Predictors of turnover of lower gastrointestinal symptoms in diabetes mellitus

BACKGROUND: Both the natural history of GI symptoms and factors influencing symptom turnover in diabetes mellitus are unknown. We aimed to determine the natural history of GI symptoms in diabetes mellitus over a 3-yr period. METHODS: Subjects with predominantly Type 2 diabetes on the mailing list of Diabetes Australia were recruited and completed a validated questionnaire (n = 892); of these, 64% completed the questionnaire again 3 yr later. Subjects were classified as never having GI symptoms (abdominal pain, constipation, diarrhea, fecal incontinence), fluctuating (only on one survey), or persistent symptoms. RESULTS: Symptoms more often fluctuated than persisted, but the prevalence at recruitment and 3 yr later was similar. Predictors of symptom turnover varied. In a multivariate model, abnormal sweating and diabetic foot problems predicted symptom turnover for abdominal pain (OR = 2.01, 95% CI = 1.07-3.76 and 2.54, 1.23-5.24, respectively), and paresthesiae ("pins and needles") and foot problems predicted fecal incontinence (OR = 2.24, 1.06-4.75 and 2.38, 1.04-5.45, respectively), but not constipation or diarrhea. Symptom turnover in constipation was associated with depression (OR = 2.73, CI = 1.89-3.94) and neuroticism (OR = 0.57, CI = 0.36-0.89), and depression was associated with abdominal pain (OR = 1.56, CI = 1.02-2.38), but psychological factors were not related to the other symptoms. The odds for symptoms persisting were not generally related to type or duration of diabetes, or self-rated glycemic control. CONCLUSION: The natural history of GI symptoms in diabetes has been described for the first time; symptoms may either persist or fluctuate, but the prevalence is constant because symptom onset is balanced by disappearance. Glycemic control does not seem to predict symptom change.     

Prevalence of delayed gastric emptying in diabetic patients and relationship to dyspeptic symptoms: a prospective study in unselected diabetic patients

OBJECTIVE: Data on the prevalence of abnormal gastric emptying in diabetic patients are still lacking. The relation between gastric emptying and dyspeptic symptoms assessed during gastric emptying measurement has not yet been investigated. The aim was to investigate the prevalence of delayed gastric emptying in a large cohort of unselected diabetic patients and to investigate the relation between gastric emptying and gastrointestinal sensations experienced in the 2 weeks before and during the test meal, prospectively. RESEARCH DESIGN AND METHODS: Gastric emptying was evaluated in 186 patients (106 with type 1 diabetes, mean duration of diabetes 11.6 +/- 11.3 years) using 100 mg (13)C-enriched octanoic acid added to a solid meal. RESULTS: Gastric emptying was significantly slower in the diabetic subjects than in the healthy volunteers (T(50): 99.5 +/- 35.4 vs. 76.8 +/- 21.4 min, P < 0.003; Ret(120 min): 30.6 +/- 17.2 vs. 20.4 +/- 9.7%, P < 0.006). Delayed gastric emptying was observed in 51 (28%) diabetic subjects. The sensations experienced in the 2 weeks before the test were weakly correlated with the sensation scored during the gastric emptying test. Sensations assessed during the gastric emptying test did predict gastric emptying to some extent (r = 0.46, P < 0.0001), whereas sensations experienced in the previous 2 weeks did not. CONCLUSIONS: This prospective study shows that delayed gastric emptying can be observed in 28% of unselected patients with diabetes. Upper gastrointestinal sensations scored during the gastric emptying tests do predict the rate of gastric emptying to some extent and sensation experienced during daily life does not.     

