Biomedical subjects

Denise M Ney

Publications and source records attributed to Denise M Ney.

15 recordsLinked to original sources

PubMed2006

Loss of exocrine pancreatic stimulation during parenteral feeding suppresses digestive enzyme expression and induces Hsp70 expression.

Luminal nutrients are essential for the growth and maintenance of digestive tissue including the pancreas and small intestinal mucosa. Long-term loss of luminal nutrients such as during animal hibernation has been shown to result in mucosal atrophy and a corresponding stress response characterized by the induction of heat shock protein (Hsp)70 expression. This study was conducted to determine if the loss of luminal nutrients during total parenteral nutrition (TPN) would result in atrophy of the exocrine pancreas and small intestinal mucosa as well as an induction of Hsp70 expression in rats. In experiment 1, the treatment groups included an orally fed control, a saline-infused surgical control, or TPN treatment for 7 days. In experiment 2, the treatment groups included an orally fed control and TPN alone or coinfused with varying doses of glucagon-like peptide (GLP)-2, a mucosal proliferation agent, for 7 days. In experiment 1, TPN resulted in a 40% reduction in pancreatic mass that was associated with a dramatic reduction in digestive enzyme expression, enhanced apoptosis, and a 200% increase in Hsp70 expression. Conversely, heat shock cognate 70, Hsp27, and Hsp60 expression was not changed in the pancreas. In experiment 2, TPN resulted in a 30% reduction in jejunal mucosa mass and a similar induction of Hsp70 expression. The inclusion of GLP-2 during TPN attenuated jejunal mucosal atrophy and inhibited Hsp70 expression, suggesting that Hsp70 induction is sensitive to cell growth. These data indicate that pancreatic and intestinal mucosal atrophy caused by a loss of luminal nutrient stimulation is accompanied by a compensatory response involving Hsp70.

Amylases↗

PubMed2006

Synergistic effect of supplemental enteral nutrients and exogenous glucagon-like peptide 2 on intestinal adaptation in a rat model of short bowel syndrome.

BACKGROUND: Short bowel syndrome (SBS) can lead to intestinal failure and require total or supplemental parenteral nutrition (TPN or PN, respectively). Glucagon-like peptide 2 (GLP-2) is a nutrient-dependent, proglucagon-derived gut hormone that stimulates intestinal adaptation. OBJECTIVE: Our objective was to determine whether supplemental enteral nutrients (SEN) modulate the intestinotrophic response to a low dose of GLP-2 coinfused with PN in a rat model of SBS (60% jejunoileal resection plus cecectomy). DESIGN: Rats were randomly assigned to 8 treatments by using a 2 x 2 x 2 factorial design and maintained with either TPN or PN for 7 d. The 3 main treatment effects were the following: transection or resection (TPN alone), +/- SEN (days 4-6), and +/- GLP-2 (100 mug . kg body wt(-1) . d(-1)). RESULTS: The treatments induced differential growth of duodenal and jejunal mucosa. Significant differences in villus height, crypt depth, dry mass, and concentrations of protein and DNA were observed between the treatments and TPN alone (SEN: 15-59% increase; GLP-2: 14-84% increase; and SEN + GLP-2: 63-160% increase). Plasma concentrations of bioactive GLP-2 were significantly greater with GLP-2 infusion (TPN alone: 25 +/- 9 pmol/L; SEN: 29 +/- 10 pmol/L; GLP-2: 59 +/- 31 pmol/L; SEN + GLP-2: 246 +/- 40 pmol/L) and correlated with mucosal growth. Jejunal sucrase activity (in U/cm) was significantly greater with SEN than without SEN. SEN + GLP-2 induced dramatic mucosal growth and greater plasma concentration of GLP-2 (SEN x GLP-2 interaction, P < 0.0001). Resection significantly increased expression of proglucagon mRNA in colon. CONCLUSIONS: Combination treatment with SEN and GLP-2 induced a synergistic response resulting in greater mucosal cellularity and digestive capacity in parenterally fed rats with SBS. This shows that SEN improve the intestinotrophic response to exogenous GLP-2, possibly by stimulating enterocyte proliferation and differentiation.

