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ABSTRACT: Obesity is associated with increased severity in patients with acute pancreatitis (AP). The underlying mechanisms are unknown. Genetically obese rats exhibit decreased survival rate in experimental AP, but the clinical relevance of this model of obesity may be questioned. It is proposed that development of organ failure in AP occurs in two stages: initial priming of leucocytes followed by a second inflammatory attack. The aim was to evaluate the impact of diet-induced obesity on outcome in a 'two-hit' model of AP.
Lipopolysaccharide (LPS) was injected i.p. 3 h after retrograde bile duct infusion of sodium taurocholate in rats. Three experiments were done: 1) an LPS dose-response experiment, 2) chronic high-fat feeding (HF) for 16 weeks, and 3) acute HF for 10 days. Control rats received normal chow. Obesity, morphology and survival rate were assessed.
LPS dose-dependently decreased survival rate and increased morphological severity. HF increased weight, intra-abdominal and liver fat. Only acute HF induced hyperlipidaemia. In AP, acute obese rats exhibited less pancreatic inflammation, but total histological severity between groups was not different. In the chronic experiment only obese animals succumbed before 24 h of pancreatitis, but 72-h survival rate was not statistically different in either high-fat experiment.
An addition of LPS to AP decreases survival rate and intensifies the peri-pancreatic processes. Despite significant obesity, neither hyperlipidaemia nor increased intra-abdominal or hepatic fat influenced local pancreatic injury or survival negatively. The amount of fat per se seems not to be responsible for the deleterious influence of obesity on acute pancreatitis.
Scandinavian Journal of Gastroenterology 02/2004; 39(1):74-80. · 2.02 Impact Factor
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ABSTRACT: A majority of patients with pancreatic cancer have obstructive jaundice and diabetes with skeletal muscle insulin resistance. Surgery for these patients is associated with significant morbidity. Uncoupling protein 2 (UCP2) has been proposed to regulate energy expenditure and promote liver vulnerability. The effects of obstructive jaundice on muscle glucose metabolism and expression of UCP2 in liver and muscle are unknown.
Rats were operated with bile duct ligation (BDL). After 7 days, UCP2 mRNA levels were determined in liver and muscle. Simultaneously, insulin-stimulated glucose transport and glycogen synthesis in skeletal muscle were analyzed in vitro.
The jaundiced rats lost more weight than pair-fed controls. UCP2 mRNA levels were increased 5-fold in liver but not in muscle in jaundiced rats compared to pair-fed controls. The jaundiced rats were hypoglycemic and hypoinsulinemic but demonstrated intact or enhanced insulin action on skeletal muscle glucose transport and glycogen synthesis in vitro. Muscle glycogen content was increased in the jaundiced rats.
Experimental obstructive jaundice in the rat is associated with increased liver expression of UCP2, rapid weight loss, and intact insulin action on skeletal muscle glucose metabolism. Obstructive jaundice, by upregulated liver UCP2, may contribute to the cachexia and high surgical morbidity observed in these patients, but not to skeletal muscle insulin resistance in pancreatic cancer patients.
Scandinavian Journal of Gastroenterology 02/2002; 37(1):104-11. · 2.02 Impact Factor
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ABSTRACT: Studies in patients with acute pancreatitis have shown a correlation between obesity and serious complications or a fatal outcome. However, the mechanisms by which obesity aggravates acute pancreatitis are not known. In the present study we used the sodium taurocholate model of pancreatitis to examine the effect of obesity on severity and outcome in acute experimental pancreatitis (AEP).
AEP was induced at two degrees of severity by retrograde infusion of sodium taurocholate (0.2 ml x 3% or 0.4 ml x 3.5%) into the pancreatic duct of rats with obesity induced by high-fat diet, genetically obese (GO) rats or lean control rats. Surviving animals were sacrificed 72 h after induction of pancreatitis.
