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Ciftel E, Ciftel S, Ciftel S, Mercantepe F, Akdogan RA. Hemorrhoidal Disease in the Diabetic Population: The Effects of Glucose Regulation and Lipid Profile. Life (Basel) 2025; 15:178. [PMID: 40003587 PMCID: PMC11856592 DOI: 10.3390/life15020178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/18/2025] [Accepted: 01/22/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Hemorrhoidal disease is a common anorectal condition characterized by the enlargement and distal displacement of the typical vascular structures in the anal canal. The relationship between DM, lipid metabolism, and hemorrhoidal disease remains underexplored. This study aims to investigate the prevalence of hemorrhoids and the association between glycemic control and lipid profile in diabetic patients. METHODS This retrospective cross-sectional study included 752 patients who underwent colonoscopy at Erzurum Regional Training and Research Hospital between June 2021 and August 2024. The study population comprised 452 patients with type 2 diabetes mellitus (mean age 63.4 ± 11.0) and 300 nondiabetic patients (mean age 62.8 ± 10.8). The presence of hemorrhoids was confirmed through colonoscopy. Glycemic control parameters, lipid profile, and other biochemical parameters were analyzed. RESULTS Hemorrhoids were found in 47.3% (n = 214) of diabetic patients and 17.3% (n = 52) of nondiabetic patients, indicating a significantly higher prevalence in the diabetic group (OR = 4.3, CI = 3.0-6.2, p < 0.001). Diabetic patients with hemorrhoids had significantly higher mean HbA1C (8.1 ± 2.1 vs. 7.5 ± 1.8, p < 0.001), low-density lipoprotein (p < 0.001), and triglyceride levels (p = 0.005) compared to those without hemorrhoids. Additionally, a longer duration of diabetes and higher hypertension prevalence were observed in the hemorrhoid group. CONCLUSIONS The findings suggest that poor glycemic control and dyslipidemia are significantly associated with an increased prevalence of hemorrhoids in diabetic patients. These results highlight the importance of comprehensive management of diabetes, including lipid control, to potentially reduce the risk of hemorrhoidal disease.
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Affiliation(s)
- Enver Ciftel
- Department of Endocrinology and Metabolism, Sivas Numune Hospital, Sivas 58040, Türkiye;
| | - Sedat Ciftel
- Department of Gastroenterology and Hepatology, Erzurum Training and Research Hospital, Erzurum 5240, Türkiye;
| | - Serpil Ciftel
- Department of Endocrinology and Metabolism, Erzurum Training and Research Hospital, Erzurum 5240, Türkiye;
| | - Filiz Mercantepe
- Department of Endocrinology and Metabolism, Recep Tayyip Erdogan University, Rize 53100, Türkiye
| | - Remzi Adnan Akdogan
- Department of Gastroenterology and Hepatology, Recep Tayyip Erdogan University, Rize 53100, Türkiye
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Aldali JA, Asseri MK, Almufarrij HA, Alromih AM, Alajlan AM, Alrashed KA, ALghadeer AI, Almutawa BI, Alshalani A. Prevalence of Gastroparesis and the Impact of Metformin in Diabetic Patients: A Cross-Sectional Study in Riyadh, Saudi Arabia. Gastroenterol Res Pract 2024; 2024:3713569. [PMID: 39664090 PMCID: PMC11634406 DOI: 10.1155/grp/3713569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 10/08/2024] [Accepted: 11/08/2024] [Indexed: 12/13/2024] Open
Abstract
Background: The prevalence of gastroparesis in individuals with diabetes mellitus varies significantly across different studies. This study is aimed at estimating the prevalence of gastroparesis among diabetic patients in Riyadh, Saudi Arabia, and evaluating the association between metformin use and clinical manifestations of gastroparesis. Methods: This cross-sectional study employed an online survey distributed via Google Forms, targeting patients at a diabetes clinic. The survey comprised three sections, including the Gastroparesis Cardinal Symptom Index (GCSI). Eligible participants were those diagnosed with either type 1 or type 2 diabetes mellitus and aged 18 or older. Results: The study included 385 participants, with the majority diagnosed with type 2 diabetes (55.6%) for over 10 years (59.5%). A significant proportion had poorly controlled blood glucose levels (56.6%) and were taking metformin (50.9%). Among gastrointestinal (GI) symptoms, "stomach fullness" was reported most frequently (53.2%), whereas "vomiting" was reported least often (17.9%). GCSI scores did not differ significantly between type 1 and type 2 diabetes patients (p = 0.88). However, patients with diabetes durations of less than 3 years, those with durations of 5-7 years controlled blood glucose levels, and those on metformin exhibited higher GCSI scores (p = 0.20, p = 0.02, and p = 0.10, respectively). Conclusion: This study identified some commonalities as well as differences in the prevalence and symptomatology of gastroparesis among diabetic patients. We observed no significant variation in GCSI scores between type 1 and type 2 diabetes. Nevertheless, higher GCSI scores were associated with shorter diabetes durations, controlled blood glucose levels, and metformin use. However, due to the small sample size and reliance on self-reported data, one should interpret the study's findings with caution.
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Affiliation(s)
- Jehad A. Aldali
- Department of Pathology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13317, Saudi Arabia
| | - Mushabbab K. Asseri
- Department of Endocrine & Diabetes, Prince Sultan Medical Military City, Riyadh 11159, Saudi Arabia
| | - Haneen A. Almufarrij
- Medical School, College of Medicine, King Saud Bin Abdul Aziz University for Health Sciences (KSAU-HS), Riyadh 11481, Saudi Arabia
| | - Aroob M. Alromih
- Medical School, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13317, Saudi Arabia
| | - Albandari M. Alajlan
- Medical School, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13317, Saudi Arabia
| | - Khawlah A. Alrashed
- Medical School, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13317, Saudi Arabia
| | - Atheer I. ALghadeer
- Medical School, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13317, Saudi Arabia
| | - Bushra I. Almutawa
- Medical School, College of Medicine, King Saud Bin Abdul Aziz University for Health Sciences (KSAU-HS), Riyadh 11481, Saudi Arabia
| | - Abdulrahman Alshalani
- Chair of Medical and Molecular Genetics Research, Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
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Alshaikh AA, Alshehri AAA, Alshehri AZA, Alobaid AS, Mohammed AA, Saeed F Alshahrani T, Albarqi AZM, Sultan HSH, Alhussen M, Shehri ADA, Ghazy RM. Prevalence of gastrointestinal manifestations among diabetic patients in the Aseer region: A cross-sectional study. Medicine (Baltimore) 2024; 103:e39895. [PMID: 39331911 PMCID: PMC11441854 DOI: 10.1097/md.0000000000039895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 09/11/2024] [Indexed: 09/29/2024] Open
Abstract
Diabetes mellitus (DM) has a systemic consequence, influencing many systems of the body, including metabolic functions. This study aimed to determine the prevalence of gastrointestinal complications among patients with type 2 DM in the Asser region of Saudi Arabia, identify sources of information, and investigate the association of these symptoms with disease duration and glycated hemoglobin. This cross-sectional study was conducted between November 13 and December 27, 2023. The questionnaire collected demographic data including age, sex, education, employment, income, and nationality, and 16 questions (5 points for each symptom) about the frequency of gastrointestinal symptoms in the past 3 months. The total score was 80, participants were categorized based on their total scores into 2 groups: those scoring 40 or below, and those scoring above 40. A total of 230 patients were included in this study, their median age was 32.0 (24.00) years, 60% were men, 63.9% were married, 38.7% earned between 5000 and 10,000 Saudi Riyal/month, 85.2% did not work in the medical field, 39.1% held university degrees, 54.8% did not have health insurance, 70.4% did not smoke, 35.7% worked in government jobs, 63% lived in urban areas, 95.2% were Saudi and 53.5% had only DM. More than half of the respondents, 57.4%, relied on doctors for information about DM. Dysmotility symptoms were common: dyspepsia affected 26.5% often and 5.7% always; early satiety impacted 24.3% often and 5.2% always; and bloating affected 28.3% often and 10.9% always. Constipation/diarrhea were a common complaint, with 23.5% of patients experiencing them often and an additional 4.8% reporting it always. Stool consistency also varied widely, with 21.7% experiencing lumpy or hardened stool. Health insurance status and having chronic diseases showed significant association with the severity of symptoms. Duration of diabetes and glycated hemoglobin were associated with the frequency of the symptoms. Gastrointestinal symptoms are common among diabetic patients in Aseer. The frequency of symptoms is associated with glycemic control, duration of diabetes, and health insurance status. These findings highlight the need for improved management and support for better gastrointestinal health in diabetes.
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Affiliation(s)
- Ayoub Ali Alshaikh
- Family & Community Medicine Department, College of Medicine, King Khalid University, Abha, Saudia Arabia
| | | | | | | | | | | | | | | | - Mohammed Alhussen
- Medical Colleague, College of Medicine, King Khalid University, Abha, Saudia Arabia
| | | | - Ramy Mohamed Ghazy
- Family & Community Medicine Department, College of Medicine, King Khalid University, Abha, Saudia Arabia
- Tropical Health Department, High Institute of Public Health, Alexandria University, Alexandria, Egypt
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Santa Maria C, O'Dell K. Dysphagia as a Manifestation of Endocrine and Metabolic Disorders. Otolaryngol Clin North Am 2024; 57:657-668. [PMID: 38575488 DOI: 10.1016/j.otc.2024.02.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/06/2024]
Abstract
Dysphagia is a common manifestation of endocrine and metabolic diseases. Swallowing is a complex neuromuscular process, with an interplay of sensory and motor function, that has voluntary and involuntary control. Disruptions in any of these processes can cause significant dysphagia. Endocrine disorders and metabolic derangements are systemic conditions that affect multiple organ systems. They contribute to the development of neuropathies, myopathies, and motility disorders that lead to swallowing difficulty. Malnutrition and critical illness can lead to deconditioning and atrophy which can cause dysphagia, which in turn can lead to further malnutrition and deconditioning.
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Affiliation(s)
- Chloe Santa Maria
- Caruso Department of Otolaryngology Head & Neck Surgery, USC Voice Center, University of Southern California, 1537 Norfolk Street, Suite 5800, Los Angeles, CA 90033, USA
| | - Karla O'Dell
- Caruso Department of Otolaryngology Head & Neck Surgery, USC Voice Center, University of Southern California, 1537 Norfolk Street, Suite 5800, Los Angeles, CA 90033, USA.
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Komori S, Akiyama J, Tatsuno N, Yamada E, Izumi A, Hamada M, Seto K, Nishiie Y, Suzuki K, Hisada Y, Otake Y, Yanai Y, Okubo H, Watanabe K, Akazawa N, Yamamoto N, Tanaka Y, Yanase M, Saito A, Yamada K, Yokoi C, Nagahara A. Prevalence and Risk Factors of Constipation Symptoms among Patients Undergoing Colonoscopy: A Single-Center Cross-Sectional Study. Digestion 2024; 105:299-309. [PMID: 38754395 PMCID: PMC11318495 DOI: 10.1159/000539366] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Accepted: 05/12/2024] [Indexed: 05/18/2024]
Abstract
INTRODUCTION Constipation is one of the most common gastrointestinal symptoms. It may compromise quality of life and social functioning and result in increased healthcare use and costs. We aimed to evaluate the prevalence and risk factors of constipation symptoms, as well as those of refractory constipation symptoms among patients who underwent colonoscopy. METHODS Over 4.5 years, patients who underwent colonoscopy and completed questionnaires were analyzed. Patients' symptoms were evaluated using the Gastrointestinal Symptoms Rating Scale. RESULTS Among 8,621 eligible patients, the prevalence of constipation symptoms was 33.3%. Multivariate analysis revealed female sex (odds ratio [OR] 1.7, p < 0.001), older age (OR 1.3, p < 0.001), cerebral stroke with paralysis (OR 1.7, p = 0.009), chronic renal failure (OR 2.6, p < 0.001), ischemic heart disease (OR 1.3, p = 0.008), diabetes (OR 1.4, p < 0.001), chronic obstructive pulmonary disease (OR 1.5, p = 0.002), benzodiazepine use (OR 1.7, p < 0.001), antiparkinsonian medications use (OR 1.9, p = 0.030), and opioid use (OR 2.1, p = 0.002) as independent risk factors for constipation symptoms. The number of patients taking any medication for constipation was 1,134 (13.2%); however, refractory symptoms of constipation were still present in 61.4% of these patients. Diabetes (OR 1.5, p = 0.028) and irritable bowel syndrome (OR 3.1, p < 0.001) were identified as predictors for refractory constipation symptoms. CONCLUSIONS Constipation occurred in one-third of patients, and more than half of patients still exhibited refractory symptoms of constipation despite taking laxatives. Multiple medications and concurrent diseases seem to be associated with constipation symptoms.
