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Kornum DS, Krogh K, Keller J, Malagelada C, Drewes AM, Brock C. Diabetic gastroenteropathy: a pan-alimentary complication. Diabetologia 2025; 68:905-919. [PMID: 39934370 PMCID: PMC12021976 DOI: 10.1007/s00125-025-06365-y] [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: 09/23/2024] [Accepted: 01/07/2025] [Indexed: 02/13/2025]
Abstract
Autonomic neuropathy contributes to the pathophysiology of diabetic gastroenteropathy, which impacts the entire gastrointestinal tract alongside pancreatic and gallbladder functions. This is evident in the widespread morphological remodelling of the enteric nervous system, smooth muscle cells, interstitial cells of Cajal and vascular supply, causing pan-enteric motor, sensory and secretory disturbances. The gastrointestinal symptoms caused by these changes are often burdensome and non-specific and frequently coexist with poor glycaemic management and even malnutrition, impacting quality of life negatively. The Gastroparesis Cardinal Symptom Index and the Gastrointestinal Symptom Rating Scale are validated questionnaires for assessing gastrointestinal symptoms. However, clinical supplementary objective measures are essential. Transit time assessments are frequently used and typically evaluated using gastric emptying scintigraphy, breath tests or colonic radiopaque markers, but they cannot measure contractile activity or fluid transport. The primary treatment goals are to prevent further disease progression and to obtain symptomatic relief. Treatments include improved glycaemic management and dietary modifications, while pharmacological treatments target gastrointestinal symptoms, small intestinal bacterial overgrowth and exocrine pancreatic insufficiency. Invasive interventions may involve gastric peroral pyloromyotomy or the implantation of a gastric neurostimulator to manage pharmacologically refractory gastroparesis. This review describes the prevalence, pathophysiology, clinical presentation, assessment and treatment of diabetic gastrointestinal dysfunction within each segment of the gastrointestinal tract and directly connected exocrine organs.
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Affiliation(s)
- Ditte S Kornum
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Klaus Krogh
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Jutta Keller
- Department of Internal Medicine, Israelitic Hospital, Academic Hospital University of Hamburg, Hamburg, Germany
| | - Carolina Malagelada
- Digestive System Research Unit, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Asbjørn M Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
| | - Christina Brock
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark.
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Pérez-Montalbán M, García-Domínguez E, Oliva-Pascual-Vaca Á. Subdiaphragmatic phrenic nerve supply: A systematic review. Ann Anat 2024; 254:152269. [PMID: 38692333 DOI: 10.1016/j.aanat.2024.152269] [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] [Received: 03/05/2024] [Revised: 04/18/2024] [Accepted: 04/23/2024] [Indexed: 05/03/2024]
Abstract
OBJECTIVE The aim of this systematic review is to study the subdiaphragmatic anatomy of the phrenic nerve. MATERIALS AND METHODS A computerised systematic search of the Web of Science database was conducted. The key terms used were phrenic nerve, subdiaphragmat*, esophag*, liver, stomach, pancre*, duoden*, intestin*, bowel, gangli*, biliar*, Oddi, gallbladder, peritone*, spleen, splenic, hepat*, Glisson, falciform, coronary ligament, kidney, suprarenal, and adrenal. The 'cited-by' articles were also reviewed to ensure that all appropriate studies were included. RESULTS A total of one thousand three hundred and thirty articles were found, of which eighteen met the inclusion and exclusion criteria. The Quality Appraisal for Cadaveric Studies scale revealed substantial to excellent methodological quality of human studies, while a modified version of the Systematic Review Centre for Laboratory Animal Experimentation Risk of Bias Tool denoted poor methodological quality of animal studies. According to human studies, phrenic supply has been demonstrated for the gastro-esophageal junction, stomach, celiac ganglia, liver and its coronary ligament, inferior vena cava, gallbladder and adrenal glands, with half of the human samples studied presenting phrenic nerve connections with any subdiaphragmatic structure. CONCLUSIONS This review provides the first systematic evidence of subdiaphragmatic phrenic nerve supply and connections. This is of interest to professionals who care for people suffering from neck and shoulder pain, as well as patients with peridiaphragmatic disorders or hiccups. However, there are controversies about the autonomic or sensory nature of this supply.
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Affiliation(s)
- María Pérez-Montalbán
- Universidad de Sevilla. Facultad de Enfermería, Fisioterapia y Podología, Departamento de Fisioterapia, Spain
| | | | - Ángel Oliva-Pascual-Vaca
- Instituto de Biomedicina de Sevilla, IBiS, Departamento de Fisioterapia, Universidad de Sevilla, Spain; Escuela de Osteopatía de Madrid, Madrid, Spain.
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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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Syrine G, Mariem MK, Hend K, Imed L. Relationship Between Esophageal Motility Disorders and Autonomic Nervous System in Diabetic Patients: Pilot North African Study. Am J Mens Health 2022; 16:15579883221098588. [PMID: 35562861 PMCID: PMC9112418 DOI: 10.1177/15579883221098588] [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] [Indexed: 11/17/2022] Open
Abstract
Little attention has been given to esophageal disorders in diabetes mellitus. Pathophysiology of esophageal motility disorders (EMD) in patients with diabetes mellitus is multifactorial. The aims of the present study were: (a) to evaluate the prevalence of EMD in patients with Type 2 diabetes mellitus and (b) to determine the relationship between EMD and autonomic neuropathy as assessed by heart rate variability (HRV). All the patients completed a questionnaire about diabetes characteristics and gastrointestinal symptoms. Conventional esophageal manometry was performed in all patients. HRV was measured in three different situations (Lying Position 1, standing position, and Lying Position 2). The temporal and frequency domain parameters were considered for analysis. The prevalence of EMD in our patients was 60.5% (n = 23). Low score physical activity was significantly more frequent in patients with EMD (p = .03). There was an increase in sympathetic activity represented by the low frequency (LF) parameter (p = .027) in the presence of EMD. Whereas parasympathetic modulation of heart rate represented by the high frequency (HF) parameter (p = .027) was declined in patients with EMD compared to those without. The LF/HF ratio was significantly higher (p = .002) in patients with EMD. EMD were prevalent in diabetes mellitus and were associated to autonomic nervous system dysfunction predominantly at the parasympathetic component.
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Affiliation(s)
- Gallas Syrine
- Research Laboratory, "Technologies et Imagerie Médicale" (LR12ES06), Faculty of Medicine of Monastir, University of Monastir, Monastir, Tunisia.,Department of Nervous System Exploration, Sahloul Hospital, Sousse, Tunisia
| | | | - Knaz Hend
- Research Laboratory, "Technologies et Imagerie Médicale" (LR12ES06), Faculty of Medicine of Monastir, University of Monastir, Monastir, Tunisia.,Department of Nervous System Exploration, Sahloul Hospital, Sousse, Tunisia
| | - Latiri Imed
- Laboratory of Physiology, Faculty of Medicine of Sousse, University of Sousse, Sousse, Tunisia.,Research Laboratory, "Heart Failure" (LR12SP09), Farhat Hached University Hospital, Sousse, Tunisia
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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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Hospital opioid use predicts the need for discharge opioid prescriptions following laparoscopic bariatric surgery. Surg Endosc 2022; 36:6312-6318. [PMID: 35024936 DOI: 10.1007/s00464-022-09035-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 01/03/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND Overprescribing of opioids after surgery increases new persistent opioid use and diversion contributing to the opioid epidemic. There is a paucity of evidence regarding discharge opioid prescribing after bariatric surgery. METHODS We conducted a retrospective, cohort study analyzing post-operative opioid use at a single institution in patients who underwent laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LGB) from July 2019 thru February 2020. Multimodal analgesia was used including 5 mg oxycodone pills as needed during hospitalization with five prescribed on discharge if requested after discussion. Opioid use was determined from medical record review and post-operative data collected from patients at a 2-week follow-up visit. The Michigan Automated Prescription System (MAPS) was used as an adjunct to evaluate perioperative opioid prescriptions. RESULTS The cohort of 84 patients included those having LSG (72) and LGB (12). Fifty-five patients (65%) received a prescription for opioids on discharge and 91% filled their prescription. Only 44% (22/50) of those filling their opioid prescription took any opioids with 24% (65/275) of the total pills prescribed actually consumed. Opioid use on the surgical ward had the strongest correlation with discharge opioid use (rho = 0.65, CI 0.494, 0.770). The number of opioid pills taken on the surgical ward was positively associated with the number of pills taken after discharge. Those who took none, 1 to 3, or 4 or more opioid pills consumed 0.14 ± 0.48, 0.95 ± 1.71, and 3.14 ± 1.86 pills after discharge (p < 0.001). No patients required an additional opioid prescription within 90 days of surgery with MAPS confirmation. CONCLUSION Postoperative in-hospital opioid use following laparoscopic bariatric surgery predicts opioid use after discharge. This knowledge can guide patient-specific discharge opioid prescribing with the potential to mitigate diversion and reduce chronic opioid use.
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Meling S, Bertoli D, Sangnes DA, Brock C, Drewes A, Ejskjaer N, Dimcevski G, Søfteland E. Diabetic Gastroenteropathy: Soothe the Symptoms or Unravel a Cure? Curr Diabetes Rev 2022; 18:e220321192412. [PMID: 34225633 DOI: 10.2174/1573399817666210322154618] [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: 11/16/2020] [Revised: 01/19/2021] [Accepted: 02/13/2021] [Indexed: 11/22/2022]
Abstract
Autonomic neuropathy in patients with diabetes mellitus, and especially complications related to gastrointestinal neuropathy, are often overlooked in the clinic. Diabetic gastroenteropathy affects every segment of the gastrointestinal tract and generates symptoms that may include nausea, early satiety, vomiting, abdominal pain, constipation, and diarrhea. Severe cases can be complicated by weight loss, dehydration, and electrolyte disturbances. The pathophysiology is complex, the diagnostics and treatment options are multidisciplinary, and there is generally a lack of evidence for the treatment options. The aims for this review are first to summarize the pathophysiology and describe possible and expected symptoms and complications.Further, we will try to supply the clinician with a straightforward tool for diagnostics, and then, we shall summarize established treatment options, including diet recommendations, pharmacological and non-pharmacological options. Finally, we will explore the multiple possibilities of novel treatment, looking at medications related to the pathophysiology of neuropathy, other manifestations of autonomic neuropathies, and symptomatic treatment for other gastrointestinal disorders, also including new knowledge of endosurgical and neuromodulatory treatment. The overall goal is to increase awareness and knowledge on this frequent diabetic complication and to provide better tools for diagnosis and treatment. Ultimately, we hope to encourage further research in this field, as there are clear shortcomings in terms of biomarkers, pathophysiology, as well as treatment possibilities. In conclusion, diagnosis and management of diabetic gastroenteropathy are challenging and often require multidisciplinary teams and multimodal therapies. Treatment options are sparse, but new pharmacological, endoscopic, and neuromodulatory techniques have shown promising results in initial studies.
