university of copenhagen

Pathophysiology and management of diabetic gastroenteropathy

Meldgaard, Theresa; Keller, Jutta; Olesen, Anne Estrup; Olesen, Søren Schou; Krogh, Klaus; Borre, Mette; Farmer, Adam; Brock, Birgitte; Brock, Christina; Drewes, Asbjørn Mohr

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Therapeutic Advances in Gastroenterology

DOI:

10.1177/1756284819852047

Publication date:

2019

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Meldgaard, T., Keller, J., Olesen, A. E., Olesen, S. S., Krogh, K., Borre, M., Farmer, A., Brock, B., Brock, C., & Drewes, A. M. (2019). Pathophysiology and management of diabetic gastroenteropathy. Therapeutic Advances in Gastroenterology, 12, 1-17. https://doi.org/10.1177/1756284819852047

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• TAG0010.1177/1756284819852047Therapeutic Advances in GastroenterologyT Meldgaard, Keller
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review-article20192019

Therapeutic Advances in Gastroenterology

Review

Ther Adv Gastroenterol

Pathophysiology and management of diabetic gastroenteropathy

2019, Vol. 12: 1–17

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https://doi.org/10.1177/1756284819852047

1756284819852047 © The Author(s), 2019. Article reuse guidelines: sagepub.com/journals- permissions

Theresa Meldgaard, Jutta Keller, Anne Estrup Olesen, Søren Schou Olesen, Klaus Krogh, Mette Borre, Adam Farmer, Birgitte Brock, Christina Brock and Asbjørn Mohr Drewes

Correspondence to:

Theresa Meldgaard

Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark

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.

Department of Clinical Medicine, Aalborg University, Denmark

[email protected]

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

Keywords: diabetes mellitus, complications, diabetic neuropathies, enteric nervous system, 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 Medicine, Aalborg University Hospital, Denmark

Introduction

Although often overlooked, effects in the auto-
The development of diabetic polyneuropathy can nomic nervous system most likely occur concurpotentially alter neuronal structure and function rently with those observed in the somatic nervous anywhere in the peripheral, central and enteric system. For example it is plausible that early damnervous systems. Where small and large fibres age to small fibres, preceding large fibre neuropa(unmyelinated C and myelinated Aβ and Aδ fibres) thy, of the somatic nerves, which can be observed in the somatic sensory nervous system are affected, in skin biopsies⁴ also take place in other small fibres the typical manifestation is a distal symmetrical such as in the enteric nervous system. Autonomic polyneuropathy.¹ Importantly, these symptoms neuropathy can be clinically silent and is often precan also be found in people with prediabetes.² The sent when polyneuropathy of the somatic nerves is somatic polyneuropathy is characterised by altera- present. The diagnosis is typically based on cardiotions in the sensory system, and classically presents vascular abnormalities. In particular, studies of with marked changes in a number of sensations RR-complexes in electrocardiograms have been (including temperature and fine touch, balance, used to describe heart rate variability, leading to etc.) and can be painful or painless, although the the diagnosis of cardiac autonomic neuropathy. former predominates.² In community samples However, autonomic neuropathy also leads to gaswith diabetes, the prevalence of clinical symptoms trointestinal (GI) complications such as diabetic is in the order of 30%, although this is likely to gastroenteropathy, which may affect the entire represent an underestimate as many people are not length of the GI tract. The underlying pathophysi-

Department of Clinical Medicine, Aalborg University, 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

• formally diagnosed.³
• ology, which is driven by a multitude of factors,

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Therapeutic Advances in Gastroenterology 12

Klaus Krogh

including microenvironmental factors such as cues from interstitial cells of Cajal (which are also

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark

hyperglycaemia, have a negative impact on the reduced in number).⁹ This link between reduced enteric motor and sensory functions and manifest numbers of interstitial cells of Cajal and smooth as symptoms related to, e.g., motility and secretory muscle myopathy has been observed in animal dysfunctions.^5–7 Hence, people with diabetic gas- models of diabetic gastroparesis and likely controenteropathy may experience a variety of bur- tributes to abnormal motility.

Mette Borre

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark

densome symptoms, including dysphagia, dyspepsia, pain, bloating, diarrhoea, constipation The autonomic nervous system comprises (a) and faecal incontinence, all of which adversely the sympathetic nervous system, (b) the para-

Adam Farmer

Department of Gastroenterology, University Hospitals of North Midlands, Stoke on Trent, Staffordshire, UK

• influences quality of life.
• sympathetic nervous system (whose main neural

substrate is the vagus nerve) and, according to
Although the focus of this review is diabetic gas- the early and recently re-established definition, troenteropathy, it should be emphasized that (c) the enteric nervous system.^10,11 Alterations in functional GI disorders are prevalent in the com- either of these systems are involved in the undermunity. Hence, the presentation of diabetic gas- lying mechanism of burdensome GI complicatroenteropathy and functional disorders such as tions in diabetes. As both the enteric nervous functional dyspepsia and irritable bowel syn- system and central nervous system (CNS) are drome overlap and cannot be distinguished on involved in the bidirectional regulation and conthe basis of symptoms or medical history (i.e. trol of the GI homeostasis, any changes in either diabetes) alone. In fact, examinations of small of these interconnected systems may result in bowel biopsies from patients with diabetes altered GI function.