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Affiliation(s)
- Shiori Komori
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
- Course of Advanced and Specialized Medicine, Juntendo University Graduate School of Medicine, TokyoJapan
| | - Junichi Akiyama
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Naoko Tatsuno
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Erika Yamada
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Atsuko Izumi
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Mariko Hamada
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kana Seto
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yuriko Nishiie
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Keigo Suzuki
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yuya Hisada
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yuki Otake
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yuka Yanai
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Hidetaka Okubo
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kazuhiro Watanabe
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Naoki Akazawa
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Natsuyo Yamamoto
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yasuo Tanaka
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Mikio Yanase
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Akiko Saito
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kazuhiko Yamada
- Course of Advanced and Specialized Medicine, Juntendo University Graduate School of Medicine, TokyoJapan
- Department of Esophageal Surgery, National Center for Global Health and Medicine, Tokyo, Japan
| | - Chizu Yokoi
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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Uppaluri S, Jain MA, Ali H, Shingala J, Amin D, Ajwani T, Fatima I, Patel N, Kaka N, Sethi Y, Kapoor N. Pathogenesis and management of diabetic gastroparesis: An updated clinically oriented review. Diabetes Metab Syndr 2024; 18:102994. [PMID: 38579489 DOI: 10.1016/j.dsx.2024.102994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 02/25/2024] [Accepted: 03/20/2024] [Indexed: 04/07/2024]
Abstract
BACKGROUND AND AIMS Diabetic gastroparesis (DGp) is a common and preventable complication of uncontrolled diabetes mellitus (D.M.) and significantly affects the Quality of Life of patients. Diagnosis and management present as a clinical challenge due to the disease's complexity and limited effective therapeutic options. This review aims to comprehensively outline the pathogenesis, diagnosis, and management of diabetic gastroparesis, evaluating evolving approaches to guide clinicians and provide future recommendations. METHODS A literature review was conducted on scholarly databases of PubMed, Google Scholar, Scopus and Web of Science encompassing published articles, gray literature and relevant clinical guidelines. Data were synthesized and analyzed to provide a comprehensive overview of diabetic gastroparesis, focusing on pathogenesis, diagnosis, and management. RESULTS The review intricately explores the pathogenesis contributing to diabetic gastroparesis, emphasizing autonomic neuropathy, oxidative stress, inflammation, hormonal dysregulation, microbiota alterations, and gastrointestinal neuropathy. Primary management strategies are underscored, including lifestyle modifications, symptom relief, and glycemic control. The discussion encompasses pharmacological and surgical options, highlighting the importance of a multidisciplinary approach involving various healthcare professionals for comprehensive patient care. CONCLUSION This review offers a thorough understanding of pathogenesis, diagnosis, and management of diabetic gastroparesis, underlining evolving approaches for clinicians. A multidisciplinary approach is crucial to address both the physical and mental health aspects of diabetes and its complications.
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Affiliation(s)
- Srikar Uppaluri
- Kamineni Academy of Medical Sciences and Research Center, Hyderabad, India; PearResearch, Dehradun, India.
| | - Manisha Ashok Jain
- PearResearch, Dehradun, India; Shri Bhausaheb Hire Govt. Medical College, Dhule, Maharashtra, India.
| | - Hira Ali
- PearResearch, Dehradun, India; Chifeng University Medical College, China.
| | - Jay Shingala
- PearResearch, Dehradun, India; B.J. Medical College, Ahmedabad, India.
| | - Dhruti Amin
- PearResearch, Dehradun, India; GMERS Medical College and Hospital, Gotri, Vadodara, India.
| | - Trisha Ajwani
- PearResearch, Dehradun, India; Baroda Medical College, Gujarat, India.
| | - Irum Fatima
- PearResearch, Dehradun, India; Osmania Medical College, Hyderabad, India.
| | - Neil Patel
- PearResearch, Dehradun, India; GMERS Medical College, Himmatnagar, Gujarat, India.
| | - Nirja Kaka
- PearResearch, Dehradun, India; GMERS Medical College, Himmatnagar, Gujarat, India.
| | - Yashendra Sethi
- PearResearch, Dehradun, India; Government Doon Medical College, Dehradun, India.
| | - Nitin Kapoor
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, India.
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Imai M, Hiramoto K, Tanaka S, Ooi K. Interactions between Age-Related Type 2 Diabetes and the Small Intestine. Biol Pharm Bull 2024; 47:791-795. [PMID: 38583950 DOI: 10.1248/bpb.b24-00065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
The number of patients with type 2 diabetes is increasing worldwide. The mechanisms leading to type 2 diabetes and its complications is being researched; however, the pathological mechanisms of diabetes in the small intestine remain unclear. Therefore, we examined these pathological mechanisms in the small intestine using a mouse model of type 2 diabetes (KK-Ay/TaJcl) aged 10 and 50 weeks. The results showed that diabetes worsened with age in the mice with type 2 diabetes. In these mice, advanced glycation end products (AGEs) in the small intestine and mast cell expression increased, whereas diamine oxidase (DAO) decreased; increased tumor necrosis factor (TNF)-α and histamine levels in the plasma and small intestine were also detected. Additionally, the expression of zonula occludens (ZO)-1 and Claudin1 and cell adhesion molecules in the small intestine reduced. These results exacerbated with age. These findings indicate that type 2 diabetes causes AGE/mast cell/histamine and TNF-α signal transmission in the small intestine and decreases small intestinal wall cell adhesion molecules cause TNF-α and histamine to flow into the body, worsening the diabetic condition. In addition, this sequence of events is suggested to be strengthened in aged mice with type 2 diabetes, thus exacerbating the disease. These findings of this study may facilitate the elucidation of the pathological mechanisms of type 2 diabetes and its associated complications.
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Affiliation(s)
- Masashi Imai
- Department of Pharmaceutical Sciences, Suzuka University of Medical Science
| | - Keiichi Hiramoto
- Department of Pharmaceutical Sciences, Suzuka University of Medical Science
| | - Shota Tanaka
- Department of Pharmaceutical Sciences, Suzuka University of Medical Science
| | - Kazuya Ooi
- Department of Pharmaceutical Sciences, Suzuka University of Medical Science
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Shah AA, Wigley FM. Overlooked Manifestations. SCLERODERMA 2024:587-611. [DOI: 10.1007/978-3-031-40658-4_38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Quan X, Chen W, Liang C, Jia Y, Wang Y, Luo H, Wang J. Downregulation of BDNF-TrkB signaling may contribute to the colonic motility disorders in mice with streptozocin-induced diabetes. Neurogastroenterol Motil 2023; 35:e14647. [PMID: 37417388 DOI: 10.1111/nmo.14647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 03/04/2023] [Accepted: 06/27/2023] [Indexed: 07/08/2023]
Abstract
BACKGROUND Brain-derived neurotrophic factor (BDNF) acts as a neuromodulator to regulate gut motility, but the role of BDNF in diabetes-related dysmotility is uncertain. The aim of this study was to investigate the possible involvement of BDNF and its receptor TrkB in the colonic hypomotility of mice with streptozotocin (STZ)-induced diabetes. METHODS A single intraperitoneal injection of STZ was used to establish a type 1 diabetes model. An organ bath system was applied to observe the contractile activities of colonic muscle strips. Immunofluorescence and western blotting were performed to evaluate the expression of BDNF and TrkB in the colon. ELISA was used to detect BDNF and SP levels in the serum and colon. The patch-clamp technique was applied to record the currents of L-type calcium channels and large conductance Ca2+ -activated K+ channels on smooth muscle cells. KEY RESULTS Compared with healthy controls, diabetic mice showed attenuated colonic muscle contraction (p < 0.001), which was partly reversed by BDNF supplementation. TrkB protein expression was significantly reduced in diabetic mice (p < 0.05). In addition, both BDNF and substance P (SP) levels were decreased, and exogenous administration of BDNF increased SP levels in diabetic mice (p < 0.05). Both the TrkB antagonist and the TrkB antibody inhibited the spontaneous contraction of colonic muscle strips (p < 0.01). Moreover, the BDNF-TrkB signaling system enhanced SP-induced muscle contraction. CONCLUSIONS Downregulation of BDNF/TrkB signaling and reduced SP release from the colon may contribute to the colonic hypomotility associated with type 1 diabetes. Brain-derived neurotrophic factor supplementation may have therapeutic potential for diabetes-related constipation.
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Affiliation(s)
- Xiaojing Quan
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wei Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chunni Liang
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yuan Jia
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yonghua Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Hesheng Luo
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jinhai Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Han Y, Srinivasan S, Yun CC. Inhibition of protein kinase C-α and activation of ezrin by Lactobacillus acidophilus restore Na +/H + exchange activity and fluid absorption in db/db mice. Am J Physiol Endocrinol Metab 2023; 325:E214-E226. [PMID: 37467022 PMCID: PMC10511175 DOI: 10.1152/ajpendo.00145.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/03/2023] [Accepted: 07/03/2023] [Indexed: 07/20/2023]
Abstract
Gastrointestinal (GI) complications, including diarrhea, constipation, and gastroparesis, are common in patients with diabetes. Dysregulation of the Na+/H+ exchanger NHE3 in the intestine is linked to diarrhea and constipation, and recent studies showed that NHE3 expression is reduced in type 1 diabetes and metformin causes diarrhea in the db/db mouse model of type 2 diabetes (T2D) via inhibition of NHE3. In this study, we investigated whether NHE3 expression is altered in type 2 diabetic intestine and the underlying mechanism that dysregulates NHE3. NHE3 expression in the brush border membrane (BBM) of the intestine of diabetic mice and humans was decreased. Protein kinase C (PKC) activation is associated with pathologies of diabetes, and immunofluorescence (IF) analysis revealed increased BBM PKCα abundance. Inhibition of PKCα increased NHE3 BBM abundance and NHE3-mediated intestinal fluid absorption in db/db mice. Previous studies have shown that Lactobacillus acidophilus (LA) stimulates intestinal ion transporters. LA increased NHE3 BBM expression and mitigated metformin-mediated inhibition of NHE3 in vitro and in vivo. To understand the underlying mechanism of LA-mediated stimulation of NHE3, we used Caco-2bbe cells overexpressing PKCα that mimic the elevated state of PKCα in T2D. LA diminished PKCα BBM expression, increased phosphorylation of ezrin, and the interaction of NHE3 with NHE regulatory factor 2 (NHERF2). In addition, inhibition of PKCι blocked phosphorylation of ezrin and activation of NHE3 by LA. These findings demonstrate that NHE3 is downregulated in T2D, and LA restores NHE3 expression via regulation of PKCα, PKCι, and ezrin.NEW & NOTEWORTHY We used mouse models of type 2 diabetes (T2D) and human patient-derived samples to show that Na+/H+ exchanger 3 (NHE3) expression is decreased in T2D. We show that protein kinase C-α (PKCα) is activated in diabetes and inhibition of PKCα increased NHE3 expression and mitigates diarrhea. We show that Lactobacillus acidophilus (LA) stimulates NHE3 via inhibition of PKCα and phosphorylation of ezrin.
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Affiliation(s)
- Yiran Han
- Gastroenterology Research, Atlanta Veterans Administration Medical Center, Decatur, Georgia, United States
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States
| | - Shanthi Srinivasan
- Gastroenterology Research, Atlanta Veterans Administration Medical Center, Decatur, Georgia, United States
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States
| | - C Chris Yun
- Gastroenterology Research, Atlanta Veterans Administration Medical Center, Decatur, Georgia, United States
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States
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Wei L, Ji L, Miao Y, Han X, Li Y, Wang Z, Fu J, Guo L, Su Y, Zhang Y. Constipation in DM are associated with both poor glycemic control and diabetic complications: Current status and future directions. Biomed Pharmacother 2023; 165:115202. [PMID: 37506579 DOI: 10.1016/j.biopha.2023.115202] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/15/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Constipation is a major complications of diabetes mellitus. With the accelerating prevalence of diabetes worldwide and an aging population, there is considerable research interest regarding the altered function and structure of the gastrointestinal tract in diabetic patients. Despite current advances in hyperglycemic treatment strategies, the specific pathogenesis of diabetic constipation remains unknown. Patients with constipation, may be reluctant to eat regularly, which may worsen glycemic control and thus worsen symptoms associated with underlying diabetic bowel disease. This paper presents a review of the complex relationship between diabetes and constipation, exploring the morphological alterations and biomechanical remodeling associated with intestinal motility dysfunction, as well as alterations in intestinal neurons, cellular signaling pathways, and oxidative stress. Further studies focusing on new targets that may play a role in the pathogenesis of diabetic constipation may, provide new ideas for the development of novel therapies to treat or even prevent diabetic constipation.
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Affiliation(s)
- Luge Wei
- Tianjin University of Traditional Chinese Medicine, China.
| | - Lanqi Ji
- Tianjin University of Traditional Chinese Medicine, China
| | - Yulu Miao
- Tianjin University of Traditional Chinese Medicine, China
| | - Xu Han
- Tianjin University of Traditional Chinese Medicine, China
| | - Ying Li
- Tianjin University of Traditional Chinese Medicine, China
| | - Zhe Wang
- Tianjin University of Traditional Chinese Medicine, China
| | - Jiafeng Fu
- Tianjin University of Traditional Chinese Medicine, China
| | - Liuli Guo
- Tianjin University of Traditional Chinese Medicine, China
| | - Yuanyuan Su
- Tianjin University of Traditional Chinese Medicine, China
| | - Yanjun Zhang
- Tianjin University of Traditional Chinese Medicine, China; First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, China
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12
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Silva-Reis R, Faustino-Rocha AI, Silva J, Valada A, Azevedo T, Anjos L, Gonçalves L, Pinto MDL, Ferreira R, Silva AMS, Cardoso SM, Oliveira PA. Studying and Analyzing Humane Endpoints in the Fructose-Fed and Streptozotocin-Injected Rat Model of Diabetes. Animals (Basel) 2023; 13:ani13081397. [PMID: 37106960 PMCID: PMC10135389 DOI: 10.3390/ani13081397] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/10/2023] [Accepted: 04/15/2023] [Indexed: 04/29/2023] Open
Abstract
This work aimed to define a humane endpoint scoring system able to objectively identify signs of animal suffering in a rat model of type 2 diabetes. Sprague-Dawley male rats were divided into control and induced group. The induced animals drink a 10% fructose solution for 14 days. Then, received an administration of streptozotocin (40 mg/kg). Animals' body weight, water and food consumption were recorded weekly. To evaluate animal welfare, a score sheet with 14 parameters was employed. Blood glucose levels were measured at three time points. After seven weeks of initiating the protocol, the rats were euthanized. The induced animals showed weight loss, polyuria, polyphagia, and polydipsia. According to our humane endpoints table, changes in animal welfare became noticeable after the STZ administration. None of the animals hit the critical score limit (four). Data showed that the most effective parameters to assess welfare in this type 2 diabetes rat induction model were dehydration, grooming, posture, abdominal visualization, and stool appearance. The glycemia was significantly higher in the induced group when compared to the controls (p < 0.01). Induced animals' murinometric and nutritional parameters were significantly lower than the controls (p < 0.01). Our findings suggest that in this rat model of type 2 diabetes with STZ-induced following fructose consumption, our list of humane endpoints is suitable for monitoring the animals' welfare.
