Glucagon-like peptide 2 (GLP-2) accelerates the growth of colonic neoplasms in mice.

BACKGROUND: Glucagon-like peptide 2 (GLP-2) is an intestinotrophic mediator with therapeutic potential in conditions with compromised intestinal capacity. However, growth stimulation of the intestinal system may accelerate the growth of existing neoplasms in the intestine. AIMS: In the present study, the effects of GLP-2 treatment on the growth of chemically induced colonic neoplasms were investigated. METHODS: In 210 female C57bl mice, colonic tumours were initially induced with the methylating carcinogen 1,2-dimethylhydrazine (DMH) and mice were then treated with GLP-2. Two months after discontinuation of the carcinogen treatment, 135 of the mice were allocated to one of six groups which were treated twice daily with 25 microg GLP-2, 25 microg Gly2-GLP-2 (stable analogue), or phosphate buffered saline for a short (10 days) or long (one month) period. The remaining 75 mice had a treatment free period of three months and were then allocated to groups subjected to long term treatment, as above. RESULTS: Colonic polyps developed in 100% of the mice, regardless of treatment. Survival data revealed no statistical significant differences among the different groups but histopathological analysis demonstrated a clear and significant increase in tumour load of mice treated with Gly2-GLP-2. The tumour promoting effect of native GLP-2 was less pronounced but the number of small sized polyps increased following long term treatment. CONCLUSIONS: The present results clearly indicate that GLP-2 promotes the growth of mucosal neoplasms. Our findings highlight the need for future investigations on the effects of GLP-2 in conditions needing long time treatment or with increased gastrointestinal cancer susceptibility.

Glucagon-like peptide 2 (GLP-2), an intestinotrophic mediator.

Glucagon-like peptide 2 (GLP-2) is a newly discovered gastrointestinal peptide with 33% sequence homology to glucagon. GLP-2 has attracted interest because of its potent intestinotrophic endocrine/paracrine actions. The peptide, consisting of 33-amino-acid, results from expression of the glucagon gene in the enteroendocrine L-cells of the intestinal mucosa, from where it is released mainly in response to luminal contact with unabsorbed nutrients. In addition to mucosal growth, GLP-2 enhances activities of several intestinal brush-border enzymes, and it delays gastric transit, thereby increasing the intestinal capacity for nutrient absorption. Thus, it appears that GLP-2 serves to ensure an optimal intestinal capacity. The physiological responses following exogenous administration of GLP-2 have been intensely investigated, and these appear to be rather specific for the gut, which is concordant with the localization of the GLP-2 receptor. In addition, treatment with GLP-2 in experimental animal models of several enteropathies indicates that GLP-2 ameliorates most of the observed intestinal abnormalities in these conditions. Following secretion to the blood stream, the intact peptide is degraded rather rapidly by an aminopeptidase. To circumvent the rapid and widespread metabolization of intact GLP-2, degradation-resistant synthetic GLP-2 analogues have been developed together with other approaches, such as inhibition of the GLP-2 degrading enzyme. This is of particular interest with respect to developing GLP-2 into a useful therapeutic agent in conditions with compromised intestinal function, since the first clinical trial has already indicated the potential of GLP-2 treatment in patients with short bowel syndrome.

Injected TFF1 and TFF3 bind to TFF2-immunoreactive cells in the gastrointestinal tract in rats.