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

revealed neuropathy and myopathy only in a minority of patients.⁸ It is also clear that individuals 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 facthe 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 antiinflammatory effects in the GI wall and promote the secretion of the incretin hormone glucagonlike peptide-1 (GLP-1). Lower levels of GLP-1

Pathophysiology of diabetes-induced gastrointestinal complications

The term diabetic gastroenteropathy encom- influence glucose metabolism and can increase passes the cumulative impact that diabetes exerts low-grade inflammation.^14–18 on the GI tract. The pathophysiology is multifactorial and to date remains incompletely under- Various components of the enteric nervous sysstood. However, changes in the neuronal tem, (including enteric neurons, interstitial cells of microenvironment are believed to be a major Cajal, enteric glial cells) and smooth muscle cells driver in the pathogenesis. Microvascular compli- are affected by the changes described above. cations to diabetes lead to alterations of blood Enteric neurons and interstitial cells of Cajal are flow in the GI wall, and hence also to alterations particularly vulnerable to hyperglycaemia.¹⁹ When in the microenvironment. Smooth muscle myo- hyperglycaemic episodes are frequent, or when pathy is also thought to be a contributing factor to hyperglycaemia is persistent, shifts in the intraceldiabetic gastroenteropathy. However, smooth lular glucose metabolism of neurons occur, consemuscle myopathy may not be a primary distur- quently leading to the formation of advanced bance, but is more likely a result of smooth mus- glycation end-products, osmotic and oxidative cle cell atrophy induced through reduced trophic stress as well as inflammation. Collectively, this

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T Meldgaard, J Keller et al.

leads to cellular damage and ultimately to cell been investigated in detail in healthy subjects, death, a process often referred to as glucose neu- but similar mechanisms are likely involved in rotoxicity. These mechanisms are primarily diabetes.³¹ described in the peripheral nervous system, but similar mechanisms are present in the enteric nervous system.²⁰

Changes at the level of the autonomic nervous system

The pathophysiological changes described above Autonomic afferent and efferent signalling may lead to various degrees of diabetes-induced through the vagus nerve is directly involved in damage to enteric neurones. Preferential loss of the extensive communication with the brain, large fibre neurons in the dorsal root ganglion forming the so-called gut-brain-axis. In both and inhibitory motor neurons in the gut wall people with diabetes and in animal models, the have been observed. In particular, selective loss number of neurons in the sympathetic and paraof nitric oxide synthase and neuropeptideY sympathetic ganglions of the vagus nerve conexpressing inhibitory motor neurons has been nected to the GI tract is reduced^32–34 as well as shown in the human diabetic colon.²¹ This obvi- structural changes in the axons have been ously has consequences for the contractile activ- reported.^35,36 In consequence, autonomic neuity of the smooth muscle layers in the GI tract ropathy, influencing the vagus nerve, contributes and hence the motility pattern. Furthermore, loss to reduced GI function. of interstitial cells of Cajal throughout the GI tract has been reported in both animal models and in humans,^22,23 causing reduced frequency of Changes at the level of the CNS spontaneous muscular contractions. In addition, Although the blood–brain barrier offers some decreased activity of gastric enteric glial cells has protection to the brain against hyperglycaemia, it been observed in animal models of diabetes.²⁴ has been observed that the microstructure in speThis may contribute to the development of gas- cific brain regions (diabetic encephalopathy) troenteropathy in diabetes mainly because enteric involved in visceral sensory processing is changed glial cell functions such as neurotrophic support, in diabetes.³⁷ immunosuppression and anti-inflammation is

• diminished with decreased activity.^25,26
• Manifestation of sensory symptoms from the

