Effect of DA-9701 on the Gastrointestinal Motility in the Streptozotocin-Induced Diabetic Mice

Background: Compared to the general population, diabetic patients experience more frequent episodes of gastrointestinal (GI) motility dysfunction, owing to the disruption of functional innervations. DA-9701 is a new prokinetic agent formulated from the extracts of Pharbitidis semen and Corydalis tuber. Aim: To investigate the effect of DA-9701 on GI motility in an animal model of streptozotocin (STZ)-induced diabetes. Methods: Diabetes was induced in mice by intraperitoneal injection of STZ (40 mg/kg of body weight in 0.1 M citrate buffer) for 3 days. Diabetic mice were divided into four groups and administered DA-9701 in different doses (1, 3, and 10 mg/kg) or placebo for 2 weeks. Intestinal transit was assessed using charcoal meal movement. GI isometric contraction was measured by applying an isometric force transducer on a circular muscle strip of the antrum, ileum, and proximal colon of sacrificed mice. Gastric emptying rate was evaluated by measuring the dye percentage remaining in the stomach relative to the total dye amount recovered in a standardization group of mice. Results: Body weight and antral and small intestinal motility were less in diabetic mice than in control mice, and colonic motility was similar in both. DA-9701 showed a dose-dependent increase in the amplitude of spontaneous phasic contractions in the antrum, ileum, and colon in diabetic mice without influencing body weight or blood glucose levels. The degree of improvement was comparable between diabetic and control mice. Intestinal transit was significantly more delayed in diabetic mice than in controls (43 ± 7% vs. 67 ± 8%, p < 0.05); however, DA-9701 restored the delayed intestinal transit more effectively compared to placebo (75% vs. 50%). The gastric emptying rate was significantly more delayed in diabetic mice than in controls (43 ± 10% vs. 62 ± 12%, p < 0.05), and was improved by DA-9701 in a dose-dependent manner (50%, 55%, and 60% in mice treated with 1, 3, and 10 mg/kg of DA-9701, respectively, vs. 43% in placebo-treated and 60% in control mice). Conclusions: DA-9701 improved GI contractility without affecting blood sugar and body weight in diabetic mice. DA-9701 could improve the decreased GI motility and clinical symptoms in progressive diabetic patients.

Disorders of Gastrointestinal Motility in Diabetes Mellitus: An Unattended Borderline Between Diabetologists and Gastroenterologists

Gastrointestinal (GI) symptoms represent an important and often poorly appreciated reason of morbidity in diabetes mellitus. Diabetes can affect nearly all parts of the GI tract; however, data on the prevalence of ‘diabetic gastroenteropathy’ are inconsistent. The significance of disturbed GI motility in diabetes across the patient spectrum and pathophysiological basis also remain inadequately defined. Fluctuating glucose levels, altered drug pharmacokinetics, variable absorption of nutrients, and impaired quality of life are important consequences of GI dysfunction. Diabetic gastroparesis is the best characterised manifestation of GI motility disorder in diabetes. Since there is a poor correlation between subjective GI symptoms and objective motility findings, a diagnosis of delayed emptying in diabetes requires a proper measurement of gastric emptying. There are fewer studies on intestinal motility in diabetes than those on the stomach. Several established modalities exist for the assessment of gastroenteropathy but the lack of standardisation, exposure to radiation, advanced data interpretation, and high cost limit their widespread use. While existing therapeutic choices for the management of diabetic gastroenteropathy are suboptimal, many potential novel agents are in progress. Both endocrinology and gastroenterology specialties working together will facilitate screening and treating patients with diabetes and GI dysmotility.

Motilin Comparative Study: Structure, Distribution, Receptors, and Gastrointestinal Motility

Motilin, produced in endocrine cells in the mucosa of the upper intestine, is an important regulator of gastrointestinal (GI) motility and mediates the phase III of interdigestive migrating motor complex (MMC) in the stomach of humans, dogs and house musk shrews through the specific motilin receptor (MLN-R). Motilin-induced MMC contributes to the maintenance of normal GI functions and transmits a hunger signal from the stomach to the brain. Motilin has been identified in various mammals, but the physiological roles of motilin in regulating GI motility in these mammals are well not understood due to inconsistencies between studies conducted on different species using a range of experimental conditions. Motilin orthologs have been identified in non-mammalian vertebrates, and the sequence of avian motilin is relatively close to that of mammals, but reptile, amphibian and fish motilins show distinctive different sequences. The MLN-R has also been identified in mammals and non-mammalian vertebrates, and can be divided into two main groups: mammal/bird/reptile/amphibian clade and fish clade. Almost 50 years have passed since discovery of motilin, here we reviewed the structure, distribution, receptor and the GI motility regulatory function of motilin in vertebrates from fish to mammals.

Prokinetics in the management of upper gastrointestinal motility disorders: an Indian expert opinion review

Functional gastrointestinal disorders (FGIDs) are disorders of gut-brain interaction. Nearly 40% of individuals globally suffer from FGIDs and have chronic fluctuating symptoms. Of all GI conditions, 30-45% are referable to intestinal motility disorders. Prokinetics act by different mechanisms and are effective in FGIDs with delayed gastric emptying or postprandial distress. When choosing a prokinetic, safety is the primary concern, particularly with regard to the central nervous system and cardiovascular risk. Here, we review the efficacy and safety of prokinetics in functional GI motility disorders and provide expert opinions for the use of prokinetics to manage upper GI motility disorders in the Indian context.