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Affiliation(s)
- Sondre Meling
- Department of Medicine, Stavanger University Hospital, Stavanger, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Davide Bertoli
- Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Dag A Sangnes
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Christina Brock
- Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
- Steno Diabetes Center North Jutland, Aalborg, Denmark
| | - Asbjørn Drewes
- Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
- Steno Diabetes Center North Jutland, Aalborg, Denmark
| | - Niels Ejskjaer
- Steno Diabetes Center North Jutland, Aalborg, Denmark
- Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark
| | - Georg Dimcevski
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Eirik Søfteland
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
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Sangnes DA, Dimcevski G, Frey J, Søfteland E. Diabetic diarrhoea: A study on gastrointestinal motility, pH levels and autonomic function. J Intern Med 2021; 290:1206-1218. [PMID: 34089624 DOI: 10.1111/joim.13340] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Chronic diarrhoea is a common, but poorly investigated diabetes complication. Autonomic neuropathy is a leading pathophysiological theory founded on old, small studies. Studies of gastrointestinal motility and pH levels are lacking. OBJECTIVES Using new diagnostic methods, we aimed to find out if diabetic diarrhoea was associated with alterations in gastrointestinal motility, pH levels and autonomic function. METHODS Fifty-seven patients (42 women, 46 with type 1 diabetes) were prospectively included. Symptoms were evaluated with the gastrointestinal symptom rating scale, defining ≥4 points as cases with diarrhoea. Patients scoring <4 were used as controls. We used the wireless motility capsule to measure gastrointestinal transit times, pH levels and contractility parameters. Autonomic function was assessed by measuring heart rate variability, baroreflex sensitivity and orthostatic hypotension. RESULTS Seventeen patients (30%) had diarrhoea. Compared with controls, cases had slower gastric emptying (21:46 vs. 4:14, h:min, p = 0.03) and faster colonic transit (18:37 vs. 54:25, p < 0.001). Cases had increased intraluminal pH in the antrum (2.4 vs. 1.2, p = 0.009), caecum (7.3 vs. 6.4, p = 0.008) and entire colon (7.1 vs. 6.7, p = 0.05). They also had a decreased pH difference across the pylorus (3.3 vs. 4.9, p = 0.004) and ileocaecal junction (0.6 vs 1.0, p = 0.009). The groups did not differ in autonomic function, but diastolic blood pressure drop correlated rs = -0.34 (p = 0.04) with colonic transit time. CONCLUSIONS Patients with diabetic diarrhoea had altered gastrointestinal transit and intraluminal pH levels, but minimal changes in autonomic function. Our results suggest that tests of gastrointestinal function are clinically useful in diabetic diarrhoea.
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Affiliation(s)
- Dag A Sangnes
- Department of Medicine, Haukeland University Hospital, Bergen, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Georg Dimcevski
- Department of Clinical Medicine, University of Bergen, Bergen, Norway.,National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway
| | - Jakub Frey
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Eirik Søfteland
- Department of Medicine, Haukeland University Hospital, Bergen, Norway.,Hormone Laboratory, Haukeland University Hospital, Bergen, Norway
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The Outcomes of Laparoscopic Biliopancreatic Diversion with Duodenal Switch on Gastro-esophageal Reflux Disease: the Mayo Clinic Experience. Obes Surg 2021; 31:4363-4370. [PMID: 34292439 DOI: 10.1007/s11695-021-05581-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/26/2021] [Accepted: 07/08/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE The outcomes of laparoscopic biliopancreatic diversion with duodenal switch (BPD-DS) on gastro-esophageal reflux disease (GERD) are not well elucidated. MATERIAL/METHODS This retrospective review included patients undergoing laparoscopic primary BPD-DS at Mayo Clinic from 2009 to 2019. GERD parameters analyzed included subjective symptom report/anti-reflux medication intake and/or endoscopic findings. GERD-HRQL questionnaire was also utilized post-operatively. Three subgroups were employed to stratify patients depending on GERD outcomes: the "No-effect" subgroup included patients where surgery did not affect either positively (GERD resolution) or negatively (de novo GERD) GERD outcome, "De novo GERD" subgroup, and "GERD-resolved" subgroup. Multinomial logistic modeling was used to examine associations with the 3-level GERD subgroup (p<0.05). RESULTS Seventy-six patients were included in the analysis. Thirty-four (44.7%) patients were found to be in the "GERD-resolved" subgroup, 28 (36.8%) patients in the "No-effect" subgroup, and 14 (18.4%) patients in the "De novo GERD" subgroup. Multinomial logistic modeling showed that patients with pre-surgery diabetes mellitus (DM) had lesser odds (OR= 0.248, (95% CI: 0.085-0.724, p=0.0108)) of GERD resolution than patients without pre-surgery DM. An association was also established between %TWL at 6 and 12 months following the procedure and GERD outcome (p=0.017 and 0.008, respectively). Finally, the mean (SD) post-operative GERD-HRQL score was 8.7 (8.1) points, and 69 (91%) patients were currently satisfied with their post-operative condition. CONCLUSION Laparoscopic BPD-DS appears to have a satisfactory GERD outcome in most patients undergoing the operation. There appears to be an association between pre-operative DM, %TWL at 6 and 12 months, and GERD prognosis in this population.
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Erosive Esophagitis and Symptoms of Gastroesophageal Reflux Disease in Patients with Morbid Obesity with and without Type 2 Diabetes: a Cross-sectional Study. Obes Surg 2021; 30:2667-2675. [PMID: 32193740 DOI: 10.1007/s11695-020-04545-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Type 2 diabetes (T2DM) is associated with gastroesophageal reflux disease (GERD) in the general population, but the relationship between these conditions in candidates for bariatric surgery is uncertain. We compared the prevalence of GERD and the association between GERD symptoms and esophagitis among bariatric candidates with and without T2DM. METHODS Cross-sectional study of baseline data from the Oseberg study in Norway. Both groups underwent gastroduodenoscopy and completed validated questionnaires: Gastrointestinal Symptom Rating Scale and Gastroesophageal Reflux Disease Questionnaire. Participants with T2DM underwent 24-h pH-metry. RESULTS A total of 124 patients with T2DM, 81 women, mean (SD) age 48.6 (9.4) years and BMI 42.3 (5.5) kg/m2, and 64 patients without T2DM, 46 women, age 43.0 (11.0) years and BMI 43.0 (5.0) kg/m2, were included. The proportions of patients reporting GERD-symptoms were low (< 29%) and did not differ significantly between groups, while the proportions of patients with esophagitis were high both in the T2DM and non-T2DM group, 58% versus 47%, p = 0.16. The majority of patients with esophagitis did not have GERD-symptoms (68-80%). Further, 55% of the patients with T2DM had pathologic acid reflux. Among these, 71% also had erosive esophagitis, whereof 67% were asymptomatic. CONCLUSIONS The prevalence of GERD was similar in bariatric patients with or without T2DM, and the proportion of patients with asymptomatic GERD was high independent of the presence or absence of T2DM. Accordingly, GERD may be underdiagnosed in patients not undergoing a preoperative endoscopy or acid reflux assessment. TRIAL REGISTRATION Clinical Trials.gov number NCT01778738.
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11
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Wegeberg AML, Brock C, Ejskjaer N, Karmisholt JS, Jakobsen PE, Drewes AM, Brock B, Farmer AD. Gastrointestinal symptoms and cardiac vagal tone in type 1 diabetes correlates with gut transit times and motility index. Neurogastroenterol Motil 2021; 33:e13885. [PMID: 32573076 DOI: 10.1111/nmo.13885] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 04/02/2020] [Accepted: 04/25/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although gastrointestinal (GI) symptoms are common in diabetes, they frequently do not correlate with measurable sensorimotor abnormalities. The wireless motility capsule (WMC) measures pressure, temperature, and pH as it traverses the GI tract wherefrom transit times and motility indices are derived. The aim was to investigate whether GI symptoms correlate with changes in (a) segmental transit times, (b) segmental motility index, (c) cardiac vagal tone, or (d) presence/absence of peripheral neuropathy in type 1 diabetes. METHODS Gastrointestinal symptoms in 104 participants with type 1 diabetes were measured using Gastroparesis Cardinal Symptoms Index and Gastrointestinal Symptom Rating Scale. All underwent standardized WMC investigation measuring segmental transit time and motility. Cardiac vagal tone and presence of peripheral neuropathy were measured using electrocardiographic and nerve conduction velocity testing. KEY RESULTS Colonic transit time was correlated with postprandial fullness (P = .01) and constipation (P = .03), while decreased colonic motility index was correlated with diarrhea (P = .01) and decreased bloating (P < .05). Symptoms were not correlated with gastric or small bowel transit time or motility index. In participants with low cardiac vagal tone, gastric motility index (P < .01) and colonic transit time (P < .05) were increased, but not in those with peripheral neuropathy. Abdominal pain was decreased with both peripheral neuropathy (P = .04) and decreased cardiac vagal tone (P = .02). CONCLUSIONS AND INFERENCES This study supports the rationale for whole gut investigation, using not only transit times but incorporating contractility indices as well. Furthermore, a decreased parasympathetic modulation and an increased hyposensate state appear to be present in type 1 diabetes.
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Affiliation(s)
- Anne-Marie L Wegeberg
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Christina Brock
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Niels Ejskjaer
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark.,Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
| | | | - Poul-Erik Jakobsen
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
| | - Asbjørn M Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.,Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
| | | | - Adam D Farmer
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.,Neurogastroenterology Group, Centre for Neuroscience and Trauma, Blizard Institute, Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Department of Gastroenterology, University Hospitals of North Midlands, Stoke on Trent, UK
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Guerrero-Fernández de Alba I, Orlando V, Monetti VM, Mucherino S, Gimeno-Miguel A, Vaccaro O, Forjaz MJ, Poblador Plou B, Prados-Torres A, Riccardi G, Menditto E. Comorbidity in an Older Population with Type-2 Diabetes Mellitus: Identification of the Characteristics and Healthcare Utilization of High-Cost Patients. Front Pharmacol 2020; 11:586187. [PMID: 33746740 PMCID: PMC7970761 DOI: 10.3389/fphar.2020.586187] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 10/29/2020] [Indexed: 01/11/2023] Open
Abstract
Objectives: Little is known about the specific comorbidities contributing to higher costs in patients with type-2 diabetes mellitus (T2DM), particularly in older cases. We aimed to evaluate the prevalence, type, and cost of comorbidities occurring in older T2DM patients versus older non-T2DM patients, and the factors associated with high cost (HC) T2DM patients. Methods: Retrospective cohort study using information from the Campania Region healthcare database. People aged ≥65 years who received ≥2 prescriptions for antidiabetic drugs were identified as "T2DM patients." Comorbidities among T2DM and non-T2DM groups were assessed through the RxRiskV Index (modified version). T2DM individuals were classified according to the total cost distribution as HC or "non-high cost." Two sub-cohorts of HC T2DM patients were assessed: above 90th and 80th percentile of the total cost. Age- and sex-adjusted logistic regression models were created. Results: Among the T2DM cohort, concordant and discordant comorbidities occurred significantly more frequently than in the non-T2DM cohort. Total mean annual cost per T2DM patient due to comorbidities was €7,627 versus €4,401 per non-T2DM patient. Among T2DM patients identified as being above 90th and 80th percentiles of cost distribution, the total annual costs were >€19,577 and >€2,563, respectively. The hospitalization cost was higher for T2DM cases. Strongest predictors of being a HC T2DM patient were having ≥5 comorbidities and renal impairment. Conclusion: HC patients accrued >80% of the total comorbidities cost in older T2DM patients. Integrated care models, with holistic and patient-tailored foci, could achieve more effective T2DM care.
