Symptoms Of Diabetic Gastroparesis Research Articles

Metoclopramide Nasal Spray in Women with Symptomatic Diabetic Gastroparesis: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study

Background & AimsMetoclopramide nasal spray (MNS) was developed as an alternative to oral metoclopramide. Prior phase 2 studies demonstrated efficacy in reducing symptoms in women, but not men with diabetic gastroparesis. The aim of this phase 3 study was to further determine the safety and efficacy of MNS compared to placebo in reducing symptoms of diabetic gastroparesis in women. MethodsThis US multi-center, randomized, double-blind, parallel group study enrolled women aged 18 to 75 years with diabetic gastroparesis and delayed gastric emptying. Subjects were randomized 1:1 to receive placebo or MNS 10 mg. The primary efficacy endpoint was change in mean daily Gastroparesis Symptom Assessment (GSA) total score from baseline to week 4. The GSA daily diary is a validated patient-reported outcome instrument that averages scores of nausea, early satiety, prolonged fullness, bloating, and upper abdominal pain on a five-point ordinal scale. ResultsTwo-hundred-five subjects were randomized to receive placebo (n = 103) or MNS (n = 102). Overall, the MNS group did not experience a significant reduction in symptoms compared to the placebo group from baseline to week 4 (P = 0.881). However, subjects with moderate to severe symptoms at baseline had a significant treatment effect from weeks 1 to 3 (P < 0.05) and experienced a significant reduction in nausea and upper abdominal pain for all four weeks versus placebo (P < 0.05). Treatment-emergent adverse events were primarily mild to moderate with headache and abdominal pain reported most frequently. ConclusionsAlthough the primary endpoint was not met using all enrolled patients, treatment with MNS provided significant relief for women with moderate to severe diabetic gastroparesis symptoms. MNS was well tolerated and demonstrated a similar safety profile to placebo. ClinicalTrials.gov identifier: NCT02025725.

Gastroparesis-Related Symptoms in Patients With Type 2 Diabetes Mellitus: Early Detection, Risk Factors, and Prevalence.

Background The symptoms of gastroparesis, such as bloating, postprandial fullness, early satiety, nausea, and abdominal discomfort, progressively worsen the quality of life of the affected individuals. The diagnosis is established on the assessment of gastric function that confirms delayed gastric emptying in the absence of structural etiologies. This study aimed to detect gastroparesis-related clinical symptoms early in patients with type 2 diabetes mellitus (T2DM), investigate the concomitant risk factors, and evaluate the prevalence. Methodology This study was conducted at the Department of Medicine and Diabetes Outdoor Clinic of Sheikh Zayed Hospital, Rahim Yar Khan from February 13, 2022, to February 11, 2023. The study involved 175 patients with T2DM who reported gastroparesis-related symptoms. The demographic and clinical characteristics, symptom severity, complications, related risk factors, duration of disease, medications, body mass index (BMI), fasting plasma glucose, and glycated hemoglobin (HbA1C) levels were assessed. The severity of diabetic gastroparesis was established using the disease-specific Patient Assessment of Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM) and the Gastroparesis Cardinal Symptom Index (GCSI). The five-point scale of the PAGI-SYM and the four-degree severity scores of GCSI were assessed. Neuropathy disability scores and motor evacuation functions were analyzed. Data were analyzed from these questionnaires, special proforma, and patient interviews. Results The clinical features of diabetic gastroparesis were observed in 44% of T2DM patients with mild-grade gastroparesis in 38 (21.7%), moderate in 30 (17.1%), and severe-grade gastroparesis-related symptoms in nine (5.2%) patients. The main manifestations were early satiety (45.1%), stomach fullness (44.5%), bloating (38.3%), and nausea (33.1%). Diabetic gastroparesis symptoms were considerably linked to disease duration of more than 10 years (p = 0.02), high HbA1c (p = 0.001), increased fasting blood glucose (p = 0.003), polyneuropathy, cigarette smoking, and history of comorbid conditions (p = 0.009). Obesity and the female gender were the forecasters of the manifestation of at least one cardinal gastroparesis symptom. Conclusions Gastric emptying is significant in the pathogenesis of gastroparesis-related symptoms. Disease duration of more than 10 years, poor glycemic control with hyperglycemia, high HbA1C, polyneuropathy, and cigarette smoking must be considered as predictors for early detection and risk factors for the advancement of gastroparesis in T2DM. Gastroparesis-related common symptoms of early satiety, bloating, and stomach fullness were considerably linked to the additional risk factors of hypercholesteremia, chronic microvascular complications, concomitant cardiovascular diseases, and a positive family history of diabetes mellitus. There was no relationship between BMI, age, types of treatment, and the degree of gastroparesis severity. The prevalence and severity of gastroparesis symptoms were particularly high among obese females with poor glycemic control and longer disease duration.