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Affiliation(s)
- Rita Silva-Reis
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
- CITAB Inov4Agro-Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production, University of Trás-Os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
| | - Ana I Faustino-Rocha
- CITAB Inov4Agro-Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production, University of Trás-Os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Department of Zootechnics, School of Sciences and Technology, University of Évora, 7000-812 Évora, Portugal
- Comprehensive Health Research Center, 7000-812 Évora, Portugal
| | - Jéssica Silva
- CITAB Inov4Agro-Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production, University of Trás-Os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
| | - Abigaël Valada
- CITAB Inov4Agro-Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production, University of Trás-Os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
| | - Tiago Azevedo
- CITAB Inov4Agro-Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production, University of Trás-Os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
| | - Lara Anjos
- CITAB Inov4Agro-Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production, University of Trás-Os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
| | - Lio Gonçalves
- Engineering Department, University of Trás-Os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Institute for Systems and Computer Engineering, Technology and Science, 4200-465 Porto, Portugal
| | - Maria de Lurdes Pinto
- Animal and Veterinary Research Center (CECAV), University of Trás-Os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Department of Veterinary Sciences, University of Trás-Os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
| | - Rita Ferreira
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Artur M S Silva
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Susana M Cardoso
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Paula A Oliveira
- CITAB Inov4Agro-Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production, University of Trás-Os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Department of Veterinary Sciences, University of Trás-Os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
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Alibrahim NTY, Chasib MG, Hamadi SS, Mansour AA. Predictors of Metformin Side Effects in Patients with Newly Diagnosed Type 2 Diabetes Mellitus. IBNOSINA JOURNAL OF MEDICINE AND BIOMEDICAL SCIENCES 2023. [DOI: 10.1055/s-0043-1761215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
Abstract
Abstract
Introduction Metformin has become the first-line agent for the treatment of type 2 diabetes mellitus (T2DM) in several international guidelines. Up to 25% of patients suffer from gastrointestinal side-effects, with approximately 5% unable to tolerate metformin at all.
Objective We aimed to study the effect of variables that may influence the development of metformin side effects and/or intolerance.
Method A prospective study was conducted from April 1, 2021 to March 30, 2022. One-hundred and forty-eight patients newly diagnosed with T2DM were enrolled in the study, and divided into two groups—those who were escalate to the maximum dose of metformin over 2 weeks (n = 43) and the other group over 4 weeks (n = 105). We studied the variables that may affect the development of side effects including age, gender, body mass index (BMI), lipid profile, glycemic level, and the use of other antidiabetic medications besides the duration of dose escalation.
Results Total number of patients who developed side effects was 59 (39.9%). Twenty-four (55.8%) and 35 (33.3%) patients were put in the rapid and slow escalation groups, respectively. Twenty-six (17.6%) patients developed diarrhea that was the most common side effect. Two (2.7%) men and ten women (13.5%) had stopped metformin due to severe side effects developed after initiation (p = 0.016). The mean BMI for the patients who discontinued metformin was 34.7 ± 4.1 kg/m2 in the rapid escalation arm and 31.6 ± 3.3 kg/m2 in the slow escalation arm (p = 0.003). The mean of fasting blood glucose for the patients who discontinued metformin in the rapid and slow escalation arms was 200.6 ± 25.6 and 173.4 ± 36.5 mg/dL, respectively (p = 0.022).
Conclusion The severity of metformin side effects is higher in women than in men, making more women to discontinue the drug. Besides, a higher fasting blood sugar and BMI are associated with a higher rate of discontinuation. A rapid dose escalation is associated with a higher frequency of side effects. Diarrhea is the commonest side effect encountered.
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Affiliation(s)
| | - Mohammed Ghazi Chasib
- Faiha Specialized Diabetes, Endocrine and Metabolism Center, University of Basrah, Basrah, Iraq
| | | | - Abbas Ali Mansour
- Faiha Specialized Diabetes, Endocrine and Metabolism Center, University of Basrah, Basrah, Iraq
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14
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Quan X, Zhang J, Liu Y, Sun C, Luo H, Wang J. Role of Hydrogen Sulfide in the Development of Colonic Hypomotility in a Diabetic Mouse Model Induced by Streptozocin. J Pharmacol Exp Ther 2023; 384:287-295. [PMID: 36357158 DOI: 10.1124/jpet.122.001392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 10/05/2022] [Accepted: 11/01/2022] [Indexed: 11/12/2022] Open
Abstract
Hydrogen sulfide (H2S), a novel gasotransmitter, is involved in the regulation of gut motility. Alterations in the balance of H2S play an important role in the pathogenesis of diabetes. This study was conducted to investigate the role of H2S in the colonic hypomotility of mice with streptozotocin (STZ)-induced diabetes. A single intraperitoneal injection of STZ was used to induce the type 1 diabetes model. Male C57BL/6 mice were randomized into a control group and an STZ-treated group. Immunohistochemistry, Western blotting, H2S generation, organ bath studies and whole-cell patch clamp techniques were carried out in single smooth muscle cells (SMCs) of the colon. We found that STZ-induced diabetic mice showed decreased stool output, impaired colonic contractility, and increased endogenous generation of H2S (p < 0.05). H2S-producing enzymes were upregulated in the colon tissues of diabetic mice (p < 0.05). The exogenous H2S donor sodium hydrosulfide (NaHS) elicited a biphasic action on colonic muscle contraction with excitation at lower concentrations and inhibition at higher concentrations. NaHS (0.1 mM) increased the currents of voltage-dependent calcium channels (VDCCs), while NaHS at 0.5 mM and 1.5 mM induced inhibition. Furthermore, NaHS reduced the currents of both voltage-dependent potassium (KV) channels and large conductance calcium-activated potassium (BK) channels in a dose-dependent manner. These results show that spontaneous contraction of colonic muscle strips from diabetic mice induced by STZ was significantly decreased, which may underlie the constipation associated with diabetes mellitus (DM). H2S overproduction with subsequent suppression of muscle contraction via VDCCs on SMCs may contribute in part to the pathogenesis of colonic hypomotility in DM. SIGNIFICANCE STATEMENT: Hydrogen sulfide may exhibit a biphasic effect on colonic motility in mice by regulating the activities of voltage-dependent calcium channels and voltage-dependent and large conductance calcium activated potassium channels. H2S overproduction with subsequent suppression of muscle contraction via VDCCs may contribute to the pathogenesis of colonic hypomotility in diabetes mellitus.
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Affiliation(s)
- Xiaojing Quan
- Department of Gastroenterology (X.Q., Y.L., C.S., J.W.) and Department of Endocrinology and Metabolic Diseases (J.Z.), the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; and Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China (H.L.)
| | - Jie Zhang
- Department of Gastroenterology (X.Q., Y.L., C.S., J.W.) and Department of Endocrinology and Metabolic Diseases (J.Z.), the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; and Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China (H.L.)
| | - Yanli Liu
- Department of Gastroenterology (X.Q., Y.L., C.S., J.W.) and Department of Endocrinology and Metabolic Diseases (J.Z.), the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; and Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China (H.L.)
| | - Ceng Sun
- Department of Gastroenterology (X.Q., Y.L., C.S., J.W.) and Department of Endocrinology and Metabolic Diseases (J.Z.), the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; and Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China (H.L.)
| | - Hesheng Luo
- Department of Gastroenterology (X.Q., Y.L., C.S., J.W.) and Department of Endocrinology and Metabolic Diseases (J.Z.), the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; and Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China (H.L.)
| | - Jinhai Wang
- Department of Gastroenterology (X.Q., Y.L., C.S., J.W.) and Department of Endocrinology and Metabolic Diseases (J.Z.), the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; and Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China (H.L.)
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15
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Kokabi F, Ebrahimi S, Mirzavi F, Ghiasi Nooghabi N, Hashemi SF, Hashemy SI. The neuropeptide substance P/neurokinin-1 receptor system and diabetes: From mechanism to therapy. Biofactors 2023. [PMID: 36651605 DOI: 10.1002/biof.1935] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 12/22/2022] [Indexed: 01/19/2023]
Abstract
Diabetes is a significant public health issue known as the world's fastest-growing disease condition. It is characterized by persistent hyperglycemia and subsequent chronic complications leading to organ dysfunction and, ultimately, the failure of target organs. Substance P (SP) is an undecapeptide that belongs to the family of tachykinin (TK) peptides. The SP-mediated activation of the neurokinin 1 receptor (NK1R) regulates many pathophysiological processes in the body. There is also a relation between the SP/NK1R system and diabetic processes. Importantly, deregulated expression of SP has been reported in diabetes and diabetes-associated chronic complications. SP can induce both diabetogenic and antidiabetogenic effects and thus affect the pathology of diabetes destructively or protectively. Here, we review the current knowledge of the functional relevance of the SP/NK1R system in diabetes pathogenesis and its exploitation for diabetes therapy. A comprehensive understanding of the role of the SP/NK1R system in diabetes is expected to shed further light on developing new therapeutic possibilities for diabetes and its associated chronic conditions.
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Affiliation(s)
- Fariba Kokabi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Safieh Ebrahimi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farshad Mirzavi
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | | | | | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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16
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Drewes AM, Brock C, Drewes AM. Autonomic Visceral Neuropathy and Gastrointestinal Disorders. THE DIABETES TEXTBOOK 2023:967-978. [DOI: 10.1007/978-3-031-25519-9_58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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17
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Shi CJ, Lian JJ, Zhang BW, Cha JX, Hua QH, Pi XP, Hou YJ, Xie X, Zhang R. TGFβR-1/ALK5 inhibitor RepSox induces enteric glia-to-neuron transition and influences gastrointestinal mobility in adult mice. Acta Pharmacol Sin 2023; 44:92-104. [PMID: 35794374 DOI: 10.1038/s41401-022-00932-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 05/30/2022] [Indexed: 01/18/2023]
Abstract
Promoting adult neurogenesis in the enteric nervous system (ENS) may be a potential therapeutic approach to cure enteric neuropathies. Enteric glial cells (EGCs) are the most abundant glial cells in the ENS. Accumulating evidence suggests that EGCs can be a complementary source to supply new neurons during adult neurogenesis in the ENS. In the brain, astrocytes have been intensively studied for their neuronal conversion properties, and small molecules have been successfully used to induce the astrocyte-to-neuron transition. However, research on glia-to-neuron conversion in the ENS is still lacking. In this study, we used GFAP-Cre:Rosa-tdTomato mice to trace glia-to-neuron transdifferentiation in the ENS in vivo and in vitro. We showed that GFAP promoter-driven tdTomato exclusively labelled EGCs and was a suitable marker to trace EGCs and their progeny cells in the ENS of adult mice. Interestingly, we discovered that RepSox or other ALK5 inhibitors alone induced efficient transdifferentiation of EGCs into neurons in vitro. Knockdown of ALK5 further confirmed that the TGFβR-1/ALK5 signalling pathway played an essential role in the transition of EGCs to neurons. RepSox-induced neurons were Calbindin- and nNOS-positive and displayed typical neuronal electrophysiological properties. Finally, we showed that administration of RepSox (3, 10 mg· kg-1 ·d-1, i.g.) for 2 weeks significantly promoted the conversion of EGCs to neurons in the ENS and influenced gastrointestinal motility in adult mice. This study provides a method for efficiently converting adult mouse EGCs into neurons by small-molecule compounds, which might be a promising therapeutic strategy for gastrointestinal neuropathy.
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Affiliation(s)
- Chang-Jie Shi
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Jun-Jiang Lian
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Bo-Wen Zhang
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Jia-Xue Cha
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Qiu-Hong Hua
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Xiao-Ping Pi
- CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yu-Jun Hou
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Xin Xie
- CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Ru Zhang
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
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Tao Y, Li C, Gao T, Huo J. Molecular mechanism of Sishen pills in the treatment of diarrheal diabetic enteropathy based on network pharmacology. Medicine (Baltimore) 2022; 101:e30096. [PMID: 36107605 PMCID: PMC9439763 DOI: 10.1097/md.0000000000030096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
This study aimed to explore the effectiveness and safety of Sishen pills for the treatment of diarrheal diabetic enteropathy (DDE). The Traditional Chinese Medicine (TCM) Systems Pharmacology and BATMAN-TCM databases were used to determine the chemical composition of Sishen pills and thus predict information on protein targets. We searched for potential targets of DDE in the GeneCards, DrugBank, Therapeutic Target (TTD), and DisGeNET databases. Using the intersection of the drug and disease targets, protein-protein interaction (PPI) networks and molecular interaction modules were constructed, and key targets were screened. The intersecting gene targets were imported into the Metascape database to conduct Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The core targets and active ingredients were then docked at the molecular level. Sishen pills contain 70 active ingredients, 463 targets, and 566 disease targets. A module analysis of the targets revealed that the module was mainly related to adrenergic receptor activity, the adenosine phosphate kinase signaling pathway, and the G protein-coupled receptor signaling pathway. The GO and KEGG pathway enrichment results indicated that the protein genes regulated by Sishen pills were mainly enriched in the response to lipopolysaccharides, the AMPK signaling pathway, the JAK-STAT signaling pathway, and other signaling pathways. The molecular docking results showed that the core active compounds exhibited good binding activity with the predicted targets. Sishen pills can regulate the immune function of the body through anti-inflammatory and antibacterial effects for the treatment of DDE.