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Affiliation(s)
- Inmaculada Guerrero-Fernández de Alba
- EpiChron Research Group, Aragon Health Sciences Institute (IACS), IIS Aragón, Miguel Servet University Hospital, Zaragoza, Spain
- Health Services Research on Chronic Patients Network (REDISSEC), ISCIII, Madrid, Spain
| | - Valentina Orlando
- CIRFF, Center of Pharmacoeconomics and Drug utilization Research, Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Valeria M. Monetti
- CIRFF, Center of Pharmacoeconomics and Drug utilization Research, Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Sara Mucherino
- CIRFF, Center of Pharmacoeconomics and Drug utilization Research, Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Antonio Gimeno-Miguel
- EpiChron Research Group, Aragon Health Sciences Institute (IACS), IIS Aragón, Miguel Servet University Hospital, Zaragoza, Spain
- Health Services Research on Chronic Patients Network (REDISSEC), ISCIII, Madrid, Spain
| | - Olga Vaccaro
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Maria João Forjaz
- National Centre of Epidemiology, Institute of Health Carlos III and REDISSEC, Madrid, Spain
| | - Beatriz Poblador Plou
- EpiChron Research Group, Aragon Health Sciences Institute (IACS), IIS Aragón, Miguel Servet University Hospital, Zaragoza, Spain
- Health Services Research on Chronic Patients Network (REDISSEC), ISCIII, Madrid, Spain
| | - Alexandra Prados-Torres
- EpiChron Research Group, Aragon Health Sciences Institute (IACS), IIS Aragón, Miguel Servet University Hospital, Zaragoza, Spain
- Health Services Research on Chronic Patients Network (REDISSEC), ISCIII, Madrid, Spain
| | - Gabriele Riccardi
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Enrica Menditto
- CIRFF, Center of Pharmacoeconomics and Drug utilization Research, Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
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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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Implications of rectal preconditioning for interpretation of sensory-motor data. J Biomech 2020; 99:109541. [PMID: 31787257 DOI: 10.1016/j.jbiomech.2019.109541] [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: 09/21/2019] [Revised: 11/16/2019] [Accepted: 11/19/2019] [Indexed: 11/23/2022]
Abstract
Testing of biomechanical properties of intestine requires the tissue to be preconditioned by applying cyclic loading to obtain repeatable mechanical data. However, little is known about the mechanosensory properties during intestinal preconditioning. We aimed to study the relationship between mechanical preconditioning of the human rectum and sensory response. Three fast rectal bag distensions to the pain threshold were done in seven healthy females. A visual analog scale (VAS) was used for sensory assessment. At each distension, we determined (1) time, bag cross-sectional area (CSA), radius (r), r/r0, pressure and tension to reach VAS = 1, 3 and 5 (pain threshold); (2) the same parameters at induced contraction start; (3) CSA where the pressure started to increase (CSAP>baseline) and (4) the number of contractions. The time, CSA, r/r0 and tension to reach VAS = 1 and VAS = 3 increased from distension 1 to 3 (4.9 < F < 11.5, 0.05 > P > 0.007), primarily due to difference between the first and second distension. For VAS = 5, r/r0 was smaller in distension 3 than distension 1 (P < 0.05), whereas time, CSA and tension did not differ between distensions (P > 0.5). Compared with distension 1, CSA, r/r0 and tension at contraction start, and CSAP>baseline were bigger in distensions 2 and 3 (5.5 < F < 10.9, 0.05 > P > 0.009). The pressure to reach the VAS levels, the contraction numbers and pressure at contraction start did not differ among distensions (P > 0.6). During mechanical preconditioning, CSA, tension and deformation increased at sub-pain levels, reflecting sensory adaptation. The data point to acute remodeling of a strain-dependent mechanism in the rectal wall.
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15
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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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16
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Meldgaard T, Keller J, Olesen AE, Olesen SS, Krogh K, Borre M, Farmer A, Brock B, Brock C, Drewes AM. Pathophysiology and management of diabetic gastroenteropathy. Therap Adv Gastroenterol 2019; 12:1756284819852047. [PMID: 31244895 PMCID: PMC6580709 DOI: 10.1177/1756284819852047] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 04/26/2019] [Indexed: 02/04/2023] Open
Abstract
Polyneuropathy is a common complication to diabetes. Neuropathies within the enteric nervous system are associated with gastroenteropathy and marked symptoms that severely reduce quality of life. Symptoms are pleomorphic but include nausea, vomiting, dysphagia, dyspepsia, pain, bloating, diarrhoea, constipation and faecal incontinence. The aims of this review are fourfold. First, to provide a summary of the pathophysiology underlying diabetic gastroenteropathy. Secondly to give an overview of the diagnostic methods. Thirdly, to provide clinicians with a focussed overview of current and future methods for pharmacological and nonpharmacological treatment modalities. Pharmacological management is categorised according to symptoms arising from the upper or lower gut as well as sensory dysfunctions. Dietary management is central to improvement of symptoms and is discussed in detail, and neuromodulatory treatment modalities and other emerging management strategies for diabetic gastroenteropathy are discussed. Finally, we propose a diagnostic/investigation algorithm that can be used to support multidisciplinary management.
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Affiliation(s)
| | - Jutta Keller
- Israelitic Hospital in Hamburg, Academic
Hospital University of Hamburg, Germany
| | - Anne Estrup Olesen
- Mech-Sense, Department of Gastroenterology and
Hepatology and Department of Clinical Medicine, Aalborg University Hospital,
Denmark,Department of Clinical Medicine, Aalborg
University, Denmark
| | - Søren Schou Olesen
- Mech-Sense, Department of Gastroenterology and
Hepatology and Department of Clinical Medicine, Aalborg University Hospital,
Denmark,Department of Clinical Medicine, Aalborg
University, Denmark
| | - Klaus Krogh
- Department of Hepatology and Gastroenterology,
Aarhus University Hospital, Denmark
| | - Mette Borre
- Department of Hepatology and Gastroenterology,
Aarhus University Hospital, Denmark
| | - Adam Farmer
- Department of Gastroenterology, University
Hospitals of North Midlands, Stoke on Trent, Staffordshire, UK,Centre for Digestive Diseases, Blizard
Institute of Cell and Molecular Science, Wingate Institute of
Neurogastroenterology, Barts and the London School of Medicine and
Dentistry, Queen Mary University of London, UK
| | - Birgitte Brock
- Department of Clinical Research, Steno Diabetes
Center Copenhagen (SDCC), Denmark
| | - Christina Brock
- Mech-Sense, Department of Gastroenterology and
Hepatology and Department of Clinical Medicine, Aalborg University Hospital,
Denmark,Department of Clinical Medicine, Aalborg
University, Denmark
| | - Asbjørn Mohr Drewes
- Mech-Sense, Department of Gastroenterology and
Hepatology and Department of Clinical Medicine, Aalborg University Hospital,
Denmark,Department of Clinical Medicine, Aalborg
University, Denmark
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17
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Chakraborty S, Halland M, Burton D, Desai A, Neja B, Low P, Singer W, Camilleri M, Zinsmeister AR, Bharucha AE. GI Dysfunctions in Diabetic Gastroenteropathy, Their Relationships With Symptoms, and Effects of a GLP-1 Antagonist. J Clin Endocrinol Metab 2019; 104:1967-1977. [PMID: 30358871 PMCID: PMC6467444 DOI: 10.1210/jc.2018-01623] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 10/19/2018] [Indexed: 12/15/2022]
Abstract
CONTEXT Delayed gastric emptying (GE) is common but often asymptomatic in diabetes. The relationship between symptoms, glycemia, and neurohormonal functions, including glucagonlike peptide 1 (GLP-1), are unclear. OBJECTIVES To assess whether GE disturbances, symptoms during a GE study, and symptoms during enteral lipid infusion explain daily symptoms and whether GLP-1 mediates symptoms during enteral lipid infusion. DESIGN In this randomized controlled trial, GE, enteral lipid infusion, gastrointestinal (GI) symptoms during these assessments, autonomic functions, glycosylated hemoglobin (HbA1c), and daily GI symptoms (2-week Gastroparesis Cardinal Symptom Index diary) were evaluated. During enteral lipid infusion, participants received the GLP-1 antagonist exendin 9-39 or placebo. SETTING Single tertiary referral center. PARTICIPANTS 24 healthy controls and 40 patients with diabetic gastroenteropathy. MAIN OUTCOME MEASURES GE, symptoms during enteral lipid infusion, and the effect of exendin 9-39 on the latter. RESULTS In patients, GE was normal (55%), delayed (33%), or rapid (12%). During lipid infusion, GI symptoms tended to be greater (P = 0.06) in patients with diabetes mellitus (DM) than controls; exendin 9-39 did not affect symptoms. The HbA1c was inversely correlated with the mean symptom score during the GE study (r = -0.46, P = 0.003) and lipid infusion (r = -0.47, P < 0.01). GE and symptoms during GE study accounted for 40% and 32%, respectively, of the variance in daily symptom severity and quality of life. CONCLUSIONS In DM gastroenteropathy, GE and symptoms during a GE study explain daily symptoms. Symptoms during enteral lipid infusion were borderline increased but not reduced by a GLP-1 antagonist.
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Affiliation(s)
| | - Magnus Halland
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Duane Burton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Anshuman Desai
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Bridget Neja
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Phillip Low
- Department of Neurology, Mayo Clinic, Rochester, Minnesota
| | | | - Michael Camilleri
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Alan R Zinsmeister
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Adil E Bharucha
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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18
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Gregersen H, Lo KM. What Is the Future of Impedance Planimetry in Gastroenterology? J Neurogastroenterol Motil 2018; 24:166-181. [PMID: 29605974 PMCID: PMC5885717 DOI: 10.5056/jnm18013] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 02/09/2018] [Indexed: 12/13/2022] Open
Abstract
The gastrointestinal (GI) tract is efficient in transporting ingested material to the site of delivery in healthy subjects. A fine balance exists between peristaltic forces, the mixing and delivery of the contents, and sensory signaling. This fine balance is easily disturbed by diseases. It is mandatory to understand the pathophysiology to enhance our understanding of GI disorders. The inaccessibility and complex nervous innervation, geometry and mechanical function of the GI tract make mechanosensory evaluation difficult. Impedance planimetry is a distension technology that assesses luminal geometry, mechanical properties including muscle dynamics, and processing of nociceptive signals from the GI tract. Since standardized models do not exist for GI muscle function in vivo, models, concepts, and terminology must be borrowed from other medical fields such as cardiac mechanophysiology. The review highlights the impedance planimetric technology, muscle dynamics assessment, and 3 applied technologies of impedance planimetry. These technologies are the multimodal probes that assesses sensory function, the functional luminal imaging probe that dynamically measures the geometry of the lumen it distends, and Fecobionics that is a simulated feces providing high-resolution measurements during defecation. The advanced muscle analysis and 3 applied technologies can enhance the quality of future interdisciplinary research for gaining more knowledge about mechanical function, sensory-motor disorders, and symptoms. This is a step in the direction of individualized treatment for GI disorders based on diagnostic subtyping. There seems to be no better alternatives to impedance planimetry, but only the functional luminal imaging probe is currently commercially available. Wider use depends on commercialization of the multimodal probe and Fecobionics.
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Affiliation(s)
- Hans Gregersen
- GIOME, Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong.,California Medical Innovations Institute, San Diego, California, USA
| | - Kar Man Lo
- GIOME Doublecove, Wu Kai Sha, New Territories, Hong Kong
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19
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Zhao J, Yang J, Liao D, Gregersen H. Interdependency between mechanical parameters and afferent nerve discharge in remodeled diabetic Goto-Kakizaki rat intestine. Clin Exp Gastroenterol 2017; 10:303-314. [PMID: 29238211 PMCID: PMC5716675 DOI: 10.2147/ceg.s145016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Background Gastrointestinal disorders are very common in diabetic patients, but the pathogenesis is still not well understood. Peripheral afferent nerves may be involved due to the complex regulation of gastrointestinal function by the enteric nervous system. Objective We aimed to characterize the stimulus–response function of afferent fibers innervating the jejunum in the Goto-Kakizaki (GK) type 2 diabetic rat model. A key question is whether changes in afferent firing arise from remodeled tissue or from adaptive afferent processes. Design Seven 32-week-old male GK rats and seven age-matched normal Wistar rats were studied. Firing from mesenteric afferent nerves was recorded in excised jejunal segments of seven GK rats and seven normal Wistar rats during ramp test, stress relaxation test, and creep test. The circumferential stress–strain, spike rate increase ratio (SRIR), and single unit firing rates were calculated for evaluation of interdependency of the mechanical stimulations and the afferent nerve discharge. Results Elevated sensitivity to mechanical stimuli was found for diabetic nerve bundles and single unit activity (P<0.05). The stress relaxed less in the diabetic intestinal segment (P<0.05). Linear association between SRIR and the thickness of circumferential muscle layer was found at high stress levels as well as for SRIR and the glucose level. Conclusion Altered viscoelastic properties and elevated mechanosensitivity were found in the GK rat intestine. The altered nerve signaling is related to muscle layer remodeling and glucose levels and may contribute to gastrointestinal symptoms experienced by diabetic patients.
