glucagon-like-peptide-2 and Body-Weight

Malabsorption of nutrients, fluids and electrolytes is a key finding in patients with short bowel syndrome. If not compensated for by increased intake, it leads to diminished body stores and subclinical, and eventually clinical, deficiencies. Until recently, management options were limited to interventions aimed at provision of adequate macro- and micronutrients and fluids to prevent malnutrition, nutrient deficiencies and dehydration, treatment of associated infections and correction and prevention of acid-base disturbances. Identification of novel gut hormones, combined with the growing understanding of their pivotal role in intestinal adaptation, has provoked interest in developing more specific therapies.. To provide an update on the recent advances on the use of teduglutide in patients with short bowel syndrome.. A comprehensive Medline search using the terms teduglutide, ALX-0600, dipeptidyl peptidase IV (DPP-IV) and glucagon like peptide-2 (GLP-2).. Teduglutide (GATTEX, ALX-0600; NPS Allelix Corp) is a synthetic DPP-IV-resistant recombinant human GLP-2 analog that differs from GLP-2 only by an N-terminus substitution of glycine for alanine in position 2 of the peptide that renders the component resistant to enzymatic degradation. Based on the results of the few Phase II studies and the preliminary results of a Phase III trial, teduglutide at doses of 0.05 or 0.10 mg/kg/day may improve many clinical, laboratory and histologic abnormalities in short bowel syndrome patients. It appears to be safe and well tolerated.. Teduglutide is a first-in-class therapy with the potential to create a new standard of care for patients suffering from short bowel syndrome. Future studies to address the appropriate initial and maintenance dosage and optimal duration of treatment are needed.

Topics: Adaptation, Physiological; Adult; Amino Acid Substitution; Body Weight; Child; Clinical Trials, Phase III as Topic; Crohn Disease; Dipeptidyl Peptidase 4; Gastrointestinal Hormones; Glucagon-Like Peptide 2; Half-Life; Human Growth Hormone; Humans; Inactivation, Metabolic; Intestinal Absorption; Peptides; Recombinant Proteins; Short Bowel Syndrome

Malabsorption is a key finding in patients with short-bowel syndrome. Malabsorption of nonessential and essential nutrients, fluids, and electrolytes, if not compensated for by increased intake, leads to diminished body stores and subclinical and (eventually) clinical deficiencies. After intestinal resection, adaptation (a spontaneous progressive recovery from the malabsorptive disorder) may be evident. This article describes selected factors responsible for the morphologic and functional changes in the adaptive processes and presents results of clinical trials that use either growth hormone or glucagon-like peptide-2 to facilitate a condition of hyperadaptation in short-bowel patients.

Topics: Adaptation, Physiological; Body Composition; Body Weight; Creatinine; Energy Metabolism; Glucagon-Like Peptide 2; Glutamine; Growth Hormone; Humans; Intestinal Absorption; Short Bowel Syndrome

To date, the hormonal factors used in the treatment of patients with short-bowel syndrome have been growth hormone and glucagon-like peptide (GLP)-2. In high-dose growth hormone studies, the effects on wet-weight absorption of approximately 0.7 kg/day have mainly been described in short-bowel syndrome patients with a preserved colon who also received oral rehydration solutions. Treatment with high doses of growth hormone is associated with severe adverse effects in the majority of patients. Low-dose growth hormone increased energy absorption by approximately 1.8 MJ/day in a group of 12 short-bowel syndrome patients (9 with a preserved colon), but it did not affect wet-weight absorption. Growth hormone does not seem to affect either wet-weight or energy absorption in patients with a jejunostomy. GLP-2 and the analogue teduglutide mainly affect wet-weight absorption, resulting in a mean increase in wet-weight absorption of 0.4-0.7 kg/day. The effects on energy absorption are minor at 0.4-0.8 MJ/day. However, these effects are seen in all short-bowel syndrome patients, regardless of anatomy, and the adverse effects are minor. In all studies employing growth hormone or GLP-2, the effects are transient, disappearing when treatments are discontinued. With the need for long-term treatment, adverse effects and safety issues become important. Therefore, it is recommended that treatment is initiated in research settings only and that close monitoring of the long-term effects is a part of the protocol.

Topics: Body Composition; Body Weight; Creatinine; Drug Monitoring; Energy Intake; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Glutamine; Growth Hormone; Humans; Hyperplasia; Intestinal Absorption; Intestinal Mucosa; Intestines; Peptides; Randomized Controlled Trials as Topic; Short Bowel Syndrome; Time Factors

Although most humans experience an underlying upwards drift of the body-weight set-point, body weight appears tightly regulated throughout life. The present review describes the structural basis of the adipostat and hypothesise, which components may constitute available targets for pharmacotherapy of excess body weight. Hypothalamic neurones constitute the major components of the body weight homeostasis maintaining device. Together with neurones of the nucleus of the solitary tract, neurones of the hypothalamic arcuate nucleus constitute the sensory components of the adipostat. The arcuate nucleus neurones respond to circulating levels of leptin and insulin, both of which reflect the levels of energy stored as triacylglycerol in adipocytes. The arcuate nucleus projects heavily to the hypothalamic paraventricular nucleus. Neurones of the hypothalamic paraventricular nucleus are hypothesised to constitute, at least partly, the adipostat motor pattern generator, which upon stimulation activates either net anabolic or catabolic physiological responses. The overall sensitivity of the adipostat is influenced by gain setting neurones hypothesised to be located in the dorsomedial hypothalamic nucleus and lateral hypothalamic area. Cocaine amphetamine regulated transcript (CART) peptides and pre-proglucagon derived peptides, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are catabolic neurotransmitters synthesised in neurones of the arcuate nucleus and the nucleus of the solitary tract, respectively. The present review summarises the available evidence that both families of peptides constitute endogenous transmitters mediating satiety and touch upon potential pharmacological exploitation of this knowledge.

Topics: Adipose Tissue; Animals; Body Weight; Eating; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Homeostasis; Humans; Hypothalamus; Nerve Tissue Proteins; Neurons; Neuropeptides; Peptide Fragments; Peptides; Protein Precursors

Neonatal calf diarrhoea is one of the most important health challenges in cattle herds causing substantial economic losses and antimicrobial use. Due to the raising problem of antimicrobial resistance, effective alternatives are urgently required, in line with European policies. The aim of this study was to evaluate the effect of tributyrin supplementation in milk replacer on diarrhoea, performance and metabolic status in preweaning Holstein calves. Twelve newborn calves, after colostrum administration, were randomly allotted in two experimental groups for 42 days: control (CTRL) fed milk replacer, tributyrin (TRIB) fed milk replacer supplemented with 0.3% of liquid tributyrin on milk powder weight. Calves BW was recorded on a weekly basis from day 7 to day 42, and feed intake was recorded daily to calculate zootechnical performance. Faecal consistency was assessed daily through the faecal score (0-3 scale; considering diarrhoea moderate = 2 and severe = 3). Faecal samples were collected weekly from rectal ampulla for microbiological analysis by plate counting method evaluating the number of total bacteria, lactic acid bacteria and coliform bacteria. On day 0 and day 42, individual blood samples were collected from jugular vein for metabolic profile analysis. Serum samples of day 42 were also evaluated for the antioxidant barrier using a colorimetric test, while glucagon-like peptide 2 and diamine oxidase concentrations were measured through immunoenzymatic assays. Tributyrin supplementation did not influence the zootechnical performance of calves over 42 days of trial. Diarrhoea frequency was significantly lower in TRIB compared to CTRL group (27.91 and 38.37%; P < 0.01) considering the whole experimental period. In particular, the major effect was observed for moderate diarrhoea in TRIB group that showed a significantly reduced frequency compared to CTRL (P < 0.01) thus suggesting a preventive effect of tributyrin. Faecal total bacterial, lactic acid and coliform bacteria counts did not show differences between groups. Urea serum concentrations tended to be lower in TRIB compared to CTRL, indicating an efficient utilisation of dietary protein. Antioxidant barrier and glucagon-like peptide 2 were comparable between CTRL and TRIB on day 42. Diamine oxidase concentrations were significantly decreased in TRIB compared to CTRL group after 42 days of trial (P < 0.01), suggesting a higher gut epithelial integrity probably due to lower diarrhoea frequency and t

Topics: Amine Oxidase (Copper-Containing); Animal Feed; Animals; Antioxidants; Body Weight; Cattle; Diarrhea; Diet; Dietary Supplements; Glucagon-Like Peptide 2; Milk; Weaning

Inadequate feed consumption reduces intestinal barrier function in both ruminants and monogastrics. Objectives were to characterize how progressive feed restriction (FR) affects inflammation, metabolism, and intestinal morphology, and to investigate if glucagon-like peptide 2 (GLP2) administration influences the aforementioned responses. Twenty-eight Holstein cows (157 ± 9 d in milk) were enrolled in 2 experimental periods. Period 1 [5 d of ad libitum (AL) feed intake] served as baseline for period 2 (5 d), during which cows received 1 of 6 treatments: (1) 100% of AL feed intake (AL100; n = 3), (2) 80% of AL feed intake (n = 5), (3) 60% of AL feed intake (n = 5), (4) 40% of AL feed intake (AL40; n = 5), (5) 40% of AL feed intake + GLP2 administration (AL40G; 75 µg/kg of BW s.c. 2×/d; n = 5), or (6) 20% of AL feed intake (n = 5). As the magnitude of FR increased, body weight and milk yield decreased linearly. Blood urea nitrogen and insulin decreased, whereas nonesterified fatty acids and liver triglyceride content increased linearly with progressive FR. Circulating endotoxin, lipopolysaccharide binding protein, haptoglobin, serum amyloid A, and lymphocytes increased or tended to increase linearly with advancing FR. Circulating haptoglobin decreased (76%) and serum amyloid A tended to decrease (57%) in AL40G relative to AL40 cows. Cows in AL100, AL40, and AL40G treatments were euthanized to evaluate intestinal histology. Jejunum villus width, crypt depth, and goblet cell area, as well as ileum villus height, crypt depth, and goblet cell area, were reduced (36, 14, 52, 22, 28, and 25%, respectively) in AL40 cows compared with AL100 controls. Ileum cellular proliferation tended to be decreased (14%) in AL40 versus AL100 cows. Relative to AL40, AL40G cows had improved jejunum and ileum morphology, including increased villus height (46 and 51%), villus height to crypt depth ratio (38 and 35%), mucosal surface area (30 and 27%), cellular proliferation (43 and 36%), and goblet cell area (59 and 41%). Colon goblet cell area was also increased (48%) in AL40G relative to AL40 cows. In summary, progressive FR increased circulating markers of inflammation, which we speculate is due to increased intestinal permeability as demonstrated by changes in intestinal architecture. Furthermore, GLP2 improved intestinal morphology and ameliorated circulating markers of inflammation. Consequently, FR is a viable model to study consequences of intestinal barrier dysfunction and a

Topics: Animals; Biomarkers; Body Weight; Cattle; Diet; Fatty Acids, Nonesterified; Female; Food Deprivation; Glucagon-Like Peptide 2; Inflammation; Intestinal Mucosa; Intestines; Lactation; Milk

A multifunctional diet (MFD) was previously shown to reduce blood lipids, CRP and blood pressure in a 4-week intervention under weight-maintenance conditions. Here, MFD effects were evaluated in an 8-week intervention with no restriction for weight changes.. Healthy subjects consumed MFD (23 subjects) or a control diet (CD) devoid of the functional components (24 subjects) in a "free-living" randomized controlled experiment. MFD included several functional concepts: low-glycemic-impact meals, antioxidant-rich foods, oily fish, viscous dietary fibers, soybean and whole barley kernel products, almonds and plant stanols. Measured outcomes were fasting blood values of lipids, glucose, insulin, GGT, CRP, HbA1c, PAI-1, GLP-1, GLP-2, body weight, blood pressure and breath hydrogen.. At baseline, participants were 51-72 years old, with BMI between 25 and 34 and fasting glycemia  ≤ 6.1 mmol/L. Consumption of both diets resulted in similar weight loss after 8 weeks (-4 %; P  <  0.001). Compared to baseline, consumption of MFD reduced total serum cholesterol (-26 %; P  <  0.0001), LDL cholesterol (-35 %; P  <  0.0001), triglycerides (-16 %; P  < 0.05), LDL/HDL (-27 %; P  <  0.0001) and ApoB/ApoA1 (-15 %; P  <  0.0001). There were important net differences between diets, which remained significant after adjustment for body weight. Reduced systolic blood pressure, circulating GGT, HbA1c and insulin concentrations were observed with both MFD and CD with no difference between diets. The Reynolds cardiovascular risk score was decreased by 36 % (P  <  0.0001) with MFD. MFD increased breath hydrogen levels (120 %; P  <  0.05).. Consumption of MFD decreased blood lipids and improved several other aspects of the cardiometabolic risk profile. This effect was not dependent on weight loss.