Adaptation, Physiological↗

PubMed2006

Vagal afferents are essential for maximal resection-induced intestinal adaptive growth in orally fed rats.

Small bowel resection stimulates intestinal adaptive growth by a neuroendocrine process thought to involve both sympathetic and parasympathetic innervation and enterotrophic hormones such as glucagon-like peptide-2 (GLP-2). We investigated whether capsaicin-sensitive vagal afferent neurons are essential for maximal resection-induced intestinal growth. Rats received systemic or perivagal capsaicin or ganglionectomy before 70% midjejunoileal resection or transection and were fed orally or by total parenteral nutrition (TPN) for 7 days after surgery. Growth of residual bowel was assessed by changes in mucosal mass, protein, DNA, and histology. Both systemic and perivagal capsaicin significantly attenuated by 48-100% resection-induced increases in ileal mucosal mass, protein, and DNA in rats fed orally. Villus height was significantly reduced in resected rats given capsaicin compared with vehicle. Sucrase specific activity in jejunal mucosa was not significantly different; ileal mucosal sucrase specific activity was significantly increased by resection in capsaicin-treated rats. Capsaicin did not alter the 57% increase in ileal proglucagon mRNA or the 150% increase in plasma concentration of bioactive GLP-2 resulting from resection in orally fed rats. Ablation of spinal/splanchnic innervation by ganglionectomy failed to attenuate resection-induced adaptive growth. In TPN rats, capsaicin did not attenuate resection-induced mucosal growth. We conclude that vagal afferents are not essential for GLP-2 secretion when the ileum has direct contact with luminal nutrients after resection. In summary, vagal afferent neurons are essential for maximal resection-induced intestinal adaptation through a mechanism that appears to involve stimulation by luminal nutrients.

Adaptation, Physiological↗

PubMed2005

Suppressor of cytokine signaling-2 modulates the fibrogenic actions of GH and IGF-I in intestinal mesenchymal cells.

Growth hormone (GH) and IGF-I play important roles in wound healing during intestinal injury and inflammation, but there is also indirect evidence that locally expressed IGF-I may act to induce excessive collagen deposition, which can lead to intestinal fibrosis. Factors that dictate the balance between normal wound healing and excessive healing responses are unknown. Using RNase protection assay and in situ hybridization, we determined whether GH and/or IGF-I increase type I collagen deposition in the intestine of rats fed by total parenteral nutrition (TPN), a feeding modality used for many patients following intestinal surgery and resection. We also used an in vitro model system to confirm our in vivo effects and to directly evaluate the relative potency of GH and IGF-I on DNA synthesis and collagen deposition in intestinal myofibroblasts. Both GH and IGF-I stimulated collagen production in vivo and in vitro, and IGF-I, but not GH, stimulated DNA synthesis in vitro. In collagen production, GH was less potent than IGF-I. Suppressors of cytokine signaling (SOC) are cytokine-inducible proteins that negatively feedback to inhibit the actions of cytokines and we recently found that GH selectively upregulates SOC-2 in the intestine of TPN-fed rats. We examined whether SOC-2 may be responsible for the difference in magnitude of action of GH and IGF-I on collagen accumulation. GH, but not IGF-I, induced SOC-2 in isolated myofibroblasts, and overexpression of SOC-2 led to a suppression of GH- and IGF-I-induced collagen accumulation. SOC-2 null mice infused with IGF-I showed greater collagen gene expression compared with wild-type (WT) mice. Myofibroblasts isolated from SOC-2 null mice showed increased IGF-I-stimulated DNA synthesis compared with WT cells. Taken together, these findings suggest that SOC-2 induced by GH may play an important role in suppressing collagen accumulation and mesenchymal cell proliferation induced by GH or GH-induced IGF-I, providing a mechanism for the differing potencies of GH and IGF-I on intestinal mesenchyme and collagen synthesis.