Efficacy of prokinetic agents in diabetic gastroparesis comparing symptomatology and scintigraphy - An open-label trial.

It is pertinent to objectively assess the severity of diabetic gastroparesis and tailor treatment accordingly. The current study was planned to document gastroparesis by gastric emptying scintigraphy (GES) objectively and see the effect of medications and diet control on clinical and GES after four weeks. A prospective, open-label randomized trial was conducted in the Department of Internal Medicine at a tertiary care teaching hospital over twelve months. Type 2 diabetic patients aged 18-65 years diagnosed with a case of delayed gastric emptying by gastric scintigraphy were included. All baseline GSCI was recorded, and then they were allotted to 3 groups - Group-1 (Levosulpiride 25mg once daily), group-2 (Cinitapride 1mg thrice daily), and Group-3 (Waitlisted control) by block randomization and followed-up weekly till four weeks. After four weeks duration, if not improved clinically, then Group-3 on diet and diabetic control only, were randomized into Levosulpiride 25mg once daily (Group 1), and Cinitapride 1mg Thrice daily (Group 2) for the next four weeks. Forty confirmed cases with diabetic gastroparesis documented by Gastroparesis Symptom Cardinal Index (GCSI) scoring and later by Scintigraphy (GES) were included in this study. However, there was no statistically significant difference between the Levosulpiride and Cinitapride groups when all symptoms were taken into account. Levosulpiride was significantly more effective than Cinitapride in improving individual symptoms like nausea, vomiting, stomach fullness, and early satiety. Levosulpiride is better than Cinitapride in improving the symptoms of diabetic gastroparesis but no significant effect on gastric scintigraphy.

Diet consistency modification improves postprandial glycemic and gastroparesis symptoms.

Diabetic gastroparesis (DGP) is an autonomic neuropathy resulting from long-standing poorly controlled diabetes, and it is also linked to fluctuations in glycemic control due to variability on nutrient absorption. Considering the scarcity of information, the aim of this study was to identify the impact of modifications on diet consistency on post-prandial glucose variability using a continuous glucose monitoring (CGM) and its effect on the perception and severity of gastrointestinal symptoms. This proof-of-concept study was carried out in a cross-sectional cohort of six individuals with type 1 diabetes mellitus with confirmed diagnosis of DGP. Two types of diet were used to evaluate glycemic control and DGP symptoms, general consistency standard meal (SD) and modified consistency test diet (MD), associated with an application of rapid acting insulin at the time of food intake. Glycemic control was evaluated by CGM, and the Gastroparesis Cardinal Symptom Index (GCSI) was applied after meals. The CGM curve was different for MD + insulin and SD + insulin. There was a smaller increment of interstitial glucose with 2h after MD + insulin, returning almost to the basal level 4h later. Patients scored significantly lower GCSI after MD + insulin compared to the same index after they received SD + insulin. Moreover, there was a decrease in important clinical scores present in the index, like: "Not able to finish meal", "Loss of appetite" and "Stomach or belly feels larger". This study showed that a modified diet can improve postprandial glycemic excursion and the perception and severity of gastroparesis symptoms. The online version contains supplementary material available at 10.1007/s40200-022-01117-w.