In the low-dose experiment, there were no significant differences in pancreatic histology or survival rate between the groups. In the high-dose experiment, the GO rats had a significantly lower 72-h survival rate than the high-fat obese (HFO) or lean control (LC) groups (GO 25% versus HFO 73%, P < 0.05; GO 25% versus LC 100%, P < 0.001). Survival rates in the high-dose experiment correlated strongly with basal liver fat content (R2 = 0.86). Pancreatic histology showed significantly more fat necrosis and a higher total pathological mean score in the HFO rats than in the LC animals (both P < 0.05).
Obesity had a negative influence on the outcome of necrotizing pancreatitis that was related to the magnitude of the pancreatic insult. The sodium taurocholate model in obese rats would be useful for future mechanistic studies of the effect of obesity on pancreatitis.
Scandinavian Journal of Gastroenterology 07/2001; 36(6):658-63. · 2.02 Impact Factor
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ABSTRACT: In-vitro and in-vivo studies have shown that autocrine growth factors and receptors are frequently expressed in human malignancies. Few of these studies, however, provide evidence that the identified autocrine pathway is functional. In this study, a functional autocrine growth pathway in pancreatic cancer has been identified using an in-vitro cell culture system. When pancreatic cancer cells were grown without change of medium, proliferation was greater than when either medium was replaced frequently (HPAF, CAPAN-2, PANC-1 or SW1990) or cells were grown in the presence of the EGF receptor tyrosine kinase inhibitor AG1478 or the MEK inhibitor PD098059 (HPAF or CAPAN-2). Activity of extracellular-regulated kinases (ERK) 1 and 2 and c- jun and c- fos mRNA levels were significantly elevated in CAPAN-2 cells cultured continuously in serum-free medium. Collectively, the observations indicate that the EGF receptor and the ERK MAP kinase pathway mediate autocrine signals. In contrast to previous reports, the GRP and IGF-I receptors were shown not to be required for autocrine effects on pancreatic cancer cell proliferation. Autocrine stimulation of the EGF receptor can contribute to sustained mitogenic activity and proliferation of pancreatic cancer cells.
British Journal of Cancer 05/2001; 84(7):926-35. · 5.04 Impact Factor
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ABSTRACT: Overexpression of autocrine growth factors and their receptors has been reported in many human cancers. The study of autocrine-regulated pathways using in vitro culture systems can be hindered by the presence of fetal bovine serum in culture medium. A human pancreatic cancer cell line (HPAF) was slowly weaned from its dependence on fetal bovine serum and subsequently maintained in serum-free conditions. Growth factor secretion studies showed that production of autocrine growth factors such as transforming growth factor alpha, gastrin-releasing peptide, and insulin-like growth factor I from weaned cells increased three times compared with nonweaned cells (p < 0.01). The epidermal growth factor and gastrin-releasing peptide receptor densities were also increased in weaned cells (2 times and 2.5 times, respectively, p < 0.05). The proliferation of weaned cells cultured continuously in the same medium was significantly greater than of nonweaned cells (p < 0.05). Collectively, these data indicate that weaned pancreatic cancer cells can proliferate in the absence of serum by up-regulating autocrine pathways.