Animals↗

PubMed2005

Insulin-like growth factor-I (IGF-I) attenuates jejunal atrophy in association with increased expression of IGF-I binding protein-5 in parenterally fed mice.

Total parenteral nutrition (TPN) induces dramatic mucosal hypoplasia in rat small intestine that is attenuated by insulin-like growth factor-I (IGF-I). Our aim was to determine the extent of TPN-induced intestinal atrophy and its response to infusion of IGF-I in mice. Male C57BL/6 mice (18-22 g) were maintained with TPN, TPN plus co-infusion of recombinant human IGF-I [2.5 mg/(kg . d)] or oral feeding for 5 d. Body weights did not differ among the groups although serum IGF-I was increased by 78% with IGF-I infusion. IGF-I prevented the significant 25% reduction in mass of the intact small intestine due to TPN compared with oral feeding. Greater TPN-induced atrophy was noted in duodenum and jejunum than ileum. Jejunal atrophy induced by TPN reflected significant decreases in muscularis mass and concentrations of protein and DNA; mucosal cellularity was not altered by TPN. TPN induced a significant decrease in jejunal muscularis width that was reversed by IGF-I with no differences in mucosal villus height and crypt depth. Local expression of IGF-I binding protein (IGFBP)-5 positively modulates the intestinotrophic effects of IGF-I. Jejunal atrophy due to TPN and growth due to IGF-I were directly associated with expression of IGFBP-5 mRNA. TPN decreased IGFBP-5 mRNA by 60% and IGF-I increased IGFBP-5 mRNA by 200% with no change in IGF-I mRNA compared with oral feeding. In summary, TPN induces significant 25% atrophy of the mouse small intestine that is attenuated by IGF-I in association with increased expression of IGFBP-5. Compared with rats, TPN-induced atrophy is less severe and occurs primarily in the jejunal muscularis layer in mice.

Animals↗

PubMed2005

Hypoenergetic high-carbohydrate or high-fat parenteral nutrition induces a similar metabolic response with differential effects on hepatic IGF-I mRNA in dexamethasone-treated rats.

The optimal level of energy for critically ill patients who require parenteral nutrition (PN) is unclear. Our objective was to determine whether 50% energy (50%E) restriction due to a reduction in carbohydrate or fat, with provision of adequate protein and micronutrients, ameliorates the detrimental effects of dexamethasone (Dex) on body protein catabolism, insulin resistance, and insulin-like growth factor-I (IGF-I) responses in rats administered PN. The experiment included 6 PN groups, adequate energy (AE) +/- Dex, 50% AE with high carbohydrate (50%E CHO) +/- Dex and 50% AE with high fat (50%E FAT) +/- 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 approximately 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%E CHO and 50%E FAT had differential effects on hepatic IGF-I mRNA with a 40% decrease in IGF-I mRNA due to 50%E FAT+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.

Animals↗

PubMed2004

Suppressor of cytokine signaling-2: a growth hormone-inducible inhibitor of intestinal epithelial cell proliferation.