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Affiliation(s)
- Jingbo Zhao
- Giome Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Jian Yang
- Giome Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Donghua Liao
- Giome Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Hans Gregersen
- Giome Center, Department of Surgery, Chinese University of Hong Kong and Prince of Wales Hospital, Shatin, Hong Kong
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20
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Zhao M, Liao D, Zhao J. Diabetes-induced mechanophysiological changes in the small intestine and colon. World J Diabetes 2017; 8:249-269. [PMID: 28694926 PMCID: PMC5483424 DOI: 10.4239/wjd.v8.i6.249] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 04/05/2017] [Accepted: 05/05/2017] [Indexed: 02/05/2023] Open
Abstract
The disorders of gastrointestinal (GI) tract including intestine and colon are common in the patients with diabetes mellitus (DM). DM induced intestinal and colonic structural and biomechanical remodeling in animals and humans. The remodeling is closely related to motor-sensory abnormalities of the intestine and colon which are associated with the symptoms frequently encountered in patients with DM such as diarrhea and constipation. In this review, firstly we review DM-induced histomorphological and biomechanical remodeling of intestine and colon. Secondly we review motor-sensory dysfunction and how they relate to intestinal and colonic abnormalities. Finally the clinical consequences of DM-induced changes in the intestine and colon including diarrhea, constipation, gut microbiota change and colon cancer are discussed. The final goal is to increase the understanding of DM-induced changes in the gut and the subsequent clinical consequences in order to provide the clinicians with a better understanding of the GI disorders in diabetic patients and facilitates treatments tailored to these patients.
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21
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Grabauskas G, Wu X, Song I, Zhou SY, Lanigan T, Owyang C. Increased Activation of the TRESK K + Mediates Vago-Vagal Reflex Malfunction in Diabetic Rats. Gastroenterology 2016; 151:910-922.e7. [PMID: 27475306 PMCID: PMC5159314 DOI: 10.1053/j.gastro.2016.07.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 06/29/2016] [Accepted: 07/07/2016] [Indexed: 12/28/2022]
Abstract
BACKGROUND & AIMS Patients with diabetes have defects in the vagal afferent pathway that result in abnormal gastrointestinal function. We investigated whether selective increased activation of the 2-pore domain potassium channel TRESK (2-pore-domain weak inward-rectifying potassium channel-related spinal cord potassium channel) contributes to nodose ganglia (NG) malfunction, disrupting gastrointestinal function in diabetic rats. METHODS We conducted whole-cell current-clamp and single-unit recordings in NG neurons from diabetes-prone BioBreeding/Worcester rats and streptozotocin-induced diabetic (STZ-D) rats and compared them with control rats. NG neurons in rats or cultured NG neurons were exposed to pharmacologic antagonists and/or transfected with short hairpin or small interfering RNAs that reduced expression of TRESK. We then made electrophysiologic recordings and studied gastrointestinal functions. RESULTS We observed reduced input resistance, hyperpolarized membrane potential, and increased current threshold to elicit action potentiation in NG neurons of STZ-D rats compared with controls. NG neuron excitability was similarly altered in diabetes-prone rats. In vivo single-unit NG neuronal discharges in response to 30 and 60 pmol cholecystokinin octapeptide were significantly lower in STZ-D rats compared with controls. Reducing expression of the TRESK K+ channel restored NG excitability in vitro and in vivo, as well as cholecystokinin 8-stimulated secretion of pancreatic enzymes and secretin-induced gastrointestinal motility, which are mediated by vago-vagal reflexes. These abnormalities resulted from increased intracellular Ca2+ in the NG, activating calcineurin, which, in turn, bound to an nuclear factor of activated T cell-like docking site on the TRESK protein, resulting in neuronal membrane hyperpolarization. CONCLUSIONS In 2 rate models of diabetes, we found that activation of the TRESK K+ channel reduced NG excitability and disrupted gastrointestinal functions.
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Affiliation(s)
- Gintautas Grabauskas
- Division of Gastroenterology, Department of Internal Medicine, Ann Arbor, Michigan
| | - Xiaoyin Wu
- Division of Gastroenterology, Department of Internal Medicine, Ann Arbor, Michigan
| | - Il Song
- Division of Gastroenterology, Department of Internal Medicine, Ann Arbor, Michigan
| | - Shi-Yi Zhou
- Division of Gastroenterology, Department of Internal Medicine, Ann Arbor, Michigan
| | - Thomas Lanigan
- Department of Internal Medicine, Center for Gene Therapy, Ann Arbor, Michigan
| | - Chung Owyang
- Division of Gastroenterology, Department of Internal Medicine, Ann Arbor, Michigan.
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Ravages of Diabetes on Gastrointestinal Sensory-Motor Function: Implications for Pathophysiology and Treatment. Curr Gastroenterol Rep 2016; 18:6. [PMID: 26768896 DOI: 10.1007/s11894-015-0481-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Symptoms related to functional and sensory abnormalities are frequently encountered in patients with diabetes mellitus. Most symptoms are associated with impaired gastric and intestinal function. In this review, we discuss basic concepts of sensory-motor dysfunction and how they relate to clinical findings and gastrointestinal abnormalities that are commonly seen in diabetes. In addition, we review techniques that are available for investigating the autonomic nervous system, neuroimaging and neurophysiology of sensory-motor function. Such technological advances, while not readily available in the clinical setting, may facilitate stratification and individualization of therapy in diabetic patients in the future. Unraveling the structural, mechanical, and sensory remodeling in diabetes disease is based on a multidisciplinary approach that can bridge the knowledge from a variety of scientific disciplines. The final goal is to increase the understanding of the damage to GI structures and to sensory processing of symptoms, in order to assist clinicians with developing an optimal mechanics based treatment.
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Zhao J, Gregersen H. Diabetes-induced mechanophysiological changes in the esophagus. Ann N Y Acad Sci 2016; 1380:139-154. [PMID: 27495976 DOI: 10.1111/nyas.13180] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 06/17/2016] [Accepted: 06/20/2016] [Indexed: 12/13/2022]
Abstract
Esophageal disorders are common in diabetes mellitus (DM) patients. DM induces mechanostructural remodeling in the esophagus of humans and animal models. The remodeling is related to esophageal sensorimotor abnormalities and to symptoms frequently encountered by DM patients. For example, gastroesophageal reflux disease (GERD) is a common disorder associated with DM. This review addresses diabetic remodeling of esophageal properties and function in light of the Esophagiome, a scientifically based modeling effort to describe the physiological dynamics of the normal, intact esophagus built upon interdisciplinary approaches with applications for esophageal disease. Unraveling the structural, biomechanical, and sensory remodeling of the esophagus in DM must be based on a multidisciplinary approach that can bridge the knowledge from a variety of scientific disciplines. The first focus of this review is DM-induced morphodynamic and biomechanical remodeling in the esophagus. Second, we review the sensorimotor dysfunction in DM and how it relates to esophageal remodeling. Finally, we discuss the clinical consequences of DM-induced esophageal remodeling, especially in relation to GERD. The ultimate aim is to increase the understanding of DM-induced remodeling of esophageal structure and sensorimotor function in order to assist clinicians to better understand the esophageal disorders induced by DM and to develop better treatments for those patients.
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Affiliation(s)
- Jingbo Zhao
- Giome Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
| | - Hans Gregersen
- GIOME, Department of Surgery, Prince of Wales Hospital and Chinese University of Hong Kong, Shatin, Hong Kong SAR.,GIOME, College of Bioengineering, Chongqing University, Chongqing, China
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Azpiroz F, Malagelada C. Diabetic neuropathy in the gut: pathogenesis and diagnosis. Diabetologia 2016; 59:404-8. [PMID: 26643877 DOI: 10.1007/s00125-015-3831-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 11/04/2015] [Indexed: 12/27/2022]
Abstract
The activity of the digestive tract is usually regulated to match its content: physiological stimuli in the gut induce modulatory reflexes that control digestive function so that digestion is normally not perceived. However, under certain circumstances, digestive stimuli may activate sensory afferents and give rise to conscious sensations. Both reflex and sensory signals are modulated by a balance of excitatory and inhibitory mechanisms. Patients with diabetes may develop a neuropathy affecting the control of gastric and/or intestinal motor function and the sensory innervation as well. During fasting the stomach is contracted and relaxes to accommodate a meal. After ingestion the stomach progressively recontracts and this contraction gently produces gastric emptying. Impairment of excitatory pathways affects the contraction of the stomach, which may result in delayed gastric emptying and vomiting of retained food. Conversely, alteration of the inhibitory neural pathways results in impaired relaxation of the stomach in response to a meal; in this case increased wall tension may produce early satiation, fullness and nausea. Diabetic neuropathy may distort the control of intestinal motility, which can lead to diverse symptoms such as diarrhoea, constipation, intestinal distension and abdominal pain. Neuropathy in diabetes may also affect the sensory nerves of the gut, and depending on which pathways are involved, perception may be increased or reduced. In summary, in patients with diabetic neuropathy, disorders of gut motor function are associated with sensory abnormalities, and the combination of impaired pathways determines the clinical consequences. This review summarises a presentation given at the 'Diagnosis and treatment of autonomic diabetic neuropathy in the gut' symposium at the 2015 annual meeting of the EASD. It is accompanied by another mini-review on a topic from this symposium (by Hans Törnblom, DOI: 10.1007/s00125-015-3829-9 ) and a commentary by the Session Chair, Péter Kempler (DOI: 10.1007/s00125-015-3826-y ).
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Affiliation(s)
- Fernando Azpiroz
- Digestive System Research Unit, Hospital General Vall d'Hebron, 08035, Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain, .
- Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Cerdanyola del Vallès, Spain.
| | - Carolina Malagelada
- Digestive System Research Unit, Hospital General Vall d'Hebron, 08035, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain
- Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Cerdanyola del Vallès, Spain
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Drewes AM, Søfteland E, Dimcevski G, Farmer AD, Brock C, Frøkjær JB, Krogh K, Drewes AM. Brain changes in diabetes mellitus patients with gastrointestinal symptoms. World J Diabetes 2016; 7:14-26. [PMID: 26839652 PMCID: PMC4724575 DOI: 10.4239/wjd.v7.i2.14] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 09/14/2015] [Accepted: 10/27/2015] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus is a common disease and its prevalence is increasing worldwide. In various studies up to 30%-70% of patients present dysfunction and complications related to the gut. To date several clinical studies have demonstrated that autonomic nervous system neuropathy and generalized neuropathy of the central nervous system (CNS) may play a major role. This systematic review provides an overview of the neurodegenerative changes that occur as a consequence of diabetes with a focus on the CNS changes and gastrointestinal (GI) dysfunction. Animal models where diabetes was induced experimentally support that the disease induces changes in CNS. Recent investigations with electroencephalography and functional brain imaging in patients with diabetes confirm these structural and functional brain changes. Encephalographic studies demonstrated that altered insular processing of sensory stimuli seems to be a key player in symptom generation. In fact one study indicated that the more GI symptoms the patients experienced, the deeper the insular electrical source was located. The electroencephalography was often used in combination with quantitative sensory testing mainly showing hyposensitivity to stimulation of GI organs. Imaging studies on patients with diabetes and GI symptoms mainly showed microstructural changes, especially in brain areas involved in visceral sensory processing. As the electrophysiological and imaging changes were associated with GI and autonomic symptoms they may represent a future therapeutic target for treating diabetics either pharmacologically or with neuromodulation.
