TAG0010.1177/1756284819852047Therapeutic Advances in GastroenterologyT Meldgaard, J Keller 852047review-article20192019 Therapeutic Advances in Gastroenterology Review Ther Adv Gastroenterol Pathophysiology and management of 2019, Vol. 12: 1–17 DOI:https://doi.org/10.1177/1756284819852047 10.1177/ diabetic gastroenteropathy 1756284819852047https://doi.org/10.1177/1756284819852047 © The Author(s), 2019. Article reuse guidelines: Theresa Meldgaard, Jutta Keller, Anne Estrup Olesen, Søren Schou Olesen, Klaus Krogh, sagepub.com/journals- Mette Borre, Adam Farmer, Birgitte Brock, Christina Brock and Asbjørn Mohr Drewes permissions Abstract: Polyneuropathy is a common complication to diabetes. Neuropathies within the Correspondence to: Theresa Meldgaard enteric nervous system are associated with gastroenteropathy and marked symptoms that Mech-Sense, Department of Gastroenterology and severely reduce quality of life. Symptoms are pleomorphic but include nausea, vomiting, Hepatology, Aalborg dysphagia, dyspepsia, pain, bloating, diarrhoea, constipation and faecal incontinence. The University Hospital, aims of this review are fourfold. First, to provide a summary of the pathophysiology underlying Denmark Department of Clinical diabetic gastroenteropathy. Secondly to give an overview of the diagnostic methods. Thirdly, to Medicine, Aalborg University, Denmark provide clinicians with a focussed overview of current and future methods for pharmacological [email protected] and nonpharmacological treatment modalities. Pharmacological management is categorised Jutta Keller Israelitic Hospital in according to symptoms arising from the upper or lower gut as well as sensory dysfunctions. Hamburg, Academic Dietary management is central to improvement of symptoms and is discussed in detail, and Hospital University of neuromodulatory treatment modalities and other emerging management strategies for Hamburg, Germany Anne Estrup Olesen diabetic gastroenteropathy are discussed. Finally, we propose a diagnostic/investigation Mech-Sense, Department of Gastroenterology algorithm that can be used to support multidisciplinary management. and Hepatology and Department of Clinical Medicine, Aalborg Keywords: diabetes mellitus, complications, diabetic neuropathies, enteric nervous system, University Hospital, Denmark gastrointestinal motility, gastrointestinal transit, pharmacology, enteropathy Department of Clinical Medicine, Aalborg University, Denmark Received: 5 February 2019; revised manuscript accepted: 26 April 2019. Søren Schou Olesen Mech-Sense, Department of Gastroenterology and Hepatology and Department of Clinical Introduction Although often overlooked, effects in the auto- Medicine, Aalborg University Hospital, The development of diabetic polyneuropathy can nomic nervous system most likely occur concur- Denmark potentially alter neuronal structure and function rently with those observed in the somatic nervous Department of Clinical anywhere in the peripheral, central and enteric system. For example it is plausible that early dam- Medicine, Aalborg University, Denmark nervous systems. Where small and large fibres age to small fibres, preceding large fibre neuropa- Christina Brock (unmyelinated C and myelinated Aβ and Aδ fibres) thy, of the somatic nerves, which can be observed Mech-Sense, Department 4 of Gastroenterology in the somatic sensory nervous system are affected, in skin biopsies also take place in other small fibres and Hepatology and the typical manifestation is a distal symmetrical such as in the enteric nervous system. Autonomic Department of Clinical 1 Medicine, Aalborg polyneuropathy. Importantly, these symptoms neuropathy can be clinically silent and is often pre- University Hospital, can also be found in people with prediabetes.2 The sent when polyneuropathy of the somatic nerves is Denmark somatic polyneuropathy is characterised by altera- present. The diagnosis is typically based on cardio- Department of Clinical Medicine, Aalborg tions in the sensory system, and classically presents vascular abnormalities. In particular, studies of University, Denmark with marked changes in a number of sensations RR-complexes in electrocardiograms have been Asbjørn Mohr Drewes (including temperature and fine touch, balance, used to describe heart rate variability, leading to Mech-Sense, Department of Gastroenterology etc.) and can be painful or painless, although the the diagnosis of cardiac autonomic neuropathy. and Hepatology and former predominates.2 In community samples However, autonomic neuropathy also leads to