Nikrad Shahnavaz

Colonic motor dysfunction in human diabetes is associated with enteric neuronal loss and increased oxidative stress

Background  Gastrointestinal dysfunction is very common in diabetic patients. We assessed the changes in the colonic enteric nervous system using colectomy specimens and intestinal biopsies from diabetic subjects and age‐matched controls.

BMP2 promotes differentiation of nitrergic and catecholaminergic enteric neurons through a Smad1-dependent pathway

The bone morphogenetic protein (BMP) family is a class of transforming growth factor (TGF-beta) superfamily molecules that have been implicated in neuronal differentiation. We studied the effects of BMP2 and glial cell line-derived neurotrophic factor (GDNF) on inducing differentiation of enteric neurons and the signal transduction pathways involved. Studies were performed using a novel murine fetal enteric neuronal cell line (IM-FEN) and primary enteric neurons. Enteric neurons were cultured in the presence of vehicle, GDNF (100 ng/ml), BMP2 (10 ng/ml), or both (GDNF + BMP2), and differentiation was assessed by neurite length, markers of neuronal differentiation (neurofilament medium polypeptide and beta-III-tubulin), and neurotransmitter expression [neuropeptide Y (NPY), neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase (TH), choline acetyltransferase (ChAT) and Substance P]. BMP2 increased the differentiation of enteric neurons compared with vehicle and GDNF-treated neurons (P < 0.001). BMP2 increased the expression of the mature neuronal markers (P < 0.05). BMP2 promoted differentiation of NPY-, nNOS-, and TH-expressing neurons (P < 0.001) but had no effect on the expression of cholinergic neurons (ChAT, Substance P). Neurons cultured in the presence of BMP2 have higher numbers of TH-expressing neurons after exposure to 1-methyl 4-phenylpyridinium (MPP(+)) compared with those cultured with MPP(+) alone (P < 0.01). The Smad signal transduction pathway has been implicated in TGF-beta signaling. BMP2 induced phosphorylation of Smad1, and the effects of BMP2 on differentiation of enteric neurons were significantly reduced in the presence of Smad1 siRNA, implicating the role of Smad1 in BMP2-induced differentiation. The effects of BMP2 on catecholaminergic neurons may have therapeutic implications in gastrointestinal motility disturbances.

Glial cell line-derived neurotrophic factor enhances human islet posttransplantation survival.

Background. Development of pretransplantation islet culture strategies that preserve or enhance &bgr;-cell viability would eliminate the requirement for the large numbers of islets needed to restore insulin independence in type 1 diabetes patients. We investigated whether glial cell line–derived neurotrophic factor (GDNF) could improve human islet survival and posttransplantation function in diabetic mice. Methods. Human islets were cultured in medium supplemented with or without GDNF (100 ng/mL) and in vitro islet survival and function assessed by analyzing &bgr;-cell apoptosis and glucose stimulated insulin release. In vivo effects of GDNF were assessed in streptozotocin-induced diabetic nude mice transplanted under the kidney capsule with 2000 islet equivalents of human islets precultured in medium supplemented with or without GDNF. Results. In vitro, human islets cultured for 2 to 10 days in medium supplemented with GDNF showed lower &bgr;-cell death, increased Akt phosphorylation, and higher glucose-induced insulin secretion than islets cultured in vehicle. Human islets precultured in medium supplemented with GDNF restored more diabetic mice to normoglycemia and for a longer period after transplantation than islets cultured in vehicle. Conclusions. Our study shows that GDNF has beneficial effects on human islet survival and could be used to improve islet posttransplantation survival.

A Randomized, Double-Blind, Placebo-Controlled Trial to Examine the Effectiveness of Lubiprostone on Constipation Symptoms and Colon Transit Time in Diabetic Patients

Objectives:Constipation is the most common GI symptom in patients with diabetes mellitus (DM). Importantly, patients with constipation have lower health-related quality of life than those without constipation. Effective therapies for constipation are limited and there is a paucity of data evaluating the treatment of constipation in diabetics.Methods:Diabetic patients with chronic idiopathic constipation (CIC) as defined by Rome III criteria were recruited from outpatient clinics at a tertiary-care center and a Veterans Administration Hospital. Demographic data, baseline stool patterns, and a constipation-specific quality of life survey (Patient Assessment of Constipation Quality of Life (PAC-QOL)) were obtained. Baseline colonic transit time (CTT) was evaluated utilizing the wireless motility capsule. Patients were randomized in a double-blind fashion to 48 mcg per day lubiprostone or placebo for 8 weeks. The primary end point measured was the difference in number of spontaneous bowel movements (SBMs) per week vs. baseline for each group at each week after initiation of therapy. Secondary end points included changes in CTT after 4 weeks of therapy, PAC-QOL after 8 weeks of therapy, and changes from baseline in associated gastrointestinal (GI) symptoms as well as need for rescue medication at 2, 4, and 8 weeks.Results:Seventy-six patients (mean age, 56.9±9.1 years, 62% females) were randomized. There were no significant differences between the two groups’ baseline data or demographics. During the 8-week treatment period, patients in the lubiprostone group experienced an average of 1.83±0.80 (P=0.02) more SBMs per week than those in the placebo group as compared with baseline. The duration of CTT at Week 4 was shorter by an average of 13 h compared with baseline in the lubiprostone group, and was prolonged by an average of 7 h compared with baseline in the placebo group, leading to a treatment effect of 20.3±7.3 h (P=0.006). PAC-QOL improved in both the groups; however, there was no significant difference between the groups. There was no difference in associated GI symptoms and need for rescue medication between the two groups after 8 weeks. There were no serious adverse events reported during the study.Conclusions:This study suggests that lubiprostone is a safe and effective treatment for increasing weekly SBMs and decreasing CTT in patients with DM and CIC.