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Affiliation(s)
- Yunxia Tao
- Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning Province, China
| | - Chongchai Li
- Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning Province, China
| | - Tianshu Gao
- Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning Province, China
| | - Jingjing Huo
- Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning Province, China
- *Correspondence: Jingjing Huo, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, No. 33, Beiling Street, Huanggu District, Shenyang City 110033, Liaoning Province, China (e-mail: )
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Sang M, Wu T, Zhou X, Horowitz M, Jones KL, Qiu S, Guo H, Wang B, Wang D, Rayner CK, Sun Z. Prevalence of Gastrointestinal Symptoms in Chinese Community-Dwelling Adults with and without Diabetes. Nutrients 2022; 14:3506. [PMID: 36079764 PMCID: PMC9459935 DOI: 10.3390/nu14173506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/19/2022] [Accepted: 08/23/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Gastrointestinal symptoms have been reported to occur frequently in diabetes, but their prevalence in Chinese community-dwelling individuals with diabetes is unknown. The present study aimed to address this issue and explore the risk factors for gastrointestinal symptoms. METHODS A total of 1304 community-dwelling participants (214 with diabetes, 360 with prediabetes and 730 with normoglycemia) were surveyed for gastrointestinal symptoms using the Diabetes Bowel Symptom Questionnaire. Logistic regression analyses were applied to identify risk factors for gastrointestinal symptoms. RESULTS Of the overall study population, 18.6% reported at least one gastrointestinal symptom, without a significant difference between subjects with normoglycemia (17.7%), prediabetes (19.7%) and diabetes (20.1%). In all three groups, lower gastrointestinal symptoms, particularly diarrhea and constipation, were the most frequent. There was an interaction between age (≥65 years) and diabetes on the prevalence of at least one gastrointestinal symptom (p = 0.01) and of constipation (p = 0.004), with these being most frequent in subjects with diabetes aged ≥ 65 years. After multivariable adjustment, female gender and older age were associated with increased odds of at least one gastrointestinal symptom, specifically lower gastrointestinal symptoms. Older age was also associated with an increase in upper gastrointestinal symptoms. CONCLUSIONS Gastrointestinal symptoms are common in Chinese community-dwelling adults with and without diabetes. Females, and the elderly with diabetes, are at an increased risk of symptoms.
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Affiliation(s)
- Miaomiao Sang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing 210009, China
| | - Tongzhi Wu
- Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA 5000, Australia
| | - Xiaoying Zhou
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing 210009, China
| | - Michael Horowitz
- Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA 5000, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA 5000, Australia
| | - Karen L. Jones
- Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA 5000, Australia
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA 5000, Australia
| | - Shanhu Qiu
- Department of General Practice, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing 210009, China
| | - Haijian Guo
- Department of Integrated Services, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210009, China
| | - Bei Wang
- Key Laboratory of Environmental Medicine and Engineering Ministry of Education, Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing 210009, China
| | - Donglei Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing 210009, China
| | - Christopher K. Rayner
- Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA 5000, Australia
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia
| | - Zilin Sun
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing 210009, China
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Hishida Y, Nagai Y, Tsukiyama H, Nakamura Y, Nakagawa T, Ishizaki S, Tanaka Y, Sone M. Effects of Elobixibat in Patients with Diabetes and Concomitant Chronic Constipation: an 8-week, Prospective, Single-center, Single-arm Study. Adv Ther 2022; 39:4205-4217. [PMID: 35867276 PMCID: PMC9402500 DOI: 10.1007/s12325-022-02243-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 06/23/2022] [Indexed: 11/01/2022]
Abstract
AIMS To evaluate the efficacy and safety of elobixibat in patients with diabetes and concomitant chronic constipation. METHODS This was a single-center, single-arm study. Thirty-three patients with diabetes and chronic constipation, as defined by the Rome IV criteria, were treated with elobixibat (10 mg/day) for 8 weeks. Patients recorded stool properties, including spontaneous bowel movements (SBMs) and stool consistency, according to the Bristol Stool Form Scale (BSFS). Quality of life for constipation was evaluated with the Japanese version of the Patient Assessment of Constipation Quality of Life (JPAC-QOL). RESULTS Of the 33 eligible patients, 30 completed the study. Elobixibat significantly increased the median (interquartile range) frequency of SBMs per week, from 5.0 (3.0-7.0) at baseline to 6.0 (4.0-7.0] at week 8 (p = 0.030). After 8 weeks, the BSFS score approached 4; the score for normal stool consistency and the JPAC-QOL score significantly improved from 1.05 ± 0.40 at baseline to 0.94 ± 0.53 (p = 0.048); and glycated albumin and serum lipid profiles significantly improved. Stratified analysis revealed that SBMs increased especially in patients with low SBM frequency, in particular in women, older adults, patients without overweight, patients with a long duration of constipation, and patients with diabetic neuropathy. No serious adverse events occurred. CONCLUSIONS Among patients with diabetes who met the Rome IV criteria for constipation, elobixibat was effective, especially in those with few SBMs at baseline. Improvements in lipid profiles could be an advantage of elobixibat compared with other laxatives. CLINICAL TRIAL REGISTRY Japan Registry of Clinical Trials registration number: jRCTs031190092.
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Affiliation(s)
- Yoshiaki Hishida
- Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan
| | - Yoshio Nagai
- Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan. .,Department of Diabetes and Endocrinology, Kanto Rosai Hospital, 1-1, Kizukisumiyoshi, Nakahara, Kawasaki, Kanagawa, 211-8510, Japan.
| | - Hidekazu Tsukiyama
- Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan
| | - Yuta Nakamura
- Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan
| | - Tomoko Nakagawa
- Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan
| | - Sonoko Ishizaki
- Medical Department, EA Pharma Co., Ltd., 2-1-1, Irifune, Chuo-Ku, Tokyo, 104-0042, Japan
| | - Yasushi Tanaka
- Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan.,Diabetes Center, Yokohama General Hospital, 2201-5, Kuroganechou, Aoba-ku, Yokohama, Kanagawa, 225-0025, Japan
| | - Masakatsu Sone
- Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan
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21
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Han Y, Yun CC. Metformin Inhibits Na +/H + Exchanger NHE3 Resulting in Intestinal Water Loss. Front Physiol 2022; 13:867244. [PMID: 35444557 PMCID: PMC9014215 DOI: 10.3389/fphys.2022.867244] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/07/2022] [Indexed: 11/14/2022] Open
Abstract
Glycemic control is the key to the management of type 2 diabetes. Metformin is an effective, widely used drug for controlling plasma glucose levels in diabetes, but it is often the culprit of gastrointestinal adverse effects such as abdominal pain, nausea, indigestion, vomiting, and diarrhea. Diarrhea is a complex disease and altered intestinal transport of electrolytes and fluid is a common cause of diarrhea. Na+/H+ exchanger 3 (NHE3, SLC9A3) is the major Na+ absorptive mechanism in the intestine and our previous study has demonstrated that decreased NHE3 contributes to diarrhea associated with type 1 diabetes. The goal of this study is to investigate whether metformin regulates NHE3 and inhibition of NHE3 contributes to metformin-induced diarrhea. We first determined whether metformin alters intestinal water loss, the hallmark of diarrhea, in type 2 diabetic db/db mice. We found that metformin decreased intestinal water absorption mediated by NHE3. Metformin increased fecal water content although mice did not develop watery diarrhea. To determine the mechanism of metformin-mediated regulation of NHE3, we used intestinal epithelial cells. Metformin inhibited NHE3 activity and the effect of metformin on NHE3 was mimicked by a 5'-AMP-activated protein kinase (AMPK) activator and blocked by pharmacological inhibition of AMPK. Metformin increased phosphorylation and ubiquitination of NHE3, resulting in retrieval of NHE3 from the plasma membrane. Previous studies have demonstrated the role of neural precursor cell expressed, developmentally down-regulated 4-2 (Nedd4-2) in regulation of human NHE3. Silencing of Nedd4-2 mitigated NHE3 inhibition and ubiquitination by metformin. Our findings suggest that metformin-induced diarrhea in type 2 diabetes is in part caused by reduced Na+ and water absorption that is associated with NHE3 inhibition, probably by AMPK.
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Affiliation(s)
- Yiran Han
- Gastroenterology Research, Atlanta Veterans Administration Medical Center, Decatur, GA, United States
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
| | - C. Chris Yun
- Gastroenterology Research, Atlanta Veterans Administration Medical Center, Decatur, GA, United States
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, United States
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22
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Wegeberg AM, Bertoli D, Ejskjaer N, Brock B, Drewes AM, Brock C. Gastrointestinal function in diabetes is affected regardless of asymptomatic appearance. J Intern Med 2022; 291:505-512. [PMID: 34839554 DOI: 10.1111/joim.13416] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Gastrointestinal dysmotility may exist without concomitant symptoms. We hypothesize that asymptomatic individuals with diabetes have altered gastrointestinal function associated with age, cardiac vagal tone and glycaemic control. METHODS One hundred fifty-four asymptomatic participants (61 with type 1 diabetes (T1D), 70 type 2 diabetes (T2D) and 23 healthy volunteers (HV)) underwent wireless motility capsule investigation. Transit times, motility indices and pH were retrieved. Age, cardiac vagal tone, glucose and haemoglobin A1c levels were collected. RESULTS In T1D, prolongation of colonic (p = 0.03) and whole-gut transit times (p = 0.04) were shown. Transpyloric pH rise was decreased in T1D (p = 0.001) and T2D (p = 0.007) and was associated with cardiac vagal tone (p = 0.03) or glucose (p = 0.04) and haemoglobin A1c (p = 0.005). Ileocaecal pH fall was decreased in T2D (p < 0.001). CONCLUSIONS Gastrointestinal function was altered in asymptomatic individuals with diabetes. These findings call for further investigations of gastrointestinal function in order to identify risk factors or even predictors for diabetic enteropathy, particularly when glycaemic control is impaired.
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Affiliation(s)
- Anne-Marie Wegeberg
- Mech-Sense, Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark
| | - Davide Bertoli
- Mech-Sense, Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark
| | - Niels Ejskjaer
- Steno Diabetes Center North Denmark, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | | | - Asbjørn Mohr Drewes
- Mech-Sense, Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark.,Steno Diabetes Center North Denmark, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Christina Brock
- Mech-Sense, Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark.,Steno Diabetes Center North Denmark, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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23
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Kazeminia M, Salari N, Shohaimi S, Akbari H, Mohammadi M. Prevalence of gastrointestinal complications in patients with type 2 diabetes mellitus in Iran: a systematic review and meta-analysis. J Diabetes Metab Disord 2022; 21:1029-1036. [PMID: 35673410 PMCID: PMC9167313 DOI: 10.1007/s40200-022-00974-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 01/03/2022] [Indexed: 01/16/2023]
Abstract
Background Type 2 diabetes is the most common diabetes in the world and constitutes a high percentage of diabetes cases. This study aims to determine the overall prevalence of gastrointestinal complaints in Iranian patients with type 2 diabetes. Methods The articles were extracted based on entry and exit criteria by searching the Cochrane (Embase), ScienceDirect databases. Scopus PubMed; And Web of Science (WoS), based on PRISMA 2009. To evaluate the studies, a 22-item STROBE checklist was selected and related items were used. Results The probability of publication bias in reporting the results was examined by the Egger test (P = 0.891). The prevalence rate of gastrointestinal complaints in patients with type 2 diabetes in Iran in 10 studies was 52.3% (95% CI: 33.4-70.7%). The results of metargression showed a significant difference between the sample size and the prevalence of gastrointestinal complaints in patients with type 2 diabetes (P < 0.05). and the prevalence of gastrointestinal complaints in patients with type 2 diabetes. Conclusion The results of this study report that, the prevalence of gastrointestinal complications in type 2 diabetes patients was high. As a result, appropriate measures should be taken to improve the condition of diabetic patients through appropriate policy-making and providing feedback to hospitals and patients.
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Affiliation(s)
- Mohsen Kazeminia
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Nader Salari
- Department of Biostatistics, School of Health, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shamarina Shohaimi
- Department of Biology, Faculty of Science, University Putra Malaysia, Serdang, Selangor Malaysia
| | - Hakimeh Akbari
- Cellular and Molecular Research Center, Gerash University of Medical Sciences, Gerash, Iran
| | - Masoud Mohammadi
- Cellular and Molecular Research Center, Gerash University of Medical Sciences, Gerash, Iran
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24
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Ismail MK, Shrestha S. Gastrointestinal Complications of Neuromuscular Disorders. Neuromuscul Disord 2022. [DOI: 10.1016/b978-0-323-71317-7.00004-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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25
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Ito H, Ito K, Tanaka M, Hokamura M, Tanaka M, Kusano E, Kondo J, Izutsu T, Matsumoto S, Inoue H, Antoku S, Yamasaki T, Mori T, Togane M. Constipation Is a Frequent Problem Associated with Vascular Complications in Patients with Type 2 Diabetes: A Cross-sectional Study. Intern Med 2022; 61:1309-1317. [PMID: 35491175 PMCID: PMC9152859 DOI: 10.2169/internalmedicine.7676-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Objective Diabetes is recognized as an underlying disease of constipation. However, the prevalence of constipation varies according to the diagnostic criteria applied. We investigated the prevalence of constipation based on the new guideline for constipation in Japanese patients with type 2 diabetes and examined the relationship with the clinical background, including diabetic vascular complications. Methods Questionnaire surveys including items concerning the diagnosis and treatment status of constipation were administered to 410 patients with type 2 diabetes. Results Although 29% of the patients considered that they had experienced constipation (self-judged), only 14% had consulted a physician about constipation. The prevalence of chronic constipation based on the guideline was 26%. After including laxative users, constipation was finally found in 36%. Despite the use of laxatives (n=81), 51% of the patients were still diagnosed with chronic constipation. Patients with constipation (chronic constipation or laxative use) were significantly older and had a longer duration of diabetes than those without constipation. The body mass index (BMI) of patients with constipation (24.9±3.8 kg/m2) was significantly lower than that of those without constipation (26.3±4.6 kg/m2). Diabetic neuropathy (49% vs. 32%) and coronary heart disease (CHD) (27% vs. 13%) were significantly more frequent in the patients with constipation than in those without constipation. A multivariate logistic regression analysis revealed that gender, BMI, diabetic neuropathy, insulin use, and CHD were significantly associated with constipation. Conclusion An accurate diagnosis of constipation is desirable in patients with type 2 diabetes because constipation is independently associated with CHD.