Pancreas 04/2001; 22(3):293-8. · 2.39 Impact Factor
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ABSTRACT: Islet amyloid polypeptide (IAPP or amylin) potently reduces food intake in rats at or near physiological concentrations. Although the mechanisms of action of IAPP are not understood, the brain is a suggested site. Changes in hypothalamic and striatal neurotransmission have been reported following acute systemic administration of a pharmacological concentration of IAPP. In the current study, we evaluated the effects of chronic administration of low doses of IAPP on satiety-related neurotransmitters and neuropeptides in the hypothalamus, hippocampus, striatum, left cortex, and right cortex of the rat. Doses of 0, 5 and 25 pmol IAPP/kg-min were administered subcutaneously for 2 or 5 days. Food intake was reduced by 27 and 44% (both P<0.001) for the 5 and 25 pmol/kg-min groups, respectively, in the 2-day experiment and was decreased by 14% (P<0.01) and 24% (P<0.001), respectively, in the 5-day experiment. Body weight was significantly decreased in a dose-dependent fashion. In the 2-day experiment, norepinephrine increased in the hypothalamus in the 5 pmol IAPP/kg-min group, and neurotensin increased in the hippocampus in the 25 pmol/kg-min rats (both P<0.05). In the 5-day, 5 pmol/kg-min rats, 5-hydroxyindoleacetic acid (5-HIAA) increased in the hypothalmus and cholecystokinin (CCK) increased in the striatum (both P<0.05). In the 5-day, 25 pmol/kg-min group, neuropeptide Y (NPY) increased in the hypothalamus (P<0.01) and CCK increased in the hypothalmus and striatum (both P<0.05). The present study confirms that IAPP is a potent anorectic peptide at low doses and suggests that IAPP not only affects classical neurotransmitters in the brain but also alters concentrations of neuropeptides known to be involved in food intake.
Brain Research 01/2001; 887(2):391-8. · 2.73 Impact Factor
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ABSTRACT: Insulin-like growth factor-I (IGF-I) has been demonstrated to exert a nitrogen sparing effect, both experimentally and in patients after abdominal surgery. IGF-I is a major mediator for the anabolic effects of growth hormone (GH). Whether elevated circulating IGF-I levels are the sole mediator of the anabolic effects following GH has not been clarified. IGF-I influences glucose metabolism, both through its own specific receptor and by activating the insulin receptor, and has also been proposed to influence pancreatic islet secretion directly. In the present study, the postoperative effects of IGF-I on plasma levels of other gastrointestinal and pancreatic islet hormones and growth factors were measured in patients after abdominal surgery. Fifteen patients who were candidates for large bowel resection were randomly divided into two groups: IGF-I-treated (n=8) and placebo-treated (n=7). The IGF-I group received daily two s.c. injections of human recombinant IGF-I (80 microg/kg body weight) for five days, beginning on the morning of the first postoperative day. The other group received placebo injections. Fasting plasma levels of gastrointestinal growth factors (epidermal growth factor, transforming growth factor-alpha, IGF-II), gastrointestinal hormones (gastrin, enteroglucagon, peptide YY), and islet hormones (insulin, islet amyloid polypeptide (IAPP) and pancreatic glucagon) were determined by RIA preoperatively and after five days of treatment. No significant effects of IGF-I on other growth factors or gastrointestinal hormones were seen. A marked increase in plasma insulin postoperatively compared with the preoperative levels (42+/-3 vs 61+/-5 pM, P<0.05) was seen in the placebo group, whereas the postoperative levels in the IGF-I-treated patients remained unchanged (44+/-3 vs 45+/-4 pM). A similar pattern was observed for IAPP and cortisol concentrations. No differences in glucagon concentrations were seen. In conclusion, these results suggest that IGF-I does not influence production of other gastrointestinal hormones thought to be involved in alimentary growth or pancreatic glucagon. In contrast, IGF-I caused a marked reduction of insulin and IAPP secretion. The inhibition of beta-cell secretion could be direct or, alternatively, could involve an improvement in postoperative insulin resistance, perhaps by reducing serum cortisol.
