Ghrelin improves delayed gastrointestinal transit in alloxan-induced diabetic mice
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瞄准：在导致 alloxan 的糖尿病的老鼠在推迟的胃肠的运输上调查 ghrelin 的效果。方法：一个糖尿病的老鼠模型被腹膜内注射与阿脲建立。老鼠被使随机化进二个主要的组：正常老鼠组和在 0， 20， 50， 100 和 200 mug/kg ip 的剂量与 ghrelin 对待的糖尿病的老鼠组。胃的倒空(GE ) ，在他们有 ghrelin 的酚红饭追随者注射以后，肠的运输(信息技术) ，和结肠的运输(CT ) 在老鼠被学习。基于最有效的 ghrelin 剂量，颠茄碱为每大小在 ghrelin 注射前在 1 mg/kg 被给 15 min。在每个组的老鼠被牺牲以后的 20 min 和他们的胃，肠，和冒号立即被收获。酚红的数量被测量。GE，信息技术，和 CT 的百分比是计算的。结果：GE，信息技术，和 CT 的百分比显著地作为与控制鼠标相比在糖尿病的鼠标被减少(22.9 +/- 1.4 对 28.1 +/- 1.3， 33.5 +/- 1.2 对 43.2 +/- 1.9， 29.5 +/- 1.9 对 36.3 +/- 1.6， P < 0.05 ) 。在糖尿病的老鼠， ghrelin 改善了 GE 和它，然而并非 CT。ghrelin 的最有效的剂量是 100 mug/kg，颠茄碱堵住了职业人员 GE 和它上的 ghrelin 的运动效果。结论：Ghrelin 加速推迟的 GE 和它，但是没在糖尿病的老鼠在 CT 上有效果。Ghrelin 可以施加它的职业人员运动在伤寒神经系统经由胆碱能的小径完成，因此与推迟的上面的胃肠的运输为糖尿病的病人有治疗学的潜力。Cite
Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor, is released from the stomach. Animal studies suggest that ghrelin stimulates gastrointestinal motor activity.To investigate the influence of ghrelin on gastric emptying rate and meal-related symptoms in idiopathic gastroparesis.In six patients with idiopathic gastroparesis, a breath test was used to measure gastric emptying rates (t(1/2)) for solids and liquids after administration of saline or ghrelin 40 microg/30 min in a double-blind, randomized fashion. At each breath sampling, the patient was asked to grade the intensity of six different symptoms (epigastric pain, bloating, postprandial fullness, nausea, belching and epigastric burning) and these were added to obtain meal-related symptom severity score.Ghrelin significantly enhanced liquid emptying (t(1/2): 86 +/- 7 vs. 53 +/- 6 min, P = 0.02) and tended to enhance solid emptying (144 +/- 45 vs. 98 +/- 15 min, P = 0.06). Ghrelin pre-treatment significantly decreased cumulative meal-related symptom score (196 +/- 30 vs. 136 +/- 23, P = 0.04) and individual scores for fullness (55 +/- 8 vs. 39 +/- 8, P = 0.02), and for pain (40 +/- 8 vs. 16 +/- 5, P < 0.05).In idiopathic gastroparesis, administration of ghrelin enhances gastric emptying and improves meal-related symptoms. These observations suggest a potential for ghrelin receptor agonists in the treatment of gastroparesis.