Gastric function in diabetic gastroparesis assessed by ultrasound and scintigraphy

AbstractBackgroundGastroparesis is a severe diabetes complication characterized by delayed gastric emptying. We examined patients with symptoms of diabetic gastroparesis using gastric emptying scintigraphy and ultrasound drink test. The primary aim was to investigate how ultrasound could provide information about gastric motility features in diabetic gastroparesis.Material and methodsWe prospectively included 58 patients with diabetes (48 type 1) with symptoms of gastroparesis and 30 healthy controls. Patients were examined with ultrasound of the stomach in a seated position after drinking 500 ml low‐caloric meat soup, at the same time recording dyspeptic symptoms. The following day, they were examined with gastric emptying scintigraphy, defining gastroparesis as &gt;10% retention after 4 h.Key ResultsWe found motility disturbances in the proximal stomach measured by ultrasound in patients with diabetic gastroparesis. A linear mixed effects model including repeated ultrasound measurements revealed a slower decrease of the proximal stomach size in gastroparesis compared to healthy controls (p &lt; 0.01), and the proximal diameter at 20 min was correlated to scintigraphy at 4 h (r = 0.510, p = 0.001). The antrum in patients with diabetic gastroparesis was twice as large compared to healthy controls (p = 0.009), and fasting antral size was correlated to gastric emptying scintigraphy (r = 0.329, p = 0.013). Both diabetes patients with and without gastroparesis had impaired accommodation (p = 0.011).Conclusions and InferencesOn ultrasound, we found delayed reduction of proximal stomach size and impaired accommodation after a liquid meal in patients with gastroparesis, emphasizing the role of the proximal stomach. Furthermore, we found antral distention in gastroparesis patients.

MALAT1: A Pivotal lncRNA in the Phenotypic Switch of Gastric Smooth Muscle Cells via the Targeting of the miR-449a/DLL1 Axis in Diabetic Gastroparesis.

Diabetic gastroparesis (DGP) is a common complication of diabetes mellitus (DM). Our previous study suggested that the expression of the long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is closely related to DGP. However, the role of MALAT1 in DGP pathogenesis remains unclear. Here, we aim to characterize the role of MALAT1 in DGP. First, we analyzed the lncRNA expression profiles through lncRNA sequencing. Next, we detected MALAT1 expression in the stomach tissues of DGP model mice and diabetic patients. Then, we investigated the role and mechanisms of MALAT1 in the proliferation, migration, phenotypic switch, and carbachol-induced intracellular Ca2+ changes in human gastric smooth muscle cells (HGSMCs) under high glucose (HG) conditions, using short hairpin RNA technology, RNA immunoprecipitation, and dual-luciferase reporter assays. We show that MALAT1 expression was upregulated in the gastric tissues of DGP model mice, the adjacent healthy tissues collected from diabetic gastric cancer patients with DGP symptoms, and in HGSMCs cultured under HG conditions. Functionally, MALAT1 knockdown in vitro impacted the viability, proliferation, migration and promoted the phenotypic switch of HGSMCs under HG conditions. Additionally, we show that MALAT1 sponged miR-449a, regulating Delta-like ligand 1 (DLL1) expression in HGSMCs; any disturbance of the MALAT1/miR-449a/DLL1 pathway affects the proliferation, migration, phenotypic switch, and carbachol-induced Ca2+ transient signals in HGSMCs under HG conditions. Collectively, our data highlight a novel regulatory signaling pathway, the MALAT1/miR-449a/DLL1 axis, in the context of DGP.

415-P: Prevalence of Gastroparesis Symptoms in Diabetic Patients in the Western Region of Saudi Arabia, 2019