Topics: Aged; Biomarkers; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; C-Reactive Protein; Cardiovascular Diseases; Cross-Over Studies; Diet; Female; gamma-Glutamyltransferase; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glycated Hemoglobin; Humans; Insulin; Lipids; Male; Metabolic Syndrome; Middle Aged; Obesity; Overweight; Plasminogen Activator Inhibitor 1; Risk Factors; Waist Circumference

An experiment was conducted to determine the effect of injecting glucagon-like peptide 2 (GLP-2) on the small intestinal weight, morphology, and nutrient transporter expression in pharmacologically stressed broiler chickens. A total of 144 seven-day-old birds were fed either a basal diet (CTRL) or a basal diet plus 30 mg of corticosterone (CORT)/kg of diet for a total of 14 d. Half of the birds from each group were injected daily with GLP-2 (6.7 nmol/kg of BW) or saline for 14 d. The average final BW, ADG, ADFI, and the ratio of feed intake to weight gain (F:G) was recorded over 21 d for the 4 groups of 36 birds, namely CTRL + saline, CTRL + GLP-2, CORT + saline, and CORT + GLP-2. In addition, the absolute and relative small intestinal weight, villus height (VH), and crypt depth (CD) of the duodenum and jejunum, as well as the abundance of sodium and glucose co-transporter 1 (SGLT-1), vitamin D-dependent calcium-binding protein-28,000 molecular weight (CaBP-D28k), and peptide transporter 1 (PepT-1) mRNA in the duodenum and of liver fatty acid-binding protein (L-FABP) mRNA in the jejunum. The total DNA, RNA, and protein content in small intestinal mucosa were also determined. The results showed that CORT administration significantly lowered average final BW, ADG, ADFI, absolute small intestinal weight, VH, and CD of duodenum and jejunum (P < 0.05) while increasing the relative small intestinal weight, F:G, relative abundance of SGLT-1, CaBP-D28k, PepT-1, and L-FABP mRNA (P < 0.05). Glucagon-like peptide 2 injection increased the average final BW, ADG, VH, and CD in duodenum and jejunum and relative abundance of SGLT-1, CaBP-28k, PepT1, and PepT1 mRNA of broiler chickens, respectively (P < 0.05), and decreased F:G (P < 0.05). In chickens fed basal diet plus CORT, injecting GLP-2 decreased F:G (P < 0.05); increased VH and CD of duodenum and CD of jejunum; and increased relative abundance of SGLT-1, CaBP-D28k, PepT-1, and L-FABP mRNA, RNA, and total protein content in small intestine compared with the injection of saline (P < 0.05). In birds fed the basal diet, GLP-2 injection decreased F:G (P < 0.05) and increased final BW, ADG, small bowel weight, CD of jejunum, and relative abundance of CaBP-D28k and PepT-1 mRNA compared with injecting saline (P < 0.05). In conclusion, GLP-2 injection reversed the negative effect of stress on the weight and morphology and the absorptive function of small bowel of broiler chickens. Glucagon-like peptide 2 injection also had

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Carrier Proteins; Chickens; Corticosterone; Gene Expression Regulation; Glucagon-Like Peptide 2; Intestine, Small; RNA, Messenger; Stress, Physiological

We aimed to test the effects of three different weight maintenance diets on appetite, glucose and fat metabolism following an initial low-energy diet (LED) induced body weight loss. Following an 8-week LED and a 2-3-week refeeding period, 131 subjects were randomized to three diets for 6 months: MUFA, moderate-fat (35-45 energy percentage (E%) fat), high in MUFA with low glycaemic index; LF, low fat (20-30 E% fat) or CTR, control (35 E% fat). A meal test study was performed in a subgroup, before and after the 6-month dietary intervention, with forty-two subjects completing both meal tests. No difference in body weight, energy intake or appetite ratings were observed between diets. Both the LF and MUFA diets compared to CTR diet reduced postprandial glycaemia and insulinaemia and lowered fasting insulin from month 0 to month 6. Following the 8-week LED period lower levels of the appetite regulating peptides, pancreatic polypeptide, peptide YY, glucagon-like peptide-1 and glucagon-like peptide-2, along with increased appetite scores were seen in comparison to measurements performed after the 6-month dietary intervention. In conclusion, the two competing diets, MUFA and LF, were equally good with respect to glucose metabolism, whereas the CTR diet resembling the typical Western diet, high in SFA, sugar and high glycaemic carbohydrates, indicated associations to lowering of insulin sensitivity. Lower levels of appetite regulatory peptides along with increased appetite scores following an 8-week LED and 2-3-week refeeding period, suggest that strategies for physiological appetite control following a LED period are needed, in order to prevent weight regain.

Topics: Adult; Analysis of Variance; Appetite Regulation; Area Under Curve; Blood Glucose; Body Mass Index; Body Weight; Diet, Fat-Restricted; Energy Intake; Fatty Acids, Monounsaturated; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glycemic Index; Humans; Insulin; Male; Obesity; Pancreatic Polypeptide; Peptide YY; Time Factors; Triglycerides

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.. 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.. 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.. 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.

Topics: Adult; Body Composition; Body Weight; Creatinine; Female; Gastrointestinal Hormones; Gastrointestinal Transit; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Hormones; Humans; Injections, Subcutaneous; Intestinal Absorption; Intestines; Male; Middle Aged; Nutritional Status; Patient Compliance; Peptides; Short Bowel Syndrome

Kraft pulp (KP), an intermediate product obtained when wood chips are converted to paper, contains highly digestible fiber. This study evaluated the effect of KP inclusion in calf starters on growth performance, health, and plasma glucagon-like peptide 2 (GLP-2) concentration in calves. Twenty-five Holstein heifer calves were raised on a high plane of nutrition program using milk replacer containing 29% crude protein and 18% fat until 49 d after birth, and were fed calf starters containing KP at 0 (CON; n = 14) or 12% (KPS; n = 11) on a dry matter basis. All calves were fed the treatment calf starters and timothy hay ad libitum. Blood was collected at 4, 14, 21, 35, 49, 70, and 91 d after birth. Dry matter intake (DMI) of milk replacer and hay was not affected by treatment, whereas calf starter DMI was lower for KPS (0.93 kg/d) than for CON (1.03 kg/d). Higher neutral detergent fiber (NDF) content in KPS (31.7%) than in the CON starter (22.1%) resulted in higher NDF intake for KPS (0.55 kg/d) than for CON (0.47 kg/d). However, the consumption of starch was lower for KPS (0.29 kg/d) than for CON (0.33 kg/d). Despite the lower starter intake for KPS, body weight and average daily gain did not differ between treatments. No significant difference was observed in the plasma concentrations of metabolites, except for β-hydroxybutyrate (BHB); BHB concentration was lower for KPS (216 μmol/L) than for CON (257 μmol/L). The area under the curve for plasma GLP-2 concentration was higher for KPS (54.1 ng/mL × d) than for CON (36.0 ng/mL × d). Additionally, the fecal score postweaning (1.19 and 1.48 for KPS and CON, respectively) and the number of days that calves developed diarrhea throughout the experimental period (2.50 d and 8.10 d for KPS and CON, respectively) were lower for KPS than for CON. These results indicate that feeding KP reduces the severity and frequency of diarrhea without adversely affecting growth performance. This could be attributed to the increased plasma GLP-2 concentration induced by higher NDF intake.

Topics: 3-Hydroxybutyric Acid; Animal Feed; Animals; Body Weight; Cattle; Diarrhea; Diet; Female; Glucagon-Like Peptide 2; Weaning

Extensive intestinal resection may lead to short bowel (SB) syndrome, resulting in intestinal insufficiency or intestinal failure (IF). Intestinal insufficiency and IF involve deficiency of the proglucagon-derived hormones glucagon-like peptide-1 (GLP-1) and GLP-2. Two major problems of SB are epithelial surface loss and accelerated transit. Standard treatment now targets intestinal adaptation with a GLP-2 analogue to enlarge absorptive surface area. It is possible that additional benefit can be gained from a combination of GLP-1 and GLP-2 activity, with the aim to enlarge intestinal surface area and slow intestinal transit.. The GLP-1- and GLP-2-specific effects of the novel dual GLP-1 receptor (GLP-1R) and GLP-2 receptor (GLP-2R) agonist dapiglutide (rINN) were characterized in rodents. Furthermore, in a murine SB model of intestinal insufficiency with 40% ileocecal resection, the influence of dapiglutide on intestinal growth, body weight, food intake, volume status, and stool water content was tested against vehicle and sham-operated male mice.. Dapiglutide significantly improves oral glucose tolerance, reduces intestinal transit time, and promotes intestinal growth. In the SB mouse model, dapiglutide promotes body weight recovery, despite unchanged intake of liquid diet. Dapiglutide promotes significant intestinal growth, as indicated by significantly increased villus height as well as intestinal length. Furthermore, dapiglutide reduces stool water losses, resulting in reduced plasma aldosterone.. Dapiglutide possesses specific and potent GLP-1R and GLP-2R agonist effects in rodents. In the murine SB model, combined unimolecular GLP-1R and GLP-2R stimulation with dapiglutide potently attenuates intestinal insufficiency and potentially also IF.

Topics: Animals; Body Weight; Disease Models, Animal; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-2 Receptor; Male; Mice; Short Bowel Syndrome; Water

Glucagon-like peptide-2 (GLP-2) is a gastrointestinal hormone released in response to nutritional intake that exerts a wide range of effects by activating GLP-2 receptors. In addition to its intestinotrophic effects, GLP-2 also positively influences glucose metabolism under conditions of obesity, but the mechanisms behind this remain unclear. Here, we have investigated the molecular role of the GLP-2/GLP-2 receptor axis in energetic metabolism, focusing on its potential modulatory effects on adipose tissue.. Physiological measurements (body weight, food intake, locomotor activity, and energy expenditure) and metabolic studies (glucose and insulin tolerance tests) were performed on lean and obese mice treated with the protease-resistant GLP-2 analogue teduglutide.. Acute but not chronic centrally administered teduglutide decreased food intake and weight-gain. By contrast, chronic activation of peripheral GLP-2 receptors increased body weight-independent glucose tolerance and had anti-inflammatory effects on visceral adipose tissue. Using a gene silencing approach, we found that adipose tissue is necessary for these beneficial effects of teduglutide. Finally, teduglutide regulates the inflammatory state and acts as an anabolic signal in human adipocytes.. Overall, our data identify adipose tissue as a new, clinically relevant, site of action for GLP-2 activity in obesity.. This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc.