Peptides of the trefoil factor family (TFF1, TFF2 and TFF3) are co-secreted with mucus in most organ systems and are believed to interact with mucins to produce high-viscosity, stable gel complexes. We have previously demonstrated that cells in the GI tract possess binding sites to TFF2 and that injected TFF2 ends up in the mucus layer. In the present study, tissue binding and metabolism of parenterally administered human TFF1 and TFF3 in rats were described and compared to the immunohistochemical localization of the TFF peptides. 125I-TFF1 monomer and 125I-TFF3 mono- and dimer were given intravenously to female Wistar rats. The tissue distribution was assessed by gamma counting of organ samples and by autoradiography of histological sections. The degradation of 125I-TFF3 was studied by means of trichloracetic acid (TCA) precipitation and the saturability of the binding by administration of excess unlabelled peptide. The TFF peptides were localized in histologic sections from the GI tract by immunohistochemistry. Injected TFF3 dimer (12%) was taken up by the GI tract. At autoradiography, grains were localized to the same cells that were immunoreactive to TFF2. The binding could be displaced by excess TFF3. Similar binding was observed for the TFF1 and TFF3 monomers apart from binding in the stomach, where the uptake was only 15% in comparison to the dimer. There was no specific binding outside the GI tract and no binding to TFF1 or TFF3 immunoreactive cells. In conclusion, the TFF2-binding cells in the gastrointestinal tract seem to have basolateral, receptor-like activity to all three TFF peptides. The mucous neck cells of the stomach predominantly take up TFFs with two trefoil domains, indicating a different receptor-like activity in the stomach compared to the rest of the GI tract.

Short-term administration of glucagon-like peptide-2. Effects on bone mineral density and markers of bone turnover in short-bowel patients with no colon.

BACKGROUND: Glucagon-like peptide 2 (GLP-2) is a newly discovered intestinotrophic hormone. We have recently reported that a 5-week GLP-2 treatment improved the intestinal absorptive capacity of short-bowel patients with no colon. Additionally, GLP-2 treatment was associated with changes in body composition that included a significant increase in total body bone mass. This article describes the effect of GLP-2 on spinal and hip bone mineral density (BMD) and biochemical markers of bone turnover in these patients. METHODS: In an open-labelled pilot study, eight short-bowel patients (3M, 5F; mean age 49 years) with small-bowel resection and no colon received 400 microg s.c. of GLP-2 twice daily for 5 weeks. Four received home parenteral nutrition (mean length of residual jejunum 83 cm) and 4 did not (mean length of ileum resected 106 cm). The outcome measures were the mean percent change from baseline in spinal and hip BMD measured by dual-energy X-ray absorptiometry, changes in four biochemical markers of bone-turnover, PTH, 25-hydroxy vitamin-D, and the intestinal absorption of calcium. RESULTS: Mean +/- s(x) (SEM) percent changes in spinal and hip BMD were 1.1+/-0.4% (P < 0.05) and 1.9+/-0.8% (P = 0.06), respectively. The intestinal calcium absorption increased by 2.7% (P = 0.87). Serum ionized calcium increased in 5/8 patients with a concomitant decrease in serum PTH values. Three of the four markers of bone turnover decreased. CONCLUSION: A 5-week GLP-2 administration significantly increased spinal BMD in short-bowel patients with no colon. The mechanism by which GLP-2 affects bone metabolism remains unclear, but may be related to an increased mineralization of bone resulting from an improved intestinal calcium absorption.

Skin morphological changes in growth hormone deficiency and acromegaly.

OBJECTIVE: To evaluate the histomorphology of skin and its appendages, especially eccrine sweat glands, in patients with GH disorders, because reduced sweating ability in patients with growth hormone deficiency (GHD) is associated with increased risk of hyperthermia under stressed conditions. DESIGN AND METHODS: A skin biopsy was obtained from 17 patients with GHD treated with GH, five patients with untreated GHD, 10 patients with active acromegaly and 13 healthy controls. RESULTS: The sweat secretion rate (SSR) was significantly decreased in both the untreated (median 41 mg/30 min, range 9-79 mg/30 min) and the GH-treated (median 98 mg/30 min, range 28-147 mg/30 min) patients with GHD compared with that in controls (median 119 mg/30 min, range 90-189 mg/30 min; P=0.001 and 0.01 respectively). Epidermal thickness was significantly decreased in both untreated (median 39 microm, range 28-55 microm) and GH-treated patients with GHD (median 53 microm, range 37-100 microm), compared with that in controls (median 66 microm, range 40-111 microm; P<0.02). A statistically non-significant tendency towards thinner epidermis (median 59 microm, range 33-83 microm) was recorded in acromegalic patients (P=0.08) compared with controls. There was no significant difference in the area of the sebaceous glands in the biopsies between the three groups and the controls. The area of eccrine sweat gland glomeruli was significantly decreased in the untreated patients with GHD (median 16407 microm2, range 12758-43976 microm2) compared with that in controls (median 29446 microm2, range 13511-128661 microm2; P=0.03), but there was no significant difference between the GH-treated patients with GHD and controls. CONCLUSIONS: We conclude that GH, either directly or via IGF-I, may have both a structural and a functional effect on human skin and its appendages, and that patients with GHD have histomorphological changes in skin compared with controls. Importantly, these changes are not fully reversed despite long-term and adequate GH treatment in patients with childhood onset GHD.