Gastroparesis is a well-established diabetes complication with conflicting data regarding its prevalence. Gastroparesis impacts quality of life, increases direct health-care costs and is associated with morbidity and mortality. Other possible consequences include erratic glycemic control, alteration in drug absorption and hypoglycemia. Objectives: To estimate the prevalence of diabetic gastroparesis symptoms in T2DM patients attending PHC centers and to determine the associated factors Methods: A cross sectional study which included a representative sample of patients attending PHC centers of the Ministry of National Guards Health Affairs, Western Region-Saudi Arabia. Simple random sampling technique was adopted to select the study population. Patient interviewing technique was adopted to fill the Arabic version of GSCI. Information on demographics and personal characteristics, diabetes duration, type of treatment and other variables were obtained. Results: The study involved 365 participants, 66.3% were females, 52.9% aged 40-59 years and 31.8% with disease duration 10-20 years. A GCSI with a score of ≥ 1.9 was used to diagnose gastroparesis symptoms. Prevalence of gastroparesis symptoms was 7.9%. The most frequent symptoms were bloating (34.8%) then stomach fullness (26.6%) and the least frequent was vomiting (4.1%). The most frequently used agent was metformin (84.9%). 47.1% of participants had HbA1C between (7-9%) and 37.9% of them have gastroparesis symptoms (p 0.318). 69% of participants with gastroparesis symptoms were using metformin (p 0.012). 10.3% of participants with gastroparesis symptoms were not using any diabetes medications (p 0.037). 25% of participants with CHD had gastroparesis symptoms (p 0.001). Conclusion: Up to our knowledge, this is the 1st local multi-city and primary care-based study. The prevalence of gastroparesis symptoms was 7.9%. Gastroparesis symptoms were significantly associated with the use of metformin, CHD and participants not on any medication. Disclosure A. A. Bukhari: None. M. M. Alsayari: None.

557-P: Gastric Electrical Neurostimulation Combined with Pyloroplasty for Refractory Diabetic Gastroparesis Improves Subjective and Objective Outcomes

Background: Gastric electrical stimulation (GES) improves symptoms in diabetic gastroparesis (DM GP) refractory to medical therapies but does not increase gastric emptying (GE). This study investigates the clinical outcomes of GES combined with pyloroplasty (PP) to improve GE as well as the pathophysiological characteristics of the responding patients. Methods: Overall 39 DM (13 type I) GP patients with 16.6 (range 3-50) years of DM had GES with PP. Antral and pyloric biopsies were assessed for interstitial cells of Cajal (ICC) status. Depletion of ICC was defined as &amp;lt;10 cells/HPF. GE scintigraphy (normal &amp;lt;60% retention at 2h or &amp;lt;10% at 4 h) was performed, and GP total symptoms score (TTS) of vomiting, nausea, early satiety, bloating, fullness and epigastric pain was assessed with a 5-point Likert scale pre and post-surgery. Results: The 39 patients, (23F) mean age 45 (25-83) years, mean 5.2 years of GP symptoms, were enrolled. TSS improvement after mean follow up of 17 (1-42) months post-surgery was 62% (19.1±3.4) vs.(7.6±6.2), while almost 70% of patients improved TTS by ≥60%. GE at 2h improved from 77% to 45%, and from 55% to 20% at 4h while 47% completely normalized their GE. Both DM1 and DM2 patients responded with improved TSS and GE. Antral ICC were depleted in 28% of DM GP with a mean number of 12 (±5.2)/HPF, while 70% of patients had &amp;lt;10 pyloric ICC with mean 7.4(±5.0)/HPF. Patients with &amp;lt;10 pyloric ICC had a 64% improvement in TSS vs. 41% if pyloric ICC was ≥10/HPF. Conclusion: DM GP patients treated by combining GES and PP show significant symptomatic improvement with accelerated and often normalized GE. Patients with depleted pyloric ICC were the most improved, emphasizing the key role of the pylorus in GP, and explains why adding PP to GES addresses the specific pathophysiological challenges in severe diabetic GP. Disclosure T. Bright: None. I. Sarosiek: None. A. Shanker: None. B.R. Davis: None. O. Padilla: None. J.R. Diaz: None. K. Espino: None. R.M. McCallum: None.

Diabetic gastroparesis: what can complementary and alternative medicines do?

Diabetic gastroparesis (DGP) is a complication of long-standing diabetes mellitus (DM) and a chronic motility disorder of the stomach. Up to 50% of patients with type 1 and 2 DM have the gastrointestinal manifestations, especially delayed gastric emptying (GE). And DM accounted for almost one-third of all cases of gastroparesis. The most common symptoms of DGP include postprandial fullness, early satiety, nausea, vomiting, bloating, and abdominal pain, which markedly lead to poor quality of life. Therapeutic strategies in western medicine for DGP involve dietary modification, the control of blood glucose, medications that stimulate gastric motor activity, anti-emetic and prokinetic drug therapy, and nonpharmacological measures. However, the limited effectiveness and the side effects of the strategies above mentioned may be restricted for their applications sometimes. Complementary and alternative therapy like Chinese herbs, acupuncture, moxibustion, and massage has been widely used for thousands of years and there are an increasing number of studies in DGP about them, suggesting that Chinese medicine could bring multiple benefits in the treatment of refractory nausea and vomiting and also help to alleviate abdominal distension with fewer side effects. Here, we focus on the general treatment strategies of complementary and alternative therapy, as discovered through PubMed and CNKI in English and Chinese publications, respectively.