Topics: Adipose Tissue; Body Weight; Eating; Glucagon-Like Peptide 2; Humans; Obesity

Topics: Animal Feed; Animals; Bacteria; Body Weight; Cytokines; Diet; Dietary Supplements; Feces; Gastrointestinal Microbiome; Glucagon-Like Peptide 2; RNA, Ribosomal, 16S; Saccharomyces cerevisiae; Swine; Weaning

Chemotherapy-induced alimentary mucositis (AM) is difficult to prevent and treatment is rarely effective. Recent study have been showed that glucagon-like peptide (GLP)-1 and GLP-2 has protective in chemotherapy-induced AM. While the DPP-4 enzyme degrades this GLP-1, the DPP-4 inhibitor blocks the degradation process and raises the concentration of GLP-1. This study aimed to assess the role of DPP-4 inhibitor, a well-known hypoglycemic agent, on chemotherapy-induced AM.. Twenty-four 6-week-old male C57BL/6 mice were divided into 4 groups: control, 5-fluorouracil (5-FU), DPP-4 inhibitor, and saline (DPP-4i), and DPP-4 inhibitor and 5-FU (DPP-4i + 5-FU). Mucositis was induced by intraperitoneal injection of 5-FU (400 mg/kg). DPP-4 inhibitor (50 mg/kg) was administered orally for four days starting the day before 5-FU administration. Post 72 h of 5-FU injection, mice were sacrificed and body weight change, diarrhea score, villus height, villus/crypt ratio, histologic characteristics including goblet cell count, and mRNA expression of inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6, were assessed.. Daily body weight change was not statistically significant between the 5-FU and the DPP-4i + 5-FU group (P = 0.571). Diarrhea score was significantly different between these two groups (P = 0.033). In the 5-FU group, the villus height was not maintained well, the epithelial lining was irregular, and inflammatory cell infiltration was observed. Goblet cell count in the DPP-4i + 5-FU group was significantly higher than in the 5-FU group (P = 0.007). However, in the DPP-4i + 5-FU group, the villus height, epithelial lining, and crypt structure were better maintained than in the 5-FU group. Compared with the control group, mRNA expression of TNF-α was significantly up-regulated in the 5-FU group. Moreover, mRNA expression of TNF-α in the DPP-4i + 5-FU group was down-regulated compared to the 5-FU group. However, IL-6 in the 5-FU group was significantly down-regulated compared to the control, there was no significant difference in expression of IL-6 between the 5-FU and DPP4i + 5-FU group.. DPP-4 inhibitor can improve 5-FU induced AM and, therefore, has potential as an alternative treatment for chemotherapy-induced AM.

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Body Weight; Diarrhea; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Fluorouracil; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Goblet Cells; Injections, Intraperitoneal; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Mucositis; Protective Agents; Tumor Necrosis Factor-alpha

In this study, we evaluate the effects of glucagon-like peptide 2 (GLP-2) on bone microarchitecture, bone turnover markers (BTMs) and inflammation markers in ovariectomized (OVX) rats.. In total, 31 Sprague-Dawley rats were divided into the following three groups: sham (control sham-operated with vehicle, n = 7), OV (OVX with vehicle, n = 12), and GLP-2 (OVX with GLP-2, n = 12). Intervention began at the 12th week after surgery and lasted for 4 weeks. The dosage of the GLP-2 was 160 μg/kg/d through subcutaneous injections, and normal saline was used as the vehicle agent. After 4 weeks of treatment, serum BTM and inflammation marker levels were measured by ELISA, and femora samples were analyzed by qRT-PCR, micro-CT, histology and histomorphometry.. After 4 weeks of treatment, serum TRAcP-5b and RANKL levels as well as the CTX-1/P1NP ratio in the GLP-2 group decreased, and ALP activity, P1NP level, and OPG/RANKL ratio increased significantly; qRT-PCR analysis showed that mRNA levels of RANKL decreased, and Runx2, ALP, and Col-1 levels as well as the OPG/RANKL ratio increased significantly in the GLP-2 group compared with the OV group. In bone histology analysis, GLP-2 significantly decreased the AV/MV, Oc.N and Oc.S but increased the Ob.N, BFR and MAR. Analysis with μ-CT showed that the BMD, BV/TV, Tb.N and Conn.D increased significantly in the GLP-2 group compared with the OV group. The levels of serum inflammation markers TNF-α, IL-1β and IL-6 decreased, and TGF-β levels increased in the GLP-2 group compared with the OV group.. GLP-2 may have a positive impact on osteoporosis by promoting bone formation, inhibiting bone resorption and decreasing circulatory inflammation in ovariectomized rats.

Topics: Animals; Body Weight; Bone and Bones; Bone Density; Bone Remodeling; Bone Resorption; Female; Femur; Glucagon-Like Peptide 2; Osteogenesis; Osteoporosis; Osteoprotegerin; Ovariectomy; Random Allocation; Rats; Rats, Sprague-Dawley; X-Ray Microtomography

Intestinal adaptation is the natural compensatory mechanism that occurs when the bowel is lost due to trauma. The adaptive responses, such as crypt cell proliferation and increased nutrient absorption, are critical in recovery, yet poorly understood. Understanding the molecular mechanism behind the adaptive responses is crucial to facilitate the identification of nutrients or drugs to enhance adaptation. Different approaches and models have been described throughout the literature, but a detailed descriptive way to essentially perform the procedures is needed to obtain reproducible data. Here, we describe a method to estimate important endpoints and proliferative markers of small intestinal injury and compensatory hyperproliferation using a model of chemotherapy-induced mucositis in mice. We demonstrate the detection of proliferating cells using a cell cycle specific marker, as well as using small intestinal weight, crypt depth, and villus height as endpoints. Some of the critical steps within the described method are the removal and weighing of the small intestine and the rather complex software system suggested for the measurement of this technique. These methods have the advantages that they are not time-consuming, and that they are cost-effective and easy to carry out and measure.

Topics: Acute Disease; Adaptation, Physiological; Animals; Antineoplastic Agents; Biomarkers; Body Weight; Bromodeoxyuridine; Cell Proliferation; Disease Models, Animal; Endpoint Determination; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Intestinal Mucosa; Intestine, Small; Mice, Inbred C57BL; Mucositis

The objective of this study was to investigate the effects of different sources of starch in starter feed on small intestinal growth and endogenous glucagon-like peptide 2 (GLP-2) secretion in preweaned lambs. Twenty-four 10-d-old lambs were divided into three groups that were treated with different iso-starch diets containing purified cassava starch (CS, n = 8), maize starch (MS, n = 8), and pea starch (PS, n = 8). At 56 d old, there was no significant difference in final body weight (BW) of lambs among the three groups. However, different starch source in starter significantly affected the average daily feed intake (ADFI) and average daily gain (ADG) of lambs among three groups. Compared with the CS and MS diets, the PS diet significantly increased the GLP-2 concentration in blood plasma (P < 0.001), the crypt depth of the jejunum (P = 0.006), and the villus height of the ileum (P = 0.039). Meanwhile, PS diet significantly increased the mRNA expression of proglucagon and the glucagon-like peptide 2 receptor (GLP-2R) in the jejunum and ileum (P < 0.001). Furthermore, the PS diet significantly upregulated the mRNA expression of cyclin D1 (P < 0.001), cyclin E (P = 0.006), and cyclin-dependent kinases 6 (CDK6) (P = 0.048) in the jejunum and cyclin A (P < 0.001), cyclin D1 (P < 0.001), and CDK6 (P = 0.002) in the ileum. Correlation analysis showed that endogenous GLP-2 secretion was positively related to the mRNA levels of cell cycle proteins in small intestinal mucosa. In summary, all results showed that PS in starter feed promoted small intestinal growth that may, in part, be related to cell cycle acceleration and endogenous GLP-2 secretion in preweaned lambs. These findings provide new insights into nutritional interventions that promote the development of small intestines in young ruminants.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Body Weight; Diet; Dietary Carbohydrates; Gene Expression Regulation; Glucagon-Like Peptide 2; Intestinal Mucosa; Intestine, Small; Male; Proglucagon; RNA, Messenger; Sheep; Starch

Analogues of several gastrointestinal peptide hormones have been developed into effective medicines for treatment of diseases such as type 2 diabetes mellitus (T2DM), obesity and short bowel syndrome (SBS). In this study, we aimed to explore whether the combination of glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) into a potent co-agonist could provide additional benefits compared to existing monotherapies.. A short-acting (GUB09-123) and a half-life extended (GUB09-145) GLP-1/GLP-2 co-agonist were generated using solid-phase peptide synthesis and tested for effects on food intake, body weight, glucose homeostasis, and gut proliferation in lean mice and in diabetic db/db mice.. Sub-chronic administration of GUB09-123 to lean mice significantly reduced food intake, improved glucose tolerance, and increased gut volume, superior to monotherapy with the GLP-2 analogue teduglutide. Chronic administration of GUB09-123 to diabetic mice significantly improved glycemic control and showed persistent effects on gastric emptying, superior to monotherapy with the GLP-1 analogue liraglutide. Due to the short-acting nature of the molecule, no effects on body weight were observed, whereas a marked and robust intestinotrophic effect on mainly the small intestine volume and surface area was obtained. In contrast to GUB09-123, sub-chronic administration of a half-life extended GUB09-145 to lean mice caused marked dose-dependent effects on body weight while maintaining its potent intestinotrophic effect.. Our data demonstrate that the GLP-1/GLP-2 co-agonists have effects on gut morphometry, showing a marked increase in intestinal volume and mucosal surface area. Furthermore, effects on glucose tolerance and long-term glycemic control are evident. Effects on body weight and gastric emptying are also observed depending on the pharmacokinetic properties of the molecule. We suggest that this novel co-agonistic approach could exemplify a novel concept for treatment of T2DM or SBS.

Topics: Animals; Body Weight; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Eating; Gastrointestinal Agents; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucose; Homeostasis; Hypoglycemic Agents; Liraglutide; Male; Mice, Inbred C57BL; Peptides; Random Allocation

Therapeutic interventions that improve glucose homeostasis such as attenuation of glucagon receptor (Gcgr) signaling and bariatric surgery share common metabolic features conserved in mice and humans. These include increased circulating levels of bile acids (BA) and the proglucagon-derived peptides (PGDPs), GLP-1 and GLP-2. Whether BA acting through TGR5 (Gpbar1) increases PGDP levels in these scenarios has not been examined. Furthermore, although the importance of GLP-1 action has been interrogated in Gcgr. To assess whether BA acting through Gpbar1 mediates improved glucose homeostasis in Gcgr. Circulating levels of BA were markedly elevated yet similar in Gcgr. These findings reveal that GLP-2R controls BA levels and relative proportions of BA species in Gcgr

Topics: Animals; Bile Acids and Salts; Blood Glucose; Body Weight; Diet, High-Fat; Gastrectomy; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide-2 Receptor; Glucose; Glucose Tolerance Test; Homeostasis; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Proglucagon; Receptors, G-Protein-Coupled; Receptors, Glucagon; Signal Transduction; Weight Loss

This study was conducted to investigate the effects of in ovo feeding (IOF) of Arg solution on the hatchability, growth performance, gastrointestinal hormones, serum AA, activities of digestive enzymes, and mRNA expressions of sensing receptors and nutrient transporters in the jejunum of posthatch broilers. One thousand two hundred embryonated eggs with similar weight were randomly allocated to 5 groups consisting of 8 replicates of 40 eggs each. The 5 treatments were arranged as a noninjected control, a diluent-injected (0.75% NaCl solution) group, and Arg solution-injected groups with 0.5%, 1.0%, and 2.0% Arg, all dissolved in diluent. At 17.5 d of incubation, 0.6 mL of IOF solution was injected into the amniotic fluid of each egg of the injected groups. Results showed the hatchability of the 2% Arg group was lower (linear, = 0.025) than that of the other groups, and the BW of 21-d-old broilers increased (linear, = 0.008; quadratic, = 0.003) with increasing IOF concentration of Arg. The ADFI (linear, = 0.005; quadratic, = 0.001) and ADG (linear, = 0.010; quadratic, = 0.004) increased during d 1 to 21 with increasing IOF concentration of Arg. For 7- and 21-d-old broilers, the weights of digestive organs increased (linear, < 0.05) with increasing IOF concentrations of Arg; the greatest values were observed in the 1% Arg group. For 21-d-old broilers, IOF of the 1% Arg solution increased ( < 0.05) the concentrations of ghrelin and glucagon-like peptide 2; the activities of digestive enzymes, alkaline phosphatase, maltase, and sucrase in the jejunum; and the concentrations of serum AA of Val, Met, Ile, Leu, Arg, and Pro compared with those of the noninjected control and diluent-injected group. In ovo feeding of the 1% Arg solution also increased ( < 0.05) the mRNA expressions of jejunal sensing receptors of taste receptor type 1 members 1 and 3; the G protein-coupled receptor, class C, group 6, subtype A; nutrient transporters of solute carrier family 7, members 4, 6, and 7; sodium-glucose transporter 1; and fatty acid-binding protein 1. In conclusion, the 1% Arg solution was the appropriate injection level. In ovo feeding of the 1% Arg solution did not affect the hatchability but facilitated the release of gastrointestinal hormones, increasing the digestive and absorptive capacity and finally improving the growth performance of 21-d-old broilers. Therefore, IOF of the appropriate Arg solution could be an effective technology for regulating early nutrition s