Intestinal growth adaptation and glucagon-like peptide 2 in rats with ileal--jejunal transposition or small bowel resection.

Glucagon-like peptide 2 (GLP-2), produced by enteroendocrine L-cells, regulates intestinal growth. This study investigates circulating and intestinal GLP-2 levels in conditions with altered L-cell exposure to nutrients. Rats were allocated to the following experimental groups: ileal-jejunal transposition, resection of the proximal or distal half of the small intestine, and appropriate sham-operated controls. After two weeks, ileal-jejunal transposition led to pronounced growth of the transposed segment and also of the remaining intestinal segments. Plasma GLP-2 levels increased twofold, whereas GLP-2 levels in the intestinal segments were unchanged. In resected rats with reduced intestinal capacity, adaptive small bowel growth was more pronounced following proximal resection than distal small bowel resection. Circulating GLP-2 levels increased threefold in proximally resected animals, and twofold in the distally resected group. Tissue GLP-2 levels were unchanged in resected rats. The data indicate that transposition of a distal part of the small intestine, and thereby exposure of L cells to a more nutrient-rich chyme, leads to intestinal growth. The adaptive intestinal growth is associated with increased plasma levels of GLP-2, and GLP-2 seems to act in an endocrine as well as a paracrine manner.

Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon.

BACKGROUND & AIMS: Glucagon-like peptide 2 (GLP-2) is intestinotrophic, antisecretory, and transit-modulating in rodents, and it is mainly secreted from the intestinal mucosa of the terminal ileum and colon after food ingestion. We assessed the effect of GLP-2 on the gastrointestinal function in patients without a terminal ileum and colon who have functional short-bowel syndrome with severe malabsorption of wet weight (>1.5 kg/day) and energy (>2.3 MJ/day) and no postprandial secretion of GLP-2. METHODS: Balance studies were performed before and after treatment with GLP-2, 400 microg subcutaneously twice a day for 35 days, in 8 patients (4-17 years from last bowel resection; 6 with Crohn's disease). Four patients received home parenteral nutrition (mean residual jejunum, 83 cm), and 4 did not (mean ileum resection, 106 cm). Biopsy specimens were taken from jejunal/ileal stomas, transit was measured by scintigraphy, and body composition was measured by dual-energy x-ray absorptiometry. RESULTS: Treatment with GLP-2 improved the intestinal absorption of energy 3.5% +/- 4.0% (mean +/- SD) from 49.9% to 53.4% (P = 0.04), wet weight 11% +/- 12% from 25% to 36% (P = 0.04), and nitrogen 4.7% +/- 5.4% from 47.4% to 52.1% (P = 0.04). Body weight increased 1.2 +/- 1.0 kg (P = 0.01), lean body mass increased 2.9 +/- 1.9 kg (P = 0.004), fat mass decreased 1.8 +/- 1.3 kg (P = 0.007), and 24-hour urine creatinine excretion increased (P = 0.02). The time to 50% gastric emptying of solids increased 30 +/- 16 minutes from 89 to 119 minutes (P < 0.05). Small bowel transit time was not changed. Crypt depth and villus height were increased in 5 and 6 patients, respectively. CONCLUSIONS: Treatment with GLP-2 improves intestinal absorption and nutritional status in short-bowel patients with impaired postprandial GLP-2 secretion in whom the terminal ileum and the colon have been resected.