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Dong L, Liang X, Sun B, Ding X, Han H, Zhang G, Rong W. Impairments of the primary afferent nerves in a rat model of diabetic visceral hyposensitivity. Mol Pain 2015; 11:74. [PMID: 26652274 PMCID: PMC4676135 DOI: 10.1186/s12990-015-0075-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 11/03/2015] [Indexed: 12/11/2022] Open
Abstract
Background Diabetic neuropathy in visceral organs such as the gastrointestinal (GI) tract is still poorly understood, despite that GI symptoms are among the most common diabetic complications. The present study was designed to explore the changes in visceral sensitivity and the underlying functional and morphological deficits of the sensory nerves in short-term diabetic rats. Here, we compared the colorectal distension (CRD)-induced visceromotor response (VMR, an index of visceral pain) in vivo, the mechanosensitivity of colonic afferents ex vivo as well as the expression of protein gene product (PGP) 9.5 and calcitonin gene-related peptide (CGRP) in colon between diabetic (3–6 weeks after streptozotocin injection) and control (age-matched vehicle injection) rats. Results VMR was markedly decreased in the diabetic compared to the control rats. There was a significant decrease in multiunit pelvic afferent nerve responses to ramp distension of the ex vivo colon and single unit analysis indicated that an impaired mechanosensitivity of low-threshold and wide dynamic range fibers may underlie the afferent hyposensitivity in the diabetic colon. Fewer PGP 9.5- or CGRP-immunoreactive fibers and lower protein level of PGP 9.5 were found in the colon of diabetic rats. Conclusions These observations revealed the distinctive feature of colonic neuropathy in short-term diabetic rats that is characterized by a diminished sensory innervation and a blunted mechanosensitivity of the remnant sensory nerves.
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Affiliation(s)
- Li Dong
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, 1111 Xianxia Road, Shanghai, 200050, China. .,Department of Physiology, Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.
| | - Xizi Liang
- Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, 659 Zhizhaoju Road, Shanghai, 200011, China.
| | - Biying Sun
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, 1111 Xianxia Road, Shanghai, 200050, China. .,Department of Physiology, Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.
| | - Xiaowei Ding
- Department of Physiology, Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.
| | - Hongxiu Han
- Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, 659 Zhizhaoju Road, Shanghai, 200011, China.
| | - Guohua Zhang
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, 1111 Xianxia Road, Shanghai, 200050, China. .,Department of Physiology, Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.
| | - Weifang Rong
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, 1111 Xianxia Road, Shanghai, 200050, China. .,Department of Physiology, Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.
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Sun XM, Tan JC, Zhu Y, Lin L. Association between diabetes mellitus and gastroesophageal reflux disease: A meta-analysis. World J Gastroenterol 2015; 21:3085-3092. [PMID: 25780309 PMCID: PMC4356931 DOI: 10.3748/wjg.v21.i10.3085] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2014] [Revised: 06/21/2014] [Accepted: 08/28/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether there is a link between diabetes mellitus (DM) and gastroesophageal reflux disease (GERD).
METHODS: We conducted a systematic search of PubMed and Web of Science databases, from their respective inceptions until December 31, 2013, for articles evaluating the relationship between DM and GERD. Studies were selected for analysis based on certain inclusion and exclusion criteria. Data were extracted from each study on the basis of predefined items. A meta-analysis was performed to compare the odds ratio (OR) in DM between individuals with and without GERD using a fixed effect or random effect model, depending on the absence or presence of significant heterogeneity. Subgroup analyses were used to identify sources of heterogeneity. Publication bias was assessed by Begg’s test. To evaluate the results, we also performed a sensitivity analysis.
RESULTS: When the electronic database and hand searches were combined, a total of nine eligible articles involving 9067 cases and 81 968 controls were included in our meta-analysis. Based on the random-effects model, these studies identified a significant association between DM and the risk of GERD (overall OR = 1.61; 95%CI: 1.36-1.91; P = 0.003). Subgroup analyses indicated that this result persisted in studies on populations from Eastern countries (OR = 1.71; 95%CI: 1.38-2.12; P = 0.003) and in younger patients (mean age < 50 years) (OR = 1.70; 95%CI: 1.22-2.37; P = 0.001). No significant publication bias was observed in this meta-analysis using Begg’s test (P = 0.175). The sensitivity analysis also confirmed the stability of our results.
CONCLUSION: This meta-analysis suggests that patients with DM are at greater risk of GERD than those who do not have DM.
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Arendt-Nielsen L, Madsen H, Jarrell J, Gregersen H, Drewes AM. Pain evoked by distension of the uterine cervix in women with dysmenorrhea: evidence for central sensitization. Acta Obstet Gynecol Scand 2014; 93:741-8. [DOI: 10.1111/aogs.12403] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 04/10/2014] [Indexed: 12/15/2022]
Affiliation(s)
- Lars Arendt-Nielsen
- Center for Sensory-Motor Interactions (SMI); Department of Health Science and Technology; School of Medicine; Aalborg University; Aalborg Denmark
| | - Hans Madsen
- Department of Obstetrics and Gynecology; Aalborg University Hospital; Aalborg Denmark
| | - John Jarrell
- Calgary Chronic Pain Centre and Department of Obstetrics and Gynecology; University of Calgary; Calgary Alberta Canada
| | - Hans Gregersen
- Mech-Sense; Department of Gastroenterology; Aalborg University Hospital; Aalborg Denmark
| | - Asbjørn M. Drewes
- Center for Sensory-Motor Interactions (SMI); Department of Health Science and Technology; School of Medicine; Aalborg University; Aalborg Denmark
- Mech-Sense; Department of Gastroenterology; Aalborg University Hospital; Aalborg Denmark
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Søfteland E, Brock C, Frøkjær JB, Brøgger J, Madácsy L, Gilja OH, Arendt-Nielsen L, Simrén M, Drewes AM, Dimcevski G. Association between visceral, cardiac and sensorimotor polyneuropathies in diabetes mellitus. J Diabetes Complications 2014; 28:370-7. [PMID: 24355661 DOI: 10.1016/j.jdiacomp.2013.10.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Revised: 09/13/2013] [Accepted: 10/21/2013] [Indexed: 12/13/2022]
Abstract
AIMS Gastrointestinal complaints are common in diabetes mellitus. However, its association to peripheral sensorimotor and autonomic neuropathies is not well investigated. The aim was to assess skin, muscle, bone and visceral sensitivity in diabetes patients with sensorimotor neuropathy, and correlate these with gastrointestinal symptoms and degree of cardiac autonomic neuropathy. METHODS Twenty patients with sensorimotor neuropathy (65% type 2 diabetes, aged 58.3±12.0 years, diabetes duration 15.8±10.0 years) and 16 healthy controls were recruited. Cutaneous sensitivity to von Frey filaments, mechanical allodynia, muscle/bone/rectosigmoid sensitivities, and heart rate variability were examined. Gastrointestinal symptom scores (PAGI-SYM) and health-related quality of life (SF-36) were also recorded. RESULTS Patients displayed hypesthesia to von Frey filaments (p=0.028), but no difference to muscle and bone pain sensitivities. Also, patients were hyposensitive to multimodal rectal stimulations (all p<0.05), although they suffered more gastrointestinal complaints. Heart rate variability was reduced in the patient cohort. Rectal mechanical and cutaneous sensitivities correlated (p<0.001), and both were associated with heart rate variability as well as PAGI-SYM and SF-36 scores (p<0.01). CONCLUSIONS In diabetic sensorimotor neuropathy there is substantial evidence of concomitant cutaneous, cardiac and visceral autonomic neuropathies. The neuropathy may reduce quality of life and explain the higher prevalence of gastrointestinal complaints.
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Affiliation(s)
- Eirik Søfteland
- Department of Medicine, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
| | - Christina Brock
- Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Jens B Frøkjær
- Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark
| | - Jan Brøgger
- Section for Clinical Neurophysiology, Department of Neurology, Haukeland University Hospital, Bergen, Norway
| | - László Madácsy
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Odd H Gilja
- Department of Clinical Medicine, University of Bergen, Bergen, Norway; National Centre for Ultrasound in Gastroenterology, Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Lars Arendt-Nielsen
- Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Magnus Simrén
- Institute of Medicine, Department of Internal Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Asbjørn M Drewes
- Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark; Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Georg Dimcevski
- Department of Clinical Medicine, University of Bergen, Bergen, Norway; National Centre for Ultrasound in Gastroenterology, Department of Medicine, Haukeland University Hospital, Bergen, Norway
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Lelic D, Brock C, Simrén M, Frøkjaer JB, Søfteland E, Dimcevski G, Gregersen H, Drewes AM. The brain networks encoding visceral sensation in patients with gastrointestinal symptoms due to diabetic neuropathy. Neurogastroenterol Motil 2014; 26:46-58. [PMID: 24050116 DOI: 10.1111/nmo.12222] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Accepted: 08/02/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Increasing evidence points to association between long-term diabetes mellitus and abnormal brain processing. The aim of this study was to investigate central changes due to electrical stimulation in esophagus in patients with upper gastrointestinal (GI) symptoms due to diabetic neuropathy. METHODS Twenty-three diabetes patients with upper GI symptoms and 27 healthy controls were included. A standard ambulatory 24-h electrocardiography was carried out. 122-channel esophageal evoked brain potentials to electrical stimulation were acquired. Brain source/network analysis was performed. Gastroparesis Cardinal Symptom Index was used to evaluate upper GI symptoms and SF-36 questionnaire was utilized to assess patients' quality of life (QOL). KEY RESULTS Diabetes patients with GI symptoms showed modifications in three brain networks: (i) brainstem/operculum/frontal cortex, (ii) operculum/cingulate, and (iii) mid-cingulate/anterior-cingulate/operculum/deep limbic structures. Operculum brain source in patients was localized deeper and more anterior in all three networks. The shift of operculum source was correlated with the severity of upper GI symptoms, decreased heart beat-to-beat interval, and decreased SD of the intervals. The activation of the first network was delayed in patients. Operculum source had higher activity than cingulate in the second network in patients, and this was correlated with decreased physical QOL. Deep limbic source was localized deeper in patients, which also correlated with decreased physical QOL. CONCLUSIONS & INFERENCES This study indicates involvement of central nervous system in diabetes. Reorganization within opercular cortex was correlated with GI symptoms suggesting that operculo-cingulate cortex could contribute to development and maintenance of GI symptoms in diabetes patients.