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Affiliation(s)
- Hiroyuki Ito
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Japan
| | - Kiyoko Ito
- Department of Nursing, Edogawa Hospital, Japan
| | | | | | | | - Eiji Kusano
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Japan
| | - Jiro Kondo
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Japan
| | - Takuma Izutsu
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Japan
| | - Suzuko Matsumoto
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Japan
| | - Hideyuki Inoue
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Japan
| | - Shinichi Antoku
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Japan
| | - Tomoko Yamasaki
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Japan
| | - Toshiko Mori
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Japan
| | - Michiko Togane
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Japan
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26
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Li Y, Ao J, Huang X, Lu H, Fu H, Song N, Xu W, Chen J. Involvement of PAR2 in platelet-derived growth factor receptor-α-positive cell proliferation in the colon of diabetic mice. Physiol Rep 2021; 9:e15099. [PMID: 34755491 PMCID: PMC8578889 DOI: 10.14814/phy2.15099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 08/09/2021] [Accepted: 08/09/2021] [Indexed: 11/26/2022] Open
Abstract
Our previous study indicated that streptozotocin (STZ)-induced diabetes leads to colonic platelet-derived growth factor receptor-α-positive (PDGFRα+ ) cell proliferation accompanied by slow colonic transit in mice; however, the mechanism of this effect is unclear. The present study used western blotting, immunohistochemistry, and quantitative PCR to investigate whether proteinase-activated receptor 2 (PAR2) mediates PDGFRα+ cell proliferation. Our results showed that PDGFRα, PAR2, and Ki-67 coexpression was increased in the diabetic colonic muscle layer. PDGFRα and PAR2 mRNA and protein expression levels were also markedly enhanced in the diabetic colonic muscle layer. Mice treated with 2-furoyl-LIGRLO-amide (2-F-L-a), a PAR2 agonist, exhibited significant colon elongation and increased smooth muscle weight. In the 2-F-L-a-treated mice, PDGFRα, PAR2, and Ki-67 coexpression was increased and PDGFRα and PAR2 mRNA and protein expression was significantly enhanced in the colonic smooth muscle layer. 2-F-L-a also increased proliferation and PDGFRα expression in NIH/3T3 cells cultured in high glucose, while LY294002, a PI3K antagonist, decreased cell proliferation and PDGFRα expression. PI3K and Akt protein and mRNA expression and p-Akt protein expression in diabetic and 2-F-L-a-treated mice were markedly reduced in colonic smooth muscle. 2-F-L-a also reduced PI3K, Akt, and p-Akt protein expression in NIH/3T3 cells, while the PI3K antagonist LY294002 increased this expression. The results indicate that PAR2 is involved in the proliferation of PDGFRα+ cells through the PI3K/Akt signaling pathway in the colon of STZ-induced diabetic mice, which may contribute to the slow transit and constipation that are associated with diabetes.
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MESH Headings
- Animals
- Cell Proliferation
- Cells, Cultured
- Colon/cytology
- Colon/drug effects
- Colon/metabolism
- Diabetes Mellitus, Experimental/metabolism
- Male
- Mice
- Mice, Inbred ICR
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/physiology
- NIH 3T3 Cells
- Oligopeptides/pharmacology
- Phosphatidylinositol 3-Kinases/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- Receptor, PAR-2/agonists
- Receptor, PAR-2/genetics
- Receptor, PAR-2/metabolism
- Receptor, Platelet-Derived Growth Factor alpha/genetics
- Receptor, Platelet-Derived Growth Factor alpha/metabolism
- Signal Transduction
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Affiliation(s)
- Yu‐Jia Li
- Department of Anatomy and PhysiologyShanghai Jiao Tong University College of Basic Medical ScienceShanghaiChina
- Department of Pediatric SurgeryXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jun‐Ping Ao
- State Key Laboratory of Oncogenes and Related GenesSchool of MedicineShanghai Cancer InstituteRenji HospitalShanghai Jiao Tong UniversityShanghaiChina
| | - Xu Huang
- Department of Anatomy and PhysiologyShanghai Jiao Tong University College of Basic Medical ScienceShanghaiChina
| | - Hong‐Li Lu
- Department of Anatomy and PhysiologyShanghai Jiao Tong University College of Basic Medical ScienceShanghaiChina
| | - Han‐Yue Fu
- Department of Anatomy and PhysiologyShanghai Jiao Tong University College of Basic Medical ScienceShanghaiChina
| | - Ni‐Na Song
- Department of Anatomy and PhysiologyShanghai Jiao Tong University College of Basic Medical ScienceShanghaiChina
| | - Wen‐Xie Xu
- Department of Anatomy and PhysiologyShanghai Jiao Tong University College of Basic Medical ScienceShanghaiChina
- Department of Pediatric SurgeryXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jie Chen
- Department of Pediatric SurgeryXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
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27
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Abstract
As liver is one of the primary organs involved in glucose homeostasis, it is not surprising that patients with liver dysfunction in chronic liver disease usually develop impaired glucose tolerance and subsequently overt diabetes later in their natural course. Diabetes that develops after the onset of cirrhosis of liver is usually referred to as hepatogenous diabetes (HD). It is an underrecognized and a hallmark endocrinological event in chronic liver disease. HD is associated with a higher risk of developing hepatic decompensations, such as ascites, variceal bleeding, hepatic encephalopathy, renal dysfunction, refractory ascites, and hepatocellular carcinoma along with reduced survival rates than normoglycemic patients with cirrhosis of liver. It is quite different from type 2 diabetes mellitus with the absence of classical risk factors, dissimilar laboratory profiles, and decreased incidence of microvascular complications. Furthermore, the management of patients with HD is challenging because of altered pharmacokinetics of most antidiabetic drugs and increased risk of hypoglycemia and other adverse effects. Hence, a clear understanding of the epidemiology, pathophysiology, clinical implications, laboratory diagnosis, and management of HD is essential for both hepatologists as well as endocrinologists, which is narrated briefly in this review.
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Affiliation(s)
- Preetam Nath
- Department of Gastroenterology & Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha 751024, India
| | - Anil C. Anand
- Department of Gastroenterology & Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha 751024, India
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28
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Jin B, Ha SE, Wei L, Singh R, Zogg H, Clemmensen B, Heredia DJ, Gould TW, Sanders KM, Ro S. Colonic Motility Is Improved by the Activation of 5-HT 2B Receptors on Interstitial Cells of Cajal in Diabetic Mice. Gastroenterology 2021; 161:608-622.e7. [PMID: 33895170 PMCID: PMC8532042 DOI: 10.1053/j.gastro.2021.04.040] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 04/15/2021] [Accepted: 04/17/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Constipation is commonly associated with diabetes. Serotonin (5-HT), produced predominantly by enterochromaffin (EC) cells via tryptophan hydroxylase 1 (TPH1), is a key modulator of gastrointestinal (GI) motility. However, the role of serotonergic signaling in constipation associated with diabetes is unknown. METHODS We generated EC cell reporter Tph1-tdTom, EC cell-depleted Tph1-DTA, combined Tph1-tdTom-DTA, and interstitial cell of Cajal (ICC)-specific Kit-GCaMP6 mice. Male mice and surgically ovariectomized female mice were fed a high-fat high-sucrose diet to induce diabetes. The effect of serotonergic signaling on GI motility was studied by examining 5-HT receptor expression in the colon and in vivo GI transit, colonic migrating motor complexes (CMMCs), and calcium imaging in mice treated with either a 5-HT2B receptor (HTR2B) antagonist or agonist. RESULTS Colonic transit was delayed in males with diabetes, although colonic Tph1+ cell density and 5-HT levels were increased. Colonic transit was not further reduced in diabetic mice by EC cell depletion. The HTR2B protein, predominantly expressed by colonic ICCs, was markedly decreased in the colonic muscles of males and ovariectomized females with diabetes. Ca2+ activity in colonic ICCs was decreased in diabetic males. Treatment with an HTR2B antagonist impaired CMMCs and colonic motility in healthy males, whereas treatment with an HTR2B agonist improved CMMCs and colonic motility in males with diabetes. Colonic transit in ovariectomized females with diabetes was also improved significantly by the HTR2B agonist treatment. CONCLUSIONS Impaired colonic motility in mice with diabetes was improved by enhancing HTR2B signaling. The HTR2B agonist may provide therapeutic benefits for constipation associated with diabetes.
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Affiliation(s)
- Byungchang Jin
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, Nevada
| | - Se Eun Ha
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, Nevada
| | - Lai Wei
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, Nevada
| | - Rajan Singh
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, Nevada
| | - Hannah Zogg
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, Nevada
| | - Brooke Clemmensen
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, Nevada
| | - Dante J Heredia
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, Nevada
| | - Thomas W Gould
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, Nevada
| | - Kenton M Sanders
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, Nevada
| | - Seungil Ro
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, Nevada.
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29
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Allemeyer E, Müssig K. Chronische Obstipation und Diabetes mellitus. DIABETOL STOFFWECHS 2021. [DOI: 10.1055/a-1320-9358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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30
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Ohkuma T, Iwase M, Fujii H, Ide H, Komorita Y, Yoshinari M, Oku Y, Higashi T, Oshiro A, Nakamura U, Kitazono T. Constipation and diabetic kidney disease: The Fukuoka Diabetes Registry. Clin Exp Nephrol 2021; 25:1247-1254. [PMID: 34173920 DOI: 10.1007/s10157-021-02105-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 06/21/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND Constipation was shown to be associated with higher risk of end-stage kidney disease or incident chronic kidney disease, although evidence in diabetic patients is lacking. The objective of the present study was to examine the association between constipation and diabetic kidney disease (DKD). METHODS In total, 4826 Japanese outpatients with type 2 diabetes were classified according to presence or absence of constipation (defecation frequency < 3 times/week and/or taking laxative medication). DKD was defined as presence of decreased estimated glomerular filtration rate (eGFR < 60 ml/min/1.73 m2), and/or albuminuria (urinary albumin-to-creatinine ratio ≥ 30 mg/g). Odds ratios for the presence of DKD were computed by a logistic regression model. RESULTS Compared with participants without constipation, the age- and sex-adjusted odds ratio for presence of DKD was 1.58 (95% confidence interval 1.38-1.82) for those with constipation. This association persisted following adjustment for potential confounding factors. Decreased defecation frequency and laxative use were also significantly associated with higher prevalence of DKD. Overall, these findings were identical even when decreased eGFR and albuminuria were separately analyzed. CONCLUSIONS Constipation was associated with higher likelihood of DKD in patients with diabetes, suggesting the importance of clinical assessment of constipation to identify patients at high risk of progression of kidney disease.
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Affiliation(s)
- Toshiaki Ohkuma
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.
| | - Masanori Iwase
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.,Diabetes Center, Hakujyuji Hospital, Fukuoka, Japan
| | - Hiroki Fujii
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.,Division of Internal Medicine, Fukuoka Dental College, Fukuoka, Japan
| | - Hitoshi Ide
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.,Diabetes Center, Hakujyuji Hospital, Fukuoka, Japan
| | - Yuji Komorita
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Masahito Yoshinari
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.,Division of General Internal Medicine, School of Oral Health Science, Kyushu Dental University, Kitakyushu, Japan
| | - Yutaro Oku
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Taiki Higashi
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Ayaka Oshiro
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Udai Nakamura
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.,Diabetes Center, Steel Memorial Yawata Hospital, Kitakyushu, Japan
| | - Takanari Kitazono
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan
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Kornum DS, Terkelsen AJ, Bertoli D, Klinge MW, Høyer KL, Kufaishi HHA, Borghammer P, Drewes AM, Brock C, Krogh K. Assessment of Gastrointestinal Autonomic Dysfunction: Present and Future Perspectives. J Clin Med 2021; 10:jcm10071392. [PMID: 33807256 PMCID: PMC8037288 DOI: 10.3390/jcm10071392] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 11/16/2022] Open
Abstract
The autonomic nervous system delicately regulates the function of several target organs, including the gastrointestinal tract. Thus, nerve lesions or other nerve pathologies may cause autonomic dysfunction (AD). Some of the most common causes of AD are diabetes mellitus and α-synucleinopathies such as Parkinson’s disease. Widespread dysmotility throughout the gastrointestinal tract is a common finding in AD, but no commercially available method exists for direct verification of enteric dysfunction. Thus, assessing segmental enteric physiological function is recommended to aid diagnostics and guide treatment. Several established assessment methods exist, but disadvantages such as lack of standardization, exposure to radiation, advanced data interpretation, or high cost, limit their utility. Emerging methods, including high-resolution colonic manometry, 3D-transit, advanced imaging methods, analysis of gut biopsies, and microbiota, may all assist in the evaluation of gastroenteropathy related to AD. This review provides an overview of established and emerging assessment methods of physiological function within the gut and assessment methods of autonomic neuropathy outside the gut, especially in regards to clinical performance, strengths, and limitations for each method.
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Affiliation(s)
- Ditte S. Kornum
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK8200 Aarhus, Denmark; (M.W.K.); (K.L.H.); (K.K.)
- Steno Diabetes Centre Aarhus, Aarhus University Hospital, DK8200 Aarhus, Denmark
- Correspondence:
| | - Astrid J. Terkelsen
- Department of Neurology, Aarhus University Hospital, DK8200 Aarhus, Denmark;
| | - Davide Bertoli
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, DK9100 Aalborg, Denmark; (D.B.); (A.M.D.); (C.B.)
| | - Mette W. Klinge
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK8200 Aarhus, Denmark; (M.W.K.); (K.L.H.); (K.K.)
| | - Katrine L. Høyer
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK8200 Aarhus, Denmark; (M.W.K.); (K.L.H.); (K.K.)
- Steno Diabetes Centre Aarhus, Aarhus University Hospital, DK8200 Aarhus, Denmark
| | - Huda H. A. Kufaishi
- Steno Diabetes Centre Copenhagen, Gentofte Hospital, DK2820 Gentofte, Denmark;
| | - Per Borghammer
- Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital, DK8200 Aarhus, Denmark;
| | - Asbjørn M. Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, DK9100 Aalborg, Denmark; (D.B.); (A.M.D.); (C.B.)
