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OBJECTIVE Glucagon-like peptide (GLP)-1 receptor is encoded by GLP1R. The effect of genetic variation at this locus on the response to GLP-1 is unknown. This study assessed the effect of GLP1R polymorphisms on insulin secretion in response to hyperglycemia and to infused GLP-1 in nondiabetic subjects. RESEARCH DESIGN AND METHODS Eighty-eight healthy individuals (aged 26.3 ± 0.6 years, fasting glucose 4.83 ± 0.04 mmol/l) were studied using a hyperglycemic clamp. GLP-1 was infused for the last 2 h of the study (0.75 pmol/kg/min over 121–180 min, 1.5 pmol/kg/min over 181–240 min). β-Cell responsivity (ΦTotal) was measured using a C-peptide minimal model. The effect of 21 tag single nucleotide polymorphisms (SNPs) in GLP1R on ΦTotal was examined. RESULTS Two SNPs (rs6923761 and rs3765467) were nominally associated with altered β-cell responsivity in response to GLP-1 infusion. CONCLUSIONS Variation in GLP1R may alter insulin secretion in response to exogenous GLP-1. Future studies will determine whether such variation accounts for interindividual differences in response to GLP-1–based therapy.

BACKGROUND Prucalopride (R093877) is a selective and specific 5HT 4 agonist, the first of a new chemical class of benzofurans, with gastrointestinal prokinetic activities in vitro. AIMS To evaluate the effects of prucalopride on gastrointestinal and colonic transit. METHODS A validated scintigraphic technique was used to measure gastrointestinal and colonic transit over 48 hours in 50 healthy volunteers. For seven days, each subject received a daily dose of 0.5, 1, 2, or 4 mg prucalopride, or placebo in a double blind, randomised fashion. The transit test was performed over the last 48 hours. RESULTS There were significant accelerations of overall colonic transit at 4, 8, 24, and 48 hours (p<0.05) and proximal colonic emptying t 1/2 (p<0.05). The 0.5, 2, and 4 mg doses of prucalopride were almost equally effective and accelerated colonic transit compared with placebo. Prucalopride did not significantly alter gastric emptying (p>0.5) or small bowel transit (overall p=0.12). The medication appeared to be well tolerated during the seven day treatment of healthy subjects. CONCLUSION Prucalopride accelerates colonic transit, partly by stimulating proximal colonic emptying, but does not alter gastric or small bowel transit in healthy human subjects. Prucalopride deserves further study in patients with constipation.

Background The pathophysiological mechanisms in non-ulcer dyspepsia are incompletely understood. Aims To compare gastric motor and sensory functions in Helicobacter pylori positive or negative patients with non-ulcer dyspepsia. Patients Seventeen patients with non-ulcer dyspepsia and 16 asymptomatic controls. Methods The following were evaluated: gastrointestinal symptoms; gastric emptying and orocaecal transit of solids; abdominal vagal function; gastric compliance; fasting and postprandial gastric tone and phasic contractions; symptoms during ingestion of cold water and during the distension of an intragastric bag; and somatic sensitivity and personality profile (Minnesota Multiphasic Personality Inventory, MMPI). Results Gastric accommodation was reduced in H pylori negative dyspeptics relative to controls; the degree of accommodation was unrelated to H pylori status in dyspeptics. Increased postprandial gastric sensation was more frequent among H pylori positive patients (4/5 H pylori positive versus 4/12 H pylori negative patients). Intragastric meal distribution and orocaecal transit were normal; gastric emptying at four hours was abnormal in 4/17 patients. Vagal dysfunction was rare. Eight of 17 patients had somatisation or depression on MMPI. Conclusion Impaired gastric accommodation is frequent in non-ulcer dyspepsia and seems to be unrelated to vagal efferent dysfunction. H pylori infection does not seem to influence gastric accommodation, but is associated with heightened sensitivity in dyspeptics. Therapeutic approaches that restore normal postprandial accommodation and gastric sensitivity should be tested in non-ulcer dyspepsia.

Background —Carcinoid diarrhoea is associated with rapid small bowel and proximal colonic transit. Intravenous administration of a serotonin type 3 receptor (5HT 3 ) antagonist restores postprandial colonic tone towards normal in carcinoid patients. Aims —To evaluate the medium term effects of an oral 5HT 3 antagonist, alosetron, on symptoms, stool fat, and transit in patients with carcinoid diarrhoea. Methods —In 27 patients with carcinoid diarrhoea, symptoms were recorded daily and gastrointestinal transit was measured by scintigraphy in a three dose (0.1, 0.5, 2.0 mg, twice daily), randomised (1:1:1), parallel group, four week study. Placebo was given during the first week. Loperamide (2 mg capsules) was used as rescue medication. Results —There were numerical improvements in median diarrhoea score, stool weight, loperamide use, and overall colonic transit at four hours, but no overall significant drug effect was shown. Alosetron reduced the proximal colon emptying rate (p<0.05 in 20 evaluable comparisons), but did not significantly alter small bowel transit. Conclusions —Alosetron retardation of proximal colonic emptying in patients with carcinoid diarrhoea confirms the potential role of a 5HT 3 mechanism in this disorder. Doses of alosetron higher than 2.0 mg twice daily will be required for symptomatic benefit in carcinoid diarrhoea.