Topics: Animals; Arginine; Body Weight; Chickens; Digestion; Fatty Acid-Binding Proteins; Female; Gastrointestinal Hormones; Glucagon-Like Peptide 2; Jejunum; Male; Sodium-Glucose Transporter 1

Diarrhea episodes in dairy calves involve profound alterations in the mechanism controlling gut barrier function that ultimately compromise intestinal permeability to macromolecules, including pathogenic bacteria. Intestinal dysfunction models suggest that a key element of intestinal adaptation during the neonatal phase is the nutrient-induced secretion of glucagon-like peptide (GLP)-2 and associated effects on mucosal cell proliferation, barrier function, and inflammatory response. Bioactive molecules found in Olea europaea have been shown to induce the release of regulatory peptides from model enteroendocrine cells. The ability to enhance GLP-2 secretion via the feeding of putative GLP-2 secretagogues is untested in newborn calves. The objectives of this study were to determine whether feeding a bioactive extract from Olea europaea (OBE) mixed in the milk replacer (1) can stimulate GLP-2 secretion beyond the response elicited by enteral nutrients and, thereby, (2) improve intestinal permeability and animal growth as well as (3) reduce the incidence of diarrhea in preweaning dairy calves. Holstein heifer calves (n = 60) were purchased, transported to the research facility, and blocked by body weight and total serum protein and assigned to 1 of 3 treatments. Treatments were control (CON), standard milk replacer (MR) and ad libitum starter; CON plus OBE added into MR at 30 mg/kg of body weight (OBE30); and CON plus OBE added into MR at 60 mg/kg of body weight (OBE60). The concentration of GLP-2 was measured at the end of wk 2. Intestinal permeability was measured at the onset of the study and the end of wk 2 and 6, with lactulose and d-mannitol as markers. Treatments did not affect calf growth and starter intake. Compared with CON, administration of OBE60 increased the nutrient-induced response in GLP-2 by about 1 fold and reduced MR intake during the second week of study. Throughout the study, however, all calves had compromised intestinal permeability and a high incidence of diarrhea. The GLP-2 response elicited by OBE60 did not improve intestinal permeability (lactulose-to-d-mannitol ratio) and incidence of diarrhea over the course of the preweaning period. The response in GLP-2 secretion to the administration of OBE reported herein warrants further research efforts to investigate the possibility of improving intestinal integrity through GLP-2 secretion in newborn calves.

Topics: Animal Feed; Animals; Body Weight; Cattle; Diet; Female; Glucagon-Like Peptide 2; Milk; Olea

Polyethylene glycosylated (PEGylated) porcine glucagon-like peptide-2 (pGLP-2) considerably increases half-life and stability compared with the native pGLP-2, but the effective dose for intestinal damage is still unclear. This study aims to evaluate the available dose of polyethylene glycosylated porcine glucagon-like peptide-2 (PEG-pGLP-2), a modified, long-acting form of pGLP-2 in an experimental rat model of ulcerative colitis.. Thirty-five male rats were randomly assigned into five groups: control, dextran sodium sulphate (DSS), DSS + PEG-pGLP-2(L), DSS + PEG-pGLP-2(M) and DSS + PEG-pGLP-2(H). Rats in control group received only water; other rats were fed with 5% (w/v) DSS and intraperitoneally administered with 12.5, 25 and 100 nmol/kg PEG-pGLP-2 daily for 6 days.. Compared with the control treatment, DSS treatment significantly (p < 0.05) decreased body weight change, colonic length, duodenal villus height and expression of zonula occludens-1, whereas significantly (p < 0.05) increased colonic damage score and expression of claudin-1, interleukin (IL)-1, IL-7, IL-10, interferon-γ and tumour necrosis factor (TNF)-α in colon. However, the three doses of PEG-pGLP-2 all reduced these effects; these treatments significantly (p < 0.05) increased body weight change and duodenal villus height, whereas significantly (p < 0.05) decreased colonic damage score and expression of IL-1, IL-7 and TNF-α in colon. Specifically, low-dose (12.5 nmol/kg/d) PEG-pGLP-2 was effective.. These results indicated that PEG-pGLP-2 is a novel and potentially effective therapy for intestinal healing in a relatively low dose.

Topics: Animals; Body Weight; Claudin-1; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Duodenum; Glucagon-Like Peptide 2; Intestinal Mucosa; Male; Polyethylene Glycols; Rats; Zonula Occludens-1 Protein

Chronic exposure to lipopolysaccharide (LPS) contributes to metabolic abnormalities, but there has been no study to evaluate plasma LPS levels after ileal transposition (IT). We examined the effect of IT on gut hormone secretion and plasma LPS levels and their correlation with metabolic parameters.. Sprague-Dawley rats underwent either IT or sham operation. After 4 weeks, oral glucose tolerance tests (OGTT) were performed and fasting plasma LPS and gut histology were analyzed.. Compared with the sham group, food intake and body weight decreased, and insulin sensitivity increased in the IT group. During the OGTTs, glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, and peptide YY (PYY) were significantly higher in the IT group than the sham group. The villi length, muscle thickness, and the density of GLP-1 and glucose-dependent insulinotropic polypeptide co-expressing cells (K/L-cells) increased in the transposed ileum compared with the ileum of the sham group. Fasting plasma LPS levels were lower in the IT group than the sham group (5.6 ± 0.2 vs. 6.8 ± 0.1 EU/ml, P = 0.002) and significantly correlated with insulin resistance (r = 0.755, P < 0.001). Plasma LPS levels were negatively correlated with PYY secretion (r = -0.710, P = 0.001), and GLP-2 secretion (r = -0.561, P = 0.019).. IT surgery decreased plasma LPS levels in a non-obese non-diabetic rat model, which was associated with improved insulin sensitivity and increased L-cell secretion.

Topics: Animals; Blood Glucose; Body Weight; Drinking; Eating; Enteroendocrine Cells; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucose Tolerance Test; Ileum; Insulin Resistance; Lipopolysaccharides; Male; Obesity, Morbid; Peptide YY; Rats, Sprague-Dawley

We aimed to assess the feasibility of enhancing the intestinal development of weaned rats using glucagon-like peptide-2 (GLP-2)-expressing Saccharomyces cerevisiae (S. cerevisiae). GLP-2-expressing S. cerevisiae (GLP2-SC) was generated using a recombinant approach. The diet of weaned rats was supplemented with the GLP2-SC strain. The average daily gain (ADG), the intestinal morphology and the activities of the digestive enzymes in the jejunum were tested to assess the influence of the GLP2-SC strain on intestinal development. The proliferation of rat enterocytes was also assessed in vitro. The study revealed that the ADG of the weaned rats that received GLP2-SC was significantly greater than that of the controls fed a basal diet (Control) and S. cerevisiae harbouring an empty vector (EV-SC) (P < 0.05) but was equivalent to that of positive control rats fed recombinant human GLP-2 (rh-GLP2) (P > 0.05). Furthermore, GLP2-SC significantly increased villous height (P < 0.01) and digestive enzyme activity (P < 0.05) in the jejunum. Immunohistochemistry analysis further affirmed that enterocyte proliferation was stimulated in rats fed the GLP2-SC strain, as indicated by the greater number of enterocytes stained with proliferative cell nuclear antigen (P < 0.05). In vitro, the proliferation of rat enterocytes was also stimulated by GLP-2 expressed by the GLP2-SC strain (P < 0.01). Herein, the combination of the GLP-2 approach and probiotic delivery constitute a possible dietary supplement for animals after weaning.

Topics: Animal Feed; Animals; Body Weight; Cell Proliferation; Cells, Cultured; Diet; Enterocytes; Gastrointestinal Tract; Glucagon-Like Peptide 2; Health; Hydrolases; Probiotics; Rats; Recombinant Proteins; Saccharomyces cerevisiae; Treatment Outcome

Neonatal short bowel syndrome following massive gut resection is associated with malabsorption of nutrients. The intestinotrophic factor glucagon-like peptide 2 (GLP-2) improves gut function in adult patients with short bowel syndrome, but its effect in pediatric patients remains unknown. Our objective was to test the efficacy of the long-acting synthetic human GLP-2 analogue, teduglutide (ALX-0600), in a neonatal piglet jejunostomy model. Two-day-old pigs were subjected to resection of 50% of the small intestine (distal part), and the remnant intestine was exteriorized on the abdominal wall as a jejunostomy. All pigs were given total parenteral nutrition for 7 days and a single daily injection of the following doses of teduglutide: 0.01 (n = 6), 0.02 (n = 6), 0.1 (n = 5), or 0.2 mg · kg · day (n = 6), and compared with placebo (n = 9). Body weight increment was similar for all 4 teduglutide groups but higher than placebo (P < 0.05). There was a dose-dependent increase in weight per length of the remnant intestine (P < 0.01) and fractional protein synthesis rate in the intestine was increased in the 0.2 mg · kg · day group versus placebo (P < 0.001); however, functional and structural endpoints including activity of digestive enzymes, absorption of enteral nutrients, and immunohistochemistry (Ki67, villin, FABP2, ChgA, and GLP-2R) were not affected by the treatment. Teduglutide induces trophicity on the remnant intestine but has limited acute effects on functional endpoints. Significant effects of teduglutide on gut function may require a longer adaptation period and/or a more frequent administration of the peptide. In perspective, GLP-2 or its analogues may be relevant to improve intestinal adaptation in pediatric patients with short bowel syndrome.

Topics: Adaptation, Physiological; Animals; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gastrointestinal Agents; Glucagon-Like Peptide 2; Glucagon-Like Peptide-2 Receptor; Growth; Intestine, Small; Jejunostomy; Organ Size; Parenteral Nutrition, Total; Peptides; Protein Biosynthesis; Receptors, Glucagon; Short Bowel Syndrome; Swine

Maternal protein restriction (PR) during pregnancy is known to have numerous adverse effects on offspring, including increased adiposity and impaired glucose tolerance later in life. A few studies have shown that this adverse programming can be reversed by dietary or hormonal therapies early in postnatal life. The objective of this study was to determine if a weaning diet high in prebiotic fiber could mitigate some of the negative effects of maternal PR, such as increased adiposity and impaired glucose tolerance. Wistar rats were fed a low- (8%) or normal- (20%) protein diet during pregnancy. Male and female pups were weaned onto control (C; 5% fiber, 20% protein) or high (prebiotic) fiber (HF; 21% wt:wt, 1:1 ratio oligofructose and inulin at 4-10 wk; 10% wt:wt, 1:1 ratio oligofructose and inulin at 10-24 wk; 17.3% protein) diets. At 24 wk of age, glucose tolerance, body composition, satiety hormones, gut microbiota, and markers of intestinal permeability were measured in the offspring. Maternal PR reduced offspring birth weight by 5% and lean mass by 9% compared with the C offspring (P < 0.007). HF-fed offspring had lower body weights and percentage body fat (∼23% in males, ∼19% in females) at 24 wk than did C offspring (P < 0.02). Compared with C pups, pups fed the HF diet had greater cecal Bifidobacterium spp. (>5-fold) and plasma concentrations of the gut trophic hormone glucagon-like peptide 2 (GLP-2) (P < 0.05). In male PR offspring fed the HF diet, insulin resistance measured by the homeostasis model assessment of insulin resistance was reduced by 81% compared with those fed the C diet (P = 0.02). In female PR offspring fed the HF diet, plasma endotoxin was greater and colonic tight junction protein 1 (Tjp1) expression was lower than in those fed the C diet. A high prebiotic fiber weaning diet mitigated increased adiposity and insulin resistance associated with maternal PR, which could improve health and decrease risk of chronic disease in offspring born to malnourished dams. However, the functional importance of sex-specific changes in markers of intestinal barrier function warrants further investigation.