- Steno Diabetes Centre North Jutland, Aalborg University Hospital, DK9100 Aalborg, Denmark
| | - Christina Brock
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, DK9100 Aalborg, Denmark; (D.B.); (A.M.D.); (C.B.)
- Steno Diabetes Centre North Jutland, Aalborg University Hospital, DK9100 Aalborg, Denmark
| | - Klaus Krogh
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, DK8200 Aarhus, Denmark; (M.W.K.); (K.L.H.); (K.K.)
- Steno Diabetes Centre Aarhus, Aarhus University Hospital, DK8200 Aarhus, Denmark
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Bonetto S, Gruden G, Beccuti G, Ferro A, Saracco GM, Pellicano R. Management of Dyspepsia and Gastroparesis in Patients with Diabetes. A Clinical Point of View in the Year 2021. J Clin Med 2021; 10:1313. [PMID: 33806716 PMCID: PMC8004823 DOI: 10.3390/jcm10061313] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/12/2021] [Accepted: 03/20/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus is a widespread disease, and represents an important public health burden worldwide. Together with cardiovascular, renal and neurological complications, many patients with diabetes present with gastrointestinal symptoms, which configure the so-called diabetic enteropathy. In this review, we will focus on upper gastrointestinal symptoms in patients with diabetes, with particular attention to dyspepsia and diabetic gastroparesis (DG). These two clinical entities share similar pathogenetic mechanisms, which include autonomic neuropathy, alterations in enteric nervous system and histological abnormalities, such as interstitial cells of Cajal depletion. Moreover, the differential diagnosis may be challenging because of overlapping clinical features. Delayed gastric emptying should be documented to differentiate between DG and dyspepsia and it can be assessed through radioactive or non-radioactive methods. The clinical management of dyspepsia includes a wide range of different approaches, above all Helicobacter pylori test and treat. As regards DG treatment, a central role is played by dietary modification and glucose control and the first-line pharmacological therapy is represented by the use of prokinetics. A minority of patients with DG refractory to medical treatment may require more invasive therapeutic approaches, including supplemental nutrition, gastric electric stimulation, pyloromyotomy and gastrectomy.
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Affiliation(s)
- Silvia Bonetto
- Unit of Gastroenterology, Molinette Hospital, 10126 Turin, Italy; (G.M.S.); (R.P.)
| | - Gabriella Gruden
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (G.G.); (G.B.); (A.F.)
| | - Guglielmo Beccuti
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (G.G.); (G.B.); (A.F.)
| | - Arianna Ferro
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (G.G.); (G.B.); (A.F.)
| | - Giorgio Maria Saracco
- Unit of Gastroenterology, Molinette Hospital, 10126 Turin, Italy; (G.M.S.); (R.P.)
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy; (G.G.); (G.B.); (A.F.)
| | - Rinaldo Pellicano
- Unit of Gastroenterology, Molinette Hospital, 10126 Turin, Italy; (G.M.S.); (R.P.)
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Liu W, Guo P, Dai T, Shi X, Shen G, Feng J. Metabolic Interactions and Differences between Coronary Heart Disease and Diabetes Mellitus: A Pilot Study on Biomarker Determination and Pathogenesis. J Proteome Res 2021; 20:2364-2373. [PMID: 33751888 DOI: 10.1021/acs.jproteome.0c00879] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Comprehensive understanding of plasma metabotype of diabetes mellitus (DM), coronary heart disease (CHD), and especially diabetes mellitus with coronary heart disease (CHDDM) is still lacking. In this work, the plasma metabolic differences and links of DM, CHD, and CHDDM patients were investigated by the strategy of comparative metabolomics based on 1H NMR spectroscopy combined with network analysis for revealing their metabolic differences. A total of 17 metabolites are related to three diseases, among which valine, alanine, leucine, isoleucine, and N-acetyl-glycoprotein are positively correlated with CHD and CHDDM (odds ratios (OR) > 1). The trimethylamine oxide, glycerol, lactose, indoleacetate, and scyllo-inositol are closely related to the development of DM to CHDDM (OR > 1), and indoleactate (OR: 1.06, 95% confidence interval (CI): 1.01-1.12) and lactose (OR: 2.46, 95% CI: 1.67-3.25) are particularly prominent in CHDDM. We identified three multi-biomarkers types that were significantly associated with glycosylated hemoglobin (HbA1C) at baseline. All diseases demonstrated dysregulated glycolysis/gluconeogenesis and amino acid biosynthesis pathway. In addition, enrichment in tryptophan metabolism observed in CHDDM, enrichment in inositol phosphate metabolism observed in DM, and the metabolites related to microbiota metabolism were dysregulated in both DM and CHDDM. The comparative metabolomics strategy of multi-diseases offers a new perspective in disease-specific markers and pathogenic pathways.
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Affiliation(s)
- Wuping Liu
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen 361005, China
| | - Pengfei Guo
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen 361005, China
| | - Tao Dai
- Third Affiliated Hospital, Henan University of Science and Technology, Luoyang 471003, China
| | - Xiulin Shi
- The Xiamen Diabetes Institute and Department of Endocrinology and Diabetes, the First Affiliated Hospital of Xiamen University, Xiamen 361003, China
| | - Guiping Shen
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen 361005, China
| | - Jianghua Feng
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen 361005, China
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Lins Neto MÁDF, Moreno KAM, da Graça RCC, Lima SMG. Constipation prevalence in diabetic patients. JOURNAL OF COLOPROCTOLOGY 2021. [DOI: 10.1016/j.jcol.2014.04.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Abstract
Objective the aim of this study was to identify the prevalence of constipation in diabetic patients treated at the endocrinology outpatient clinic at Hospital Universitário Professor Alberto Antunes and PAM Salgadinho, from April to August 2013.
Methods a descriptive and cross-sectional study, carried out through a questionnaire using the Rome III criteria in 372 patients treated at the outpatient endocrinology clinic.
Results of 372 patients evaluated, the frequency of constipation found was 31.2% among diabetic patients. Females predominated in the sample (72.8%) as well as for the frequency of constipation (80.2%). The incidence of type II diabetes was 97.3% and it was observed that 80.2% of the sample was older than 50 years. One hundred and twelve patients with inadequate glycemic control (HgA1c ≥ 7) had an association with constipation.
Conclusion there was an increased frequency of constipation in patients with diabetes mellitus according to the Rome III criteria, in relation to the general population. The inadequate glycemic control in patients with diabetes mellitus increases the frequency of constipation and it is necessary to perform studies that allow the confirmation of this association to demonstrate this hypothesis.
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Affiliation(s)
| | | | | | - Sandra Maria Gicó Lima
- Division of Coloproctology, Department of General Surgery, Universidade Federal de Alagoas (UFAL), Maceió, AL, Brazil
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Ohkuma T, Iwase M, Fujii H, Ide H, Komorita Y, Yoshinari M, Oku Y, Higashi T, Nakamura U, Kitazono T. Defecation frequency and glycemic control in patients with diabetes: The Fukuoka Diabetes Registry. J Diabetes Complications 2021; 35:107751. [PMID: 33127269 DOI: 10.1016/j.jdiacomp.2020.107751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/30/2020] [Accepted: 09/26/2020] [Indexed: 02/07/2023]
Abstract
AIMS Constipation has been shown to be associated with a higher risk of diabetes. However, few studies have evaluated the relationship between defecation frequency, one of the major symptoms of constipation, and glycemic control in patients with diabetes. The aim of the present study was to determine the relationship between defecation frequency and HbA1c in patients with diabetes. METHODS We determined the relationship between defecation frequency and HbA1c in 5029 patients with diabetes in the Fukuoka Diabetes Registry, a multi-center prospective cohort study conducted in diabetes specialist outpatient clinic (mean age 64.9 years, men 55%). Participants were classified according to their defecation frequency: ≥7, 3-<7 and <3 times/week. RESULTS Low defecation frequency was linearly associated with high HbA1c, with mean levels of 7.41% (95% confidence interval, 7.37-7.44%), 7.54% (7.49-7.60%) and 7.63% (7.52-7.74%) for patients with defecation frequencies of ≥7 times/week, 3-<7 times/week and <3 times/week (p for trend <0.001). This association remained after multivariable adjustment for confounding factors. There was no evidence of heterogeneity in the association between defecation frequency and HbA1c level according to age, sex, type of diabetes, or laxative use. CONCLUSIONS The present study suggests the importance of assessing defecation frequency in the management of diabetes.
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Affiliation(s)
- Toshiaki Ohkuma
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masanori Iwase
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Diabetes Center, Hakujyuji Hospital, Fukuoka, Japan.
| | - Hiroki Fujii
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Division of Internal Medicine, Fukuoka Dental College, Fukuoka, Japan
| | - Hitoshi Ide
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Diabetes Center, Hakujyuji Hospital, Fukuoka, Japan
| | - Yuji Komorita
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masahito Yoshinari
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Division of General Internal Medicine, School of Oral Health Science, Kyushu Dental University, Kitakyushu, Japan
| | - Yutaro Oku
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Taiki Higashi
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Udai Nakamura
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Diabetes Center, Steel Memorial Yawata Hospital, Kitakyushu, Japan
| | - Takanari Kitazono
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Nyavor Y, Brands CR, Nicholson J, Kuther S, Cox KK, May G, Miller C, Yasuda A, Potter F, Cady J, Heyman HM, Metz TO, Stark TD, Hofmann T, Balemba OB. Supernatants of intestinal luminal contents from mice fed high-fat diet impair intestinal motility by injuring enteric neurons and smooth muscle cells. Neurogastroenterol Motil 2021; 33:e13990. [PMID: 32969549 DOI: 10.1111/nmo.13990] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 08/12/2020] [Accepted: 08/25/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Damage to enteric neurons and impaired gastrointestinal muscle contractions cause motility disorders in 70% of diabetic patients. It is thought that enteric neuropathy and dysmotility occur before overt diabetes, but triggers of these abnormalities are not fully known. We tested the hypothesis that intestinal contents of mice with and without high-fat diet- (HFD-) induced diabetic conditions contain molecules that impair gastrointestinal movements by damaging neurons and disrupting muscle contractions. METHODS Small and large intestinal segments were collected from healthy, standard chow diet (SCD) fed mice. Filtrates of ileocecal contents (ileocecal supernatants; ICS) from HFD or SCD mice were perfused through them. Cultured intact intestinal muscularis externa preparations were used to determine whether ICS and their fractions obtained by solid-phase extraction (SPE) and SPE subfractions collected by high-performance liquid chromatography (HPLC) disrupt muscle contractions by injuring neurons and smooth muscle cells. KEY RESULTS ICS from HFD mice reduced intestinal motility, but those from SCD mice had no effect. ICS, aqueous SPE fractions and two out of twenty HPLC subfractions of aqueous SPE fractions from HFD mice blocked muscle contractions, caused a loss of nitrergic myenteric neurons through inflammation, and reduced smooth muscle excitability. Lipopolysaccharide and palmitate caused a loss of nitrergic myenteric neurons but did not affect muscle contractions. CONCLUSIONS & INFERENCES Unknown molecules in intestinal contents of HFD mice trigger enteric neuropathy and dysmotility. Further studies are required to identify the toxic molecules and their mechanisms of action.
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Affiliation(s)
- Yvonne Nyavor
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA
| | | | - Jessica Nicholson
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA
| | - Sydney Kuther
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA
| | - Kortni K Cox
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA
| | - George May
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA
| | | | - Allysha Yasuda
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA
| | - Forrest Potter
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA
| | - Joshua Cady
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA
| | - Heino M Heyman
- Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Thomas O Metz
- Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Timo D Stark
- Lehrstuhl für Lebensmittelchemie und Molekulare Sensorik, Technische Universität München, Freising, Germany
| | - Thomas Hofmann
- Lehrstuhl für Lebensmittelchemie und Molekulare Sensorik, Technische Universität München, Freising, Germany
| | - Onesmo B Balemba
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA
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Klinge MW, Haase AM, Mark EB, Sutter N, Fynne LV, Drewes AM, Schlageter V, Lund S, Borghammer P, Krogh K. Colonic motility in patients with type 1 diabetes and gastrointestinal symptoms. Neurogastroenterol Motil 2020; 32:e13948. [PMID: 32688448 DOI: 10.1111/nmo.13948] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 06/22/2020] [Accepted: 06/25/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Gastrointestinal (GI) symptoms are common in patients with diabetes mellitus (DM). The electromagnetic 3D-Transit system allows assessment of regional transit times and motility patterns throughout the GI tract. We aimed to compare GI transit times and detailed motility patterns of the colon in patients with DM and GI symptoms to those of healthy controls (HC). We further aimed to determine whether any abnormalities in motility were reversible by cholinergic stimulation. METHODS We compared 18 patients with DM with 20 HC by means of the 3D-Transit system. Patients were studied before and during oral administration of 60 mg pyridostigmine. KEY RESULTS Compared to HC, patients had prolonged gastric emptying (DM: 3.3 hours (interquartile range (IQR) 2.6-4.6); HC: 2.3 hours (IQR 1.7-2.7) (P < .01)), colonic transit time (DM: 52.6 hours (IQR 23.3-83.0); HC: 22.4 hours (IQR 18.9-43.6) (P = .02)), and whole gut transit time (DM: 69.4 hours (IQR 32.9-103.6); HC: 30.3 hours (IQR 25.2-49.9) (P < .01)). In addition, compared to HC, patients had prolonged transit time in the ascending colon (DM: 20.5 hours (IQR 11.0-44.0); HC: 8.0 hours (IQR 3.8-21.0) (P < .05)) and more slow retrograde movements in the colon (DM: 2 movements (IQR 1-4); HC: 1 movement (IQR 0-1) (P = .01)). In patients, pyridostigmine increased the number of bowel movements (P < .01) and reduced small intestine transit times (P < .05). CONCLUSIONS Patients with DM and GI symptoms have longer than normal GI transit times. This is only partly reversible by pyridostigmine. The increased number of retrograde colonic movements in patients could potentially explain the abnormally long transit time in proximal colon.
