Epidemiology and Clinical Presentation
Constipation is a common presentation of diabetic enteropathy, affecting up to 60% of people with long-standing diabetes . Complications arising from severe constipation such as perforation and overflow diarrhea are, however, relatively rare. Based on studies with radio-opaque markers, there is evidence for a generalized slowing in transit constipation in the diabetic population . However, there does not appear to be a difference between subjects with and without autonomic neuropathy .
Diarrhea is an important and often debilitating feature of diabetic enteropathy occurring in up to 20% of patients . It may happen at any time of the day, but it is typically nocturnal. Characteristically, it is seen in patients with poorly controlled diabetes with co-existing peripheral and autonomic neuropathy.
Fecal incontinence, particularly nocturnal, related to internal and external sphincter dysfunction is a particularly troublesome symptom. Acute hyperglycemia and glucose excursions have been shown to inhibit rectal sphincter function, decreasing rectal compliance and thus leading to fecal incontinence [12, 17].
Enteropathic symptoms, in particular diarrhea and constipation, occur with many commonly used drugs in diabetes. Metformin is the most commonly recognized drug in terms of GI side effects, including abdominal discomfort, bloating, nausea, anorexia, diarrhea, and constipation. Up to 10% of people receiving metformin have been reported to experience one or more of these symptoms ; however, the incidence and severity of such symptoms may be reduced by slow dose titration, while dose reduction may also be required in some individuals to mitigate such symptoms and ensure therapy persistence.
Other blood-glucose-lowering therapies with a mechanism of action involving the modulation of intestinal physiology, such as the incretin-based therapies and the alpha-glucosidase inhibitors , are associated with a variety of GI side effects, with altered bowel function (either diarrhea or constipation) occurring in up to 20% of people receiving GLP-1 receptor agonist therapy and in 1–10% of people taking DPP-4 inhibitor therapy .
GI side effects also occur in up to 5% of people receiving statins, while fibrate therapy may also be associated with GI adverse events, including diarrhea and constipation in as many as 10% of patients .
Due to the often debilitating nature of the symptoms of diabetic enteropathy, patients can often experience social isolation, relationship difficulties, and employment and work problems. Consequently, many patients—particularly those with severe symptoms—may become depressed and require psychological support.
Investigation and Diagnosis
Given the high prevalence of enteropathic symptoms, particularly in relation to many drugs frequently prescribed for diabetes, prior to embarking on any investigations  (see Table 1) or making a presumptive diagnosis of diabetic enteropathy, attention should be focused on potential treatment changes. These may include discontinuing, reducing the dose of metformin, or switching to the modified release preparation, which has been suggested to induce fewer GI side effects . The GLP-1 receptor agonists are commonly associated with GI side effects, and switching between agents within a class, reducing dose, or discontinuing therapy are all potential considerations. Furthermore, a trial in which any other medications typically associated with GI adverse effects are discontinued should also be adopted. In addition, some diabetic foods may exert a laxative effect, and as such should also be discontinued in the setting of persistent diarrhea.
In the presence of persisting symptoms, despite appropriate therapeutic modifications as outlined above, investigations such as endoscopy, stool culture, and computed tomography should be initiated to exclude other causes (see Table 1).
Pancreatic exocrine insufficiency also needs to be excluded as a potential cause of enteropathy in diabetes. This is particularly pertinent since pancreatitis occurs 2–4 times more commonly in people with diabetes than in the nondiabetic population . Risk factors for pancreatitis tend to cluster in diabetes, including an increase in gall stone disease consequent upon gall bladder dysmotility , obesity, and the use of many medications such as angiotensin-converting enzyme inhibitors and diuretics that are associated with an increase in the risk of pancreatitis . Based on such considerations, measurement of fecal elastase should be one of the initial investigations conducted when evaluating a patient with potential diabetic enteropathy (see Table 1).
Other causes of diarrhea also need to be excluded, e.g., infectious diarrhea, celiac disease, bile salt diarrhea, and the concomitant use of drugs that may cause diarrhea such as metformin, GLP-1 receptor agonists, DPP-4 inhibitors, proton pump inhibitors, and statins (see Table 2).
Investigating colonic transit time may be useful in terms of confirming a diagnosis of enteropathy, using noninvasive radio-opaque marker methods. The demonstration of reduced anal sphincter tone, by barostat or manometry, may also be useful with respect to confirming a diagnosis of enteropathy [12, 13].
Patient questionnaires, such as the Diabetes Bowel Symptom Questionnaire (DBSQ), provide a specific measure of GI symptoms and glycemic control in patients with diabetes  and as such may be useful in quantifying the impact on quality of life or the enteropathic symptoms in people with diabetes.
Management of Diabetic Enteropathy
The management of enteropathy in diabetes represents a considerable challenge and is generally suboptimal, thus undoubtedly prevention is better than cure. The fundamental objectives of managing diabetic enteropathy revolve around symptom relief and glycemic control.
It is important to assess patients’ nutritional status, especially in cases of combined gastroparesis and diarrhea. The recognition of dehydration, weight loss, and electrolyte imbalance is particularly important and may necessitate acute hospitalization and enteral feeding, particularly in patients with >5% weight loss in 3 months.
Nutritional counseling with specialist dietetic input is an important component of the management of diabetic enteropathy, with dietary manipulation (low fat/fiber, small-portion meals) often providing symptomatic benefit .
Bacterial overgrowth is found in up to 40% of diabetic patients with diarrhea . Consequently, the treatment of enteropathic symptoms should include intermittent and even potentially long-term administration of selective antibiotics. Rifaximin is the most extensively studied agent in this context, improving symptoms in between 33% and 92% of patients while eradicating bacterial overgrowth in up to 80% of patients .
Symptomatic benefit may also be achieved with the use of opioid-based agents and, in the event of severe refractory diarrhea, somatostatin analogues may be useful , while loperamide may provide benefit in the management of fecal incontinence. In terms of somatostatin analogue therapy, octreotide and lanreotide are useful in a variety of diarrhea states, while there is a suggestion that the longer half-life of lanreotide may result in greater symptomatic benefit .
Management of constipation revolves around the use of traditional laxatives, and is still primarily aimed at symptom relief. In patients where abdominal pain is the main symptomatic manifestation of enteropathy, medications such as tricyclic and tetracyclic antidepressants, gabapentin, and pregabalin can be used with varying degrees of benefit .
Improving overall glucose control and, in particular, limiting glucose variability are important considerations in the management of patients exhibiting diabetic enteropathy, particularly in those in whom diarrhea is the main symptomatic manifestation. The use of multiple daily dosing insulin regimens, insulin pump therapy, and continuous glucose monitoring may be considered as therapeutic options in such cases.