Diabetes Ther DOI 10.1007/s13300-016-0182-y PRACTICAL APPROACH A Practical Approach to Gastrointestinal Complications of Diabetes Abigail Maisey Received: May 11, 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com ABSTRACT Keywords: Constipation; Diabetes; Diagnosis; Diarrhea; Fecal incontinence; Gastrointestinal Gastrointestinal symptoms occur frequently enteropathy; Management among people with diabetes mellitus and are associated with considerable morbidity. Enteropathy, or large bowel dysfunction, INTRODUCTION includes constipation, diarrhea and fecal incontinence, and is particularly disturbing for The gastrointestinal (GI) complications of many patients. The pathogenesis of diabetic diabetes have become increasingly prevalent as enteropathy is complex, primarily related to the rate of diabetes has increased [1]. The GI gastrointestinal autonomic dysfunction and tract manifestations of diabetes include etiologically associated with chronic gastroparesis and enteropathy, and their hyperglycemia and diabetes duration. Since symptoms are classically caused by abnormal there are many other non-iatrogenic and GI motility, which is a consequence of diabetic iatrogenic causes of the cardinal symptoms of autonomic neuropathy involving the GI tract large bowel dysfunction, patients suspected of [2]. Up to 75% of people with diabetes may having diabetic enteropathy require detailed experience GI symptoms, leading to both a evaluation. The management of patients with significant decrement in patient quality of life diabetic enteropathy is challenging, and often and an increase in health care costs. The classic requires a multidisciplinary approach focusing GI symptoms of diabetes include post-prandial on a combination of symptom mitigation and fullness with nausea, bloating, abdominal pain, glycemic control. diarrhea, and/or constipation [1]. Gastroparesis is a well-recognized GI Enhanced content To view enhanced content for this article go to http://www.medengine.com/Redeem/ manifestation of diabetes and is more FFD4F0602DB462CE. common in women. Delayed gastric emptying has been demonstrated in between 27% and A. Maisey (&) Wye Valley NHS Trust, Hereford, UK 65% of patients with type 1 diabetes mellitus e-mail: [email protected] Diabetes Ther (T1DM) and in up to 30% of patients with type Enteropathy is a less well-recognized GI 2 diabetes mellitus (T2DM) [3, 4]. Of note, manifestation of diabetes and can be obesity appears to independently predict considered to be symptoms that affect the symptoms of gastroparesis patients with T2DM large bowel. Clinical presentation includes with comorbid sensory motor neuropathy [5]. diarrhea, constipation, and fecal incontinence, There are multiple clinical features which which can often be nocturnal [1], while overt may be attributable to gastroparesis, includeing steatorrhea has been reported in a minority of nausea and vomiting as well as early satiety, patients [7]. The nature of the symptoms often combined with bloating and upper associated with diabetic enteropathy can by abdominal pain. Deteriorating glycemic definition be both distressing and often control coupled with increased glucose multifaceted. Furthermore, many commonly variability consequent upon mismatched used drugs in diabetes, such as metformin, insulin action and nutrient absorption may statins, and the incretin-based therapies [7–9], also suggest underlying gastroparesis. Up to are associated with intestinal side effects, which 53% of patients may experience weight loss, may confuse the issue with respect to while as many as 24% of patients may actually identifying and managing diabetic enteropathy. gain weight [4]. Symptom presentation can be Based on such considerations, this article either acute or insidious, with a third of cases focuses on the pathophysiology, clinical having chronic symptoms with periodic presentation, epidemiology, and management exacerbations, while a further third will of diabetic enteropathy, aiming to provide a experience chronic progressive symptoms [4]. practical approach to this often The diagnosis of gastroparesis is typically one under-recognized and challenging of exclusion, when other potential causes of complication of diabetes. presenting symptoms have been evaluated and postprandial gastric stasis is confirmed [6]. Whenever possible, patients should PATHOPHYSIOLOGY discontinue medications that exacerbate gastric dysmotility, in particular glucagon-like GI autonomic nerve dysfunction is the key peptide-1 (GLP-1)-receptor agonists, dipeptidyl pathological factor with respect to enteropathy peptidase-4 (DPP-4) inhibitors, and metformin. in people with diabetes, including Other simple therapeutic approaches include abnormalities of motor function and visceral