[Glucagon-like peptide 2, a neurotransmitter with a newly discovered role in the regulation of food ingestion]. / Glucagonlignende peptid-2, en neurotransmitter med en nyopdaget rolle i reguleringen af fødeindtagelsen.

We report here that glucagon-like peptide 2(GLP-2) and its receptor constitute a distinct projection system connecting the nucleus of the solitary tract with the dorsomedial hypothalamic nucleus (DMH). The DMH contains a dense plexus of GLP-2 immunoreactive fibres and is the only hypothalamic nucleus expressing GLP-2 receptor mRNA. Consistent with this, central application of GLP-2 activates the expression of neurones solely in the DMH. Furthermore, central administration of GLP-2 causes a dose-related, a pharmacologically and behaviourally specific inhibition of food intake in rats. Surprisingly, the alleged GLP-1 receptor antagonist, Exending (9-39), proved a functional antagonist of centrally applied GLP-2. These data implicate GLP-2 as an important neurotransmitter in the regulation of food intake and likely bodyweight. Our data therefore point to the DMH as a crossroad for endocrine and visceral information affecting feeding behaviour.

Dipeptidyl peptidase IV inhibition enhances the intestinotrophic effect of glucagon-like peptide-2 in rats and mice.

Glucagon-like peptide-2 (GLP-2) induces intestinal growth in mice; but in normal rats, it seems less potent, possibly because of degradation of GLP-2 by the enzyme dipeptidyl peptidase IV (DPP-IV). The purpose of this study was to investigate the survival and effect of GLP-2 in rats and mice after s.c. injection of GLP-2 with or without the specific DPP-IV inhibitor, valine-pyrrolidide (VP). Rats were injected s.c. with 40 microg GLP-2 or 40 microg GLP-2+15 mg VP. Plasma was collected at different time points and analyzed, by RIA, for intact GLP-2. Rats were treated for 14 days with: saline; 15 mg VP; 40 microg GLP-2, 40 microg GLP-2+15 mg VP; 40 microg GLP-2 (3-33). Mice were treated for 10 days with: saline; 5 microg GLP-2; 5 microg GLP-2+1.5 mg VP; 25 microg GLP-2; 25 microg GLP-2 (3-33). In both cases, body weight, intestinal weight, length, and morphometric data were measured. After s.c. injection, the plasma concentration of GLP-2 reached a maximum after 15 min, and elevated concentrations persisted for 4-8 h. With VP, the concentration of intact GLP-2 was about 2-fold higher for at least the initial 60 min. Rats treated with GLP-2+VP had increased (P < 0.01) small-bowel weight (4.68 +/- 0.11%, relative to body weight), compared with the two control groups, [3.01 +/- 0.06% (VP) and 2.94 +/- 0.07% (NaCl)] and GLP-2 alone (3.52 +/- 0.10%). In mice, the growth effect of 5 microg GLP-2+VP was comparable with that of 25 microg GLP-2. GLP-2 (3-33) had no effect in rats, but it had a weak effect on intestinal growth in mice. The extensive GLP-2 degradation in rats can be reduced by VP, and DPP-IV inhibition markedly enhances the intestinotrophic effect of GLP-2 in both rats and mice. We propose that DPP-IV inhibition may be considered to enhance the efficacy of GLP-2 as a therapeutic agent.

Potential targets for glucagon-like peptide 2 (GLP-2) in the rat: distribution and binding of i.v. injected (125)I-GLP-2.

Glucagon-like peptide 2 (GLP-2) is a 33-amino acid (1-33) intestinotrophic peptide. In this study, the distribution and binding of i.v. injected radiolabeled GLP-2 (1-33) were investigated in rats using autoradiography in order to target possible binding sites. The major part of (125)I-GLP-2 (1-33) was distributed to kidneys, liver, and the gastrointestinal tract. In the small intestine, a high density of grains was localized in the epithelium with a predominance in the luminal part of the villus. The saturability of (125)I-GLP-2 (1-33) was investigated by administration of excess amounts of non-radioactive GLP-2 (1-33) or the primary metabolite of GLP-2 degradation, GLP-2 (3-33). In the small intestine, (125)I-GLP-2 was displaced both by non-radioactive GLP-2 (1-33) and (3-33), suggesting that the uptake of GLP-2 (1-33) in the small intestine is receptor-specific and that the metabolite GLP-2 (3-33) may interact with the GLP-2 receptor.