New developments in the treatment of irritable bowel syndrome

The irritable bowel syndrome (IBS) is one of the most common gastrointestinal conditions encountered by general practitioners, and it accounts for a great deal of the workload of gastroenterologists in secondary care. Research to date indicates that several factors contribute to the development of IBS, of which disturbed gastrointestinal motility, altered visceral perception and psychosocial factors are regarded as the three most important mechanisms interacting in the development of this disorder. Most pharmacological research has been based on these insights. Several agents capable of modulating either motility or sensitivity are currently under investigation. Potential drugs in the treatment of diarrhoea-predominant IBS are the more selective antispasmodics, such as the M3-receptor antagonists (e.g. zamifenacin, darifenacin). In constipation-predominant IBS the colokinetic effects of the selective 5HT4 agonists prucalopride and tegaserod are of great interest. Since altered visceral perception is thought to play an important role in the genesis of abdominal pain and bloating in many patients with IBS, new drugs are targeted at modulating the sensitivity, such as 5HT3 antagonists (e.g. alosetron), kappa-agonists (e.g. fedotozine) and somatostatin analogues. Furthermore, psychosocial factors should not be overlooked, since these appear to be of great influence on the clinical outcome of IBS.     

Diabetes mellitus and gastric emptying: questions and issues in clinical practice

It is long known that both type 1 and type 2 diabetes can be associated with changes in gastric emptying; a number of publications have linked diabetes to delayed gastric emptying of variable severity and often with poor relationship to gastrointestinal symptomatology. In contrast, more recent studies have reported accelerated gastric emptying when adjusted for glucose concentration in patients with diabetes, indicating a reciprocal relationship between gastric emptying and ambient glucose concentrations. This review proposes that gastroparesis or gastroparesis diabeticorum, a severe condition characterized by a significant impairment of gastric emptying accompanied by severe nausea, vomiting, and malnutrition, is often overdiagnosed and not well contrasted with delays in gastric emptying. The article offers a clinically relevant definition of gastroparesis that should help differentiate this rare condition from (often asymptomatic) delays in gastric emptying. The fact that delayed gastric emptying can also be observed in non‐diabetic individuals under experimental conditions in which hyperglycaemia is artificially induced suggests that a delay in gastric emptying rate when blood glucose concentrations are high is actually an appropriate physiological response to hyperglycaemia, slowing further increases in blood glucose. The article discusses the strengths and weaknesses of various methodologies for assessing gastric emptying, especially with respect to the diabetes population, and reviews newer diabetes therapies that decelerate the rate of gastric emptying. These therapies may be a beneficial tool in managing postprandial hyperglycaemia because they attenuate rapid surges in glucose concentrations by slowing the delivery of meal‐derived glucose. Copyright © 2009 John Wiley & Sons, Ltd.     

The effect of motilin agonist ABT-229 on gastro-oesophageal reflux, oesophageal motility and lower oesophageal sphincter characteristics in GERD patients

BACKGROUND: ABT-229, a motilin agonist without antibacterial activity, has been shown to enhance both lower oesophageal sphincter pressure in cats and gastric emptying in humans. AIM: To investigate the effect of oral treatment with ABT-229 10 mg b.d., ABT-229 5 mg b. d. and cisapride 10 mg q.d.s. on gastro-oesophageal reflux, lower oesophageal sphincter pressure, transient lower oesophageal sphincter relaxations and symptoms in GERD patients. METHODS: Twenty-four GERD patients completed the study. A randomized, double-blind, placebo-controlled, three-period incomplete crossover design was used with three dosing periods of 7 days. All patients received ABT-229 10 mg b.d. and placebo during two of the three periods. In the remaining period 12 patients were given ABT-229 5 mg b.d. and 12 received cisapride 10 mg q.d.s. Ambulatory 24 h recordings of oesophageal pH and pharyngeal, oesophageal, lower oesophageal sphincter and gastric pressures were performed on day 7 using an assembly incorporating a Dent sleeve connected to a portable water-perfused manometric system. RESULTS: Oesophageal acid exposure was not affected by ABT-229 or cisapride, but the incidence of reflux episodes was reduced by cisapride. None of the drugs affected oesophageal motility, lower oesophageal sphincter pressure or the incidence of transient lower oesophageal sphincter relaxations. Both ABT-229 10 mg b.d. and cisapride reduced the severity of daytime heartburn. CONCLUSION: The value of ABT-229 in the treatment of GERD appears to be limited.     