Journal of Endocrinology 12/2000; 167(2):331-8. · 3.55 Impact Factor
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ABSTRACT: Glutamine is the principal energy source for enterocytes, but it is not known whether parenteral or enteral supplementation is most beneficial to gut integrity. The aim of this study was to evaluate the effects of glutamine in uni- or bidirectional supply on the viability of intestinal mucosa of starved rats during incubation in Ussing chambers. Segments of jejunum from rats starved for 48 h were randomly mounted in Ussing chambers with three nutrient solutions: Krebs buffer without glutamine; 6 mM glutamine added to the mucosal side; 6 mM glutamine added to the mucosal side and 0.6 mM glutamine to the serosal side. ATP content of the mucosa, electrophysiology, and 51Cr-ethylenediaminetetraacetate (EDTA) permeability were studied during 180 min of incubation. The addition of glutamine to both sides of the stripped mucosa improved ATP levels compared to the Krebs solution (P < 0.05), and the addition of glutamine resulted in an increase in short circuit current (P < 0.05). No significant differences were seen in 51Cr-EDTA permeability or epithelial electrical resistance. Glutamine supplementation to both the luminal and serosal side in the Ussing chamber was more effective than luminal glutamine only in maintaining ATP levels of intestinal mucosa. Bidirectional supplementation of glutamine might improve intestinal energy metabolism and viability in in vitro studies.
International Journal of Colorectal Disease 11/2000; 15(5-6):291-6. · 2.38 Impact Factor
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I Ihse,
R Andersson,
J Blind,
A Borgström,
T Gasslander,
U Haglund,
B A Henriksson,
A Hyltander, J Larsson,
C Lundstedt,
J Permert,
J Svanvik
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ABSTRACT: During recent years new concepts and methods have been introduced in the management of acute pancreatitis. Severity and risk of complications show wide variation. Outcome is also dependent on the physician's experience and on his local resources. In this light the Swedish Society of Upper Abdominal Surgery has elaborated national guidelines for management. Attention is paid to diagnosis, severity assessment and etiology. Furthermore, guidelines are offered for treatment of mild and severe pancreatitis, as well as for the management of pseudocysts. The role of multidisciplinary intensive care specialist teams in the management of severe disease is emphasized. The guidelines are supported by the Swedish Society of Gastroenterology, the Swedish Society of Gastroenterology, the Swedish Society of Anesthesiology and Intensive Care and by experts from other Nordic countries.
Lakartidningen 06/2000; 97(18):2216-8, 2221-3.
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ABSTRACT: The diabetes that frequently occurs in pancreatic cancer patients is characterized by profound peripheral insulin resistance. The intracellular mechanism of this insulin resistance was investigated in skeletal muscle biopsies from pancreatic cancer patients with or without diabetes and control subjects. Insulin receptor (IR) binding, tyrosine kinase activity, IR messenger RNA (mRNA), IR substrate-1 content, GLUT-4, and GLUT-4 mRNA content were all normal in pancreatic cancer patients. In contrast, multiple defects in glycogen synthesis were found in pancreatic cancer patients, especially in those with diabetes. Glycogen synthase I activity, total activity, and mRNA levels were significantly decreased in pancreatic cancer patients compared with controls. The fractional velocity of glycogen synthase was decreased only in the diabetic pancreatic cancer group. Glycogen phosphorylase a and b activities were increased in diabetic pancreatic cancer patients, but glycogen phosphorylase mRNA levels were not significantly different. The insulin resistance associated with pancreatic cancer is associated with a post-IR defect, which impairs skeletal muscle glycogen synthesis and glycogen storage.
Journal of Clinical Endocrinology & Metabolism 04/2000; 85(3):1232-8. · 6.50 Impact Factor
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ABSTRACT: Early postoperative enteral feeding has been reported to stimulate intestinal mucosa proliferation. Dietary components influence the intestinal adaptive response after resection and glutamine is a preferential nutrient to enterocytes. The purpose of this study was to evaluate the effects of bolus glutamine supplementation on intestinal adaptation.
Male Wistar rats underwent a 65% small bowel resection. The rats were divided into three groups receiving glutamine 2 g/kg/day, isonitrogenous glycine or saline by gavage for 10 days. All the rats were provided with ordinary rat chow ad libitum. Sampling was done 10 days after resection. Animals fed ordinary rat chow without surgery or specific treatment served as control.
Mucosal wet weight, DNA, RNA, protein contents and sucrose activity, as well as villus height increased in the ileal remnant. No significant differences in any of these parameters or body weight could be found between the three groups.