Diabetic Gastroparesis: Perspectives From a Patient and Health Care Providers.

Gastroparesis is defined as a delay in gastric emptying in the absence of mechanical obstruction in the stomach. Gastroparesis has a number of causes, including postsurgical, secondary to medications, postinfectious, idiopathic, and as a complication of diabetes mellitus, where it is underrecognized. The cardinal symptoms of diabetic gastroparesis are nausea, early satiety, bloating, and vomiting. Diabetic gastroparesis is more common in females and has a cumulative incidence of 5% in type 1 diabetes and 1% in type 2 diabetes. It is associated with a reduction in quality of life and exerts a significant burden on health care resources. The pathophysiology of this disorder is incompletely understood. Diagnosis is made based on typical symptoms associated with the demonstration of delayed gastric emptying in the absence of gastric outlet obstruction. Gastric emptying scintigraphy is the gold standard for demonstrating delayed gastric emptying, but other methods exist including breath testing and the wireless motility capsule. Diabetic gastroparesis should be managed within a specialist multidisciplinary team, and general aspects involve dietary manipulations/nutritional support, pharmacological therapy, and surgical/endoscopic interventions. Specific pharmacological therapies include prokinetics and antiemetics, with several new medications in the drug development pipeline. Surgical/endoscopic interventions include botulinum toxin injection into the pylorus, gastric peroral endoscopic myotomy and gastric electrical stimulation. This article provides a detailed review and summary of the epidemiology, pathophysiology, investigation, and management of diabetic gastroparesis, and also gives an individual patient's perspective of living with this disabling disorder.

Therapeutic effect of a temporary transpyloric stent in refractory post-surgical gastroparesis: a case report

BackgroundGastroparesis is a syndrome characterized by delayed gastric emptying with associated symptoms. It was reported that the symptoms of diabetic gastroparesis had been greatly improved by transpyloric stent placement. However, the use of stents in benign conditions is considered to be contraindicated because of the increasing risk of complications, such as stent migration, reflux, perforation, bleeding, and, most importantly, new strictures caused by stent-induced tissue hyperplasia. While temporary placement of a self-expanding metallic stent (SEMC) can drastically reduce the risk of complications, few reports are available on the treatment of refractory PSG by temporary transpyloric stent. Does it have a long-term clinical effect after the stent being retrieved?Case presentationAfter accepting partial resection of the lesser curvature in another hospital, a patient developed refractory gastroparesis. The symptoms hadn’t been improved after long-term drug therapy and balloon dilation therapy. Four months after surgery, a fully covered SEMC was placed by endoscopy in our hospital. Gastroparesis had been greatly improved. Two weeks later, the transpyloric stent was retrieved and the patient didn’t show recurrent symptoms. Follow-ups were arranged at 3 months, 6 months and 1 year respectively, and there was no evidence of recurrence was found.ConclusionsThis case indicates that temporary transpyloric SEMC is a safe, effective and less invasive alternative for post-surgical gastroparesis patients.

Diabetic Gastroparesis: Principles and Current Trends in Management.

This article is a comprehensive review of diabetic gastroparesis, defined as delayed or disordered gastric emptying, including basic principles and current trends in management. This review includes sections on anatomy and physiology, diagnosis and differential diagnosis as well as management and current guidelines for treatment of diabetic gastroparesis. Diabetic gastroparesis (DGp) is a component of autonomic neuropathy resulting from long-standing poorly controlled type 1 and type 2 diabetes. The diagnostic workup of DGp first excludes obstruction and other causes including medications that may mimic delayed/disordered gastric emptying. Targeting nutrition, hydration, symptomatic relief and glycemic control are mainstays of treatment for DGp. Additionally, optimal treatment of DGp includes good glycemic management, often involving customizing insulin delivery using basal-bolus insulin and technology, including sensor-augmented pumps and continuous glucose monitoring systems. Prokinetic medications may be helpful in DGp symptoms, although only limited number of medications is currently available in the USA. Selected medication-refractory patients with DGp may benefit from gastric neuromodulation, and some from surgical interventions including pyloric therapies that can also be done endoscopically. As is true of any of the diabetic complications, prevention of DGp by early and optimal glycemic control is more cost-effective.Funding: Hansa Medcell, India.