abdomen, such as nausea, vomiting and pain, as
In contrast to the loss of motor neurons, it has well as unspecific fullness, shooting sensations, recently been shown that levels of neurones con- etc., may relate to abnormal function of the sentaining substanceP and calcitonin gene-related sory visceral nerves in combination with the peptide are increased in the stomach of porcine encephalopathy (Figure 1). models of diabetes.²⁷ Both these molecules are primarily involved in the afferent transmission of We have previously shown that central reorganiGI sensory and nociceptive information. Hence, sation of brain responses to visceral stimuli is such alterations may be related to the pathophys- associated to the burden of GI symptoms as well iological mechanisms of sensory symptom gen- as heart rate variability as a proxy for diabetic eration. Like in the somatic system, when sensory autonomic neuropathy.^38,39 This was supported nerves are affected by enteropathy, pain from the by another study where visceral hyposensitivity gut can likely be spontaneous or evoked by exter- was correlated to an increase in somatic referred nal or internal stimuli such as disturbances in pain areas, indicating central neuropathic-like motility and glandular functions. On the other changes.²⁸ Although controversies exist regarding hand, previous experimental studies where the the pathogenesis of these changes, the findings in gut was stimulated with electrical, mechanical the CNS may be secondary to the peripheral neuand thermal stimuli, hypoalgesia to peripheral ropathy, because the reduced afferent activity stimulation of both the upper and lower gut were may cause adaptive shrinking.^37,40 Finally, there is shown, likely reflecting abnormal central pro- evidence from both neurophysiological and imagcessing of the afferent activity.²⁸ Moreover, rectal ing studies that descending pathways from the pain thresholds are correlated to cutaneous and brainstem that normally ‘gates’ the incoming autonomic dysfunction.^29,30 The autonomic nociceptive barrage is malfunctioning in people components of visceral hyperalgesia have only with diabetes.^30,41 Hence, as in somatic peripheral

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Therapeutic Advances in Gastroenterology 12

Diagnosis

As outlined above, diabetic gastroenteropathy can affect the entire GI tract, and consequently symptoms are not only very heterogeneous, they are also unspecific. The cardinal symptoms are nausea, vomiting, bloating and early satiety, however, symptoms range from dysphagia and heartburn to faecal incontinence. Thus, based on the patient reported symptoms, it is hardly possible to distinguish sequela of diabetes-associated GI dysfunction from organic diseases. This diagnostic dilemma is further aggravated by the fact that people with type2 diabetes have an increased risk for a multitude of organic GI diseases, including reflux oesophagitis, gallstones and GI malignancies.⁴⁶ An increased cancer risk has also been observed in type1 diabetes.⁴⁷ Moreover, increased prevalence of other diseases with an autoimmune component affecting the GI tract such as coeliac disease⁴⁸ are frequent and need to be taken into consideration.

Figure 1. Neural pathways and mechanisms that

may lead to pain and other sensory symptoms from the gastrointestinal system in people with diabetic neuropathy.

Accordingly, it is important to first exclude organic disease using appropriate laboratory tests, endoscopy and imaging techniques in people presenting with symptoms that could be attributed to diabetic gastroenteropathy (Figure 2). If these tests are unrevealing and symptoms do not respond to simple therapeutic measures (e.g. laxatives in chronic constipation), GI function tests can be used to diagnose disturbances associated with diabetic gastroenteropathy. Again, most clinically available function tests identify and quantify dysfunction of various GI segments and organs without being able to specifically prove the causation by or the relative importance of diabetic

Neuropathic changes in the enteric nervous system where e.g., motility dysfunction can lead to sensory symptoms: (1) autonomic neuropathy influencing the parasympathetic (2) and (3) sympathetic pathways. Due to cross-talk between the nerve pathways and involvement of inhibitory pathways, this may indirectly modulate sensations from the gut; negative impact on visceral (4) (and somatic (5) if the peritoneum is involved) afferents lead to spontaneous and evoked pain. Structural and functional changes in the spinal cord (6) and brain (7) may lead to spontaneous and evoked pain, amplify afferent barrage and give abnormal referred pain to somatic structures (8). Spino-bulbo-spinal loops (9) that normally control pain intensity often malfunction in people with diabetes.

neuropathy, abnormal central sensory processing gastroenteropathy. For instance, severe oesophaand hyper-excitability may explain the visceral geal hypomotility diagnosed by high resolution symptoms despite the peripheral hypoalgesia (as manometry can explain nonobstructive dysphagia described above).⁴² Such neuroplastic mecha- in a person with diabetes, but could also be due to nisms were also seen e.g. in people with chronic other aetiologies. Therefore, clinical plausibility pancreatitis, which is thought to have a strong and affection of other organ systems, e.g. cardiac neuropathic component, and this validated the autonomic neuropathy, should be taken into

• findings.⁴³
• account. Impaired pancreatic polypeptide release

has been suggested for specific diagnosis of gas-
In summary, long-term diabetes induces marked troenteropathy,⁴⁹ but measurements are not structural and functional changes of the GI wall, widely available. Likewise, antroduodenojenunal parasympathetic, sympathetic and CNS altera- manometry with increased frequency of phase tions. Especially, intrinsic and extrinsic neuronal III-motility and hypomotility during phase II as communication of the GI tract is altered. Taken well as postprandially is typical of autonomic neutogether, this leads to burdensome panenteric ropathy, but available only at highly specialized alteration of GI sensation and function, includ- centres and reserved for people with very severe ing the biomechanics that drive GI motility.^44,45 symptoms.⁵⁰