Postoperative enteral bolus glutamine supplementation at a dose of 2 g/kg b.w. did not enhance the adaptation of the residual intestine 10 days after massive intestinal resection in the rat.
Digestive Surgery 02/2000; 17(3):256-60. · 1.22 Impact Factor
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ABSTRACT: Starvation induces an increase in intestinal permeability that can be of importance to intestinal integrity. Glutamine is the principal energy source for intestinal enterocytes and is considered essential for gut metabolism, structure and function. The aim of this study was to investigate whether glutamine could improve the ATP content of the mucosa of starved rats and attenuate the permeability perturbation during incubation in vitro in Ussing chamber.
Segments of jejunum from rats starved for 48 h were mounted in Ussing chambers. Glutamine was added to Krebs-buffer at 0.6mM, 3mM, 6mM and 30mM concentrations on the mucosal side. Cr-EDTA permeation, ATP content of the epithelium mucosa and electrophysiology were studied during 180 min of incubation in Ussing chambers.
These was a negative linear correlation between ATP content and(51)Cr-EDTA permeability in stripped mucosa. ATP content was reduced in all groups during the experiment. When 30 mM glutamine was added on the mucosal side there was an increase in(51)Cr-EDTA permeability (P< 0.001). There was no effect of glutamine on transepithelial resistance but higher concentrations of glutamine (>3mM) significantly increased the short circuit current.
Supplementing glutamine to the mucosal side in the Ussing chamber led to an increase in ion pump activity and to an increase in paracellular permeability at the 30mM glutamine concentration. Glutamine did not restore the intracellular ATP level. The increase in permeability was inversely correlated to the mucosal ATP content.
Clinical Nutrition 10/1999; 18(5):301-6. · 3.73 Impact Factor
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ABSTRACT: Maintenance of intestinal integrity is essential after major abdominal surgery in malnourished subjects. The purpose of this experimental study was to investigate factors affecting small-bowel mucosa permeability in vitro in the immediate postoperative period in starved rats.
Male Wistar rats were randomly placed in five groups: Controls, Anesthesia, Resection, Starvation, and Starvation + resection. Controls consisted of fed rats. Anesthesia was induced intraperitoneally with xylazine and ketamine. Resection was 5 cm of the mid-jejunum, and the starvation period was 48 h. Two hours after surgery stripped mucosal segments from the jejunum and the ileum were mounted in Ussing chambers, and the transmucosal permeation of 51Cr-labeled ethylenediaminetetraacetic acid (EDTA) and dextran (40,000 Da) was studied for 120 min while electrophysiology was monitored.
Starvation increased permeability to 51Cr-EDTA in both the jejunum and ileum. In the jejunum permeability was further increased by starvation + resection. Resection or anesthesia alone did not increase permeability. The villous height in the jejunum was reduced by starvation. Mucosal permeability was correlated to the change in transepithelial resistance during experiments.
Starvation was the main cause of increased mucosal permeability in both intestinal segments of the rat, but surgical trauma had an additive effect, which was most pronounced in the jejunum.
Scandinavian Journal of Gastroenterology 03/1999; 34(2):156-62. · 2.02 Impact Factor
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ABSTRACT: Enterocyte proliferation and cellular energy status are important to intestinal integrity after starvation and trauma. The proliferative response to nutrients is expressed in the activity of ornithine decarboxylase (ODC), but ODC activity and ATP level in the intestinal mucosa the first hours after surgery and immediate refeeding are not known.
Male Wistar rats (240-280 g) were starved for 48 h and submitted to laparotomy with distal ileal transection, gastrostomy and jejunal instillation of either enteral formula or saline. The ODC activity and ATP content of the jejunal mucosa were analysed in samples taken at 1, 2, 4 and 6 h after surgery.
ODC activity increased and reached the highest peak at 2 h in the refed animals. ATP concentration and energy charge of jejunal mucosa were significantly reduced 6 h after surgery compared to initial levels, but there were no differences between animals that were refed or not. Intestinal transection did not stimulate ODC activity.