BACKGROUND & AIMS: Growth hormone (GH) and insulin-like growth factor-I (IGF-I) increase intestinal growth. GH is thought to act indirectly via IGF-I. In several models, including rats given total parenteral nutrition (TPN), IGF-I more potently stimulates mucosal growth than GH, even when GH induces similar circulating IGF-I levels. These studies test the hypothesis that GH induces a suppressor of cytokine signaling (SOCS), which inhibits intestinal epithelial cell (IEC) proliferation. METHODS: Rats on TPN received vehicle, GH, or IGF-I. Jejunal SOCS (SOCS-1, -2, -3, and cytokine-inducible SH2-domain-containing protein [CIS]) and IGF-I messenger RNA (mRNA) were quantified. Caco-2, IEC-6 cells, and SOCS-2 null and wild-type (WT) mice were used to examine the expression and functional role of SOCS-2. RESULTS: As reported previously, IGF-I, but not GH, prevented mucosal atrophy during TPN, although GH elevated plasma IGF-I and increased body weight. GH, but not IGF-I, induced jejunal SOCS-2 mRNA. SOCS-2 mRNA levels in GH and IGF-I-treated rats inversely correlated with mucosal weight. SOCS-2 is expressed in Caco-2 cells, and elevated SOCS-2 expression in postconfluent cells is associated with reduced proliferative rates. SOCS-2 overexpression in Caco-2 cells inhibited cell proliferation and promoted differentiation. In IEC-6 cells, GH induced SOCS-2 and reduced basal or IGF-I-induced proliferation. GH also reduced proliferative activity in isolated crypts from WT but not SOCS-2 null mice, and SOCS-2 null crypts showed enhanced proliferative responses to GH and IGF-I. SOCS-2 null mice have increased intestinal weight and length. CONCLUSIONS: SOCS-2 is a GH-inducible, novel inhibitor of intestinal epithelial cell proliferation and intestinal growth.

Animals↗

PubMed2004

Intestinal adaptation occurs independently of parenteral long-chain triacylglycerol and with no change in intestinal eicosanoids after mid-small bowel resection in rats.

The role of enteral or parenteral long-chain triacylglycerol (LCT) in the complex process of intestinal adaptation is poorly defined and may involve alterations in eicosanoid synthesis. Our objective was to determine whether provision of parenteral LCT stimulates eicosanoid synthesis and resection-induced intestinal adaptation. We assessed small bowel structural adaptation, the fatty acid profiles of liver, plasma and jejunal mucosa, and the profile of 11 eicosanoids derived from (n-6) PUFA of the jejunal mucosa in rats maintained with total parenteral nutrition (TPN) with 0 or 32% of nonprotein energy from Intralipid for 7 d after mid-small bowel resection or transection control surgery. There was no evidence of biochemical essential fatty acid (EFA) deficiency in the absence of parenteral fat. Resection-induced gut growth occurred independently of parenteral LCT based on significant mucosal hyperplasia in the jejunum and ileum. The mucosal profile of linoleic acid in the total lipid extract of jejunum increased with the presence of parenteral LCT, but decreased with resection without differences in arachidonic acid. There were no differences in the jejunal profile of 11 (n-6)-derived eicosanoids among the four TPN groups as determined by tandem MS. In summary, small bowel resection-induced adaptation occurs independently of parenteral LCT, and fat-free TPN without EFA deficiency does not alter the profile of jejunal (n-6)-derived eicosanoids. Thus, parenteral administration of LCT does not appear to alter jejunal eicosanoid synthesis nor is it beneficial in stimulating intestinal adaptation.

Adaptation, Physiological↗

PubMed2004

Postreceptor resistance to exogenous growth hormone exists in the jejunal mucosa of parenterally fed rats.

Our objective was to determine whether the intestinal mucosa is resistant to the mitogenic effects of exogenous growth hormone (GH) but sensitive to exogenous insulin-like growth factor-I (IGF-I) during total parenteral nutrition (TPN) because of decreased GH receptor (GHR) binding or postreceptor responsiveness to GH. First, only continuous i.v. administration of IGF-I, but neither pulsatile subcutaneous nor continuous i.v. GH, stimulated jejunal mucosal hyperplasia; however, both GH and IGF-I increased serum IGF-I and promoted similar whole-body growth after 8 d of exclusive TPN and 6 d of growth factor treatment in rats. This suggests a tissue-specific resistance to GH action in the intestinal mucosa during TPN. Second, exogenous GH during TPN did not reduce GH-specific binding in jejunum, suggesting that the inability of GH to stimulate mucosal hyperplasia is not due to low levels of the GHR. Third, IGF-I, but not GH, induced acute expression of c-fos (P < 0.009) and c-jun (P = 0.053) mRNAs in jejunum based on Northern analysis and in situ hybridization histochemistry 60 min after a single i.v. bolus of GH or IGF-I. This suggests that IGF-I, but not GH, activates early postreceptor growth-related signaling pathways in jejunum. In summary, the lack of early c-fos and c-jun induction in response to GH in TPN rats indicates that the jejunal mucosa is resistant to exogenous GH between GHR activation and induction of immediate early genes. This may contribute to the inability of mucosal cells to respond to the trophic effects of GH.