Glucose sensor-augmented continuous subcutaneous insulin infusion in patients with diabetic gastroparesis: An open-label pilot prospective study

Erratic blood glucose levels can be a cause and consequence of delayed gastric emptying in patients with diabetes. It is unknown if better glycemic control increases risks of hypoglycemia or improves hemoglobin A1c levels and gastrointestinal symptoms in diabetic gastroparesis. This study investigated the safety and potential efficacy of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) in poorly controlled diabetes with gastroparesis. Forty-five type 1 or 2 patients with diabetes and gastroparesis and hemoglobin A1c >8% from the NIDDK Gastroparesis Consortium enrolled in a 24 week open-label pilot prospective study of CSII plus CGM. The primary safety outcome was combined numbers of mild, moderate, and severe hypoglycemic events at screening and 24 weeks treatment. Secondary outcomes included glycemic excursions on CGM, hemoglobin A1c, gastroparesis symptoms, quality-of-life, and liquid meal tolerance. Combined mild, moderate, and severe hypoglycemic events occurred similarly during the screening/run-in (1.9/week) versus treatment (2.2/week) phases with a relative risk of 1.18 (95% CI 0.85–1.64, P = 0.33). CGM time in hypoglycemia (<70 mg/dL) decreased from 3.9% to 1.8% (P<0.0001), time in euglycemia (70–180 mg/dL) increased from 44.0% to 52.0% (P = 0.02), time in severe hyperglycemia (>300 mg/dL) decreased from 14.2% to 7.0% (P = 0.005), and hemoglobin A1c decreased from 9.4±1.4% to 8.3±1.3% (P = 0.001) on CSII plus CGM. Symptom scores decreased from 29.3±7.1 to 21.9±10.2 with lower nausea/vomiting, fullness/early satiety, and bloating/distention scores (P≤0.001). Quality-of-life scores improved from 2.4±1.1 to 3.1±1.1 (P<0.0001) and volumes of liquid nutrient meals tolerated increased from 420±258 to 487±312 mL (P = 0.05) at 24 weeks. In conclusion, CSII plus CGM appeared to be safe with minimal risks of hypoglycemic events and associated improvements in glycemic control, gastroparesis symptoms, quality-of-life, and meal tolerance in patients with poorly controlled diabetes and gastroparesis. This study supports the safety, feasibility, and potential benefits of improving glycemic control in diabetic gastroparesis.

LncRNA MALAT1 is up-regulated in diabetic gastroparesis and involved in high-glucose-induced cellular processes in human gastric smooth muscle cells

Recent years, widespread long non-coding RNAs (lncRNAs) were identified and known as regulator of gene expression. Diabetic gastroparesis (DGP) is one of the most common chronic complications of diabetes mellitus. There was no research reported the role of lncRNAs in DGP. In this study, we firstly established a rat model of DGP by STZ injection. Then, we detected the expression of MALAT1 and found that expression of MALAT1 was up-regulated in rat model of DGP, comparing to the control group (P < .01). Furthermore, we revealed that MALAT1 expression was increased in the samples from diabetic patients with DGP symptoms, in comparison with the control. In addition, we demonstrated that the inhibition of MALAT1 increased the expression of α-SMA and SM myosin heavy chains, reduced the cell viability, inhibited the potential of cell migration and induced cell apoptosis in human gastric smooth muscle cells (SMCs). Ultimately, we found that the regulation of MALAT1 expression modulated the function of high-glucose stimulation in human gastric SMCs. Therefore, our study firstly indicated that MALAT1 was up-regulated in DGP and played an important role in the pathogenesis of DGP.