ATP levels in intestinal mucosa decreased after surgery, and early enteral feeding did not seem to prevent this decrease during the first 6 h. Refeeding immediately after surgery elicits an early but transient increase of ODC activity in rat jejunal mucosa.
Clinical Nutrition 03/1999; 18(1):41-5. · 3.73 Impact Factor
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ABSTRACT: Intestinal resection stimulates the synthesis and release of gastrointestinal peptides that regulate the growth and adaptation of the mucosa. Luminal nutrients are necessary for optimal proliferation and glutamine is the preferential nutrient to the small bowel. The interplay between glutamine and regulatory peptides could be important in treating short bowel syndrome.
63 Sprague-Dawley rats were divided into 3 groups: resection; transection, or controls. After intestinal resection animals were orally fed either a diet without glutamine or a glutamine-supplemented diet for 2 days. Transected animals and controls without prior surgery were fed the same two diets. Epidermal growth factor (EGF), transforming growth factor-alpha, insulin-like growth factors I and II (IGF-I and IGF-II), peptide YY (PYY), and enteroglucagon were analyzed in mucosa from the proximal jejunum, distal ileum as well as in portal plasma when the animals were euthanized 72 h after surgery.
Intestinal resection resulted in an early increase in portal plasma concentrations of PYY, EGF, enteroglucagon, and mucosal IGF-II and EGF content that were significant in glutamine-treated animals. Glutamine significantly increased PYY in portal blood after resection (p < 0.05).
Glutamine could be of importance for the functional adaptation of residual small bowel mucosa by increasing PYY release.
Digestive Surgery 02/1999; 16(3):197-203. · 1.22 Impact Factor
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ABSTRACT: Glutamine is routinely added to most cell cultures. Glutamine has been found to be the preferential nutrient to the rapidly replicating intestinal mucosa, but whether this is a metabolic effect or due to other properties of this amino acid is not determined. To study the importance of glutamine on the growth of two enterocyte-like cell lines, the effects of depriving the media or supplementing it with glutamine were assessed in media with different serum and energy supplements.
CaCo-2 and HT-29 cells were grown in serum-free medium, with fetal bovine or synthetic serum, and with or without glucose or galactose. The glutamine content was varied between 0 and 4 mM. All growth assays were performed in triplicate by counting in a hemocytometer.
Both cell lines were dependent of serum factors for growth, but displayed distinct requirements on glutamine supplementation. Glutamine was an obligate supplement with dose-dependent correlation to growth (r = 0.87, p < 0.01) for CaCo-2 cells cultured in synthetic, but not in fetal bovine serum. In HT-29 cells, the correlation between glutamine and growth was significant (r = 0.68, p < 0.05) only in fetal bovine serum in the absence of galactose.
This study shows that glutamine has different growth stimulating effects on two enterocyte-like cell lines studied. This could reflect different modes of action of glutamine on proliferation and differentiation in an enterocyte cell population.
The International Journal of Biochemistry & Cell Biology 01/1999; 30(12):1331-6. · 4.63 Impact Factor
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ABSTRACT: Our objective was to study whether islet amyloid polypeptide (IAPP) produces satiety by an endocrine mechanism. We used a rat model to determine whether postprandial plasma levels of IAPP are comparable to those required to inhibit feeding when IAPP is administered by continuous intravenous infusion. Food intake in rats with aortic catheters increased plasma IAPP levels from a fasting level of 10.8 +/- 0.5 pM to a peak level of 19.0 +/- 1.0 pM at 2.2 +/- 0.5 h. In rats with jugular vein and aortic catheters, the threshold intravenous dose for IAPP suppression of feeding was between 1 and 3 pmol . kg-1 . min-1. The 3 pmol . kg-1 . min-1 dose decreased 4-h intake by approximately 25% by decreasing meal frequency rather than meal size. This dose increased plasma IAPP by approximately 24 pM. These results suggest that postprandial plasma levels of IAPP are not quite sufficient to independently produce satiety.