Fluoroscopic gastric peroral endoscopic pyloromyotomy (G-POEM) in patients with a failed gastric electrical stimulator

Abstract Background Gastric electrical stimulators (GESs) have been used to treat refractory gastroparesis in patients who fail initial therapies such as dietary modifications, control of psychological stressors and pharmacologic treatment. More recently, gastric peroral endoscopic pyloromyotomy (G-POEM) has emerged as a novel endoscopic technique to treat refractory gastroparesis. We present a case series of patients with refractory gastroparesis who failed treatment with an implanted GES that were safely treated with G-POEM performed under fluoroscopy as a salvage therapy. Methods Cases of G-POEM performed on patients with refractory gastroparesis who failed treatment with a GES were retrospectively reviewed. All G-POEM procedures were performed under fluoroscopic guidance with the GES still in place. Gastroparesis Cardinal Symptoms Index (GCSI) and gastric emptying scintigraphy were assessed before and after the procedure. Patients were followed up for up to 18 months post procedure. Results Five patients underwent G-POEM after failing treatment with a GES. Under fluoroscopy, the GES and their leads were visualized in different parts of the stomach. One GES lead was observed at the antrum near the myotomy site. All procedures were successfully completed without complications. Patients’ GCSI decreased by an average of 62% 1 month post procedure. Patients also had notable improvements in gastric emptying 2 months post procedure. Conclusion In patients with refractory gastroparesis who have failed treatment with a GES, G-POEM can be safe and effective without removing the GES. To visualize the GES and avoid cutting GES leads during myotomy, the procedure should be performed under fluoroscopy.

Gastric Peroral Endoscopic Pyloromyotomy Reduces Symptoms, Increases Quality of Life, and Reduces Health Care Use For Patients With Gastroparesis

BACKGROUND & AIMS: Gastric peroral endoscopic pyloromyotomy (GPOEM) is becoming a promising treatment option for patients with refractory gastroparesis. We aimed to systematically assess the efficacy of GPOEM and its effects on health care use. METHODS: We performed a retrospective study on 30 patients with refractory gastroparesis who underwent GPOEM from June 2015 through July 2017 at a tertiary center. We compared outcomes with those of 7 patients with refractory gastroparesis who did not undergo the procedure (controls). The primary outcomes were patient‐reported reductions in symptoms, based on the gastroparesis cardinal symptom index (GCSI), and increases in 8 aspects of quality of life, based on Short Form 36 (SF‐36) scores. Data were collected on the day of the procedure (baseline) and at 1 month, 6 months, 12 months, and 18 months afterward. Secondary outcomes included visits to the emergency department or hospitalization for gastroparesis‐related symptoms. RESULTS: GPOEM was technically successful in all patients and significantly reduced GCSI scores in repeated‐measure analysis of variance (F2.044, 38.838 = 22.319; P < .0005). The mean score at baseline was 3.5 ± 0.6, at 1 month after GPOEM was 1.8 ± 1.0 (P < .0005), at 6 months after was 1.9 ± 1.2 (P < .0005), at 12 months after was 2.6 ± 1.5 (P < .026), and at 18 months after was 2.1 ± 1.3 (P < .016). GPOEM was associated with improved quality of life: 77.8%, 76.5%, and 70% of patients had significant increases in SF‐36 scores, compared with baseline, at 1 month, 6 months, and 12 months after GPOEM, respectively (F1.71,18.83 = 14.16; P < .0005). Compared with controls, patients who underwent GPOEM had significant reductions in GCSI, after we controlled for baseline score and duration of the disease (F1,31 = 9.001; P = .005). Patients who received GPOEM had significant reductions in number of emergency department visits (from 2.2 ± 3.1 times/mo at baseline to 0.3 ± 0.8 times/mo; P = .003) and hospitalizations (from 1.7 ± 2 times/mo at baseline to 0.2 ± 0.4 times/mo; P = .0002). CONCLUSIONS: In a retrospective study of patients who underwent GPOEM for refractory gastroparesis, we found the procedure significantly improved symptoms, increased quality of life, and reduced health care use related to gastroparesis.

Sa1098 The Association Between Socioeconomic Status and Quality of Life of Diabetic Patients With Constipation

by Los Angeles (LA) classification were evaluated. Results: Seventy patients (48%) were partial responder to PPI therapy. These patients reported significantly lower scores in the mental health component summary of SF-8, PSQI and HADS including anxiety and depression than responder to PPI. Anxious or depressive state patients (HADS total score>11) are 69% in partial responder to PPI, whereas 31% in responder to PPI (P=0.006). PPI daily dose and LA classification were also significant factors that associated with the response to PPI. Conclusion: Partial responder to PPI showed decreased mental HRQoL. Persistent and troublesome reflux symptoms on PPI therapy seemed to be important factors affecting mental HRQoL including anxiety, depression and sleep disturbance in Japanese GERD patients. The scores of each questionnaire