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Affiliation(s)
- D. Lelic
- Mech-Sense; Department of Gastroenterology and Hepatology; Aalborg Hospital; Aarhus University; Aalborg Denmark
| | - C. Brock
- Mech-Sense; Department of Gastroenterology and Hepatology; Aalborg Hospital; Aarhus University; Aalborg Denmark
| | - M. Simrén
- Institute of Medicine; Department of Internal Medicine; Sahlgrenska Academy; University of Gothenburg; Gothenburg Sweden
| | - J. B. Frøkjaer
- Mech-Sense; Department of Radiology; Aalborg Hospital; Aarhus University Hospital; Aalborg Denmark
| | - E. Søfteland
- Department of Medicine; Haukeland University Hospital; Bergen Norway
- Institute of Medicine; University of Bergen; Bergen Norway
| | - G. Dimcevski
- Department of Medicine; Haukeland University Hospital; Bergen Norway
- Institute of Medicine; University of Bergen; Bergen Norway
| | - H. Gregersen
- Department of Medicine; GIOME and Sino-Danish Centre for Education and Research; Aarhus Denmark
| | - A. M. Drewes
- Mech-Sense; Department of Gastroenterology and Hepatology; Aalborg Hospital; Aarhus University; Aalborg Denmark
- Department of Health Science and Technology; Center for Sensory-Motor Interactions (SMI); Aalborg University; Aalborg Denmark
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Brock C, Søfteland E, Gunterberg V, Frøkjær JB, Lelic D, Brock B, Dimcevski G, Gregersen H, Simrén M, Drewes AM. Diabetic autonomic neuropathy affects symptom generation and brain-gut axis. Diabetes Care 2013; 36:3698-705. [PMID: 24026548 PMCID: PMC3816908 DOI: 10.2337/dc13-0347] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Long-term diabetes leads to severe peripheral, autonomous, and central neuropathy in combination with clinical gastrointestinal symptoms. The brain-gut axis thus expresses a neurophysiological profile, and heart rate variability (HRV) can be correlated with clinical gastrointestinal symptoms. RESEARCH DESIGN AND METHODS Fifteen healthy volunteers and 15 diabetic patients (12 with type 1 diabetes) with severe gastrointestinal symptoms and clinical suspicion of autonomic neuropathy were included. Psychophysics and evoked brain potentials were assessed after painful rectosigmoid electrostimulations, and brain activity was modeled by brain electrical source analysis. Self-reported gastrointestinal symptoms (per the Patient Assessment of Upper Gastrointestinal Disorder Severity Symptom Index) and quality of life (SF-36 Short Form Survey) were collected. RESULTS Diabetic patients had autonomous neuropathy, evidenced by decreased electrocardiographic R-R interval (P = 0.03) and lower HRV (P = 0.008). Patients were less sensitive to painful stimulation (P = 0.007), had prolonged latencies of evoked potentials (P ≤ 0.001), and showed diminished amplitude of the N2-P2 component in evoked potentials (P = 0.01). There was a caudoanterior shift of the insular brain source (P = 0.01) and an anterior shift of the cingulate generator (P = 0.01). Insular source location was associated with HRV assessments (all P < 0.02), and the shift (expressed in mm) correlated negatively with physical health (P < 0.001) and positively with nausea (P = 0.03) and postprandial fullness (P = 0.03). Cingulate source shift was correlated negatively with physical health (P = 0.005) and positively with postprandial fullness (P ≤ 0.001). CONCLUSIONS This study provides evidence for interaction between autonomic neuropathy and peripheral nervous degeneration, as well as changes in dipole sources in diabetic patients with gastrointestinal symptoms. The findings may lead to improved treatment modalities targeting pharmacological neuroprotection or neuromodulation.
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Zhang HH, Hu J, Zhou YL, Hu S, Wang YM, Chen W, Xiao Y, Huang LYM, Jiang X, Xu GY. Promoted interaction of nuclear factor-κB with demethylated cystathionine-β-synthetase gene contributes to gastric hypersensitivity in diabetic rats. J Neurosci 2013; 33:9028-38. [PMID: 23699514 PMCID: PMC6705038 DOI: 10.1523/jneurosci.1068-13.2013] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Revised: 04/11/2013] [Accepted: 04/16/2013] [Indexed: 12/13/2022] Open
Abstract
Patients with long-standing diabetes frequently demonstrate gastric hypersensitivity with an unknown mechanism. The present study was designed to investigate roles for nuclear factor-κB (NF-κB) and the endogenous H2S-producing enzyme cystathionine-β-synthetase (CBS) signaling pathways by examining cbs gene methylation status in adult rats with diabetes. Intraperitoneal injection of streptozotocin (STZ) produced gastric hypersensitivity in female rats in response to gastric balloon distention. Treatment with the CBS inhibitor aminooxyacetic acid significantly attenuated STZ-induced gastric hypersensitivity in a dose-dependent fashion. Aminooxyacetic acid treatment also reversed hyperexcitability of gastric-specific dorsal root ganglion (DRG) neurons labeled by the dye DiI in diabetic rats. Conversely, the H2S donor NaHS enhanced neuronal excitability of gastric DRG neurons. Expression of CBS and p65 were markedly enhanced in gastric DRGs in diabetic rats. Blockade of NF-κB signaling using pyrrolidine dithiocarbamate reversed the upregulation of CBS expression. Interestingly, STZ treatment led to a significant demethylation of CpG islands in the cbs gene promoter region, as determined by methylation-specific PCR and bisulfite sequencing. STZ treatment also remarkably downregulated the expression of DNA methyltransferase 3a and 3b. More importantly, STZ treatment significantly enhanced the ability of cbs to bind DNA at the p65 consensus site, as shown by chromatin immunoprecipitation assays. Our findings suggest that upregulation of cbs expression is attributed to cbs promoter DNA demethylation and p65 activation and that the enhanced interaction of the cbs gene and p65 contributes to gastric hypersensitivity in diabetes. This finding may guide the development and evaluation of new treatment modalities for patients with diabetic gastric hypersensitivity.
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Affiliation(s)
- Hong-Hong Zhang
- Division of Endocrinology, the Second Affiliated Hospital, Soochow University, Suzhou 215000, P.R. China
- Institute of Neuroscience, Suzhou Key Laboratory of Pain Research and Therapy, Department of Neurobiology, Soochow University, Suzhou 215123, P.R. China
| | - Ji Hu
- Division of Endocrinology, the Second Affiliated Hospital, Soochow University, Suzhou 215000, P.R. China
| | - You-Lang Zhou
- Institute of Neuroscience, Suzhou Key Laboratory of Pain Research and Therapy, Department of Neurobiology, Soochow University, Suzhou 215123, P.R. China
- Hand Surgery Research Center, Department of Hand Surgery, Affiliated Hospital of Nantong University, Nantong 226001, P.R. China, and
| | - Shufen Hu
- Institute of Neuroscience, Suzhou Key Laboratory of Pain Research and Therapy, Department of Neurobiology, Soochow University, Suzhou 215123, P.R. China
| | - Yong-Meng Wang
- Institute of Neuroscience, Suzhou Key Laboratory of Pain Research and Therapy, Department of Neurobiology, Soochow University, Suzhou 215123, P.R. China
| | - Wei Chen
- Hand Surgery Research Center, Department of Hand Surgery, Affiliated Hospital of Nantong University, Nantong 226001, P.R. China, and
| | - Ying Xiao
- Division of Endocrinology, the Second Affiliated Hospital, Soochow University, Suzhou 215000, P.R. China
| | - Li-Yen Mae Huang
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-1069
| | - Xinghong Jiang
- Institute of Neuroscience, Suzhou Key Laboratory of Pain Research and Therapy, Department of Neurobiology, Soochow University, Suzhou 215123, P.R. China
| | - Guang-Yin Xu
- Division of Endocrinology, the Second Affiliated Hospital, Soochow University, Suzhou 215000, P.R. China
- Institute of Neuroscience, Suzhou Key Laboratory of Pain Research and Therapy, Department of Neurobiology, Soochow University, Suzhou 215123, P.R. China
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Masuzaki H, Takemoto N, Kawamoto E, Nomiyama T, Tanaka H, Morita M. [Discussion meeting on the clinical update and topics in a variety of diseases closely related with diabetes mellitus]. NIHON NAIKA GAKKAI ZASSHI. THE JOURNAL OF THE JAPANESE SOCIETY OF INTERNAL MEDICINE 2013; 102:938-954. [PMID: 23772510 DOI: 10.2169/naika.102.938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Affiliation(s)
- Hiroaki Masuzaki
- Second Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology, Graduate School of Medicine, University of the Ryukyus, Japan
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Frøkjær JB, Andersen LW, Brock C, Simrén M, Ljungberg M, Søfteland E, Dimcevski G, Yavarian Y, Gregersen H, Drewes AM. Altered brain microstructure assessed by diffusion tensor imaging in patients with diabetes and gastrointestinal symptoms. Diabetes Care 2013; 36:662-8. [PMID: 23139372 PMCID: PMC3579353 DOI: 10.2337/dc12-1131] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE In patients with long-standing diabetes mellitus (DM), there is increasing evidence for abnormal processing of gastrointestinal sensations in the central nervous system. Using magnetic resonance diffusion tensor imaging, we characterized brain microstructure in areas involved in visceral sensory processing and correlated these findings to clinical parameters. RESEARCH DESIGN AND METHODS Twenty-six patients with DM and gastrointestinal symptoms and 23 healthy control subjects were studied in a 3T scanner. The apparent diffusion coefficient (i.e., diffusivity of water) and fractional anisotropy (FA) (i.e., organization of fibers) were assessed in the "sensory matrix" (cingulate cortex, insula, prefrontal and secondary sensory cortex, amygdala, and corona radiata) and in corpus callosum. RESULTS Patients had decreased FA values compared with control subjects in 1) all areas (P = 0.025); 2) anterior (P < 0.001), mid- (P = 0.001), and posterior (P < 0.001) cingulate cortex; 3) prefrontal cortex gray matter (P < 0.001); 4) corona radiata (P < 0.001); 5) secondary sensory cortex (P = 0.008); and 6) anterior white matter (P = 0.045), anterior gray matter (P = 0.002), and posterior gray matter (P = 0.002) insula. No difference was found in corpus callosum (P > 0.05). The microstructural changes in some areas correlated with clinical parameters such as bloating (anterior insula), mental well-being (anterior insula, prefrontal cortex, and mid-cingulated and corona radiata), autonomic function based on electrocardiographic results (posterior insula and anterior cingulate), and presence of gastroparesis (anterior insula). CONCLUSIONS The findings of this explorative study indicate that microstructural changes of brain areas involved in visceral sensory processing are associated with autonomic dysfunction and therefore may be involved in the pathogenesis of gastrointestinal symptoms in DM patients.
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Affiliation(s)
- Jens Brøndum Frøkjær
- Department of Radiology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.
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Brain networks encoding rectal sensation in type 1 diabetes. Neuroscience 2013; 237:96-105. [PMID: 23384609 DOI: 10.1016/j.neuroscience.2013.01.049] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2012] [Revised: 01/14/2013] [Accepted: 01/20/2013] [Indexed: 01/10/2023]
Abstract
INTRODUCTION It has been shown that patients with type 1 diabetes mellitus and gastrointestinal (GI) symptoms have abnormal processing of sensory information following stimulation in the oesophagus. In order to find less invasive stimuli to study visceral afferent processing and to further elaborate the gut-brain network in diabetes, we studied brain networks following rectal electrical stimulations. METHODS Twelve type 1 diabetes patients with GI symptoms and twelve healthy controls were included. A standard ambulatory 24-h electrocardiography was performed. 122-channel-evoked brain potentials to electrical stimulation in the rectum were recorded. Brain source-connectivity analysis was done. GI symptoms were assessed with the gastroparesis cardinal symptom index and quality of life (QOL) with SF-36. Any changes in brain source connectivity were correlated to duration of the disease, heart beat-to-beat intervals (RRs), clinical symptoms, and QOL of the patients. RESULTS Diabetic patients with GI symptoms showed changes relative to controls in the operculum-cingulate network with the operculum source localized deeper and more anterior (P≤0.001) and the cingulate source localized more anterior (P=0.03). The shift of operculum source was correlated with the duration of the disease, severity of GI symptoms, and decreased RR (P<0.05). The shift of the cingulate source was correlated with the mental QOL (P=0.04). In healthy controls, the contribution of the cingulate source to the network was higher than the contribution of the operculum source (P≤0.001), whereas in patients the contribution of the two sources was comparable. CONCLUSION This study gives further evidence for CNS involvement in diabetes. Since network reorganizations were correlated to GI symptoms, irregularities of rectal-evoked potentials can be viewed as a proxy for abnormal bottom-up visceral afferent processing. The network changes might serve as a biomarker for disturbed sensory visceral processing of GI symptoms in diabetes patients.