Topics: Adiposity; Animals; Blood Glucose; Body Composition; Body Weight; Diet; Diet, High-Fat; Diet, Protein-Restricted; Dietary Fiber; Female; Gastrointestinal Tract; Ghrelin; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Insulin; Insulin Resistance; Male; Maternal Nutritional Physiological Phenomena; Peptide YY; Permeability; Prebiotics; Pregnancy; Rats; Rats, Wistar; Satiation; Sex Factors; Weaning

Glucagon-like peptide-2 (GLP-2) action is dependent on intestinal expression of IGF-I, and IGF-I action is modulated by IGF binding proteins (IGFBP). Our objective was to evaluate whether the intestinal response to GLP-2 or IGF-I is dependent on expression of IGFBP-3 and -5. Male, adult mice in six treatment groups, three wild-type (WT) and three double IGFBP-3/-5 knockout (KO), received twice daily intraperitoneal injections of GLP-2 (0.5 μg/g body wt), IGF-I (4 μg/g body wt), or PBS (vehicle) for 7 days. IGFBP-3/-5 KO mice showed a phenotype of lower plasma IGF-I concentration, but greater body weight and relative mass of visceral organs, compared with WT mice (P < 0.001). WT mice showed jejunal growth with either IGF-I or GLP-2 treatment. In KO mice, IGF-I did not stimulate jejunal growth, crypt mitosis, sucrase activity, and IGF-I receptor (IGF-IR) expression, suggesting that the intestinotrophic actions of IGF-I are dependent on expression of IGFBP-3 and -5. In KO mice, GLP-2 induced significant increases in jejunal mucosal cellularity, crypt mitosis, villus height, and crypt depth that was associated with increased expression of the ErbB ligand epiregulin and decreased expression of IGF-I and IGF-IR. This suggests that in KO mice, GLP-2 action in jejunal mucosa is independent of the IGF-I system and linked with ErbB ligands. In summary, the intestinotrophic actions of IGF-I, but not GLP-2, in mucosa are dependent on IGFBP-3 and -5. These findings support the role of multiple downstream mediators for the mucosal growth induced by GLP-2.

Topics: Analysis of Variance; Animals; Body Weight; Colon; Genes, erbB; Glucagon-Like Peptide 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Protein 5; Insulin-Like Growth Factor I; Intestinal Mucosa; Intestine, Small; Intestines; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Size; Real-Time Polymerase Chain Reaction; RNA; Spleen

Erlotinib, an epidermal-growth-factor receptor inhibitor, belongs to a new generation of targeted cancer therapeutics. Gastrointestinal side-effects are common and have been markedly aggravated when erlotinib is combined with cytostatics. We examined the effects of erlotinib alone and combined with the cytostatic, cisplatin, on the gastrointestinal tract and examined whether glucagon-like peptide-2 (GLP-2), an intestinal hormone with potent intestinotrophic properties, might counteract the possible damaging effects of the treatments.. Groups of ten mice were treated for 10 days with increasing doses of erlotinib alone or in combination with cisplatin and/or GLP-2. Weight and length of the gastrointestinal organs were determined and histological sections were analyzed with morphometric methods as well as BrdU- and ApopTag-staining to determine mitotic and apoptotic activity.. Erlotinib was found to induce small-intestinal and colonic growth inhibition through an increased apoptotic activity but had no effect on mitotic activity. The combined treatment with cisplatin synergistically aggravated the intestinal growth inhibition. Erlotinib, and especially the combination therapy, increased the weight of the stomach contents considerably. Concomitant treatment with GLP-2 counteracted the intestinal mucosal atrophy induced both by erlotinib alone and combined with cisplatin through a reduction of the apoptotic activity. There was no influence on the mitotic activity.. The findings demonstrate that the intestinal mucosal damage induced by erlotinib alone and in combination with cisplatin can be counteracted by GLP-2 treatment, which might suggest a role for GLP-2 in the treatment of the gastrointestinal side-effects caused by these cancer therapeutics.

Topics: Animals; Antineoplastic Agents; Atrophy; Body Weight; Cisplatin; Dose-Response Relationship, Drug; Drug Interactions; Erlotinib Hydrochloride; Female; Gastroenteritis; Gastrointestinal Tract; Glucagon-Like Peptide 2; Mice; Mice, Inbred Strains; Protein Kinase Inhibitors; Quinazolines

Glucagon-like peptide-2 (GLP-2) is a gut hormone that increases gut growth, reduces mucosal cell death, and augments mesenteric blood flow and nutrient absorption. Exogenous GLP-2(1-33) also stimulates glucagon secretion and enhances gut barrier function with implications for susceptibility to systemic inflammation and subsequent metabolic dysregulation. We examined the importance of GLP-2 receptor (GLP-2R) signaling for glucose homeostasis in multiple models of metabolic stress, diabetes, and obesity.. Body weight, islet function, glucose tolerance, and islet histology were studied in wild-type, high-fat fed, lean diabetic, Glp2r(-/-) and ob/ob:Glp2r(-/-) mice.. GLP-2 did not stimulate glucagon secretion from isolated pancreatic islets in vitro, and exogenous GLP-2 had no effect on the glucagon response to insulin-induced hypoglycemia in vivo. Glp2r(-/-) mice exhibit no change in glycemia, and plasma glucagon levels were similar in Glp2r(-/-) and Glp2r(+/+) mice after hypoglycemia or after oral or intraperitoneal glucose challenge. Moreover, glucose homeostasis was comparable in Glp2r(-/-) and Glp2r(+/+) mice fed a high-fat diet for 5 months or after induction of streptozotocin-induced diabetes. In contrast, loss of the GLP-2R leads to increased glucagon secretion and alpha-cell mass, impaired intraperitoneal glucose tolerance and hyperglycemia, reduced beta-cell mass, and decreased islet proliferation in ob/ob:Glp2r(-/-) mice.. Our results show that, although the GLP-2R is not critical for the stimulation or suppression of glucagon secretion or glucose homeostasis in normal or lean diabetic mice, elimination of GLP-2R signaling in obese mice impairs the normal islet adaptive response required to maintain glucose homeostasis.

Topics: Adaptation, Physiological; Animals; Blood Glucose; Body Weight; Cell Proliferation; Diabetes Mellitus, Experimental; Disease Models, Animal; Glucagon; Glucagon-Like Peptide 2; Glucagon-Like Peptide-2 Receptor; Glucose Intolerance; Glucose Tolerance Test; Hypoglycemia; Insulin; Islets of Langerhans; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Receptors, Glucagon; Signal Transduction; Stress, Physiological; Time Factors

Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent, proglucagon-derived hormone that is a proposed treatment for human short bowel syndrome (SBS). The objective was to determine how the timing, duration, and cessation of GLP-2 administration affect intestinal adaptation and enterocyte kinetics in a rat model of human SBS that results in intestinal failure requiring total parenteral nutrition (TPN). Rats underwent 60% jejunoileal resection plus cecectomy and jugular vein cannulation and were maintained exclusively with TPN for 18 days in these treatments: TPN control (no GLP-2); sustained GLP-2 (1-18 days); early GLP-2 (1-7 days, killed at 7 or 18 days); and delayed GLP-2 (12-18 days). Body weight gain was similar across groups, and plasma bioactive GLP-2 was significantly increased with coinfusion of GLP-2 (100 μg·kg⁻¹·day⁻¹) with TPN. GLP-2-treated rats showed significant increases in duodenum and jejunum mucosal dry mass, protein, DNA, and sucrase activity compared with TPN control. The increased jejunum cellularity reflected significantly decreased apoptosis and increased crypt mitosis and crypt fission due to GLP-2. When GLP-2 infusion stopped at 7 days, these effects were reversed at 18 days. Sustained GLP-2 infusion significantly increased duodenum length and decreased 18-day mortality to 0% from 37.5% deaths in TPN control (P = 0.08). Colon proglucagon expression quantified by real-time RT-qPCR was increased in TPN controls and attenuated by GLP-2 infusion; jejunal expression of the GLP-2 receptor did not differ among groups. In summary, early, sustained GLP-2 infusion reduces mortality, induces crypt fission, and is required for intestinal adaptation, whereas cessation of GLP-2 reverses gains in mucosal cellularity in a rat model of intestinal failure.

Topics: Animals; Apoptosis; Body Weight; Drug Administration Schedule; Enterocytes; Gene Expression Regulation; Glucagon-Like Peptide 2; Intestine, Small; Male; Mitosis; Parenteral Nutrition, Total; Proglucagon; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome

Both glucagon-like peptide 2 (GLP-2) and glucocorticosteroids enhance intestinal uptake in mature animals. Maternal stimuli may cause intestinal adaptation in the offspring. We hypothesized that administering GLP-2, dexamethasone (DEX) or a combination of GLP-2+DEX to rat dams during pregnancy and lactation would enhance intestinal sugar uptake in their offspring. Rat dams were treated with GLP-2 (0.1 microg/g/day), DEX (0.128 microg/g/day), a combination of GLP-2+DEX or placebo. Glucose and fructose uptake was assessed in their suckling offspring using an in vitro intestinal ring uptake technique. The protein abundance of SGLT1, GLUT5, GLUT2, Na(+)K(+)-ATPase and selected signals was determined by immunohistochemistry; GLP-2 caused hypertrophy of the jejunal enterocytes and increased ileal villous height. Jejunal fructose uptake was reduced by GLP-2, DEX and GLP-2+DEX. V(max) for jejunal glucose uptake was reduced with DEX and GLP-2+DEX. These declines were not explained by alterations in transporter abundance. Decreases in Akt and mTOR abundance were associated with declines in transporter activity. We speculate that the intrinsic activity of the sugar transporters was modified via the P13K pathway. In conclusion, maternal GLP-2 and DEX reduced intestinal sugar uptake in their offspring. This may have nutritional implications for the offspring of mothers treated with GLP-2 or steroids.

Topics: Animals; Animals, Suckling; Body Weight; Dexamethasone; Female; Fructose; Glucagon-Like Peptide 2; Immunohistochemistry; Jejunum; Lactation; Maternal Exposure; Organ Size; Placebos; Pregnancy; Rats

Glucagon-like peptide-2 (GLP-2) is a nutrient-regulated intestinotrophic hormone derived from proglucagon in the distal intestine. Enteral nutrients (EN) potentiate the action of GLP-2 to reverse parenteral nutrition (PN)-induced mucosal hypoplasia. The objective was to determine what enteral protein component, casein, soy, or whey protein, potentiates the intestinal growth response to GLP-2 in rats with PN-induced mucosal hypoplasia. Rats received PN and continuous intravenous infusion of GLP-2 (100 microg/kg/day) for 7 days. Six EN groups received PN+GLP-2 for days 1-3 and partial PN+GLP-2 plus EN for days 4-7. EN was provided by ad libitum intake of a semielemental liquid diet with different protein sources: casein, hydrolyzed soy, whey protein concentrate (WPC), and hydrolyzed WPC+casein. Controls received PN+GLP-2 alone. EN induced significantly greater jejunal sucrase activity and gain of body weight, and improved feed efficiency compared with PN+GLP-2 alone. EN induced greater ileal proglucagon expression, increased plasma concentration of bioactive GLP-2 by 35%, and reduced plasma dipeptidyl peptidase IV (DPP-IV) activity compared with PN+GLP-2 alone, P < 0.05. However, only whey protein, and not casein or soy, potentiated the ability of GLP-2 to reverse PN-induced mucosal hypoplasia and further increase ileal villus height, crypt depth, and mucosa cellularity compared with PN+GLP-2 alone, P < 0.05. The ability of whey protein to induce greater mucosal surface area was associated with decreased DPP-IV activity in ileum and colon compared with casein, soy, or PN+GLP-2 alone, P < 0.05. In conclusion, whey protein potentiates the action of GLP-2 to reverse PN-induced mucosal hypoplasia in association with decreased intestinal DPP-IV activity.