Animals↗

PubMed2003

IGF-I augments resection-induced mucosal hyperplasia by altering enterocyte kinetics.

Our objective was to determine if exogenous insulin-like growth factor-I (IGF-I) augments the adaptive growth response to mid small bowel resection in association with changes in enterocyte kinetics. We determined structural adaptation and concomitant changes in enterocyte proliferation, apoptosis, and migration of the jejunum in growing, parenterally fed rats after mid small bowel resection or small bowel transection, and treatment with IGF-I or vehicle. IGF-I treatment in resected rats significantly increased jejunal mucosal mass by 20% and mucosal concentrations of protein and DNA by 36 and 33%, respectively, above the response to resection alone. The enhancement of resection-induced adaptive growth and cellularity by IGF-I reflected an increase in enterocyte proliferation, an expansion of the proliferative compartment in the crypt, and no further decrease in enterocyte apoptosis or increase in enterocyte migration beyond the effects of resection. The ability of IGF-I to augment the mucosal hyperplasia stimulated by the endogenous response to resection substantiates the role of IGF-I as an intestinal mitogen that promotes tissue regeneration.

Adaptation, Physiological↗

PubMed2003

Introducing a problem-based unit into a lifespan nutrition class using a randomized design produces equivocal outcomes.

Problem-based learning (PBL) is a tutorial, student-centered, problem-driven educational strategy adopted by medical and allied health educators to positively influence self-directed learning, critical thinking, and learning behavior. PBL was examined in dietetics education through random assignment of 32 undergraduate dietetics students for two weeks to either a problem-based or a lecture-based case format for the infant and elderly units of a 16-week lifespan nutrition course. Random assignment followed stratification for gender and earlier course examination performance. Expert validation of PBL curricular components and noted differences in discussion structure and information resources verified curriculum distinctiveness. Main outcome measures were pre- and post-Cognitive Behavior Survey scores for memorization, reflection, and positive learning experience scales, unit and course evaluations and unit examination scores. Students in problem-based modules demonstrated greater gains in reflective thinking with stable memorization, suggesting improved critical thinking skills. Tenets that problem-based learning promotes knowledge retention and provides a more positive learning experience were not upheld. Knowledge acquisition was not hindered by a problem-based approach. We conclude that gains in reflective thinking and evidence of increased self-directed learning argue for inclusion of PBL in dietetics curricula and that a problem-based education will help dietitians successfully respond to professional development needs.

Adult↗

PubMed2002

Role of luminal nutrients and endogenous GLP-2 in intestinal adaptation to mid-small bowel resection.

To elucidate the role of luminal nutrients and glucagon-like peptide-2 (GLP-2) in intestinal adaptation, rats were subjected to 70% midjejunoileal resection or ileal transection and were maintained with total parenteral nutrition (TPN) or oral feeding. TPN rats showed small bowel mucosal hyperplasia at 8 h through 7 days after resection, demonstrating that exogenous luminal nutrients are not essential for resection-induced adaptation when residual ileum and colon are present. Increased enterocyte proliferation was a stronger determinant of resection-induced mucosal growth in orally fed animals, whereas decreased apoptosis showed a greater effect in TPN animals. Resection induced significant transient increases in plasma bioactive GLP-2 during TPN, whereas resection induced sustained increases in plasma GLP-2 during oral feeding. Resection-induced adaptive growth in TPN and orally fed rats was associated with a significant positive correlation between increases in plasma bioactive GLP-2 and proglucagon mRNA expression in the colon of TPN rats and ileum of orally fed rats. These data support a significant role for endogenous GLP-2 in the adaptive response to mid-small bowel resection in both TPN and orally fed rats.