Elevated plasma glucagon-like peptide 1 and 2 concentrations in ileum resected short bowel patients with a preserved colon.

BACKGROUND: The glucagon-like peptides (GLP) 1 and 2 are secreted postprandially from L cells located mainly in the ileum. Both hormones prolong intestinal transit and GLP-2 is intestinotrophic in rodents. Patients with a jejunostomy have poor adaptation, rapid gastric and intestinal transit, and impaired postprandial GLP-2 secretion. Ileum resected short bowel patients with a preserved colon show evidence of functional adaptation and have normal gastric emptying. AIM: To investigate if GLP-1 and GLP-2 contribute to the positive effects of a preserved colon in short bowel patients by measuring circulating levels of GLP-1 and GLP-2 in seven ileum resected short bowel patients with a preserved colon and seven age and sex matched controls. METHODS: GLP-1 and GLP-2 immunoreactivity was measured by specific radioimmunoassays in plasma collected at fasting and at regular intervals 180 minutes after a test meal. RESULTS: Median (25-75%) fasting GLP-2 values were 72 (69-105) pmol/l versus 23 (19-27) pmol/l (p=0.001) and meal stimulated area under the curve was 21 078 (14 811-26 610) min x pmol/l versus 11 150 (7151-12 801) min x pmol/l (p=0.01) in short bowel patients with a preserved colon compared with control subjects. Fasting GLP-1 values were 10 (6-12) pmol/l versus 5 (3-5) pmol/l (p=0.01) and meal stimulated area under the curve was 3418 (2966-6850) min x pmol/l versus 2478 (1929-3199) min x pmol/l (p=0.04), respectively. CONCLUSION: Ileum resected short bowel patients with a preserved colon had elevated fasting plasma concentrations of GLP-1 and GLP-2 and significantly larger meal stimulated areas under the curve compared with age and sex matched controls. Elevated GLP-1 and GLP-2 concentrations may contribute to the positive effects of a preserved colon on intestinal motility and functional adaptation in ileum resected short bowel patients.

The proglucagon-derived peptide, glucagon-like peptide-2, is a neurotransmitter involved in the regulation of food intake.

The dorsomedial hypothalamic nucleus harbors leptin sensitive neurons and is intrinsically connected to hypothalamic nuclei involved in feeding behavior. However, it also receives ascending input from the visceroceptive neurons of the brainstem. We have identified a unique glucagon-like-peptide-2 containing neuronal pathway connecting the nucleus of the solitary tract with the dorsomedial hypothalamic nucleus. A glucagon-like-peptide-2 fiber plexus targets neurons expressing its receptor within the dorsomedial hypothalamic nucleus. Pharmacological and behavioral studies confirmed that glucagon-like-peptide-2 signaling is a specific transmitter inhibiting rodent feeding behavior and with potential long-term effects on body weight homeostasis. The glucagon-like-peptide-1 receptor antagonist, Exendin (9-39) is also a functional antagonist of centrally applied glucagon-like-peptide-2.

Renal content and output of epidermal growth factor in long-term adrenergic agonist-treated rats.

This study investigates the renal and urinary levels of epidermal growth factor (EGF) in rats under long-term treatment with alpha- or beta-adrenergic agonists. Urine samples were obtained on days 7, 14 and 21, and renal tissue samples on day 21. EGF was quantified by ELISA and tissue sections were used for immunohistochemistry and in situ hybridization. Fractional kidney weight was increased in the alpha-adrenergic agonist-treated group by 35% when compared with controls. Histological examination of the kidney revealed well-defined wedge-shaped areas of tubular dilatations and luminal amorphous material in the distal tubules. Concomitantly, reduced levels of EGF and EGF mRNA were observed, and also the urinary levels of EGF were reduced. Together, these observations indicate alpha-adrenergic treatment to affect the distal tubules. Treatment with the beta-adrenergic agonist did not change fractional kidney weight, but initially the urinary excretion of EGF was reduced. The data add further evidence to the suggestion that activity of the sympathetic nervous system influences renal homeostasis of EGF, either directly or indirectly through renal histopathological changes.