Gastroparesis
Bloating
Epigastric pain
Prokinetic agent
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Background: Diabetic gastroparesis is a disabling condition with no consistently effective treatment. In animals, ghrelin increases gastric emptying and reverses postoperative ileus. We present the results of a double blind, placebo controlled, crossover study of ghrelin in gastric emptying in patients with diabetic gastroparesis. Methods: Ten insulin requiring diabetic patients (five men, six type I) referred with symptoms indicative of gastroparesis received a two hour infusion of either ghrelin (5 pmol/kg/min) or saline on two occasions. Blood glucose was controlled by euglycaemic clamp. Gastric emptying rate (GER) was calculated by real time ultrasound following a test meal. Blood was sampled for ghrelin, growth hormone (GH), and pancreatic polypeptide (PP) levels. Cardiovagal neuropathy was assessed using the Mayo Clinic composite autonomic severity score (range 0 (normal)–3). Results: Baseline ghrelin levels were mean 445 (SEM 36) pmol/l. Ghrelin infusion achieved a peak plasma level of 2786 (188) pmol/l at 90 minutes, corresponding to a peak GH of 70.9 (19.8) pmol/l. Ghrelin increased gastric emptying in seven of 10 patients (30 (6)% to 43 (5)%; p = 0.04). Impaired cardiovagal tone correlated inversely with peak postprandial PP values (p<0.05) but did not correlate with GER. Conclusions: Ghrelin increases gastric emptying in patients with diabetic gastroparesis. This is independent of vagal tone. We propose that analogues of ghrelin may represent a new class of prokinetic agents.
Gastroparesis
Crossover study
Motilin
Pancreatic polypeptide
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To investigate the effects of ghrelin on delayed gastrointestinal transit in alloxan-induced diabetic mice.A diabetic mouse model was established by intraperitoneal injection with alloxan. Mice were randomized into two main groups: normal mice group and diabetic mice group treated with ghrelin at doses of 0, 20, 50, 100 and 200 mug/kg ip. Gastric emptying (GE), intestinal transit (IT), and colonic transit (CT) were studied in mice after they had a phenol red meal following injection of ghrelin. Based on the most effective ghrelin dosage, atropine was given at 1 mg/kg 15 min before the ghrelin injection for each measurement. The mice in each group were sacrificed 20 min later and their stomachs, intestines, and colons were harvested immediately. The amount of phenol red was measured. Percentages of GE, IT, and CT were calculated.Percentages of GE, IT, and CT were significantly decreased in diabetic mice as compared to control mice (22.9 +/- 1.4 vs 28.1 +/- 1.3, 33.5 +/- 1.2 vs 43.2 +/- 1.9, 29.5 +/- 1.9 vs 36.3 +/- 1.6, P < 0.05). In the diabetic mice, ghrelin improved both GE and IT, but not CT. The most effective dose of ghrelin was 100 mug/kg and atropine blocked the prokinetic effects of ghrelin on GE and IT.Ghrelin accelerates delayed GE and IT but has no effect on CT in diabetic mice. Ghrelin may exert its prokinetic effects via the cholinergic pathway in the enteric nervous system, and therefore has therapeutic potential for diabetic patients with delayed upper gastrointestinal transit.
Alloxan
Intraperitoneal injection
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Objective To observe the effects of Sheng qi jiang tang ke li on blood glucose,lipid and endothelin-1(ET-1) expression in the diabetic rats.Methods The diabetic rat mode was made,and then experimental groups were randomizedly divided into Sheng qi jiang tang ke li low dose group,mid-dose group,high dose group,rosiglitazone group and control group.When the treatment was effective,the rats' plasma glucose were decreased to normal level or had significant difference compared with control model.The blood glucose,total cholesterin(TC),triglyceride(TG),insulin,ET-1,and ET-1mRNA were measured in different groups.Results After intervention of medicine,the blood glucose,TC,TG,insulin were decreased significantly in Sheng qi jiang tang ke li mid-dose group,high dose group and rosiglitazone group(P0.01).The expressions of ET-1 protein and mRNA of vascular endotheline were also decreased in the rosiglitazone group and high dose group of Sheng qi jiang tang ke li.Conclusions ①Sheng qi jiang tang ke li has effects on anti-diabedic mellitues,the effects present dosage dependence as well.②Sheng qi jiang tang ke li decreases ET-1 expression,and then protects vascluar endothline and cardiac muscle function.