Novel Characterization of Constipation Phenotypes in ICR Mice Orally Administrated with Polystyrene Microplastics

Indirect evidence has determined the possibility that microplastics (MP) induce constipation, although direct scientific proof for constipation induction in animals remains unclear. To investigate whether oral administration of polystyrene (PS)-MP causes constipation, an alteration in the constipation parameters and mechanisms was analyzed in ICR mice, treated with 0.5 μm PS-MP for 2 weeks. Significant alterations in water consumption, stool weight, stool water contents, and stool morphology were detected in MP treated ICR mice, as compared to Vehicle treated group. Also, the gastrointestinal (GI) motility and intestinal length were decreased, while the histopathological structure and cytological structure of the mid colon were remarkably altered in treated mice. Mice exposed to MP also showed a significant decrease in the GI hormone concentration, muscarinic acetylcholine receptors (mAChRs) expression, and their downstream signaling pathway. Subsequent to MP treatment, concentrations of chloride ion and expressions of its channel (CFTR and CIC-2) were decreased, whereas expressions of aquaporin (AQP)3 and 8 for water transportation were downregulated by activation of the mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-κB signaling pathway. These results are the first to suggest that oral administration of PS-MP induces chronic constipation through the dysregulation of GI motility, mucin secretion, and chloride ion and water transportation in the mid colon.

Development of a Motility Frailty Index in Patients with Gastroparesis

Introduction: Patients with symptoms (Sx) of gastrointestinal (GI) motor disorders have limitations in physical strength and mobility. We hypothesized that physical frailty correlated with severity of GI symptoms, and that a motility frailty index (MFI) could be constructed. Patients: We conducted a prospective pilot study on 40 patients, (38 F, 2 M, mean age 39.9 years) with the following diagnoses: 10 with diabetes mellitus and 30 with non-diabetic/idiopathic disorders. Upper and lower GI Sx were quantified using an FDA-compliant, traditional patient-reported outcomes (PRO) system. Methods: Patients underwent a series of physical performance measures involving standing balance (SB), usual walk speed (UW), and chair sit-and-stands (CS). A GI motility frailty index (MFI) was constructed by fitting several models with a combination of physical performance measures and correlating with PRO. Pearson’s correlation compared the constructed index with the GI Sx PRO to construct a GI MFI. Results: The studied patients collectively showed marked limitations in mobility compared with standard performance values with mean (sd) ratios of SB = 0.87 (0.20), UW = 0.45 (0.13), and CS = 0.38 (0.17). Correlations between physical mobility and GI Sx were noted for upper GI Sx (rho = 0.47, p = 0.002) but not for lower GI Sx. Conclusions: In this pilot study of patients with GI motility disorders, we found increased physical limitations on performance-based testing, which had a statistically significant positive correlation with severity of upper GI motor Sx using a standardized PRO system. A motility frailty index has been constructed that may serve as a basis for better quantifying limitations in patient mobility.

Oral administration of polystyrene microplastics for 2 weeks induces chronic constipation in ICR mice

Objective: Indirect evidence has determined the possibility that microplastics (MP) induce constipation, although direct scientific proof for constipation induction in animals remains unclear. Thus, this study is aimed to investigate whether oral administration of polystyrene MP causes constipation.Methods: An alteration in the constipation parameters and their molecular mechanisms was analyzed in ICR mice treated with 0.5 μm polystyrene (PS)-MP for 2 weeks. Results: Significant alterations in water consumption, stool weight, stool water contents, and stool morphology were detected in MP treated ICR mice, as compared to Vehicle treated group. Also, the gastrointestinal (GI) motility and intestinal length were decreased, while the histopathological structure and cytological structure of the transverse colon were remarkably altered in treated mice. Mice exposed to MP also showed a significant decrease in the GI hormone concentration, muscarinic acetylcholine receptors (mAChRs) expression and their downstream signaling pathway, as well as mucin secretion and transcription of the MUC1, MUC2 and Klf4 genes. Subsequent to MP treatment, concentrations of chloride ion and expressions of its channel (CFTR and CIC-2) were decreased, whereas expressions of AQP3 and 8 for water transportation were downregulated by activation of the MAPK/NF-kB signaling pathway. These regulation on water and chloride transportation were verified in intestinal epithelioid cell line (IEC18) after MP treatment. Conclusion: These results are the first to suggest that oral administration of PS-MP induces chronic constipation through the dysregulation of GI motility, mucin secretion, and chloride ion and water transportation in the transverse colon.

Advances in colonic motor complexes in mice

The primary functions of the gastrointestinal (GI) tract are to absorb nutrients, water, and electrolytes that are essential for life. This is accompanied by the capability of the GI tract to mix ingested content to maximize absorption and effectively excrete waste material. There have been major advances in understanding intrinsic neural mechanisms involved in GI motility. This review highlights major advances over the past few decades in our understanding of colonic motor complexes (CMCs), the major intrinsic neural patterns that control GI motility. CMCs are generated by rhythmic coordinated firing of large populations of myenteric neurons. Initially, it was thought that serotonin release from the mucosa was required for CMC generation. However, careful experiments have now shown that neither the mucosa nor endogenous serotonin are required, although, evidence suggests enteroendocrine (EC) cells modulate CMCs. The frequency and extent of propagation of CMCs are highly dependent on mechanical stimuli (circumferential stretch). In summary, the isolated mouse colon emerges as a good model to investigate intrinsic mechanisms underlying colonic motility and provides an excellent preparation to explore potential therapeutic agents on colonic motility, in a highly controlled in vitro environment. In addition, during CMCs, the mouse colon facilitates investigations into the emergence of dynamic assemblies of extensive neural networks, applicable to the nervous system of different organisms.