gas- Department of Clinical Medicine, Aalborg with diabetes, the prevalence of clinical symptoms trointestinal (GI) complications such as diabetic University Hospital, is in the order of 30%, although this is likely to gastroenteropathy, which may affect the entire Denmark represent an underestimate as many people are not length of the GI tract. The underlying pathophysi- Department of Clinical Medicine, Aalborg formally diagnosed.3 ology, which is driven by a multitude of factors, University, Denmark journals.sagepub.com/home/tag 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Gastroenterology 12 Klaus Krogh Department of Hepatology including microenvironmental factors such as cues from interstitial cells of Cajal (which are also and Gastroenterology, hyperglycaemia, have a negative impact on the reduced in number).9 This link between reduced Aarhus University Hospital, Denmark enteric motor and sensory functions and manifest numbers of interstitial cells of Cajal and smooth Mette Borre as symptoms related to, e.g., motility and secretory muscle myopathy has been observed in animal Department of Hepatology dysfunctions.5–7 Hence, people with diabetic gas- models of diabetic gastroparesis and likely con- and Gastroenterology, Aarhus University Hospital, troenteropathy may experience a variety of bur- tributes to abnormal motility. Denmark densome symptoms, including dysphagia, Adam Farmer dyspepsia, pain, bloating, diarrhoea, constipation The autonomic nervous system comprises (a) Department of Gastroenterology, and faecal incontinence, all of which adversely the sympathetic nervous system, (b) the para- University Hospitals of influences quality of life. sympathetic nervous system (whose main neural North Midlands, Stoke on Trent, Staffordshire, UK substrate is the vagus nerve) and, according to Centre for Digestive Although the focus of this review is diabetic gas- the early and recently re-established definition, Diseases, Blizard Institute troenteropathy, it should be emphasized that (c) the enteric nervous system.10,11 Alterations in of Cell and Molecular Science, Wingate Institute functional GI disorders are prevalent in the com- either of these systems are involved in the under- of Neurogastroenterology, munity. Hence, the presentation of diabetic gas- lying mechanism of burdensome GI complica- Barts and the London School of Medicine and troenteropathy and functional disorders such as tions in diabetes. As both the enteric nervous Dentistry, Queen Mary functional dyspepsia and irritable bowel syn- system and central nervous system (CNS) are University of London, UK Birgitte Brock drome overlap and cannot be distinguished on involved in the bidirectional regulation and con- Department of Clinical the basis of symptoms or medical history (i.e. trol of the GI homeostasis, any changes in either Research, Steno Diabetes Center Copenhagen diabetes) alone. In fact, examinations of small of these interconnected systems may result in (SDCC), Denmark bowel biopsies from patients with diabetes altered GI function. revealed neuropathy and myopathy only in a minority of patients.8 It is also clear that indi- viduals with chronic disease have a higher preva- Changes at the level of the enteric nervous lence of psychiatric disorders and are exposed to system more stress than healthy subjects. These factors In diabetes, the microenvironment within the play an important role in the presentation and enteric nervous system is significantly altered due perceived severity of functional GI diseases. to the effect of e.g. long-term hyperglycaemia; oxi- dative stress; inflammation; reduced levels of neuro The aims of this review are, however, to describe transmitters, local hormones and nerve growth fac- the pathophysiology of GI complications to dia- tors; and increased levels of fatty acids.12,13 betic neuropathy (gastroenteropathy) and to out- Recently, altered gut luminal microbiota has also line diagnostics and recent pharmacological and been proposed to exert an influence. For example, nonpharmacological treatment modalities for this lowered numbers of bacteria involved in produc- burdensome condition. tion of short chain fatty acids have been observed in diabetes. Short chain fatty acids have anti- inflammatory effects in the GI wall and promote Pathophysiology of diabetes-induced the secretion of the incretin hormone glucagon- gastrointestinal complications like peptide-1 (GLP-1). Lower levels of GLP-1 The term diabetic gastroenteropathy encom- influence glucose metabolism and can increase passes the cumulative