Background—Flufenamic acid, a fenamate, has been shown to alter markedly the membrane potential of small intestinal smooth muscle and increase intracellular calcium in single cells. Aims—To determine the effects of flufenamic acid on myoelectrical motor activity and gastrointestinal transit in the intact animal. Methods—Myoelectrical motor activity was recorded via seromuscular platinum electrodes sutured at regular intervals in the stomach and throughout the small intestine. Fasted and fed gastrointestinal transit was assessed using technetium-99m (99mTc) as the radioactive marker linked to 1 mm amberlite pellets or added to the meal. Results—Flufenamic acid (600 mg, intravenously) induced intense spike activity in the small intestine. The mean duration of irregular spike activity was 250 (7) minutes. Spike activity was more pronounced in the lower small intestine. Flufenamic acid also accelerated initial gastric emptying and markedly shortened transit time in the small intestine. In the fasted state the 50% transit time in the small intestine was 54 (8) minutes with infusion of flufenamic acid compared with 105 (10) minutes in the control group; in the fed state 99mTc first reached the colon at 220 (10) minutes compared with 270 (12) minutes in the control group. Conclusions—Flufenamic acid had marked effects on both myoelectrical motor complex activity and small intestinal transit in the dog. The observed effects suggest that flufenamic acid may be of potential use as a prokinetic agent.

Daikenchuto (TU-100) is a traditional Japanese (Kampo) medicine used to treat postoperative ileus. TU-100 dose dependently increases gastrointestinal (GI) motility by modulating cholinergic and serotonergic mechanisms in animal studies. The aim of this study was to evaluate the effects of orally administered TU-100 on GI and colonic transit and bowel function in healthy humans. In a randomized, parallel-group, double-blind, placebo-controlled, dose-response study, 60 healthy subjects were randomly assigned to placebo or TU-100 2.5 g or 5 g tid ingested immediately before meals for 5 consecutive days. We measured GI and colonic transit by validated scintigraphy and stool frequency and consistency by daily diaries of bowel function. There were overall treatment effects on colonic filling at 6 h without any significant differences between each dose of TU-100 and placebo. There tended to be overall treatment effects on ascending colon (AC) emptying half-time; the TU-100 (7.5 g/day) treatment significantly accelerated AC emptying compared with placebo. There were numerically higher values of GC24 (which reflect overall colonic transit) with both doses of TU-100, but these changes were not statistically significant. There were no significant overall treatment effects on gastric emptying or stool frequency and consistency. One subject, who received 7.5 g/day of TU-100, had elevated creatine phosphokinase following the study. TU-100 (7.5 g/day) significantly accelerated AC emptying. Further randomized controlled trials in patients with functional constipation or irritable bowel syndrome with constipation are warranted to evaluate the clinical efficacy of TU-100 in these disorders.

To investigate the role of HLA-DQ2 in the pathogenesis of associated immune disorders, we generated transgenic mice that expressed HLA-DQ2 in the absence of endogenous murine class II molecules (AE 0 DQ2). These AE 0 DQ2 mice with a mixed genetic background spontaneously developed skin lesions on their ears, whereas control AE 0 DQ6 genotype control mice (also with a mixed genetic background) did not. The skin lesions were characterized by deep subepidermal blistering with hydropic degeneration and lymphoid infiltration in the subepidermal area as determined by histopathology. Immunofluorescence analysis revealed thick band-like granular deposition of IgG, IgM, and a thin band of IgA deposition along the basement membrane. AE 0 DQ2 mice also developed significant and progressive hematuria and proteinuria as compared with the AE 0 DQ6 mice (p < 0.05). Histopathology showed immune complex deposits in the glomeruli of AE 0 DQ2 mice. Immunofluorescence analysis showed progressive mesangial and capillary wall deposition of IgA, IgM, IgG and C1q in the kidney. With electron microscopy, the deposits showed a ‘fingerprint’ substructure; and tubuloreticular structures were identified within endothelial cells. Conversely, these changes were not observed in AE 0 DQ6 mice. Serum anti-double stranded (ds)DNA IgM and IgG levels were also significantly elevated among AE 0 DQ2 mice compared with AE 0 DQ6 mice (p < 0.001). In conclusion, AE 0 DQ2 mice spontaneously develop an autoimmune lupus-like syndrome and are useful model for this disease. It remains to be determined whether genetic admixture played a role in the development of this systemic lupus erythematosus-like syndrome in HLA-DQ2 transgenic mice. Lupus (2010) 19, 815—829.

ABSTRACTRecent in‐depth studies of irritable bowel syndrome (IBS) that assessed multiple physiological endpoints in large patient cohorts confirm evidence of abnormal motility, sensation, and psychosocial disturbances. However, the proportion with hypersensitivity has dropped from the time of the original claim that it is a “biological marker” of IBS. Discomfort thresholds in male and female IBS patients normalize over time, whereas IBS symptoms persist, and increased colonic sensitivity in IBS is strongly influenced by a psychological tendency to report pain and urge rather than increased neurosensory sensitivity. The objectives of this article are to review the classical pathophysiology of IBS, the putative roles of infection, inflammation, and bacterial flora; consider mimics of IBS; assess the evidence that IBS is a serotonergic disease; evaluate recent advances in membrane biology and neuroscience related to IBS; consider genetic association with IBS and its endophenotype; and discuss whether to treat the gut or the brain.