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Brock C, Graversen C, Frøkjaer JB, Søfteland E, Valeriani M, Drewes AM. Peripheral and central nervous contribution to gastrointestinal symptoms in diabetic patients with autonomic neuropathy. Eur J Pain 2012; 17:820-31. [PMID: 23239083 DOI: 10.1002/j.1532-2149.2012.00254.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2012] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Long-term diabetes mellitus (DM) has been associated with neuronal changes in the enteric, peripheral and/or central nervous system. Moreover, abnormal visceral sensation and gastrointestinal (GI) symptoms are seen in up to 75% of patients. To explore the role of diabetic autonomic neuropathy (DAN) in patients with long-standing DM, we investigated psychophysical responses and neuronal activity recorded as evoked brain potentials and dipolar source modelling. METHODS Fifteen healthy volunteers and 14 type-1 DM patients with DAN were assessed with a symptom score index characterizing upper GI abnormalities. Multichannel (62) electroencephalography was recorded during painful electrical stimulation of the lower oesophagus. Brain activity to painful stimulations was modelled using Brain Electrical Source Analysis (besa). RESULTS Diabetic patients had higher stimulus intensities to evoke painful sensation (p ≤ 0.001), longer latencies of N2 and P2 components (both p ≤ 0.001), and lower amplitudes of P1-N2 and N2-P2 complexes (p ≤ 0.001; p = 0.02). Inverse modelling of brain sources showed deeper bilateral insular dipolar source localization (p = 0.002). Symptom score index was negatively correlated with the depth of insular activity (p = 0.004) and positively correlated with insular dipole strength (p = 0.03). CONCLUSION DM patients show peripheral and central neuroplastic changes. Moreover, the role of abnormal insular processing may explain the appearance and persistence of GI symptoms related to DAN. This enhanced understanding of DAN may have future clinical and therapeutical implications.
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Affiliation(s)
- C Brock
- Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.
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Frøkjaer JB, Brock C, Brun J, Simren M, Dimcevski G, Funch-Jensen P, Drewes AM, Gregersen H. Esophageal distension parameters as potential biomarkers of impaired gastrointestinal function in diabetes patients. Neurogastroenterol Motil 2012; 24:1016-e544. [PMID: 22738347 DOI: 10.1111/j.1365-2982.2012.01966.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gastrointestinal (GI) symptoms, such as nausea, vomiting, bloating, postprandial fullness, and abdominal pain, are frequent in patients with diabetes mellitus (DM). The pathogenesis is complex and multi-factorial. To determine easy accessible and valid biomarkers for disordered GI function in DM patients, we aimed to study esophageal mechanical parameters and their relation to symptoms typically arising from the digestive tract. METHODS Seventeen patients with longstanding DM and GI symptoms and 13 healthy controls were studied using ultrasound monitored esophageal distension. The sensory response was recorded and their symptoms registered. Biomechanical parameters, such as compliance and stiffness were computed from luminal diameters during distension based on the ultrasound images and from pressure data. Biomechanical and sensory parameters were correlated with the clinical data. KEY RESULTS Diabetes patients had reduced esophageal sensitivity compared with controls (P = 0.046). The esophageal compliance was reduced (P = 0.004) and the esophageal stiffness was increased (P = 0.004) in the diabetes patients. Among patients, both postprandial fullness/early satiety and bloating correlated negatively to the esophageal compliance parameters (all P < 0.05). CONCLUSIONS & INFERENCES Patients with long-standing DM and GI symptoms had reduced esophageal sensitivity together with reduced compliance and increased stiffness, which were correlated to the patients' GI symptoms. Biomechanical parameters obtained during distension may serve as biomarker for similar pathophysiologic effects of diabetes in the stomach and small bowel. They may contribute to our understanding of the pathophysiology underlying GI dysfunction and symptoms in patients with longstanding DM.
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Affiliation(s)
- J B Frøkjaer
- Mech-Sense, Department of Radiology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.
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Brock C, Andresen T, Frøkjaer JB, Gale J, Olesen AE, Arendt-Nielsen L, Drewes AM. Central pain mechanisms following combined acid and capsaicin perfusion of the human oesophagus. Eur J Pain 2012; 14:273-81. [DOI: 10.1016/j.ejpain.2009.05.013] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2009] [Revised: 05/12/2009] [Accepted: 05/24/2009] [Indexed: 12/13/2022]
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Ghorbani MLM, Qin C, Wu M, Farber JP, Sheykhzade M, Fjalland B, Nyborg NCB, Foreman RD. Characterization of upper thoracic spinal neurons receiving noxious cardiac and/or somatic inputs in diabetic rats. Auton Neurosci 2011; 165:168-77. [PMID: 21862419 DOI: 10.1016/j.autneu.2011.07.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2011] [Revised: 07/19/2011] [Accepted: 07/25/2011] [Indexed: 01/11/2023]
Abstract
The aim of the present study was to examine spinal processing of cardiac and somatic nociceptive input in rats with STZ-induced diabetes. Type 1 diabetes was induced with streptozotocin (50mg/kg) in 14 male Sprague-Dawley rats and citrate buffer was injected in 14 control rats. After 4-11 weeks, the rats were anesthetized with pentobarbital, ventilated and paralyzed. A laminectomy enabled extracellular recording of T(3) spinal cord neuronal activity. Intrapericardial administration of a mixture of algogenic chemicals (bradykinin, serotonin, prostaglandin E(2) (all at 10(-5)M), and adenosine (10(-3)M)) was applied to activate nociceptors of cardiac afferent nerve endings. Furthermore, somatic receptive properties were examined by applying innocuous (brush and light pressure) and noxious (pinch) cutaneous mechanical stimuli. Diabetes-induced increases in spontaneous activity were observed in subsets of neurons exhibiting long-lasting excitatory responses to administration of the algogenic mixture. Algogenic chemicals altered activity of a larger proportion of neurons from diabetic animals (73/111) than control animals (55/115, P<0.05). Some subtypes of neurons exhibiting long-lasting excitatory responses, elicited prolonged duration and others, had a shortened latency. Some neurons exhibiting short-lasting excitatory responses in diabetic animals elicited a shorter latency and some a decreased excitatory change. The size of the somatic receptive field was increased for cardiosomatic neurons from diabetic animals. Cutaneous somatic mechanical stimulation caused spinal neurons to respond with a mixture of hyper- and hypoexcitability. In conclusion, diabetes induced changes in the spinal processing of cardiac input and these might contribute to cardiovascular autonomic neuropathy in patients with diabetes.
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Affiliation(s)
- Marie Louise M Ghorbani
- Dept. Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, Copenhagen University, DK-2100 Copenhagen, Denmark.
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Rabie ME, Al Dousary HM, Ageely HM, Shaban AN. Salmonellal acute acalcular cholecystitis complicated by biliary candidal obstruction: An unusual presentation. SURGICAL PRACTICE 2011. [DOI: 10.1111/j.1744-1633.2011.00558.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Olesen AE, Staahl C, Arendt-Nielsen L, Drewes AM. Different effects of morphine and oxycodone in experimentally evoked hyperalgesia: a human translational study. Br J Clin Pharmacol 2011; 70:189-200. [PMID: 20653672 DOI: 10.1111/j.1365-2125.2010.03700.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Previous studies using short-lasting experimental pain stimulations in healthy volunteers have shown differences in opioid effects regarding visceral pain stimulations. However, these differences can be more pronounced in patients due to a sensitized pain system. Therefore, the aim of the present study was to mimic the clinical situation by investigating opioid effects on experimental pain in healthy volunteers after experimentally evoked hyperalgesia. WHAT THIS STUDY ADDS? * We now know that morphine and oxycodone exerts different effects in the sensitized pain system as we found a greater analgesic effect of oxycodone in response to skin, muscle and oesophageal pain stimulation. This supports clinicians' experiences that oxycodone can be superior to morphine in the treatment of some pain conditions. The evoked hyperalgesia bridged findings from studies in healthy volunteers to patients, and new fundamental knowledge on different analgesic effects in hyperalgesia was found. AIM Similar analgesics may have different analgesic potencies especially in patients in whom the pain system is sensitized. The aim was to investigate different opioid effects on experimental pain after the sensitized pain system was mimicked evoking hyperalgesia in healthy volunteers. METHODS Twenty-four healthy volunteers were randomized to treatment with morphine (30 mg orally) and oxycodone (15 mg orally) or placebo in a double-blind crossover study. Hyperalgesia was induced by oesophageal perfusion with acid and capsaicin. Several exploratory endpoints were studied using skin heat, muscle pressure and oesophageal mechanical, heat and electrical stimulation. Effects on pain from deeper structures were considered most important. RESULTS Different analgesic potencies were found. Oxycodone had a greater analgesic effect than morphine attenuating pain from: (i) heat stimulation of skin (P= 0.016); difference between the means of 0.39 degrees C, 95% CI 0.22, 2.09. (ii) muscle pressure (P < 0.001); difference between the means of 11.93kPa, 95% CI 5.4, 18.5. (iii) oesophageal heat stimulation (P < 0.001); difference between the means of 38.54 cm(2), 95% CI 15.37, 61.71 and (iv) oesophageal electrical stimulation (P= 0.016); difference between the means of 6.69mA, 95% CI 1.23, 12.13. CONCLUSION After sensitization of the pain system different analgesic potencies of morphine and oxycodone were found in response to skin, muscle and oesophageal pain stimulation, in which oxycodone had a greater effect. As similar differential analgesic potencies of the two opioids have been found in patients with chronic pain, the experimental hyperalgesia model bridged findings from studies in healthy volunteers to patients.
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Affiliation(s)
- Anne Estrup Olesen
- Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.
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Gastrointestinal symptoms in type-1 diabetes: is it all about brain plasticity? Eur J Pain 2010; 15:249-57. [PMID: 20813568 DOI: 10.1016/j.ejpain.2010.08.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2010] [Revised: 06/22/2010] [Accepted: 08/06/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Autonomic neuropathy seems to play a central role in the development of gastrointestinal symptoms in diabetes. In order to explore the neuronal mechanisms behind the symptoms we evaluated the brain processing of painful visceral stimuli. METHODS Evoked brain potentials were recorded to assess the response to painful oesophageal electrical stimuli in 15 healthy volunteers and 14 type-1 diabetes patients with autonomic neuropathy and related gastrointestinal symptoms. Source reconstruction analysis (fixed Multiple Signal Classification (MUSIC) algorithm) was applied to estimate the location of the evoked electrical activity in the brain. RESULTS The patients had increased oesophageal sensory thresholds compared to the controls (P=0.004). The latencies of the evoked brain potentials at vertex (Cz) were increased (P=0.007) and amplitudes reduced (P=0.011) in diabetics. Compared with controls the patients had a posterior shift of the electrical sources in the anterior cingulate cortex at 54 ms, and additional sources close to the posterior insula at 95 ms and in medial frontal gyrus at 184 ms. CONCLUSIONS There is evidence of altered central processing to visceral stimulation, and both peripheral and central mechanisms seem involved. Central neuronal reorganisation may contribute to our understanding of the gastrointestinal symptoms in patients with diabetic autonomic neuropathy and this may guide development and evaluation of new treatment modalities.