Higenamine inhibits apoptosis and maintains survival of gastric smooth muscle cells in diabetic gastroparesis rat model via activating the β2-AR/PI3K/AKT pathway

Diabetic gastroparesis (DGP) is a common complication of diabetes mellitus (DM). The numerous clinical symptoms of DGP and the great cost on the treatment of DGP seriously lowered the patients’ life quality. However, the pathogenic mechanism of DGP is still elusive till now. In this study, we aimed to explore the effect of higenamine on the proliferation and apoptosis of gastric smooth muscle cells (SMCs) in DGP rat model. The DGP rat model was built by intraperitoneal injection of Streptozotocin (STZ) into male Sprague-Dawley (SD) rats. Compared with the healthy control group, the level of DGP indicator c-kit was strongly suppressed and the level of Gsα was largely elevated in the STZ-induced model group. By contrast, the addition of higenamine obviously counteracted the effect of STZ on the expression of c-kit and Gsα. Besides that, higenamine improved the decreased emptying ability of the stomach. In addition, the number of gastric SMCs was strongly decreased and cell morphology became irregular in STZ-induced model group. The treatment of higenamine weakened the harm of STZ on the number and morphology of gastric SMCs. Beyond that, higenamine promoted gastric SMCs proliferation and inhibited gastric SMCs apoptosis in DGP model. Further research revealed that higenamine regulated cell proliferation and apoptosis via activating the β2-AR/PI3K/AKT pathway. Taken together, our research revealed that higenamine maintained the survival of gastric SMCs in DGP rat model via the β2-AR/PI3K/AKT pathway, providing a new sight for the treatment of DGP.

Relamorelin for the treatment of gastrointestinal motility disorders

ABSTRACTIntroduction: Current treatments for gastroparesis are limited. Chronic idiopathic constipation (CIC) has more treatment options, but none are efficacious for severe cases.Areas covered: Molecular targets to accelerate GI motility are being identified, and relamorelin, a synthetic ghrelin analog, has been promising. In humans, relamorelin increases growth hormone levels and accelerates gastric emptying. Relamorelin was superior to placebo for symptom relief in phase IIA studies for diabetic gastroparesis (DG) and CIC. In phase IIB studies in DG, relamorelin did not significantly reduce vomiting frequency when compared to placebo, but it reduced four symptoms of DG (nausea, fullness, bloating and abdominal pain) and accelerated gastric emptying. To date, relamorelin has been well tolerated and safe in humans without cardiac or neurologic adverse effects. It is still in clinical trial stages and not yet approved by the Food and Drug Administration. Phase III studies are underway.Expert opinion: Relamorelin shows promise in treating DG, with a reduction in core symptoms. Relative to available treatments, it appears to be efficacious and well tolerated. The absence of neurological or cardiovascular adverse effects places it at an advantage over other available therapies. Once approved, it will likely become the drug of first choice for DG.

The Association Between Fasting C-peptide and Gastrointestinal Symptoms of Gastroparesis in Type 2 Diabetic Patients.

Background/AimsThe relationship between C-peptide levels and gastrointestinal (GI) symptoms in type 2 diabetic patients is not clear. The purpose of this study is to examine the association between fasting C-peptide and GI symptoms of gastroparesis in type 2 diabetic patients.MethodsWe recruited 333 type 2 diabetic patients into the present study. All patients filled out questionnaires of gastroparesis cardinal symptom index (GCSI) to evaluate GI symptoms. Hospital anxiety and depression scale were adopted to define anxiety and depression. Patients with GCSI scores ≥ 1.9 were regarded as having symptoms of gastroparesis.ResultsIn our study, 71 (21.3%) type 2 diabetic patients had GCSI scores ≥ 1.9. In comparison to patients with scores < 1.9, those with scores ≥ 1.9 had significantly lower fasting c-peptide levels (1.49 ng/mL vs 1.94 ng/mL, P < 0.001), higher prevalence of depression (40.9% vs 18.3%, P < 0.001) and anxiety (28.2% vs 13.0%, P = 0.002). Multivariate logistic regression revealed that fasting C-peptide was still significantly associated with symptoms of gastroparesis (odds ratio, 0.67; 95% confidence intervals, 0.48–0.94; P = 0.021), even after adjustments for age, sex, body mass index, HbA1c, current smoking and drinking status, anxiety, and depression. Furthermore, linear regressions showed that fasting C-peptide was independently and negatively related to GCSI scores (standardized regression coefficient, −0.29; P < 0.001) in patients with at least one GI symptom.ConclusionGI symptoms of diabetic gastroparesis affect approximately 20% of type 2 diabetes patients and are associated with lower fasting C-peptide levels independent of depression and anxiety status.