Epidermal growth factor and lung development in the offspring of the diabetic rat.

Fetuses of diabetic mothers who were exposed to excessive glucose show delayed maturation. Under these conditions, altered growth factor expression or signaling may have important regulatory influences. We examined the role of epidermal growth factor (EGF) in lung development and maternal diabetes in the rat. In order to evaluate the possible role of glucose for the expression of EGF and the growth of lung tissue, we performed in vitro studies with organotypic cultures of fetal alveolar cells obtained from control rats. Compared to pups of normal rats, the newborn rats of untreated diabetic rats had reduced body weight, but normal lung weight relative to body weight. The air:mesenchyme ratio and the average size of alveoli per mm(2) lung tissue were reduced. The immunoreactivity (IR) of EGF, which was quantified using a computerized image analysis system, appeared with increased intensity and was associated with a reduced intensity of surfactant protein A-IR. The only difference observed between pups of treated diabetic rats and controls was a decrease in the lung weight:body weight ratio. In organotypic cultures, the presence of 13 mmol/L glucose in the cell media increased immunoreactive staining against EGF, but decreased the incorporation of thymidine as compared to the results obtained with alveolar cells grown in a normophysiological concentration of glucose (3 mmol/L). Addition of EGF increased the thymidine incorporation only in cells grown in 3 mM glucose. These findings may indicate immaturity of the lungs of pups of untreated diabetic rats, and subtle alterations in the lungs of pups from treated diabetic rats. The results also suggest that glucose plays a role in the expression of EGF, and that cells exposed to high concentrations of glucose are less responsive to EGF.

Diabetic intestinal growth adaptation and glucagon-like peptide 2 in the rat: effects of dietary fibre.

BACKGROUND/AIMS: Dietary fibre influence growth and function of the upper gastrointestinal tract. This study investigates the importance of dietary fibre in intestinal growth in experimental diabetes, and correlates intestinal growth with plasma levels of the intestinotrophic factor, glucagon-like peptide 2 (GLP-2). METHODS: Male Wistar rats were randomised to the following groups: two streptozotocin-diabetic and two control groups fed either a fibre-containing or a fibre-free diet for three weeks. Intestinal weight, length, and morphometric data (villus height, villus area, crypt depth) were measured. Blood samples were obtained after two weeks for measurement of GLP-2 and enteroglucagon (glicentin, oxyntomodulin). RESULTS: The mean daily consumption of food in the two diabetic groups was 40% higher than in controls. In diabetic rats fed fibre, the increase in intestinal weight from day 0 to 20 was sixfold greater than that of the controls and small intestine weight per cm length was increased by 50%. In the diabetic rats fed a fibre-free diet, intestinal growth was 30% less than in diabetic rats fed fibre, and intestinal weight increased only threefold compared with controls. Morphometric data showed that the intestinal increase in diabetic rats fed fibre was due primarily to growth of the mucosal layer. Villus height and crypt depth increased 60% and 40% respectively, but by only 20% in fibre-free diabetic rats. The plasma levels of GLP-2 parallelled diabetic intestinal growth, whereas plasma levels of enteroglucagon increased regardless of the extent of intestinal growth. CONCLUSIONS: Intestinal growth in experimental diabetes is strongly influenced by the presence of dietary fibre. The effect may be mediated by GLP-2.

Metabolism of oral trefoil factor 2 (TFF2) and the effect of oral and parenteral TFF2 on gastric and duodenal ulcer healing in the rat.