Rosiglitazone
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The polysaccharide extracted from Huidouba(PEH) exihibited a significant anti-diabetic activity. The po- lysaccharide contained glucose, mannose and galactose in a content ratio of 1.00:0.34:0.32. After administration with 50― 200 mg/kg body weight of PEH to type II diabetic mice induced by alloxan for four weeks, the blood glucose level of mice was decreased significantly. Moreover, the SOD activity increased at the same time(p<0.01). PEH showed a significant anti-diabetic and anti-oxidation activity. In addition, PEH affected the BUN and ALT le- vels(p<0.05), which are important characteristics of diabetes mellitus. Through this work, PEH should be a potential anti-diabetic drug in the future.
Alloxan
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Diarrhea and constipation are frequently reported gastrointestinal complications in diabetic patients. These disorders seem to be the consequence of altered innervations of a receptor system in the gastrointestinal tract in diabetes. We investigated the functional changes of cholinergic and beta-adrenergic receptor activities in rat ileum tissue after 8 weeks of control and streptozotocin (STZ)-induced diabetes in rats. Functional changes with different agonists were observed in diabetes: In diabetic rat ileum, carbachol increased the maximal contraction without changing pD2 values, whereas with acetylcholine, no changes were observed in the maximal contractile (Emax) response and pD2 values in diabetes were comparable with controls. With the beta-adrenoceptor agonists isoproterenol and salmeterol, decreased maximal relaxation responses were observed in 8-week diabetic rat ileums as compared with age-matched controls. With isoproterenol, pD2 values were also decreased in diabetic ileum, although not with salmeterol. On the other hand, with the in vivo charcoal meal test, the percentage of transit was increased in diabetic mice. The antitransit percentage was significantly increased in diabetic mice with the muscarinic antagonist atropine and the beta 2-selective agonist salbutamol, as compared with age-matched control mice. Results obtained from these in vivo and in vitro studies indicate that gastrointestinal complications such as diabetic diarrhea may occur because of functional changes such as increased intestinal transit and decreased intestinal tone due to increased cholinergic and decreased beta-adrenergic receptor activities in diabetes mellitus.
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Background and aims: The gastroprokinetic activities of ghrelin, the natural ligand of the growth hormone secretagogue receptor (GHS-R), prompted us to compare the effect of ghrelin with that of synthetic peptide (growth hormone releasing peptide 6 (GHRP-6)) and non-peptide (capromorelin) GHS-R agonists both in vivo and in vitro. Methods: In vivo, the dose dependent effects (1–150 nmol/kg) of ghrelin, GHRP-6, and capromorelin on gastric emptying were measured by the 14C octanoic breath test which was adapted for use in mice. The effect of atropine, NG-nitro-L-arginine methyl ester hydrochloride (l-NAME), or D-Lys3-GHRP-6 (GHS-R antagonist) on the gastroprokinetic effect of capromorelin was also investigated. In vitro, the effect of the GHS-R agonists (1 µM) on electrical field stimulation (EFS) induced responses was studied in fundic strips in the absence and presence of L-NAME. Results: Ghrelin, GHRP-6, and capromorelin accelerated gastric emptying in an equipotent manner, with bell-shaped dose-response relationships. In the presence of atropine or l-NAME, which delayed gastric emptying, capromorelin failed to accelerate gastric emptying. D-Lys3-GHRP-6 also delayed gastric emptying but did not effectively block the action of the GHS-R agonists, but this may be related to interactions with other receptors. EFS of fundic strips caused frequency dependent relaxations that were not modified by the GHS-R agonists. L-NAME turned EFS induced relaxations into cholinergic contractions that were enhanced by ghrelin, GHRP-6, and capromorelin. Conclusion: The 14C octanoic breath test is a valuable technique to evaluate drug induced effects on gastric emptying in mice. Peptide and non-peptide GHS-R agonists accelerate gastric emptying of solids in an equipotent manner through activation of GHS receptors, possibly located on local cholinergic enteric nerves.
Secretagogue
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