The American journal of physiology 12/1998; 275(5 Pt 2):R1537-42.
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ABSTRACT: A 30-year-old previously healthy woman was diagnosed as having a vasoactive intestinal polypeptide (VIP)-producing tumour of the pancreas. Her medical history was typical for neuroendocrine gastrointestinal tumours, presenting initially with non-specific symptoms but eventually she developed life-threatening manifestations requiring intensive care due to severe dehydration. She immediately recovered following surgical resection. The patient had elevated serum concentrations of VIP as well as pancreastatin, and post-operatively elevated concentrations of three growth factors, IGF-I, EGF and TGF-alpha, were seen. The importance of the alterations in plasma concentrations of the different peptides for her symptomatology are discussed.
European Journal of Gastroenterology & Hepatology 12/1998; 10(11):963-7. · 1.76 Impact Factor
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ABSTRACT: Luminal nutrients and growth factors regulate postresectional intestinal growth. The interplay between glutamine and regulatory gastrointestinal peptides is not known.
The effects of intestinal resection on tissue and plasma concentrations of peptides were studied in 60 Sprague-Dawley rats divided into resected, transected, or unoperated groups. Subgroups were fed either a glutamine-free or a glutamine-supplemented diet for 7 days. Epidermal growth factor, transforming growth factor-alpha, insulin-like growth factors (IGF) I and II, peptide YY (PYY), and enteroglucagon were analyzed in intestinal mucosa and in portal plasma by radioimmunoassay.
No glutamine-specific effects were seen. The mucosal content of IGF-II (P < 0.01) and the portal levels of enteroglucagon and PYY (P < 0.05-0.01) increased after intestinal resection.
The increase in PYY and enteroglucagon in portal blood supports a hormonal role in the postresectional adaptation. The increase in IGF II in the ileal mucosa, without changes in plasma, implies autocrine or paracrine growth stimulation at this stage after resection.
Scandinavian Journal of Gastroenterology 11/1998; 33(10):1080-6. · 2.02 Impact Factor
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ABSTRACT: Interactions have been found between exocrine pancreatic adenocarcinoma and islets of Langerhans. Growth of pancreatic adenocarcinoma cells can be regulated by islet hormones such as insulin and somatostatin. Conversely, dysfunction of endocrine pancreas frequently accompanies the exocrine malignancy. The mechanisms underlying these interactions have not been defined.
Human pancreatic adenocarcinoma cells (HPAF cells) were cocultured with isolated rat pancreatic islets in two-compartment wells. HPAF cells and islets cultured in separate wells served as controls. In separate experiments, HPAF cells were incubated with two concentrations of exogenous insulin, including one reflecting the levels of insulin secretion seen in the coculture experiments.
Proliferation of HPAF cells was increased by about 50% following a 2- or 5-day incubation with pancreatic islets (P < 0.05). Coculture of HPAF cells and pancreatic islets was associated with a greater reduction in glucose concentrations (P < 0. 01) and an increase in lactate accumulation (P < 0.05) in the culture media. Insulin concentrations in the media were significantly decreased during the first 2-3 days of the coculture incubation (P < 0.05). In contrast, insulin secretion from control islets was not significantly decreased until the fifth day of the experiment. The growth of HPAF cells was stimulated by both concentrations of exogenous insulin (P < 0.05). The insulin-stimulated HPAF cells also showed an enhanced glucose consumption and lactate production (P < 0.05).
Pancreatic islets regulate both growth and glucose metabolism of adjacent exocrine cancer cells. beta-cell-derived insulin may be one of the factors inducing these effects. Insulin release from islet beta-cells is compromised in the presence of exocrine cancer cells.
Journal of Surgical Research 09/1998; 79(1):13-9. · 2.25 Impact Factor