Topics: Animals; Body Weight; Dipeptidyl Peptidase 4; Dose-Response Relationship, Drug; Eating; Glucagon-Like Peptide 2; Intestinal Mucosa; Intestines; Male; Milk Proteins; Models, Animal; Parenteral Nutrition; Proglucagon; Rats; Rats, Sprague-Dawley; Sucrase; Whey Proteins

Teduglutide, a synthetic glucagon-like peptide-2 (GLP-2) analog with activity relating to the regeneration, maintenance, and repair of the intestinal epithelium, is currently being evaluated for the treatment of short-bowel syndrome (SBS), Crohn's disease, and other gastrointestinal disorders. On the basis of promising results from teduglutide studies in adults with SBS and from studies in neonatal and juvenile animal models, a pediatric multiple-dose phase I clinical study was designed to determine the safety, efficacy, and pharmacokinetics of teduglutide in pediatric patients with SBS who have undergone resection for necrotizing enterocolitis, malrotation, or intestinal atresia. This report details the application of clinical trial simulations coupled with a novel approach using generalized additive modeling for location, scale, and shape (GAMLSS) that facilitates the simulation of demographic covariates specific to the targeted patient populations. The goal was to optimize phase I dosing strategies and the likelihood of achieving target exposure and therapeutic effect.

Topics: Adult; Age Factors; Body Weight; Clinical Trials, Phase I as Topic; Computer Simulation; Drug Dosage Calculations; Gastrointestinal Agents; Glucagon-Like Peptide 2; Humans; Infant; Infant, Newborn; Models, Biological; Peptides; Short Bowel Syndrome; Treatment Outcome

Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent, intestinotrophic hormone derived from posttranslational processing of proglucagon in the distal bowel. GLP-2 is thought to act through indirect mediators, such as IGF-I. We investigated whether intestinal expression of GLP-2 and IGF-I system components are increased with the mucosal growth induced by enteral nutrient (EN) and/or a low dose of GLP-2 in parenterally fed rats. Rats were randomized to four treatment groups using a 2 x 2 design and maintained with parenteral nutrition (PN) for 7 days: PN alone, EN, GLP-2, and EN+GLP-2; n = 7-9. The two main treatment effects are +/-GLP-2 (100 microg.kg body wt(-1).day(-1)) and +/-EN (43% of energy needs, days 4-6). Combination treatment with EN+GLP-2 induced synergistic intestinal growth in ileum, resulting in greater mucosal cellularity, sucrase segmental activity, and gain of body weight (ENxGLP-2, P < 0.04). In addition, EN+GLP-2 induced a significant 28% increase in plasma concentration of bioactive GLP-2, a significant 102% increase in ileal proglucagon mRNA with no change in ileal dipeptidyl peptidase-IV (DPP-IV) specific activity, and significantly reduced plasma DPP-IV activity compared with GLP-2. This indicates that EN potentiates the intestinotrophic action of GLP-2. Proliferation of enterocytes due to GLP-2 infusion was associated with greater expression of ileal proglucagon, GLP-2 receptor, IGF-I, IGF binding protein-3 mRNAs, and greater IGF-I peptide concentration in ileum (P < 0.032). Ileal IGF-I mRNA was positively correlated with expression of proglucagon, GLP-2R, and IGFBP-5 mRNAs (R2 = 0.43-0.56, P < 0.0001). Our findings support the hypothesis that IGF-I is one of the downstream mediators of GLP-2 action in a physiological model of intestinal growth.

Topics: Animals; Body Weight; Cell Proliferation; Dipeptidyl Peptidase 4; Enteral Nutrition; Enterocytes; Glucagon-Like Peptide 2; Glucagon-Like Peptide-2 Receptor; Humans; Ileum; Infusions, Intravenous; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Protein 5; Insulin-Like Growth Factor I; Intestinal Mucosa; Intestines; Jejunum; Male; Nitrogen; Parenteral Nutrition; Proglucagon; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Recombinant Proteins; RNA, Messenger; Signal Transduction; Sucrase; Time Factors; Up-Regulation

Intestinal function in young animals is influenced by maternal factors, such as alterations in the maternal diet. Glucagon-like peptide 2 (GLP-2) enhances intestinal growth and absorption in mature animals. Glucocorticosteroids induce intestinal maturation in neonates and increase sugar uptake in adult animals. It is not known if maternally administered GLP-2 or glucocorticosteroids have persistent effects on intestinal transport in the offspring. This study was undertaken to determine (1) the influence of maternal GLP-2, dexamethasone (DEX) and GLP-2+DEX on intestinal sugar uptake in postweaning offspring and (2) if alterations in uptake are due to variations in intestinal morphology, sugar transporter abundance or the abundance of selected signals. Nursing rat dams were treated during pregnancy and lactation with GLP-2 (0.1 mug/g per day sc), DEX (0.128 microg/g per day sc), GLP-2+DEX or placebo. The offspring were sacrificed 4 weeks after weaning, and glucose and fructose uptake was determined using an in vitro intestinal ring uptake technique. sodium-dependent glucose transporter, glucose transporter (GLUT) 5, GLUT2, sodium potassium adenosine triphosphatase and selected signals were assessed by immunohistochemistry. The treatments did not affect body weights or intestinal morphology. GLP-2 and GLP-2+DEX increased jejunal fructose uptake, and GLP-2+DEX increased the jejunal and ileal maximal transport rate for glucose uptake. Protein kinase B and mammalian target of rapamycin abundance were also increased, while transporter abundance was unchanged. We speculate that these alterations in sugar uptake may be due to changes in the intrinsic activity of the transporters mediated by the phosphatidylinositol-3-kinase pathway. These alterations in uptake may have nutritional implications for the offspring of mothers who may be treated with GLP-2 or glucocorticosteroids.

Topics: Animals; Biological Transport; Body Weight; Dexamethasone; Female; Fructose; Glucagon-Like Peptide 2; Glucose; Glucose Transporter Type 2; Glucose Transporter Type 5; Hexoses; Intestinal Mucosa; Intestines; Lactation; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Protein Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Sodium-Glucose Transporter 1; TOR Serine-Threonine Kinases; Weaning

Luminal nutrients stimulate structural and functional regeneration in the intestine through mechanisms thought to involve insulin-like growth factor I (IGF-I) and glucagon-like peptide-2 (GLP-2). We investigated the relationship between IGF-I and GLP-2 responses and mucosal growth in rats fasted for 48 h and then refed for 2 or 4 days by continuous intravenous or intragastric infusion or ad libitum feeding. Fasting induced significant decreases in body weight, plasma concentrations of IGF-I and bioactive GLP-2, jejunal mucosal cellularity (mass, protein, DNA, and villus height), IGF-I mRNA, and ileal proglucagon mRNA. Plasma IGF-I concentration was restored to fed levels with 2 days of ad libitum refeeding but not with 4 days of intravenous or intragastric refeeding. Administration of an inhibitor of endogenous GLP-2 (rat GLP-2 3-33) during ad libitum refeeding partially attenuated mucosal growth and prevented the increase in plasma IGF-I to fed levels; however, plasma GLP-2 and jejunal IGF-I mRNA were restored to fed levels. Intragastric refeeding restored intestinal cellularity and functional capacity (sucrase activity and sodium-glucose transporter-1 expression) to fed levels, whereas intravenous refeeding had no effect. Intestinal regeneration after 4 days of intragastric or 2 days of ad libitum refeeding was positively associated with increases in plasma concentrations of GLP-2 and jejunal IGF-I mRNA. These data suggest that luminal nutrients stimulate intestinal growth, in part, by increased expression of both GLP-2 and IGF-I.

Topics: Adaptation, Physiological; Animals; Body Weight; Dose-Response Relationship, Drug; Eating; Fasting; Glucagon-Like Peptide 2; Ileum; Infusions, Intravenous; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Protein 5; Insulin-Like Growth Factor I; Intestinal Mucosa; Intubation, Gastrointestinal; Jejunum; Male; Nitrogen; Parenteral Nutrition; Peptide Fragments; Proglucagon; Rats; Rats, Sprague-Dawley; Regeneration; RNA, Messenger; Sodium-Glucose Transporter 1; Sucrase; Time Factors

Functional changes induced by inflammation persist following recovery from the inflammatory response, but the mechanisms underlying these changes are not well understood. Our aim was to investigate whether the excitability and synaptic properties of submucosal neurons remained altered 8 wk post-trinitrobenzene sulfonic acid (TNBS) treatment and to determine whether these changes were accompanied by alterations in secretory function in submucosal preparations voltage clamped in Ussing chambers. Mucosal serotonin (5-HT) release measurements and 5-HT reuptake transporter (SERT) immunohistochemistry were also performed. Eight weeks after TNBS treatment, colonic inflammation resolved, as assessed macroscopically and by myeloperoxidase assay. However, fast excitatory postsynaptic potential (fEPSP) amplitude was significantly increased in submucosal S neurons from previously inflamed colons relative to those in control tissue. In addition, fEPSPs from previously inflamed colons had a hexamethonium-insensitive component that was not evident in age-matched controls. AH neurons were hyperexcitable, had shorter action potential durations, and decreased afterhyperpolarization 8 wk following TNBS adminstration. Neuronally mediated colonic secretory function was significantly reduced after TNBS treatment, although epithelial cell signaling, as measured by responsiveness to both forskolin and bethanecol in the presence of tetrodotoxin, was comparable with control tissue. 5-HT levels and SERT immunoreactivity were comparable to controls 8 wk after the induction of inflammation, but there was an increase in glucagon-like peptide 2-immunoreactive L cells. In conclusion, sustained alterations in enteric neural signaling occur following the resolution of colitis, which are accompanied by functional changes in the absence of active inflammation.

Topics: Action Potentials; Animals; Bethanechol; Body Weight; Cell Count; Colforsin; Colitis; Colon; Enteric Nervous System; Enteroendocrine Cells; Excitatory Postsynaptic Potentials; Glucagon-Like Peptide 2; Guinea Pigs; Male; Membrane Potentials; Neurons; Peptide YY; Peroxidase; Serotonin; Serotonin Plasma Membrane Transport Proteins; Submucous Plexus; Tetrodotoxin; Trinitrobenzenesulfonic Acid; Veratridine

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.

Topics: Amylases; Animals; Apoptosis; Atrophy; Body Weight; Chaperonin 60; Enzyme Precursors; Glucagon-Like Peptide 2; Heat-Shock Proteins; HSC70 Heat-Shock Proteins; HSP27 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Intestinal Mucosa; Jejunum; Lipase; Male; Neoplasm Proteins; Organ Size; Pancreas; Pancreas, Exocrine; Parenteral Nutrition, Total; Rats; Rats, Sprague-Dawley

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been introduced as antitumor agents in the treatment of cancers overexpressing the receptor. The treatment has gastrointestinal side effects which may decrease patient compliance and limit the efficacy. Glucagon-like peptide-2 (GLP-2) is an intestinal hormone with potent intestinotrophic properties and therapeutic potential in disorders with compromised intestinal capacity. The growth stimulation is highly specific to the gastrointestinal tract, and no effects are observed elsewhere. The aim of this study was to examine whether the inhibition of the EGFR induces intestinal atrophy and if this can be counteracted by treatment with GLP-2.. Mice were treated for 10 days with either gefitinib orally, GLP-2 as injections, or a combination of both. After sacrifice, the weight and length of the segments of the gastrointestinal tract were determined, and histologic sections were analyzed by morphometric methods.. A significant atrophy of the small-intestinal wall was observed after treatment with gefitinib because both intestinal weight and morphometrically estimated villus height and cross-sectional area were decreased. The same parameters were increased by GLP-2 treatment alone, and when GLP-2 was combined with the gefitinib treatment, the parameters remained unchanged.. Treatment with an EGFR tyrosine kinase inhibitor in mice results in small-intestinal growth inhibition that can be completely prevented by simultaneous treatment with GLP-2. This suggests that the gastrointestinal side effects elicited by treatment with EGFR tyrosine kinase inhibitors can be circumvented by GLP-2 treatment.

Topics: Animals; Antineoplastic Agents; Atrophy; Body Weight; ErbB Receptors; Female; Gefitinib; Glucagon-Like Peptide 2; Intestines; Mice; Mice, Inbred C57BL; Organ Size; Quinazolines

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.

Topics: Adaptation, Physiological; Animals; Body Weight; Capsaicin; Enteral Nutrition; Ganglionectomy; Glucagon-Like Peptide 2; Ileum; Intestinal Mucosa; Intestines; Jejunum; Male; Neurons, Afferent; Parenteral Nutrition; Proglucagon; Rats; Rats, Sprague-Dawley; RNA, Messenger; Serine Endopeptidases; Sucrase; Vagus Nerve

Glucagon-like peptide-2 (GLP-2) is an enteroendocrine peptide that is released in response to luminal nutrients and has unique trophic actions in the gastrointestinal tract. These features suggest GLP-2 may be important in controlling intestinal adaptation. We examined the relationship over time of GLP-2 production and adaptation to intestinal resection, the effects of resection-induced malabsorption on GLP-2 production, and the correlation of endogenous serum GLP-2 levels with adaptation as measured by crypt-cell proliferation (CCP). We initially examined the effect of nutrient malabsorption, induced by a 90% resection of the proximal intestine studied on day 4, on the time course and levels of GLP-2 release. Secondly, the degree of malabsorption was varied by performing intestinal transection or 50, 75, or 90% resection of proximal small intestine. Finally, the relationship of GLP-2 levels over time with adaptation to a 90% resection was examined by determining GLP-2 levels on days 7, 14, and 28, and correlating this with intestinal adaptation, as assessed by morphology and CCP rate. A 90% resection significantly increased basal and postprandial GLP-2 levels, with a net increase in nutrient-stimulated exposure over 90 min; GLP-2 exposure (integrated levels vs. time) increased 12.7-fold in resected animals (P < 0.001). Basal and postprandial GLP-2 levels significantly correlated with the magnitude of intestinal resection (r(2) = 0.71; P < 0.001), CCP (r(2) = 0.48; P < 0.005), and nutrient malabsorption (protein, P < 0.001; fat, P < 0.005). The increase in CCP was maintained to 28 days after small bowel resection and was associated with an ongoing elevation in GLP-2 release. These findings suggest that GLP-2 is important in initiating and maintaining the small intestinal adaptive response to resection.

Topics: Adaptation, Physiological; Animals; Antimetabolites; Body Weight; Bromodeoxyuridine; Cell Proliferation; Dietary Fats; Dietary Proteins; Enzyme-Linked Immunosorbent Assay; Food; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Intestinal Absorption; Intestinal Mucosa; Intestines; Male; Peptides; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome

Stress-induced intestinal barrier dysfunction may be involved in chronic intestinal disorders. Glucagon-like peptide-2 (GLP-2) is an intestinotrophic growth hormone that can rapidly improve intestinal epithelial barrier function. Here, we investigated whether mouse intestine is responsive to chronic psychological stress and whether pretreatment with GLP-2 can ameliorate stress-induced changes. Mice were subjected to water avoidance stress (WAS; 1 h/day for 10 days) with GLP-2 or saline administered 4 h before each WAS session. After the final stress period, the intestine was removed for assessment of physiological/morphological changes. Compared with controls (sham-stressed mice), stressed mice demonstrated enhanced ion secretion and permeability in the jejunum, ileum, and colon. In addition, increased numbers of bacteria were observed adhering to and/or penetrating the epithelium, associated with infiltration of mononuclear cells into the mucosa. GLP-2 treatment improved intestinal barrier function in stressed mice and ameliorated other aspects of impaired host defense. Our study extends previous findings in rats of stress-induced intestinal dysfunction and provides insights into potential novel therapeutics.

Topics: Animals; Bacterial Infections; Body Weight; Colon; Diffusion Chambers, Culture; Epithelium; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Horseradish Peroxidase; Inflammation; Intestines; Male; Mice; Mice, Inbred BALB C; Microscopy, Electron; Peptides; Stress, Psychological

Our understanding of the intestinotropic actions of glucagon-like peptide-2 (GLP-2)(1-33) is based on pharmacologic studies involving exogenous administration. However, the physiologic role of GLP-2 in mucosal growth and adaptation to nutritional stimulation remains poorly understood.. The properties of GLP-2(3-33), a GLP-2(1-33) metabolite, were determined in baby-hamster kidney cells transfected with the mouse GLP-2 receptor complementary DNA and in isolated murine intestinal muscle strips. To investigate the role of endogenous GLP-2(1-33) in gut adaptation, GLP-2(3-33) was administered to mice that were re-fed for 24 hours after 24 hours of fasting, and the small intestine was analyzed. GLP-2(3-33) also was injected into rats for analysis of circulating GLP-2(1-33) levels.. GLP-2(3-33) antagonized the actions of GLP-2(1-33) in vitro and ex vivo. Fasting mice exhibited small intestinal atrophy (37% +/- 1% decrease in small intestinal weight, 19% +/- 2% decrease in crypt-villus height, and 99% +/- 35% increase in villus apoptosis, P < .05-.01). Adaptive growth in re-fed mice restored all these parameters, as well as crypt-cell proliferation, to normal control levels (P < .05 vs. fasting); these adaptive changes were prevented partially or completely by co-administration of GLP-2(3-33) to refeeding mice (by 32% +/- 19% to 103% +/- 15%, P < .05-.01 vs re-fed mice). Exogenous GLP-2(3-33) did not affect endogenous GLP-2(1-33) levels.. These data show that endogenous GLP-2 regulates the intestinotropic response in re-fed mice through modulation of crypt-cell proliferation and villus apoptosis. GLP-2 is therefore a physiologic regulator of the dynamic adaptation of the gut mucosal epithelium in response to luminal nutrients.

Topics: Adaptation, Physiological; Amino Acid Sequence; Animals; Apoptosis; Body Weight; Cell Division; Cloning, Molecular; Drinking; Eating; Female; Gene Expression; Glucagon; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Intestinal Mucosa; Intestine, Small; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Organ Size; Peptide Fragments; Proglucagon; Protein Precursors; Rats; Rats, Wistar; Receptors, Glucagon

To analyze the putative interest of oligofructose (OFS) in the modulation of food intake after high-fat diet in rats and to question the relevance of the expression and secretion of intestinal peptides in that context.. Male Wistar rats were pretreated with standard diet or OFS-enriched (10%) standard diet for 35 days followed by 15 days of high-fat diet enriched or not with OFS (10%) treatment. Body weight, food intake, triglycerides, and plasma ghrelin levels were monitored during the treatment. On day 50, rats were food-deprived 8 hours and anesthetized for blood and intestinal tissue sampling for further proglucagon mRNA, glucagon-like peptide (GLP)-1, and GLP-2 quantification.. The addition of OFS in the diet protects against the promotion of energy intake, body weight gain, fat mass development, and serum triglyceride accumulation induced by a high-fat diet. OFS fermentation leads to an increase in proglucagon mRNA in the cecum and the colon and in GLP-1 and GLP-2 contents in the proximal colon, with consequences on the portal concentration of GLP-1 (increase). A lower ghrelin level is observed only when OFS is added to the standard diet of rats.. In rats exposed to high-fat diet, OFS is, thus, able to modulate endogenous production of gut peptides involved in appetite and body weight regulation. Because several approaches are currently used to treat type 2 diabetes and obesity with limited effectiveness, dietary fibers such as OFS, which promote the endogenous production of gut peptides like GLP-1, could be proposed as interesting nutrients to consider in the management of fat intake and associated metabolic disorders.

Topics: Animals; Body Weight; Dietary Fats; Dipeptidyl Peptidase 4; Eating; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Intestinal Mucosa; Liver; Male; Obesity; Oligosaccharides; Peptide Fragments; Peptide Hormones; Peptides; Proglucagon; Protein Precursors; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Triglycerides

Glucagon-like peptide-2 (GLP-2) enhances intestinal growth and absorption in mature animals, and glucocorticosteroids (GC) increase the sugar and lipid uptake in adult animals. However, the role of GC and GLP-2 in the ontogeny of lipid absorption is unknown. We hypothesized that GLP-2 and the GC dexamethasone (DEX), when administrated to rat dams during pregnancy and lactation, would enhance lipid uptake in the offspring. Rat dams were treated in the last 10 d of pregnancy and during lactation with GLP-2 [0.1 microg/g/d subcutaneous (sc)], DEX (0.128 microg/g/d sc), GLP-2 + DEX, or a placebo. Sucklings were sacrificed at 19-21 d of age, and weanlings were sacrificed 4 wk later. Lipid uptake was assessed using an in vitro ring uptake method. Although DEX and GLP-2 + DEX increased the jejunal mass, the jejunal lipid uptake was unchanged. In contrast, GLP-2, DEX, and GLP-2 + DEX reduced the ileal lipid uptake in suckling and weanling rats. This reduction was not due to alterations in intestinal morphology or to changes in fatty acid-binding protein abundance, but it was partially explained by an increase in the effective resistance of the intestinal unstirred water layer. In sucklings, DEX dramatically reduced the jejunal lipid uptake to levels similar to those seen in weanlings, such that the normal ontogenic decline in lipid uptake was not observed. Giving dams GLP-2 or DEX during pregnancy and lactation reduced lipid uptake in the offspring, and this persisted for at least 1 mon. The impact this may have on the nutritional well-being of the animal in later life is unknown.

Topics: Animals; Body Weight; Dexamethasone; Female; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Immunohistochemistry; Intestinal Mucosa; Intestine, Small; Lipid Metabolism; Malabsorption Syndromes; Rats

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.. In the present study, the effects of GLP-2 treatment on the growth of chemically induced colonic neoplasms were investigated.. 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.. 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.. 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.

Topics: Adenoma; Animals; Body Weight; Colonic Neoplasms; Colonic Polyps; Female; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Intestinal Mucosa; Intestine, Small; Mice; Mice, Inbred C57BL; Organ Size; Peptides

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.

Topics: Adaptation, Physiological; Animals; Apoptosis; Body Weight; Cell Division; Eating; Enterocytes; Glucagon; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Ileum; Jejunum; Male; Parenteral Nutrition; Peptides; Proglucagon; Protein Precursors; Rats; Rats, Sprague-Dawley; Sucrase

The therapeutic potential of the intestinotrophic mediator glucagon-like peptide-2 (1-33) [GLP-2 (1-33)] has increased interest in the pharmacokinetics of the peptide. This study was undertaken to investigate whether the primary degradation product GLP-2 (3-33) interacts with the GLP-2 receptor. Functional (cAMP) and binding in vitro studies were carried out in cells expressing the transfected human GLP-2 receptor. Furthermore, a biologic response of GLP-2 (3-33) was tested in vivo. Mice were allocated to groups treated for 10 days (twice daily) with: (1) 5 microg GLP-2 (1-33), (2) 25 microg GLP-2 (3-33), (3) 5 microg GLP-2 (1-33)+100 microg GLP-2 (3-33), or (4) 5 microg GLP-2 (1-33)+500 microg GLP-2 (3-33). The intestine was investigated for growth changes. GLP-2 (3-33) bound to the GLP-2 receptor with a binding affinity of 7.5% of that of GLP-2 (1-33). cAMP accumulation was stimulated with an efficacy of 15% and a potency more than two orders of magnitude lower than that of GLP-2 (1-33). Increasing doses of GLP-2 (3-33) (10(-7)-10(-5) M) caused a shift to the right in the dose-response curve of GLP-2 (1-33). Treatment of mice with either GLP-2 (1-33) or (3-33) induced significant growth responses in both the small and large intestines, but the response induced by GLP-2 (3-33) was much smaller. Co-administration of 500 microg of GLP-2 (3-33) and 5 microg GLP-2 (1-33) resulted in a growth response that was smaller than that of 5 microg GLP-2 (1-33) alone. Consistent with the observed in vivo activities, our functional studies and binding data indicate that GLP-2 (3-33) acts as a partial agonist with potential competitive antagonistic properties on the GLP-2 receptor.

Topics: Animals; Body Weight; Cell Line; Cricetinae; Cyclic AMP; Drug Administration Schedule; Female; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Image Processing, Computer-Assisted; Injections, Subcutaneous; Intestine, Large; Intestine, Small; Mice; Mice, Inbred C57BL; Organ Size; Peptide Fragments; Protein Binding; Random Allocation; Receptors, Glucagon; Recombinant Proteins; Transfection

Supraphysiological doses of glucagon-like peptide-2 (GLP-2) have been shown to induce intestinal growth by increasing villus height and crypt depth and by decreasing apoptosis, but a physiological effect of GLP-2 has not yet been demonstrated. Earlier, we found elevated levels of endogenous GLP-2 in untreated streptozotocin diabetic rats associated with marked intestinal growth. In the present study, we investigated the role of endogenous GLP-2 for this adaptive response. We included four groups of six rats: (1) diabetic rats treated with saline, (2) diabetic rats treated with non-specific antibodies, (3) diabetic rats treated with polyclonal GLP-2 antibodies and (4) non-diabetic control rats treated with saline. All animals were treated with once daily intraperitoneal injections for 13 days and killed on day 14. Diabetic rats treated with saline or non-specific antibodies had a significantly (P<0.01) increased area of mucosa (13.00+/-0.64 and 13.37+/-0.60 mm(2), respectively) in the proximal part of the small intestine compared with non-diabetic controls (7.97+/-0.70 mm(2)). In contrast, diabetic rats treated with GLP-2 antibodies had a significantly (P<0.01) smaller increase in area of mucosa in the proximal part of the small intestine (10.84+/-0.44 mm(2)). Antibody treatment had no effect on body weight, blood glucose concentrations and food intake. Thus, blocking of endogenous GLP-2 in a model of adaptive intestinal growth reduces the growth response, providing strong evidence for a physiological growth factor function of GLP-2.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Eating; Female; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Intestinal Mucosa; Intestines; Neutralization Tests; Organ Size; Peptides; Rats; Rats, Wistar

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.

Topics: Adaptation, Physiological; Animals; Body Weight; Energy Intake; Enteroendocrine Cells; Female; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Ileum; Jejunum; Models, Animal; Peptides; Rats; Rats, Wistar

Glucagonlike peptide 2 (GLP-2) is trophic for the small bowel; it is produced by L cells in the distal intestine in response to luminal nutrients. This study tests the hypothesis that distal small bowel and cecal resection would decrease GLP-2 levels and reduce adaptation.. Male Sprague-Dawley rats (200 to 300 g) underwent either ileal transection (controls) or resection of the ileum and cecum, leaving 10 or 20 cm jejunal remnant anastomosed to the ascending colon. Animals were followed up for up to 21 days. Endpoints were daily weights, intestinal histology, in vivo absorption of 3-0 methylglucose (a measurement of active nutrient absorptive capacity), and serum GLP-2 levels.. The control group had a maximum 6% weight loss around day 2, and then recovered with a steady weight gain. The 10-cm jejunal remnant group lost weight continuously and never recovered postsurgery. The 20-cm jejunal remnant group of animals had a maximum of 12% weight loss by day 4 and then slowly gained weight. The average villus height increased significantly (P <.01) in the 10-cm and 20-cm jejunal remnant groups compared with controls. Absorption of 3-0 methylglucose was significantly decreased (P <.01) in both resected groups. Serum GLP-2 levels were increased significantly (P <.05) when compared with controls in both resection groups.. Increased serum GLP-2 levels were found in the ileocecal resection rat model, and these levels correlated with morphologic adaptation. However, this morphologic adaptation was not sufficient to restore nutrient absorption as shown by weight changes and 3-0 methylglucose absorption. Thus, the original hypothesis of this study is incorrect: systemic GLP-2 levels do not limit adaptation following distal ileocecal resection.

Topics: 3-O-Methylglucose; Adaptation, Physiological; Animals; Body Weight; Cecum; Disease Models, Animal; Enteroendocrine Cells; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Ileum; Intestinal Absorption; Jejunum; Male; Peptides; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome

Existing data on morphological adaptation after small bowel resection are obtained by potentially biased methods. Using stereological techniques, we examined segments of bowel on days 0, 4, 7, 14, and 28 after 80% jejunoileal resection or sham operation in rats and correlated intestinal growth with plasma levels of glucagon-like peptide-2 (GLP-2). In the jejunum and ileum of the resected rats, the mucosal weight increased by 120 and 115% during the first week, and the weight of muscular layer increased by 134 and 83%, compared with sham-operated controls. The luminal surface area increased by 190% in the jejunum and by 155% in the ileum after 28 days. The GLP-2 level was increased by 130% during the entire study period in the resected rats. Small bowel resection caused a pronounced and persistent transmural growth response in the remaining small bowel, with the most prominent growth occurring in the jejunal part. The significantly elevated GLP-2 level is consistent with an important role of GLP-2 in the adaptive response.

Topics: Adaptation, Physiological; Animals; Body Weight; Colon; Digestive System Surgical Procedures; Female; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Ileum; Insulin-Like Growth Factor I; Intestinal Mucosa; Intestine, Small; Jejunoileal Bypass; Jejunum; Peptides; Rats; Rats, Wistar

Glucagon-like peptide 2 (GLP-2) is a recently identified intestinal epithelium-specific growth factor that has been shown to reduce the severity of inflammatory disorders of the intestine in rodent models. We hypothesized that GLP-2 administration would be beneficial in chemotherapy-induced enteritis either by preventing injury or by promoting recovery.. Rats received no drug (control), chemotherapy alone [5-fluorouracil (5-FU), 190 mg/kg, ip] (Chemo), 5-FU followed by 3 days of GLP-2 analog (ALX-0600, 0.1 microg, sc twice daily) (CH-G), or GLP-2 analog for 6 days prior to 5-FU and for 3 days afterward (G-CH-G). Animals were pair fed. Rats received 5-bromo-2-deoxyuridine (Br-dU, 50 mg/kg, 2.5 h prior to sacrifice on Day 3 postchemotherapy) for immunohistochemical assessment of cellular proliferation.. Chemotherapy induced significant reductions in body weight, villus height, and crypt depth compared with controls. Intestinal wet weight, villus height, and crypt depth were significantly higher for the CH-G group compared with the Chemo group. The CH-G group also showed a significant improvement in villus height compared with the G-CH-G group. Crypt depth, but not jejunal wet weight or villus height, was significantly improved in the G-CH-G group compared with the Chemo group. The percentage of Br-dU-labeled cells in the intestinal crypts did not differ among the groups.. These results suggest, for the first time, that GLP-2 treatment initiated after chemotherapy administration enhances intestinal recovery. In contrast, GLP-2 treatment initiated prior to chemotherapy administration to prevent injury has less beneficial effect. GLP-2 administration may be beneficial to patients suffering from chemotherapy-induced enteritis.

Topics: Animals; Antimetabolites, Antineoplastic; Body Weight; Bromodeoxyuridine; Enteritis; Fluorouracil; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Intestinal Mucosa; Jejunum; Male; Morbidity; Peptides; Rats; Rats, Sprague-Dawley

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.

Topics: Animals; Body Weight; Dipeptidyl Peptidase 4; Enzyme Inhibitors; Female; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Intestines; Mice; Mice, Inbred C57BL; Organ Size; Peptides; Pyrroles; Rats; Rats, Wistar; Recombinant Proteins; Valine

To determine whether treatment with a potent protease-resistant analog of human glucagon-like peptide 2 (GLP-2) might augment the adaptive response to massive intestinal resection, rats were divided into resected, which had 75% of the midjejunoileum removed, sham-resected, and nonsurgical groups. Within each group, animals were assigned to 21 days of treatment with the drug (0.1 micrograms/g of the GLP-2 analog in phosphate-buffered saline) or vehicle alone subcutaneously twice daily. Food intake; weight gain; jejunal and ileal diameters, total and mucosal wet weights per centimeter, crypt depths, and villus heights; mucosal sucrase activity, milligrams of protein per centimeter, and micrograms of DNA per centimeter; and D-xylose absorption were measured. There was a significant increase in diameter, total and mucosal wet weights per centimeter, crypt-villus height, sucrase activity, milligrams of protein per centimeter and micrograms of DNA per centimeter in both the jejunum and ileum in response to resection and a significant additive response to the GLP-2 analog in the jejunum but not in the ileum. The ratio of milligrams of protein per centimeter to micrograms of DNA per centimeter of mucosa was not different among groups, consistent with hyperplasia. D-Xylose absorption was significantly reduced in response to resection; however, the GLP-2 analog enhanced the absorptive capacity in control animals and restored the absorptive capacity in resected animals. Thus the GLP-2 analog induces mucosal hyperplasia and enhances the rate and magnitude of the proximal intestinal adaptive response to massive resection.

Topics: Adaptation, Physiological; Anastomosis, Surgical; Animals; Body Weight; DNA; Energy Intake; Gastrointestinal Hormones; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Ileum; Intestinal Mucosa; Jejunum; Organ Size; Peptides; Permeability; Proteins; Rats; Rats, Sprague-Dawley; Sucrase

The control of intestinal epithelial growth is regulated by interactions of growth factors in various cellular compartments of the small and large bowel. Little information is available on the intestinal growth response to combinations of growth factors. We studied the intestinotrophic properties of a dipeptidyl peptidase IV resistant glucagon-like peptide 2 (GLP-2) analog, human [Gly2]GLP-2 (h[Gly2]GLP-2), as well as of epidermal growth factor (EGF), long [Arg3]insulin-like growth factor I (LR3IGF-I), [Gly1]IGF-II, and human growth hormone (hGH), administered by subcutaneous injection alone or in combination in mice. At the doses tested, h[Gly2]GLP-2 was the most potent agent for increasing small and large bowel mass. Mice treated with h[Gly2]GLP-2 and either GH or IGF-I exhibited greater increases in histological parameters of small intestinal growth than did mice treated with h[Gly2]GLP-2 alone. Administration of all five growth factors together induced significant increases in crypt plus villus height and in small and large bowel length and weight. The results of these experiments define regional differences in both the cellular targets and relative activities of intestinotrophic molecules and raise the possibility that selective growth factor combinations may be useful for enhancement of intestinal adaptation in vivo.

Topics: Animals; Body Weight; Drug Interactions; Epidermal Growth Factor; Female; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Growth Substances; Human Growth Hormone; Humans; Ileum; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Intestinal Mucosa; Intestine, Large; Intestine, Small; Jejunum; Mice; Organ Size; Peptides; Rats