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Biomechanical and histomorphometric colon remodelling in STZ-induced diabetic rats. Dig Dis Sci 2009; 54:1636-42. [PMID: 18989775 DOI: 10.1007/s10620-008-0540-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2008] [Accepted: 09/11/2008] [Indexed: 12/13/2022]
Abstract
The histomorphologic and passive biomechanical properties were studied in the mid-colon of 16 non-diabetic and 20 streptozotocin (STZ)-induced diabetic rats (50 mg/kg STZ, ip). The diabetic rats were divided into groups living 4 and 8 weeks after the induction of diabetes (n = 10 for each group). The mechanical test was a ramp distension of fluid into the colon in vitro. The colon diameter and length were obtained from digitized images of the segments at pre-selected pressures and at the no-load and zero-stress states. Circumferential and longitudinal stresses and strains were computed from the length, diameter, and pressure data and from the zero-stress state geometry. The blood glucose level increased 3-4-fold in the diabetic rats compared with the controls (P < 0.001). Diabetes generated pronounced increases in the colon weight per length, wall thickness, and wall cross-sectional area (P < 0.001). Histologically, the thickness of all layers was increased during diabetes (P < 0.05), especially the mucosa layer. The opening angle, and absolute values of residual strain increased in the diabetic group (P < 0.05 and P < 0.01, respectively). Furthermore, diabetes increased the circumferential and longitudinal stiffness of the colon wall (P < 0.001). The observed changes in residual strain, opening angle, and stress-strain relation may be contributing factors to colonic dysfunction and abdominal pain in diabetic patients.
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Qin C, Ghorbani MLM, Wu M, Farber JP, Ma J, Foreman RD. Characterization of upper thoracic spinal neurons responding to esophageal distension in diabetic rats. Auton Neurosci 2009; 145:27-34. [PMID: 19027368 PMCID: PMC2658770 DOI: 10.1016/j.autneu.2008.10.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2008] [Accepted: 10/10/2008] [Indexed: 01/11/2023]
Abstract
The aim of this study was to examine spinal neuronal processing of innocuous and noxious mechanical inputs from the esophagus in diabetic rats. Streptozotocin (50 mg/kg, ip) was used to induce diabetes in 15 male Sprague-Dawley rats, and vehicle (10 mM citrate buffer) was injected into 15 rats as control. Four to eleven weeks after injections, extracellular potentials of single thoracic (T3) spinal neurons were recorded in pentobarbital anesthetized, paralyzed, and ventilated rats. Esophageal distensions (ED, 0.2, 0.4 ml, 20 s) were produced by water inflation of a latex balloon in the thoracic esophagus. Noxious ED (0.4 ml, 20 s) altered activity of 44% (55/126) and 38% (50/132) of spinal neurons in diabetic and control rats, respectively. The short-lasting excitatory responses to ED were encountered more frequently in diabetic rats (27/42 vs 15/41, P<0.05). Spinal neurons with low threshold for excitatory responses to ED were more frequently encountered in diabetic rats (33/42 vs 23/41, P<0.05). However, mean excitatory responses and duration of responses to noxious ED were significantly reduced for high-threshold neurons in diabetic rats (7.4+/-1.1 vs 13.9+/-3.3 imp/s; 19.0+/-2.3 vs 31.2+/-5.5 s; P<0.05). In addition, more large size somatic receptive fields were found for spinal neurons with esophageal input in diabetic rats than in control rats (28/42 vs 19/45, P<0.05). These results suggested that diabetes influenced response characteristics of thoracic spinal neurons receiving mechanical esophageal input, which might indicate an altered spinal visceroceptive processing underlying diabetic esophageal neuropathy.
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Affiliation(s)
- Chao Qin
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA.
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Frøkjaer JB, Ejskjaer N, Rask P, Andersen SD, Gregersen H, Drewes AM, Funch-Jensen P. Central neuronal mechanisms of gastric electrical stimulation in diabetic gastroparesis. Scand J Gastroenterol 2008; 43:1066-75. [PMID: 18609155 DOI: 10.1080/00365520802028221] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The mechanisms underlying symptom improvement in gastric electrical stimulation (GES) are not fully understood. Modulation of the central nervous system excitability may be involved. The objective of the study was to investigate the central effects of GES, including the possible modulation of the visceral sensory nervous system. MATERIAL AND METHODS A gastric electrical stimulator was implanted in seven diabetic patients with medically refractory gastroparesis. A double-blinded protocol was used to investigate the patients at baseline and one month after recovery with the stimulator turned on and off (1-month periods). The following assessments were carried out: mechanical, thermal and electrical stimulations with sensory recordings in the esophagus and duodenum, and standardized, self-administered, daily symptom questionnaires. RESULTS No difference was found between baseline and the on- and off periods in overall gut pain thresholds across all stimulus modalities in the esophagus (p=0.63), duodenum (p=0.19) or esophagus and duodenum combined (p=0.76). No difference in the sensory response to mechanical stimulation was found in the esophagus before (all p>0.31) and after (all p>0.43) smooth muscle relaxation with butylscopolamine. Similar findings were observed in the duodenum. No differences were found in thermal sensitivity (esophagus (p=0.67) and duodenum (p=0.17)), sensory response to electrical stimulation (esophagus (p=0.57) and duodenum (p=0.52)) or induced somatic referred pain areas (esophagus (p=0.75) and duodenum (p=0.51)). No difference was seen in the induced somatic referred pain areas or self-reported symptoms. CONCLUSIONS No evidence was found for GES-induced modulation of the visceral sensory system and central excitability. However, GES has been proven to modulate the central nervous system in animal studies, necessitating further human experiments in order unambiguously to establish the possible central effects of GES.
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Affiliation(s)
- Jens B Frøkjaer
- Center for Visceral Biomechanics and Pain, Aalborg Hospital, Aalborg, Denmark
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Esophageal function worsens with long duration of diabetes. J Gastroenterol 2008; 43:338-44. [PMID: 18592151 DOI: 10.1007/s00535-008-2169-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2007] [Accepted: 02/12/2008] [Indexed: 02/04/2023]
Abstract
BACKGROUND The aim of this study was to assess the relationship between the duration of diabetes and esophageal dysfunction. METHODS We examined 66 patients with type 2 diabetes. Duration of diabetes was determined by asking patients and from their medical records. The patients were divided into three groups according to the duration of their diabetes: group A, 1-4 years, n=26; group B, 5-9 years, n=20; and group C, 10+ years, n=20. Ambulatory esophageal 24-h pH and motility were monitored, and gastroesophageal reflux and esophageal motility disorders were estimated in detail. RESULTS When the duration of diabetes was long, the percentage of time with pH<4 tended to increase. The amplitude of esophageal peristaltic waves and the frequency of effective peristalsis were reduced when the duration of diabetes was long. A significant correlation was observed between the duration of diabetes and the frequency of effective peristalsis. The number of esophageal peristaltic waves per minute and the percentage of multipeaked peristaltic waves increased significantly in group B, and decreased when the duration of diabetes became longer. CONCLUSIONS Gastroesophageal reflux and esophageal motility disorders worsened with long duration of diabetes. These esophageal dysfunctions should be considered in patients with long-standing diabetes.
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Abstract
PURPOSE OF REVIEW Chronic visceral pain is one of the most common causes of morbidity in the general population. Despite a gargantuan effort from academia and the pharmaceutical industry, an integrated understanding of the pathophysiological mechanisms of chronic visceral pain, particularly with respect to functional gastrointestinal disorders, remains incomplete. RECENT FINDINGS Advances in our understanding of the structure and function of the microanatomy of nociception has led to the identification of a number of ion channels, neurotransmitter receptors and trophic factors that may be intimately involved in chronic visceral pain. These advances have been paralleled with those in the fields of genetics, neurophysiology and functional neuroimaging. These advances have allowed the objective assessment of central processing of visceral sensation and furthermore the factors that may modulate this process in health and disease. SUMMARY These findings have important implications for the future direction of research. The real challenge for the future progress is to further characterize patients with chronic visceral pain in terms of their clinical phenotype, genotyping and nociceptive physiology on an individual basis towards the development of more efficacious therapeutic strategies.
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Affiliation(s)
- Adam D Farmer
- The Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry, Whitechapel, London, UK
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Rayner CK, Jones KL, Blackshaw AL, Horowitz M. The diabetic gut--both aching and unfeeling? Pain 2007; 131:239-240. [PMID: 17728066 DOI: 10.1016/j.pain.2007.07.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2007] [Accepted: 07/25/2007] [Indexed: 02/07/2023]
Affiliation(s)
- Christopher K Rayner
- University of Adelaide, Discipline of Medicine, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000, Australia Nerve Gut Research Laboratory, Royal Adelaide Hospital, Adelaide, Australia
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Frokjaer JB, Andersen SD, Ejskjaer N, Funch-Jensen P, Drewes AM, Gregersen H. Impaired contractility and remodeling of the upper gastrointestinal tract in diabetes mellitus type-1. World J Gastroenterol 2007; 13:4881-90. [PMID: 17828820 PMCID: PMC4611767 DOI: 10.3748/wjg.v13.i36.4881] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate that both the neuronal function of the contractile system and structural apparatus of the gastrointestinal tract are affected in patients with longstanding diabetes and auto mic neuropathy.
METHODS: The evoked esophageal and duodenal contractile activity to standardized bag distension was assessed using a specialized ultrasound-based probe. Twelve type-1 diabetic patients with autonomic neuropathy and severe gastrointestinal symptoms and 12 healthy controls were studied. The geometry and biomechanical parameters (strain, tension/stress, and stiffness) were assessed.
RESULTS: The diabetic patients had increased frequency of distension-induced contractions (6.0 ± 0.6 vs 3.3 ± 0.5, P < 0.001). This increased reactivity was correlated with the duration of the disease (P = 0.009). Impaired coordination of the contractile activity in diabetic patients was demonstrated as imbalance between the time required to evoke the first contraction at the distension site and proximal to it (1.5 ± 0.6 vs 0.5 ± 0.1, P = 0.03). The esophageal wall and especially the mucosa-submucosa layer had increased thickness in the patients (P < 0.001), and the longitudinal and radial compressive stretch was less in diabetics (P < 0.001). The esophageal and duodenal wall stiffness and circumferential deformation induced by the distensions were not affected in the patients (all P > 0.14).
CONCLUSION: The impaired contractile activity with an imbalance in the distension-induced contractions likely reflects neuronal abnormalities due to autonomic neuropathy. However, structural changes and remodeling of the gastrointestinal tract are also evident and may add to the neuronal changes. This may contribute to the pathophysiology of diabetic gut dysfunction and impact on future management of diabetic patients with gastrointestinal symptoms.
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Affiliation(s)
- Jens Brondum Frokjaer
- Center for Visceral Biomechanics and Pain, Department of Radiology, Aalborg Hospital, DK-9100 Aalborg, Denmark.
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Abstract
Gastrointestinal (GI) sensory-motor abnormalities are common in patients with diabetes mellitus and may involve any part of the GI tract. Abnormalities are frequently sub-clinical, and fortunately only rarely do severe and life-threatening problems occur. The pathogenesis of abnormal upper GI sensory-motor function in diabetes is incompletely understood and is most likely multi-factorial of origin. Diabetic autonomic neuropathy as well as acute suboptimal control of diabetes has been shown to impair GI motor and sensory function. Morphological and biomechanical remodeling of the GI wall develops during the duration of diabetes, and may contribute to motor and sensory dysfunction. In this review sensory and motility disorders of the upper GI tract in diabetes is discussed; and the morphological changes and biomechanical remodeling related to the sensory-motor dysfunction is also addressed.
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Affiliation(s)
- Jingbo Zhao
- Center of Excellence in Visceral Biomechanics and Pain, the Research Building room 404, Aalborg Hospital, Sdr. Skovvej 15, DK-9000 Aalborg, Denmark.
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