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Affiliation(s)
- Mette Winther Klinge
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Anne-Mette Haase
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Esben Bolvig Mark
- Mech-Sense, Department of Gastroenterology and Hepatology and Steno Diabetes Center North, Aalborg University Hospital, Aalborg, Denmark
| | - Nanna Sutter
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Asbjørn Mohr Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology and Steno Diabetes Center North, Aalborg University Hospital, Aalborg, Denmark
| | | | - Sten Lund
- Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark
| | - Per Borghammer
- Department of Nuclear Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Klaus Krogh
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.,Steno Diabetes Center Aarhus, Aarhus, Denmark
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Wang Y, Wu Y, Sailike J, Sun X, Abuduwaili N, Tuoliuhan H, Yusufu M, Nabi XH. Fourteen composite probiotics alleviate type 2 diabetes through modulating gut microbiota and modifying M1/M2 phenotype macrophage in db/db mice. Pharmacol Res 2020; 161:105150. [DOI: 10.1016/j.phrs.2020.105150] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 07/22/2020] [Accepted: 08/11/2020] [Indexed: 02/07/2023]
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Mehrabianfar P, Dehghani F, Karbalaei N, Mesbah F. The effects of metformin on stereological and ultrastructural features of the ovary in streptozotocin -induced diabetes adult rats: An experimental study. Int J Reprod Biomed 2020; 18:651-666. [PMID: 32923931 PMCID: PMC7457152 DOI: 10.18502/ijrm.v13i8.7506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 12/18/2019] [Accepted: 04/12/2020] [Indexed: 11/29/2022] Open
Abstract
Background Diabetes is a chronic disease that can affect almost all of the body organs, including male and female reproductive systems. Objective This study was designed to investigate the preventive effects of metformin on stereological and ultrastructure characteristics of the ovary in the streptozotocin-induced diabetes adult female rats. Materials and Methods Seventy adult (8-10 wk) female Sprague-Dawley rats (180-200 gr) were equally divided, as follows: (n = 10/each) control; STZ-induced diabetes (single dose of 65 mg/kg STZ, IP); metformin-treated (50 mg/100 gr of body weight, orally); diabetic-metformin-treated; sham 1, (single dose of sodium citrate); sham 2, (0.5 ml of daily oral distilled water); and sham 3, (sodium citrate + distilled water treated). The body mass index, ovarian weight, blood sugar level, cholesterol, and triglyceride were measured. The stereological and ultrastructural features of ovary were assessed. Results The blood sugar of induced-diabetic rats was increased (p < 0.01). The BMI (p < 0.01), number of granulosa cells (p = 0.04), primordial, primary and secondary follicles (p = 0.03), total volume of ovary (p < 0.01) and cortex, nucleus diameter ratio to the ooplasm were decreased. The number of atretic follicles in the diabetic and diabetic + metformin-treated rats were increased (p < 0.01). The ultrastructural characteristics of ovary were more damaged in diabetic rats. Conclusion Diabetes has destructive effects on ovarian follicles and causes follicular atresia. Also, the size of oocytes, numbers of granulosa cells and ooplasmic organelles, which are involved in the folliculogenesis are affected by diabetes and metformin has no preventive effects.
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Affiliation(s)
- Parisa Mehrabianfar
- Department of Anatomical Sciences School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farzaneh Dehghani
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Science, Shiraz, Iran
| | - Nargess Karbalaei
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Science, Shiraz, Iran
| | - Fakhroddin Mesbah
- Department of Anatomical Sciences School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Muroi K, Miyahara R, Funasaka K, Furukawa K, Sawada T, Maeda K, Yamamura T, Ishikawa T, Ohno E, Nakamura M, Kawashima H, Onoue T, Arima H, Hirooka Y, Fujishiro M. Comparison of High-Resolution Manometry in Patients Complaining of Dysphagia among Patients with or without Diabetes Mellitus. Digestion 2020; 102:554-562. [PMID: 32906118 DOI: 10.1159/000510081] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 06/28/2020] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Dysphagia is a common symptom that occurs in patients with diabetes mellitus (DM). There have been few prospective observational studies on esophageal motility disorders in DM using high-resolution manometry (HRM). This study aimed to clarify the characteristics of esophageal motility disorders using HRM in patients with dysphagia and compare them between DM and non-DM patients. METHODS Patients with dysphagia were prospectively recruited between October 2018 and July 2019. Patients (n = 89) underwent esophagogastroduodenoscopy and HRM and completed the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire. Manometry parameters and motility disorder classifications were compared between DM and non-DM patients. We also investigated the differences in clinical backgrounds and questionnaire scores among DM patients with normal and abnormal manometry results. RESULTS A higher prevalence of esophageal motility disorder was observed in DM patients (60%, 21/35) compared to non-DM patients (29.6%, 16/54) (p = 0.001). The prevalence of minor disorders such as ineffective esophageal motor disorder and fragmented peristalsis was significantly higher (45 vs. 11%), and the distal contractile integral, integrated relaxation pressure, and contractile front velocity values were lower in the DM group. Among DM patients, those with abnormal esophageal motility had a significantly higher prevalence of neuropathy, retinopathy, and nephropathy, as well as higher reflux or constipation scores on the GSRS, than those with normal results. CONCLUSIONS Among patients with dysphagia, the frequency of minor esophageal motility disorders was higher in DM patients than in non-DM patients. Abnormal esophageal motility related to poor esophageal clearance was associated with higher prevalence of diabetic complications.
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Affiliation(s)
- Koichi Muroi
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ryoji Miyahara
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan,
| | - Kohei Funasaka
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Kazuhiro Furukawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tsunaki Sawada
- Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan
| | - Keiko Maeda
- Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan
| | - Takeshi Yamamura
- Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan
| | - Takuya Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Eizaburo Ohno
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masanao Nakamura
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroki Kawashima
- Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan
| | - Takeshi Onoue
- Department of Endocrinology and Diabetes, Nagoya University Hospital, Nagoya, Japan
| | - Hiroshi Arima
- Department of Endocrinology and Diabetes, Nagoya University Hospital, Nagoya, Japan
| | - Yoshiki Hirooka
- Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Signaling pathways underlying changes in the contractility of the stomach fundus smooth muscle in diabetic rats. Arch Pharm Res 2020; 43:666-675. [PMID: 32607942 DOI: 10.1007/s12272-020-01244-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 06/25/2020] [Indexed: 10/24/2022]
Abstract
Dysfunction of gastrointestinal (GI) motility is a common complication in patients with diabetes mellitus (DM). Studies related to changes in fundus contraction induced by inhibitors in DM are not well known. Therefore, this study aimed to investigate the signaling pathways involved in the changes in the contraction of fundus smooth muscle obtained from control and DM rats. DM was induced by injecting streptozotocin (65 mg/kg) into Sprague-Dawley rats. The rats were sacrificed after 14 days. Fundus smooth muscle contraction was stimulated using electrical field stimulation (amplitude, 50 V; duration, 1 min; frequency, 2-20 Hz) and acetylcholine (0.1 mM). The inhibitor-mediated cell membrane was pre-treated with atropine, verapamil, methysergide, ketanserin, ondansetron, and GR 113808. Inhibitors related to intracellular signaling, such as U73122, chelerythrine, L-NNA, were also used. ML-9 and Y-27632 were identified as inhibitors of factors of myosin light chain (MLC). The contractility was observed to be lower in the DM group than in the control group. Further, the activities of phospholipase C (PLC), protein kinase C (PKC), and myosin light chain kinase (MLCK) were decreased in the DM group. DM reduced the activity of PLC, PKC, and MLCK, which resulted in a decrease in the contractility of the fundus smooth muscle. Therefore, our results present the mechanism of this DM-mediated GI disorder.
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Thein W, Po WW, Kim DM, Sohn UD. The Altered Signaling on EFS-Induced Colon Contractility in Diabetic Rats. Biomol Ther (Seoul) 2020; 28:328-336. [PMID: 32126734 PMCID: PMC7327146 DOI: 10.4062/biomolther.2019.181] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/24/2019] [Accepted: 01/07/2020] [Indexed: 01/18/2023] Open
Abstract
Diabetes mellitus affects the colonic motility developing gastrointestinal symptoms, such as constipation. The aim of the study was to examine the role of intracellular signaling pathways contributing to colonic dysmotility in diabetes mellitus. To generate diabetes mellitus, the rats were injected by a single high dose of streptozotocin (65 mg/kg) intraperitoneally. The proximal colons from both normal and diabetic rats were contracted by applying an electrical field stimulation with pulse voltage of 40 V in amplitude and pulse duration of 1 ms at frequencies of 1, 2, 4, and 6 Hz. The muscle strips from both normal rats and rats with diabetes mellitus were pretreated with different antagonists and inhibitors. Rats with diabetes mellitus had lower motility than the control group. There were significant differences in the percentage of inhibition of contraction between normal rats and rats with diabetes mellitus after the incubation of tetrodotoxin (neuronal blocker), atropine (muscarinic receptor antagonist), prazosin (α1 adrenergic receptor antagonist), DPCPX (adenosine A1 receptor antagonist), verapamil (L-type Ca2+ channel blocker), U73122 (PLC inhibitor), ML-9 (MLCK inhibitor), udenafil (PDE5 inhibitor), and methylene blue (guanylate cyclase inhibitor). The protein expression of p-MLC and PDE5 were decreased in the diabetic group compared to the normal group. These results showed that the reduced colonic contractility resulted from the impaired neuronal conduction and decreased muscarinic receptor sensitivity, which resulted in decreased phosphorylation of MLC via MLCK, and cGMP activity through PDE5.
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Affiliation(s)
- Wynn Thein
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Wah Wah Po
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Dong Min Kim
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Uy Dong Sohn
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
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Nyavor Y, Brands CR, May G, Kuther S, Nicholson J, Tiger K, Tesnohlidek A, Yasuda A, Starks K, Litvinenko D, Linden DR, Bhattarai Y, Kashyap PC, Forney LJ, Balemba OB. High-fat diet-induced alterations to gut microbiota and gut-derived lipoteichoic acid contributes to the development of enteric neuropathy. Neurogastroenterol Motil 2020; 32:e13838. [PMID: 32168415 PMCID: PMC7319907 DOI: 10.1111/nmo.13838] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 01/28/2020] [Accepted: 02/21/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND High-fat diet, microbial alterations and lipopolysaccharide (LPS) are thought to cause enteric diabetic neuropathy and intestinal dysmotility. However, the role of the gut microbiota, lipoteichoic acid (LTA) from Gram-positive bacteria and short-chain fatty acids (SCFAs) in the development of diabetic enteric neuropathy and intestinal dysmotility is not well understood. Our aim was to examine the role of the gut microbiota, LTA and SCFAs in the development of diabetic enteric neuropathy and intestinal dysmotility. METHODS We fed germ-free (GF) and conventionally raised (CR) mice either a high-fat (HFD) or standard chow diet (SCD) for 8 weeks. We analyzed the microbial community composition in CR mice using 16S rRNA sequencing and damage to myenteric neurons using immunohistochemistry. We also studied the effects of LPS, LTA, and SCFAs on duodenal muscularis externa contractions and myenteric neurons using cultured preparations. KEY RESULTS High-fat diet ingestion reduced the total number and the number of nitrergic myenteric neurons per ganglion in the duodenum of CR but not in GF-HFD mice. GF mice had fewer neurons per ganglion compared with CR mice. CR mice fed a HFD had increased abundance of Gram-positive bacteria. LTA and LPS did not affect the frequency of duodenal muscularis contractions after 24 hours of cultured but reduced the density of nitrergic myenteric neurons and increased oxidative stress and TNFα production in myenteric ganglia. SCFAs did not affect muscularis contractions or injure myenteric neurons. CONCLUSIONS & INFERENCES Gut microbial alterations induced increase in Gram-positive bacterial LTA may contribute to enteric neuropathy.
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Affiliation(s)
- Yvonne Nyavor
- University of Idaho, 875 Perimeter Drive, LSS 252 Moscow, ID 83844
| | | | - George May
- University of Idaho, 875 Perimeter Drive, LSS 252 Moscow, ID 83844
| | - Sydney Kuther
- University of Idaho, 875 Perimeter Drive, LSS 252 Moscow, ID 83844
| | | | - Kathryn Tiger
- University of Idaho, 875 Perimeter Drive, LSS 252 Moscow, ID 83844
| | | | - Allysha Yasuda
- University of Idaho, 875 Perimeter Drive, LSS 252 Moscow, ID 83844
| | - Kiefer Starks
- University of Idaho, 875 Perimeter Drive, LSS 252 Moscow, ID 83844
| | - Diana Litvinenko
- University of Idaho, 875 Perimeter Drive, LSS 252 Moscow, ID 83844
| | - David R. Linden
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
| | - Yogesh Bhattarai
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | - Purna C. Kashyap
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA,Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
| | - Larry J. Forney
- University of Idaho, 875 Perimeter Drive, LSS 252 Moscow, ID 83844
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Gölaç H, Atalık G, Türkcan AK, Yapar D, Sel AT, Karakoç MA, Yılmaz M. Fiberoptic Endoscopic Evaluation of Swallowing in Patients with Type 2 Diabetes Who Have Self-Reported Swallowing Difficulties. Folia Phoniatr Logop 2020; 73:289-297. [PMID: 32434209 DOI: 10.1159/000507623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 03/30/2020] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION People with diabetes frequently have gastrointestinal problems and related deglutition disorders. OBJECTIVE The aims of the present study are to determine the symptomatic swallowing complaints and to evaluate the functionality of oropharyngeal swallowing in patients with type 2 diabetes mellitus (T2DM) by using the Turkish Eating Assessment Tool-10 (T-EAT-10) and fiberoptic endoscopic evaluation of swallowing (FEES). METHODS In this descriptive cross-sectional study, the T-EAT-10 questionnaire was completed by 121 patients with diabetes, and FEES was planned for each individual whose baseline score of the T-EAT-10 was ≥3. Before swallowing trials via samples of nectar-thick consistency, laryngeal sensation and severity of secretion in the hypopharynx were observed. While the swallowing safety was determined using the Penetration-Aspiration Scale (PAS), the Yale Pharyngeal Residue Severity Rating Scale was used to assess the swallowing efficiency. RESULTS Of the total participants, 22.3% (n = 27) were found to have abnormal swallowing function (T-EAT-10 ≥3), 27.3% (n = 33) had concomitant neuropathy and 28.1% (n = 34) mentioned a reflux complaint. The results of the multivariate linear regression analysis exposed that the T-EAT-10 score was significantly associated with neuropathy (r = 3.763, p < 0.001) and reflux complaint (r = 2.254, p = 0.031). Of the total FEES-tested subjects (n = 20), 95% (n = 19) had a safe swallowing function (PAS = 1). However, diminished laryngeal sensation, increased secretion and presence of residue revealed that patients with T2DM who have self-reported swallowing difficulties have reduced swallowing efficiency. CONCLUSIONS This study has demonstrated that almost 1 out of 4 T2DM patients reported to have swallowing-related problems, and the score of the T-EAT-10 was found to be independently associated with both neuropathy and reflux complaint. FEES results pointed out that swallowing efficiency was relatively reduced in the target population. However, further research is still necessary before obtaining a definitive answer to oropharyngeal swallowing problems in patients with T2DM.