Effects of hemin on heme oxygenase-1, gastric emptying, and symptoms in diabetic gastroparesis.

Therapeutic options for management of diabetic gastroparesis are limited. Failure to maintain upregulation of heme oxygenase (HO1) leads to loss of interstitial cells of Cajal and delayed gastric emptying (GE) in non-obese diabetic mice. Our hypothesis was that hemin upregulation of HO1 would restore normal GE in humans with gastroparesis. To compare effects of hemin and placebo infusions on HO1 activity and protein, GE, autonomic function, and gastrointestinal symptoms in diabetic gastroparesis. In a single-center, double-blind, placebo-controlled, randomized clinical trial, we compared intravenous hemin, prepared in albumin, or albumin alone (placebo) in 20 patients, aged 41 ± 5 (SEM) years with diabetic gastroparesis. After infusions on days 1, 3, and 7, weekly infusions were administered for 7 additional weeks. Assessments included blood tests for HO1 protein and enzyme activity levels, GE with 13 C-spirulina breath test, autonomic functions (baseline and end), and gastrointestinal symptoms every 2 weeks. Nine of 11 patients randomized to hemin completed all study procedures. Compared to placebo, hemin increased HO1 protein on days 3 (p = 0.0002) and 7 (p = 0.008) and HO1 activity on day 3 (p = 0.0003) but not after. Gastric emptying, autonomic functions, and symptoms did not differ significantly in the hemin group relative to placebo. Hemin failed to sustain increased HO1 levels beyond a week and did not improve GE or symptoms in diabetic gastroparesis. Further studies are necessary to ascertain whether more frequent hemin infusions or other drugs would have a more sustained effect on HO1 and improve GE.

Relamorelin Reduces Vomiting Frequency and Severity and Accelerates Gastric Emptying in Adults With Diabetic Gastroparesis

Gastroparesis is an important complication of diabetes. We investigated the effects of relamorelin (a pentapeptide-selective agonist of the ghrelin receptor that speeds gastric emptying in patients with diabetes) in patients with diabetic gastroparesis. We performed a double-blind trial of 204 patients (78% Caucasian; 67% female; mean age, 55 y; 88% with type 2 diabetes) with diabetic gastroparesis with moderate to severe symptoms and delayed gastric emptying at 27 clinical centers, from June 2012 until August 2013. Patients were assigned randomly (1:1:1) to groups given placebo or subcutaneous relamorelin 10 μg once or twice daily. The primary end point was the half-time of gastric emptying. Secondary end points included nausea, abdominal pain, bloating, early satiety, as well as the composite score of these 4 subjective symptoms and vomiting frequency and severity. Twice-daily relamorelin significantly accelerated gastric emptying (P < .03) and reduced vomiting frequency (by ∼60%) and severity vs placebo (P ≤ .033). Compared with placebo, relamorelin did not improve other gastrointestinal symptoms, such as abdominal pain and satiety. In the 119 patients (58.3%) with baseline vomiting, twice-daily relamorelin significantly reduced the half-time of gastric emptying and vomiting, as well as nausea, abdominal pain, bloating, and early satiety compared with placebo (composite score, P= .043). No overall safety concerns were identified. In a clinical trial of patients with diabetic gastroparesis, relamorelin (10 μg twice daily) significantly accelerated gastric emptying and significantly reduced vomiting, compared with placebo. Among patients with baseline vomiting, relamorelin had prokinetic effects and significantly reduced vomiting and also improved other symptoms of diabetic gastroparesis compared with placebo. ClincialTrials.gov number: NCT01571297.

Mo1586 Effects of Hemin on Heme Oxygenase-1, Gastric Emptying, and Symptoms in Diabetic Gastroparesis

Mo1586 Effects of Hemin on Heme Oxygenase-1, Gastric Emptying, and Symptoms in Diabetic Gastroparesis