Adaptation, Physiological↗

PubMed2002

IGF-I treatment facilitates transition from parenteral to enteral nutrition in rats with short bowel syndrome.

The goal of growth factor treatment in patients with short bowel syndrome (SBS) is to facilitate transition from parenteral to enteral feedings. Ideal use of growth factors would be acute treatment that produces sustained effects. We investigated the ability of acute insulin-like growth factor I (IGF-I) treatment to facilitate weaning from total parenteral nutrition (TPN) to enteral feeding in a rat model of SBS. After a 60% jejunoileal resection + cecectomy, rats treated with IGF-I or vehicle were maintained exclusively with TPN for 4 days and transitioned to oral feeding. TPN and IGF-I were stopped 7 days after resection, and rats were maintained with oral feeding for 10 more days. In IGF-I-treated rats, serum concentration of IGF-I and final body weight were significantly greater because of a proportionate increase in carcass lean body mass than in vehicle-treated rats. Acute IGF-I treatment induced sustained jejunal hyperplasia on the basis of significantly greater concentrations of jejunal mucosal protein and DNA without a change in histology or sucrase activity. These results demonstrate that acute IGF-I facilitates weaning from parenteral to enteral nutrition in association with maintenance of a greater body weight and serum IGF-I concentration in rats with SBS.

Animals↗

PubMed2002

Securing the future of nutritional sciences through integrative graduate education.

The new millennium has ushered in unprecedented opportunities for research and discovery in the nutritional sciences. These have arisen from major advancements in the social and biological sciences, notably genetics, genomic technologies, computational statistics, and behavioral sciences. The most exciting academic challenges and employment opportunities for nutritional sciences graduates interface with other disciplines, and doctoral training programs in the nutritional sciences must respond to the wealth of these emerging opportunities. The American Society for Nutritional Sciences (ASNS) Graduate Nutrition Education Committee suggests that three major challenges face the nutritional sciences: (a) to train doctoral students to be full and active participants in interdisciplinary research and discovery, and (b) to achieve this goal while maintaining nutrition's unique academic identity and (c) fostering a cohesive academic community. The committee proposes that these objectives are best engaged at the level of graduate education and that the future of ASNS will be secured by strengthening graduate nutrition programs. This manuscript reviews educational strategies that address these challenges and advocates that ASNS actively engage graduate doctoral programs in nutritional sciences.

Education, Graduate↗

PubMed2002

Alterations in enterocyte proliferation and apoptosis accompany TPN-induced mucosal hypoplasia and IGF-I-induced hyperplasia in rats.

The mechanisms underlying nutrient regulation of intestinal cell turnover are poorly understood. The total parenteral nutrition (TPN) model allows examination of how eliminating the growth-promoting signals stimulated by luminal nutrients, without the confounding factor of malnutrition due to food deprivation, influences enterocyte renewal. Our objective was to determine the contribution of enterocyte proliferation and apoptosis to the mucosal hypoplasia induced by TPN and the mucosal hyperplasia induced by insulin-like growth factor-I (IGF-I). We investigated the composition and structure of the jejunum and associated changes in enterocyte proliferation and apoptosis in growing rats maintained exclusively with TPN for 7 d and concurrent treatment with IGF-I or vehicle for 6 d. TPN-induced hypoplasia, specific to the small bowel mucosa, was associated with reduced enterocyte proliferation and increased apoptosis throughout the crypt and bottom half of the villus. In contrast, the hyperplastic effect of IGF-I reflected increased enterocyte proliferation and decreased apoptosis, particularly in the stem cell zone. In summary, the ability of IGF-I to prevent or reverse the decreased enterocyte proliferation and increased apoptosis accompanying TPN-induced mucosal hypoplasia substantiates the role of growth factors in tissue regeneration and emphasizes the importance of the growth-promoting signals stimulated by luminal nutrients in maintaining intestinal integrity.

Animals↗