BACKGROUND: Trefoil factors (TFFs) are peptides produced by mucus-secreting cells in the gastrointestinal tract. A functional association between these peptides and mucus, leading to stabilisation of the viscoelastic gel overlying the epithelia, has been suggested. Both oral and parenteral administration of the peptides increase the resistance of the gastric mucosa. AIM: To study the effect in rats of oral and parenteral porcine trefoil factor 2 (pTFF2) on the healing of gastric and duodenal ulcerations and to clarify the distribution and metabolism of orally administered pTFF2 in the gastrointestinal tract. METHODS: Gastric ulcers were induced in female Sprague-Dawley rats by indomethacin and duodenal ulcers by mercaptamine. The rats were treated for up to seven days with oral or subcutaneous pTFF2. Ulcer size after treatment was assessed by stereomicroscopy after whole mount staining with periodic acid-Schiff stain. (125)I-labelled pTFF2 was given orally to rats, and tissues were investigated by gamma counting of samples and by autoradiography of paraffin embedded sections. RESULTS: pTFF2 accelerated gastric ulcer healing after both oral and subcutaneous administration. Duodenal ulcers were aggravated by both treatments. After oral administration of (125)I-pTFF2, intact peptide was recovered from the superficial part of the mucus layer in the stomach; it passed through the small intestine but was degraded in the caecum. Only a minor part of the labelled pTFF2 entered the colon and was excreted in the faeces. Most of the label was excreted in the urine. CONCLUSIONS: Oral as well as parenteral pTFF2 accelerates the healing of gastric ulceration and aggravates duodenal ulcers. Oral pTFF2 binds to the mucus layer of the stomach and the small intestine but does not reach the colonic mucosa.

Impaired meal stimulated glucagon-like peptide 2 response in ileal resected short bowel patients with intestinal failure.

BACKGROUND: Glucagon-like peptide 2 (GLP-2) is a growth factor for the intestinal epithelium in rodents and may affect intestinal transit. AIMS: To study the GLP-2 response to nutrient ingestion in seven short bowel patients with intestinal failure and seven controls. METHODS: The patients and controls were admitted twice for two test meals after a night of fasting. Meal A was liquid (300 ml, 1.88 MJ); meal B was a regular breakfast (755 g, 3.92 MJ). Plasma samples were collected for 180 minutes; GLP-2 immunoreactivity was measured with an NH(2) terminal specific radioimmunoassay. RESULTS: Both meals elicited significant increases in plasma GLP-2 in controls. The magnitude and duration of the responses were dependent on the meal size: the maximum median (25-75%) increases after meal A and B were 24 (3-28) and 48 (33-56) pmol/l. Plasma GLP-2 returned to basal concentrations 180 minutes after meal A, but remained at 50% of peak values after meal B. In the patients neither meal significantly changed the GLP-2 concentration; the maximum median elevation after meal B was 5 (2-8) pmol/l. There were significant differences between patients and controls with respect to the GLP-2 responses to meals A and B. CONCLUSION: Identification of GLP-2 as a tissue specific intestinal growth factor and demonstration of an impaired meal stimulated GLP-2 response in short bowel patients raises the possibility that GLP-2 administration may constitute a new therapeutic strategy, enhancing jejunal adaptation in ileum resected short bowel patients with intestinal failure.

Ureteral growth in animal models with increased renal excretion of urine.

The influence of increased functional load on the macroscopical and histological appearance of the ureter was investigated. Sixty rats were divided into five groups: (1) sucrose-fed rats with non-osmotic polyuria; (2) diabetic rats with osmotic polyuria; (3) uninephrectomized rats; (4) sham-operated control rats; and (5) control rats. The 24-hour urinary volume was measured on days 7, 14 and 21. Growth of the kidney, ureter and bladder was investigated and the histological appearance of the ureter was further evaluated. Diabetic and sucrose-fed rats had comparable polyuria with a seven-fold increase in urinary output. The urinary volume for the remaining kidney was doubled in uninephrectomized rats. After 3 weeks, diabetic rats had increased weight of the kidney, ureter and bladder, sucrose-fed rats had increased weight of the bladder, whereas uninephrectomized rats had increased weight of the kidney and ureter. The cross-sectional area (CSA) of the ureter wall from control rats increased from the proximal to the distal portion. The size of the whole ureter from diabetic rats was dramatically increased, the CSA of the wall of the distal ureter portion being four times that of the controls. The CSA of the ureter wall from sucrose-fed rats was increased only in the distal portion, whereas the ureter from uninephrectomized rats was increased only in the proximal portion. The results demonstrate the importance of differentiating between different portions of the rat ureter when examining histological sections of this organ. Moreover, polyuria per se is shown to induce growth of the bladder and of the adjacent distal part of the ureter, whereas uninephrectomy and diabetes caused growth of the kidney and the upper parts of the ureter, in addition to the growth induced by polyuria.