Intraduodenal conjugated bile salts exert negative feedback control on gall bladder emptying in the fasting state without affecting cholecystokinin release or antroduodenal motility

BACKGROUND: Intraduodenal bile salts exert negative feedback control on postprandial gall bladder emptying. Aims: We wished to examine whether a similar control mechanism occurs in the fasting state. METHODS: Intraduodenal bile salt depletion was achieved by 12 g of cholestyramine. Thereafter, in study A (seven subjects), the effects on gall bladder volume (by ultrasound) and antroduodenal motility of intraduodenal infusions of taurocholate egg yolk-phosphatidylcholine micelles were assessed. In study B (nine subjects), the effects on gall bladder volume of infusing mixed micelles composed of taurocholate (100 mM) and low (26 mM) or high (68 mM) amounts of egg yolk-phosphatidylcholine, or low amounts of dipalmitoylphosphatidylcholine were determined. RESULTS: Cholestyramine induced strong and prolonged gall bladder contraction without cholecystokinin release. In study A, micellar infusions increased gall bladder volume without affecting migrating motor complex cycle length. In study B, intraduodenal infusion induced strong increases in gall bladder volume in the case of taurocholate micelles containing low amounts of egg yolk-phosphatidylcholine, moderate increases in micelles containing low amounts of dipalmitoylphosphatidylcholine but no change in micelles containing high amounts of egg yolk-phosphatidylcholine, in all cases without altered plasma cholecystokinin levels. Phosphatidylcholine hydrolysis was significantly higher after infusion of egg yolk-phosphatidylcholine compared with infusion of dipalmitoylphosphatidylcholine containing micelles. Intermixed micellar-vesicular bile salt concentrations (responsible for detergent effects) were higher in egg yolk-phosphatidylcholine than in dipalmitoylphosphatidylcholine containing model biles and if lyso-phosphatidylcholine was included. CONCLUSIONS: Intraduodenal bile salts exert negative feedback on fasting gall bladder volume. The modulating effects of various phospholipids may relate to their effects on intermixed micellar-vesicular bile salt concentrations.     

Pneumothorax complicating botulinum toxin injection in the body of a dilated oesophagus in achalasia

Botulinum toxin is used for an increasing number of indications in the field of gastroenterology. We report a case in which injection of botulinum toxin in the dilated tubular oesophagus in a patient with achalasia was complicated by a pneumothorax necessitating suction drainage.     

Nasal tolerance induces antigen-specific CD4+CD25- regulatory T cells that can transfer their regulatory capacity to naive CD4+ T cells

The mucosal immune system is uniquely adapted to elicit immune responses against pathogens but also to induce tolerogenic responses to harmless antigens. In mice, nasal application of ovalbumin (OVA) leads to suppression of both T(h)1 and T(h)2 responses. This tolerance can be transferred to naive mice by CD4(+) T(r) cells from the spleen. Using the allotypic Ly5 system, we were able to demonstrate in vivo that T(r) cells not only suppress naive CD4(+) T cells, but also induce them to differentiate into T(r) cells. The effector function of these mucosal T(r) cells is not restricted by cytokine polarization, since T(r) cells from T(h)1-tolerant mice can suppress a T(h)2 response and vice versa. Transfer of splenic CD4(+)CD25(+) and CD4(+)CD25(-) T cell subsets from OVA-tolerized mice revealed that both subsets were equally able to suppress a delayed-type hypersensitivity response in acceptor mice. In contrast to the CD25(-) T cell subset, the CD25(+) cells were not specific for the antigen used for tolerization. Together, these findings demonstrate a role for CD4(+)CD25(-) T(r) cells in mucosal tolerance, which suppresses CD4(+) T cells in an antigen-specific fashion, irrespective of initial T(h)1/T(h)2 skewing of the immune response. This offers a major advantage in the manipulation of mucosal tolerance for the treatment of highly cytokine-polarized disorders such as asthma and autoimmune diseases.