN.