Diabetic intestinal growth adaptation and glucagon-like peptide 2 in the rat: effects of dietary fibre.
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BACKGROUND/AIMS: Dietary fibre influence growth and function of the upper gastrointestinal tract. This study investigates the importance of dietary fibre in intestinal growth in experimental diabetes, and correlates intestinal growth with plasma levels of the intestinotrophic factor, glucagon-like peptide 2 (GLP-2). METHODS: Male Wistar rats were randomised to the following groups: two streptozotocin-diabetic and two control groups fed either a fibre-containing or a fibre-free diet for three weeks. Intestinal weight, length, and morphometric data (villus height, villus area, crypt depth) were measured. Blood samples were obtained after two weeks for measurement of GLP-2 and enteroglucagon (glicentin, oxyntomodulin). RESULTS: The mean daily consumption of food in the two diabetic groups was 40% higher than in controls. In diabetic rats fed fibre, the increase in intestinal weight from day 0 to 20 was sixfold greater than that of the controls and small intestine weight per cm length was increased by 50%. In the diabetic rats fed a fibre-free diet, intestinal growth was 30% less than in diabetic rats fed fibre, and intestinal weight increased only threefold compared with controls. Morphometric data showed that the intestinal increase in diabetic rats fed fibre was due primarily to growth of the mucosal layer. Villus height and crypt depth increased 60% and 40% respectively, but by only 20% in fibre-free diabetic rats. The plasma levels of GLP-2 parallelled diabetic intestinal growth, whereas plasma levels of enteroglucagon increased regardless of the extent of intestinal growth. CONCLUSIONS: Intestinal growth in experimental diabetes is strongly influenced by the presence of dietary fibre. The effect may be mediated by GLP-2. (+info)
Modulation by colonic fermentation of LES function in humans.
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Colonic fermentation of carbohydrate has been shown to influence gastric and intestinal motility. Our aim was to investigate the effects of colonic infusion of lactose and short-chain fatty acids (SCFAs) on lower esophageal sphincter (LES) function in humans. LES pressure (LESP), transient relaxations of LES (TLESRs), and esophageal pH were monitored over 6 h on 4 different days in 7 healthy volunteers. After 1 h of baseline recording, the effects of different colonic infusions (270 ml of isotonic or hypertonic saline, 30 g lactose, or 135 mmol SCFAs) were tested in fasting conditions and after a standard meal. Peptide YY (PYY) and oxyntomodulin (OLI) were also measured in plasma. Both lactose and SCFA infusions increased the number of TLESRs as well as the proportion of TLESRs associated with acid reflux episodes, but saline solutions did not. The postprandial fall of LESP was enhanced by previous SCFA infusion. Plasma PYY and OLI increased similarly after all colonic infusions. Colonic fermentation of lactose markedly affected LES function, and this effect was reproduced by SCFA infusion. Whether the mechanisms of this feedback phenomenon are of hormonal nature, neural nature, or both remains to be determined. (+info)
Glucagon-like peptide isolated from the eel intestine: effects on atrial beating.
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A new glucagon-like peptide was isolated from the intestine of the eel Anguilla japonica. The primary structure was determined by sequence analysis after cleavage with lysyl endopeptidase, quantitative amino acid analysis and fast atom bombardment mass spectrometry as HSQGTFTNDY(10)SKYLETRRAQ(20)DFVQWLMNSK(30)RSGGPT. Since its structure is similar to that of oxyntomodulins (OXMs) reported in various vertebrates, we named this peptide eel oxyntomodulin (eOXM). We found that eOXM enhanced the contractile force and the beating rate of the eel atrium in a dose-dependent manner. These effects of eOXM were not inhibited by betaxolol, a beta(1)-adrenoceptor antagonist, indicating that the actions of eOXM were independent of those of adrenaline. eOXM enhanced the intracellular Ca(2+) concentration of the myocardium. The contractility of the eel atrium was greatly reduced after omitting Ca(2+) from the bathing medium or after treatment with verapamil, a Ca(2+) channel blocker. After inhibiting Ca(2+) entry under these conditions, the inotropic effect of eOXM was markedly reduced, but the chronotropic effect was not altered significantly. These results indicate that the inotropic effect of eOXM is via a stimulation of Ca(2+) influx but that the chronotropic effect may be independent of extracellular Ca(2+). (+info)
Repeated ICV administration of oxyntomodulin causes a greater reduction in body weight gain than in pair-fed rats.
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Oxyntomodulin (OXM) is a product of proglucagon processing in the intestine and the central nervous system. We reported that intracerebroventricular (ICV) and intranuclear administration of OXM caused an inhibition of food intake in rats (Dakin CL, Gunn I, Small CJ, Edwards CM, Hay DL, Smith DM, Ghatei MA, and Bloom SR. Endocrinology 142: 4244-4250, 2001). In this study, we investigated the effect of twice-daily ICV administration of OXM, 1 nmol, for 7 days. A pair-fed control was included. These animals were restricted to the food intake of the OXM group but injected twice daily with saline. OXM-treated animals gained significantly less weight than either control group (day 8: OXM, 12.2 +/- 1.9 g vs. pair fed, 21.0 +/- 2.1 g; P < 0.005). OXM treatment caused a reduction in epididymal white adipose tissue (OXM, 1.13 +/- 0.03 g vs. pair fed, 1.29 +/- 0.04 g; P < 0.05) and interscapular brown adipose tissue (OXM, 0.15 +/- 0.01 g vs. pair fed, 0.18 +/- 0.01 g; P < 0.05) and increased core temperature compared with saline control, suggestive of enhanced energy expenditure. The food restriction-induced suppression in plasma TSH, seen in the pair-fed group, was prevented by OXM, potentially via increased release of hypothalamic TRH. In summary, ICV OXM causes reduced body weight gain and body adiposity following chronic administration. (+info)
Gastrointestinal satiety signals III. Glucagon-like peptide 1, oxyntomodulin, peptide YY, and pancreatic polypeptide.
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Many peptides are synthesized and released from the gastrointestinal tract and pancreas, including pancreatic polypeptide (PP) and the products of the gastrointestinal L cells, glucagon-like peptide 1 (GLP-1), oxyntomodulin, and peptide YY (PYY). Whereas their roles in regulation of gastrointestinal function have been known for some time, it is now evident that they also influence eating behavior. This review considers the anorectic peptides PYY, PP, GLP-1, and oxyntomodulin, which decrease appetite and promote satiety in both animal models and humans. (+info)
Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial.
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This study investigated the effect of subcutaneously administered oxyntomodulin on body weight in healthy overweight and obese volunteers. Participants self-administered saline or oxyntomodulin subcutaneously in a randomized, double-blind, parallel-group protocol. Injections were self-administered for 4 weeks, three times daily, 30 min before each meal. The volunteers were asked to maintain their regular diet and level of physical exercise during the study period. Subjects' body weight, energy intake, and levels of adipose hormones were assessed at the start and end of the study. Body weight was reduced by 2.3 +/- 0.4 kg in the treatment group over the study period compared with 0.5 +/- 0.5 kg in the control group (P = 0.0106). On average, the treatment group had an additional 0.45-kg weight loss per week. The treatment group demonstrated a reduction in leptin and an increase in adiponectin. Energy intake by the treatment group was significantly reduced by 170 +/- 37 kcal (25 +/- 5%) at the initial study meal (P = 0.0007) and by 250 +/- 63 kcal (35 +/- 9%) at the final study meal (P = 0.0023), with no change in subjective food palatability. Oxyntomodulin treatment resulted in weight loss and a change in the levels of adipose hormones consistent with a loss of adipose tissue. The anorectic effect was maintained over the 4-week period. Oxyntomodulin represents a potential therapy for obesity. (+info)
Oxyntomodulin differentially affects glucagon-like peptide-1 receptor beta-arrestin recruitment and signaling through Galpha(s).
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The glucagon-like peptide (GLP)-1 receptor is a promising target for the treatment of type 2 diabetes and obesity, and there is great interest in characterizing the pharmacology of the GLP-1 receptor and its ligands. In the present report, we have applied bioluminescence resonance energy transfer assays to measure agonist-induced recruitment of betaarrestins and G-protein-coupled receptor kinase (GRK) 2 to the GLP-1 receptor in addition to traditional measurements of second messenger generation. The peptide hormone oxyntomodulin is described in the literature as a full agonist on the glucagon and GLP-1 receptors. Surprisingly, despite being full agonists in GLP-1 receptor-mediated cAMP accumulation, oxyntomodulin and glucagon were observed to be partial agonists in recruiting betaarrestins and GRK2 to the GLP-1 receptor. We suggest that oxyntomodulin and glucagon are biased ligands on the GLP-1 receptor. (+info)
Oxyntomodulin ameliorates glucose intolerance in mice fed a high-fat diet.
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We evaluated the acute effects of OXM on glucose metabolism in diet-induced insulin-resistant male C57Bl/6 mice. To determine the effects on glucose tolerance, mice were intraperitoneally injected with OXM (0.75, 2.5, or 7.5 nmol) or vehicle prior to an ip glucose tolerance test. OXM (0.75 nmol/h) or vehicle was infused during a hyperinsulinemic euglycemic clamp to quantify insulin action on glucose production and disposal. OXM dose-dependently improved glucose tolerance as estimated by AUC for glucose (OXM: 7.5 nmol, 1,564 +/- 460, P < 0.01; 2.5 nmol, 1,828 +/- 684, P < 0.01; 0.75 nmol, 2,322 +/- 303, P < 0.05; control: 2,790 +/- 222 mmol.l(-1).120 min). Insulin levels in response to glucose administration were higher in 7.5 nmol OXM-treated animals compared with controls. In basal clamp conditions, OXM increased EGP (82.2 +/- 14.7 vs. 39.9 +/- 5.7 micromol.min(-1).kg(-1), P < 0.001). During insulin infusion, insulin levels were twice as high in OXM-treated mice compared with controls (10.6 +/- 2.8 vs. 4.4 +/- 2.2 ng/ml, P < 0.01). Consequently, glucose infusion rate (118.6 +/- 30.8 vs. 38.8 +/- 26.4 microl/h, P < 0.001) and glucose disposal (88.1 +/- 13.0 vs. 45.2 +/- 6.9 micromol.min(-1).kg(-1), P < 0.001) were enhanced in mice that received OXM. In addition, glucose production was more suppressed during OXM infusion (35.7 +/- 15.5 vs. 15.8 +/- 11.4% inhibition, P < 0.05). However, if these data were expressed per unit concentration of circulating insulin, OXM did not affect insulin action on glucose disposal and production. These results indicate that OXM beneficially affects glucose metabolism in diet-induced insulin-resistant C57Bl/6 mice. It ameliorates glucose intolerance, most likely because it elevates glucose-induced plasma insulin concentrations. OXM does not appear to impact on insulin action. (+info)