improving blood glucose control, increasing hypersensitivity [10]. Additional factors dietary liquid content, consuming smaller thought to play a role in the pathogenesis of meals, and discontinuing the use of tobacco diabetic enteropathy include altered GI and alcohol. Qualitative dietary changes should hormone secretion and a proinflammatory also be made, namely, reducing the intake of diathesis combined with a genetic insoluble dietary fiber, foods high in fat, and predisposition [10]. All these are enhanced in alcohol. Prokinetic agents (e.g., the presence of acute or chronic hyperglycemia, metoclopramide, erythromycin) may also be the latter exerting a particularly noxious effect helpful in managing the symptoms of on the interstitial Cajal cells, ultimately leading gastroparesis [6]. to impaired intestinal motility. Diabetes Ther While enteropathy can affect people with EPIDEMIOLOGY, CLINICAL T1DM and T2DM, it occurs more commonly in PRESENTATION, AND DIAGNOSIS people with T1DM [11]. There does not, however, appear to be any differential Epidemiology and Clinical Presentation mechanism, with the relatively higher risk in T1DM being potentially attributable to the Constipation is a common presentation of longer duration of hyperglycemia, which, in diabetic enteropathy, affecting up to 60% of turn, aggravates intestinal motility. people with long-standing diabetes [13]. In both T1DM and T2DM, insulin-growth Complications arising from severe factor I (IGF-I) are reduced, which may result in constipation such as perforation and overflow smooth muscle atrophy, contributing to diarrhea are, however, relatively rare. Based on impaired GI function [10]. Diabetes duration studies with radio-opaque markers, there is and the level of glucose control are both factors evidence for a generalized slowing in transit that are related to reduced IGF-1 expression in constipation in the diabetic population [14]. diabetes, and this process may partly explain However, there does not appear to be a the epidemiological associations between difference between subjects with and without diabetes duration and glycemic control with autonomic neuropathy [15]. diabetic enteropathy. Diarrhea is an important and often Other candidate mechanisms involved in the debilitating feature of diabetic enteropathy pathogenesis of enteropathy in diabetes include occurring in up to 20% of patients [16]. It may an impaired synthesis of neuronal nitric oxide, happen at any time of the day, but it is typically which is an important neurotransmitter within nocturnal. Characteristically, it is seen in the bowel. Enhanced oxidative stress, an patients with poorly controlled diabetes with autoimmune diathesis, and imbalance between co-existing peripheral and autonomic inhibitory and excitatory enteric neuropeptide neuropathy. ratios have also been implicated as potential Fecal incontinence, particularly nocturnal, contributory factors [10]. related to internal and external sphincter The diarrhea of diabetic enteropathy reflects dysfunction is a particularly troublesome perturbations in small bowel motility and is symptom. Acute hyperglycemia and glucose often associated with bacterial overgrowth [10]. excursions have been shown to inhibit rectal Hyperglycemia and in particular glucose sphincter function, decreasing rectal variability may influence sphincter function. compliance and thus leading to fecal Indeed, acute hyperglycemia inhibits external incontinence [12, 17]. anal sphincter function and decreases rectal Enteropathic symptoms, in particular compliance, potentially leading to fecal diarrhea and constipation, occur with many incontinence [12]. Furthermore, depression commonly used drugs in diabetes. Metformin is rather than glycemic control may also be the most commonly recognized drug in terms linked with the development of GI symptoms of GI side effects, including abdominal in diabetes, suggesting that emotional status discomfort, bloating, nausea, anorexia, may be a factor, which many clinicians may diarrhea, and constipation. Up to 10% of under-recognize, in the development of diabetic people receiving metformin have been enteropathy [10]. reported to experience one or more of these Diabetes Ther symptoms [7]; however, the incidence and release preparation, which has been suggested severity of such symptoms may be reduced by to induce fewer GI side effects [7]. The GLP-1 slow dose titration, while dose reduction may receptor agonists are commonly associated with also be required in some individuals to mitigate GI side effects, and switching between agents such symptoms and ensure therapy persistence. within a class, reducing dose, or discontinuing Other blood-glucose-lowering therapies with therapy are all potential considerations.