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Affiliation(s)
- Hakan Gölaç
- Department of Speech and Language Therapy, Faculty of Health Sciences, Gazi University, Ankara, Turkey,
| | - Güzide Atalık
- Department of Speech and Language Therapy, Faculty of Health Sciences, Gazi University, Ankara, Turkey
| | | | - Dilek Yapar
- Department of Public Health, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Aydın Tuncer Sel
- Department of Endocrinology and Metabolism, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Mehmet Ayhan Karakoç
- Department of Endocrinology and Metabolism, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Metin Yılmaz
- Department of Otolaryngology, Faculty of Medicine, Gazi University, Ankara, Turkey
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Selbuz S, Buluş AD. Gastrointestinal symptoms in pediatric patients with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2020; 33:185-190. [PMID: 31846427 DOI: 10.1515/jpem-2019-0350] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 10/03/2019] [Indexed: 12/12/2022]
Abstract
Background Various gastrointestinal (GI) symptoms are associated with diabetes. Common GI complaints associated with the manifestation of the disease include abdominal pain, diarrhea, nausea, bloating and vomiting. There have been very few studies examining GI problems of pediatric patients with type 1 diabetes mellitus (T1DM). The aims of this study were to find out the prevalence of GI symptoms in pediatric patients with T1DM and to determine the correlation among such symptoms, duration of diabetes and glycemic control. Methods One hundred and thirty-seven (median age 13.2 years, female 45.3%) patients with T1DM were examined. Demographic features, GI symptoms, signs and physical examination findings of the patients were recorded by pediatric gastroenterology specialists for the differential diagnosis and exclusion of other etiologies. Complete blood count, blood glucose, lipid profile, electrolytes, amylase, lipase, celiac antibodies and glycated hemoglobin (HbA1c) levels were evaluated and stool examination was performed. Endoscopy was performed on the patients who had refractory GI complaints. Gastric emptying (GE) time was evaluated using GE scintigraphy. Results Overall, 74 (54%) patients had ≥1 GI complaints. Patients often reported gastroesophageal reflux (32.8%) and abdominal pain (18%). The most significant findings in terms of GI symptoms were determined when patients were classified according to the glycemic control status. Reflux and dyspeptic symptoms were significantly more common in poorly or very poorly controlled diabetic patients (p=0.003 and p=0.004, respectively). Conclusions Diabetes can affect the entire GI tract, and GI symptoms are common in pediatric patients. We recommend that T1DM patients be evaluated for GI symptoms.
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Affiliation(s)
- Suna Selbuz
- Keçiören Research and Training Hospital, Pediatric Endocrinology, Ankara, Turkey
| | - Ayşe Derya Buluş
- Keçiören Research and Training Hospital, Pediatric Endocrinology, Ankara, Turkey
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Rahmani B, Gandhi J, Joshi G, Smith NL, Reid I, Khan SA. The Role of Diabetes Mellitus in Diseases of the Gallbladder and Biliary Tract. Curr Diabetes Rev 2020; 16:931-948. [PMID: 32133965 DOI: 10.2174/1573399816666200305094727] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 02/18/2020] [Accepted: 02/21/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The increasing prevalence of diabetes mellitus worldwide continues to pose a heavy burden. Though its gastrointestinal impact is appropriately recognized, the lesser known associations may be overlooked. OBJECTIVE We aim to review the negative implications of diabetes on the gallbladder and the biliary tract. METHODS A MEDLINE® database search of literature was conducted with emphasis on the previous five years, combining keywords such as "diabetes," "gallbladder," and "biliary". RESULTS The association of diabetes to the formation of gallstones, gallbladder cancer, and cancer of the biliary tract are discussed along with diagnosis and treatment. CONCLUSION Though we uncover the role of diabetic neuropathy in gallbladder and biliary complications, the specific individual diabetic risk factors behind these developments is unclear. Also, in addition to diabetes control and surgical gallbladder management, the treatment approach also requires further focus.
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Affiliation(s)
- Benjamin Rahmani
- Department of Physiology and Biophysics, Renaissance School of Medicine at Stony Brook University, Stony Brook,
NY, USA
| | - Jason Gandhi
- Department of Physiology and Biophysics, Renaissance School of Medicine at Stony Brook University, Stony Brook,
NY, USA
- Medical Student Research Institute, St. George’s University School of Medicine, Grenada, West Indies
| | - Gunjan Joshi
- Department of Internal Medicine, Stony Brook Southampton Hospital, Southampton, NY, USA
| | | | - Inefta Reid
- Department of Physiology and Biophysics, Renaissance School of Medicine at Stony Brook University, Stony Brook,
NY, USA
| | - Sardar Ali Khan
- Department of Physiology and Biophysics, Renaissance School of Medicine at Stony Brook University, Stony Brook,
NY, USA
- Department of Urology, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
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An J, Noh H, Kim E, Lee J, Woo K, Kim H. Neuromuscular blockade reversal with sugammadex versus pyridostigmine/glycopyrrolate in laparoscopic cholecystectomy: a randomized trial of effects on postoperative gastrointestinal motility. Korean J Anesthesiol 2019; 73:137-144. [PMID: 31636242 PMCID: PMC7113156 DOI: 10.4097/kja.19360] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 10/17/2019] [Indexed: 12/19/2022] Open
Abstract
Background Acetylcholinesterase inhibitors (e.g., pyridostigmine bromide) are used for neuromuscular blockade (NMB) reversal in patients undergoing surgery under general anesthesia (GA). Concurrent use of anticholinergic agents (e.g., glycopyrrolate) decreases cholinergic side effects but can impede bowel movements. Sugammadex has no cholinergic effects; its use modifies recovery of gastrointestinal (GI) motility following laparoscopic cholecystectomy compared to pyridostigmine/glycopyrrolate. This study evaluated the contribution of sugammadex to the recovery of GI motility compared with pyridostigmine and glycopyrrolate. Methods We conducted a prospective study of patients who underwent laparoscopic cholecystectomy. Patients were randomly allocated to the experimental group (sugammadex, Group S) or control group (pyridostigmine-glycopyrrolate, Group P). After anesthesia (propofol and rocuronium, and 2% sevoflurane), recovery was induced by injection of sugammadex or a pyridostigmine-glycopyrrolate mixture. As a primary outcome, patients recorded the time of their first passage of flatus (‘gas-out time’) and defecation. The secondary outcome was stool types. Results One-hundred and two patients participated (Group S [n = 49], Group P [n = 53]). Mean time from injection of NMB reversal agents to gas-out time was 15.03 (6.36–20.25) h in Group S and 20.85 (16.34–25.86) h in Group P (P = 0.001). Inter-group differences were significant. Time until the first defecation as well as types of stools was not significantly different. Conclusions Sugammadex after laparoscopic cholecystectomy under GA resulted in an earlier first postoperative passage of flatus compared with the use of a mixture of pyridostigmine and glycopyrrolate. These findings suggest that the use of sugammadex has positive effects on the recovery of GI motility.
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Affiliation(s)
- Jihyun An
- Department of Anesthesiology and Pain Medicine, Daegu Fatima Hospital, Daegu, Korea
| | - Heeyun Noh
- Department of Anesthesiology and Pain Medicine, Daegu Fatima Hospital, Daegu, Korea
| | - Eunju Kim
- Department of Anesthesiology and Pain Medicine, Daegu Fatima Hospital, Daegu, Korea
| | - Jihyang Lee
- Department of Anesthesiology and Pain Medicine, Daegu Fatima Hospital, Daegu, Korea
| | - Kyeongyoon Woo
- Department of Anesthesiology and Pain Medicine, Daegu Fatima Hospital, Daegu, Korea
| | - Hyunkyum Kim
- Department of Anesthesiology and Pain Medicine, Daegu Fatima Hospital, Daegu, Korea
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Ravi R, Gunjawate DR. Effect of diabetes mellitus on voice: a systematic review. PRACTICAL DIABETES 2019. [DOI: 10.1002/pdi.2240] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Rohit Ravi
- Department of Audiology and Speech Language PathologyKasturba Medical College, Mangalore, Manipal Academy of Higher Education Manipal Karnataka India
| | - Dhanshree R Gunjawate
- Department of Audiology and Speech Language PathologyKasturba Medical College, Mangalore, Manipal Academy of Higher Education Manipal Karnataka India
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Abstract
This review covers the epidemiology, pathophysiology, clinical features, diagnosis, and management of diabetic gastroparesis, and more broadly diabetic gastroenteropathy, which encompasses all the gastrointestinal manifestations of diabetes mellitus. Up to 50% of patients with type 1 and type 2 DM and suboptimal glycemic control have delayed gastric emptying (GE), which can be documented with scintigraphy, 13C breath tests, or a wireless motility capsule; the remainder have normal or rapid GE. Many patients with delayed GE are asymptomatic; others have dyspepsia (i.e., mild to moderate indigestion, with or without a mild delay in GE) or gastroparesis, which is a syndrome characterized by moderate to severe upper gastrointestinal symptoms and delayed GE that suggest, but are not accompanied by, gastric outlet obstruction. Gastroparesis can markedly impair quality of life, and up to 50% of patients have significant anxiety and/or depression. Often the distinction between dyspepsia and gastroparesis is based on clinical judgement rather than established criteria. Hyperglycemia, autonomic neuropathy, and enteric neuromuscular inflammation and injury are implicated in the pathogenesis of delayed GE. Alternatively, there are limited data to suggest that delayed GE may affect glycemic control. The management of diabetic gastroparesis is guided by the severity of symptoms, the magnitude of delayed GE, and the nutritional status. Initial options include dietary modifications, supplemental oral nutrition, and antiemetic and prokinetic medications. Patients with more severe symptoms may require a venting gastrostomy or jejunostomy and/or gastric electrical stimulation. Promising newer therapeutic approaches include ghrelin receptor agonists and selective 5-hydroxytryptamine receptor agonists.
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Affiliation(s)
- Adil E Bharucha
- Clinical Enteric Neuroscience Translational and Epidemiological Research Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Yogish C Kudva
- Division of Endocrinology. Mayo Clinic, Rochester, Minnesota
| | - David O Prichard
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Mori H, Suzuki H, Hirai Y, Okuzawa A, Kayashima A, Kubosawa Y, Kinoshita S, Fujimoto A, Nakazato Y, Nishizawa T, Kikuchi M. Clinical features of hypermagnesemia in patients with functional constipation taking daily magnesium oxide. J Clin Biochem Nutr 2019; 65:76-81. [PMID: 31379418 PMCID: PMC6667383 DOI: 10.3164/jcbn.18-117] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 03/27/2019] [Indexed: 01/10/2023] Open
Abstract
Although magnesium oxide is widely used as a laxative, alterations in serum magnesium concentrations among patients taking daily magnesium oxide have not been clarified. The present retrospective, cross-sectional study investigated the risk factors for hypermagnesemia in patients taking daily oral magnesium oxide. Of 2,176 patients administered daily magnesium oxide, 193 (8.9%) underwent assays of serum magnesium concentrations and were evaluated. High serum magnesium concentration and hypermagnesemia were defined as serum magnesium concentrations ≥2.5 mg/dl and ≥3.0 mg/dl, respectively. Of the 193 patients taking daily magnesium oxide, 32 (16.6%) had high serum magnesium concentration and 10 (5.2%) had hypermagnesemia. Factors associated with hypermagnesemia included chronic kidney disease (CKD) grade 4 (p = 0.014) and magnesium oxide dosage (p = 0.009). Factors associated with high serum magnesium concentration included magnesium oxide dosage >1,000 mg/day (p = 0.004), CKD grades 4 (p = 0.000) and concomitant use of stimulant laxatives (p = 0.035). Age, however, was not associated with hypermagnesemia or high serum magnesium concentration. In conclusion, renal function and magnesium oxide dosage, but not age, were associated with hypermagnesemia and high serum magnesium concentration in patients with functional constipation taking daily magnesium oxide.
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Affiliation(s)
- Hideki Mori
- Department of Gastroenterology, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan
| | - Hidekazu Suzuki
- Department of Gastroenterology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan
| | - Yuichiro Hirai
- Department of Gastroenterology, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan
| | - Anna Okuzawa
- Department of Gastroenterology, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan
| | - Atsuto Kayashima
- Department of Gastroenterology, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan
| | - Yoko Kubosawa
- Department of Gastroenterology, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan
| | - Satoshi Kinoshita
- Department of Gastroenterology, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan
| | - Ai Fujimoto
- Department of Gastroenterology, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan
| | - Yoshihiro Nakazato
- Department of Gastroenterology, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan
| | - Toshihiro Nishizawa
- Department of Gastroenterology, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan
- Digestive Disease Center, International University of Health and Welfare, Mita Hospital, 1-4-3 Mita, Minato-ku, Tokyo 108-8329, Japan
| | - Masahiro Kikuchi
- Department of Gastroenterology, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan
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