Adrenergic blockade in diabetic and uninephrectomized rats: effects on renal size and on renal and urinary contents of epidermal growth factor.

The present study reports on the effects of adrenergic blocking agents on the renal growth and on the renal content and urinary excretion of epidermal growth factor (EGF) in streptozotocin-induced diabetic or uninephrectomized rats. Diabetic and uninephrectomized rats were allocated to groups treated with either saline or adrenergic antagonists and compared to controls and sham-operated controls, respectively. 24-hour urine samples were obtained on days 7, 14, and 21 and renal tissue samples on day 21. The 24-hour urinary excretion of EGF from controls and saline-treated diabetic rats was comparable. In adrenergic antagonist treated diabetic rats, it was reduced by at least 40% throughout the study period. Uninephrectomy caused a 50% reduction in the urinary excretion of EGF. This was not influenced by treatment with an adrenergic antagonist. After 3 weeks, saline-treated diabetic rats had an increase of 33% in kidney weight when compared to controls. The adrenergic antagonist treated diabetic groups had a significantly lower increase of 15%. Postnephrectomized renal growth was not affected by adrenergic antagonists. The total renal content of EGF was comparable in the saline-treated diabetic group and the control group, but was reduced by approximately 50% in the kidneys from the adrenergic antagonist treated diabetic groups. Renal EGF mRNA levels were also reduced in adrenergic antagonist treated diabetic rats. In contrast to diabetes, the renal growth following nephrectomy was not affected by adrenergic blocking agents. These results provide evidence for fundamental differences between diabetes-related renal growth and that observed in compensation to nephrectomy and suggest a connection between adrenergic activity, renal growth, and EGF in diabetes.

Time-dependent changes of levels of endogenous epidermal growth factor in submandibular glands, in kidneys, and in urine in rats during systemic treatment with EGF.

BACKGROUND: Exogenous EGF influences the levels of endogenous EGF differently in the submandibular glands (SMG) and the kidneys. The aim of the present study was to examine the time-dependent changes in levels of endogenous EGF during 1-4 weeks of EGF treatment. METHODS: Female rats were allocated into five groups receiving EGF subcutaneously (150 microg/kg/day) for 0 (controls), 1, 2, 3 and 4 weeks prior to sacrifice at an age of 12 weeks. At the end of the study period, 24-h urine samples were collected. RESULTS: The weight of the SMG increased during EGF treatment (303+/-33 (controls), 359+/-37 (1 week EGF, P < 0.01), 390+/-30 (4 weeks EGF, P < 0.001) (mg mean+/-S.D.)). The EGF content of the SMG was unchanged after 1 week but threefold decreased after 4 weeks of treatment, respectively. The expression of EGF mRNA was decreased after 1 and 4 weeks as assessed with in situ hybridization. The weight of the kidneys was unchanged after 1 week and increased after 4 weeks of treatment (828+/-105 mg (controls) vs. 935+/-44 mg (4 weeks EGF, P < 0.005)). The renal content and the urinary excretion of EGF were significantly increased by 20-30% only in the group treated for 4 weeks. CONCLUSION: EGF treatment induces a time-dependent decrease in the EGF content in the SMG most likely by reducing the biosynthesis of endogenous EGF. In contrast, the EGF content in kidneys and in urine was unchanged after 1 week and increased after prolonged treatment.