Gastrointestinal manifestations of diabetes mellitus
Gastrointestinal manifestations in people with type 1 or type 2 diabetes are common, varied and observed throughout the gastrointestinal tract. People with diabetes report a higher frequency of gastrointestinal symptoms compared with those without diabetes. Gastroparesis, or abnormally delayed gastric emptying, is the most well-characterised gastrointestinal manifestation in diabetes. A number of routinely prescribed antidiabetic medicines are also associated with adverse gastrointestinal effects.
- The gastrointestinal (GI) tract is commonly affected in both type 1 and type 2 diabetes, leading to increased morbidity and healthcare costs, and often presents a diagnostic and therapeutic challenge.
- Abnormalities of the function of the stomach remain the most studied in diabetes, although motility abnormalities have also been described in other parts of the GI tract such as the oesophagus, intestines and gallbladder.
- The correlation between GI motility and symptoms is relatively modest.
- There is a bidirectional relationship between gastric emptying and post-meal glucose levels irrespective of the presence of diabetes.
- Abnormally delayed gastric emptying (gastroparesis) is the characteristic upper GI abnormality in diabetes, and current treatment strategies for management are suboptimal.
- Routinely used antidiabetic medications such as metformin and glucagon-like peptide-1 receptor agonists often induce GI symptoms.
- Medical case reports of glucagon-like peptide-1 receptor agonist-induced gastroparesis have been published recently, and there are concerns of an increased risk of aspiration during the perioperative period while on these medications.
Diabetes can affect the entire gastrointestinal (GI) tract, and hence, symptomatology and presentations vary widely. GI symptoms can be classified according to their organ of origin in the GI tract. Accordingly, oesophageal symptoms can include dysphagia, heartburn or reflux; gastric symptoms can include nausea, vomiting, early satiety, postprandial fullness, abdominal pain and bloating; and intestinal symptoms can include constipation, diarrhoea and faecal incontinence. However, people may present with upper and lower GI symptoms, which can result in delayed diagnosis and treatment, and also represent a more severe phenotype.1,2
Many studies suggest that GI symptoms are reported more commonly in people with diabetes than in those without.3,4 The exact prevalence of GI symptoms in diabetes is not known, and reports vary widely, in part because of differences in methodologies, study populations and settings. For example, GI symptoms are more commonly reported when patients are evaluated at a tertiary referral centre compared with a community setting, but allowing for this, estimates suggest up to 70% of people with diabetes are affected.4-8 There may be a difference in the prevalence of GI symptoms between people with type 1 and type 2 diabetes, with a greater prevalence in the latter.9-11 Certain GI symptoms, particularly those arising from the lower GI tract, such as faecal incontinence, can be embarrassing and are often not volunteered by people unless specifically asked, which may lead to under-reporting. A phenomenon known as ‘symptom turnover’ is seen in those experiencing GI symptoms where individual symptoms appear or disappear over time, while the overall prevalence in a given population may remain stable.4,12
There is also likely a significant central neurological role in the manifestation of GI symptoms. GI symptoms are independently associated with anxiety and depression, as well as diabetes-related stress, and they negatively affect quality of life.13 We recently reported a high frequency and independent association between diabetes distress and GI symptoms in people with type 2 diabetes.13 Unfortunately, many studies continue to rely solely on self-reports when assessing GI symptoms. Validated questionnaires exist to quantify and monitor GI symptoms and should be used more frequently. Examples of these instruments include the Patient Assessment of Gastrointestinal Disorders Symptoms questionnaire, Gastroparesis Cardinal Symptom Index and Diabetes Bowel Symptom Questionnaire. The effect of acute glycaemic control on the improvement of GI symptoms remains uncertain.14
The oesophagus
Impaired oesophageal function is common in people with diabetes, although it has not been extensively studied. Some studies have also revealed an improvement in oesophageal symptoms, such as heartburn and nausea, in populations with type 1 diabetes compared with control populations, although this has not been consistently confirmed and the implications are unclear.15 Diabetes is regarded as an independent risk factor for ‘pill-induced oesophagitis’, which occurs due to the delayed transit of medication through the oesophagus as a result of impaired oesophageal motility, leading to prolonged exposure of the oesophagus to the medication.16 Autonomic neuropathy is believed to play at least a role in oesophageal dysmotility.17 Oesophageal dysmotility is affected by acute glycaemic changes and is known to be suppressed by hyperglycaemia.18,19 There is a poor correlation between oesophageal transit and gastric emptying.15 Oesophageal motility is weakly measured using oesophageal manometry, which is particularly useful in patients exhibiting dysphagia or unexplained chest pain, especially when structural causes have been excluded.20 Scintigraphy has been used for the measurement of oesophageal motility, but this has not been standardised and is not routinely used in clinical practice.
The management of oesophageal disorders in diabetes revolves around lifestyle interventions and metabolic control, including weight loss, dietary modifications, increased physical activity and improved glycaemic control. However, it should be appreciated that these recommendations lack a solid evidence base. Prokinetic agents, such as metoclopramide, domperidone and erythromycin, can be trialled in the management of oesophageal dysmotility; however, their clinical efficacy has not been established.21-23 In the case of pill-induced oesophagitis, treatment involves withdrawal of the offending medication where possible and the use of proton pump inhibitors. If ingesting the pill cannot be avoided, a general recommendation is to drink about 100 mL of water immediately after taking the pill and to avoid a recumbent position for a few minutes after swallowing. For nonerosive gastro-oesophageal reflux disease, treatment includes lifestyle measures, elevating the head of the bed by 30° while sleeping and the use of proton pump inhibitors.
The stomach
The stomach is the most comprehensively studied GI organ in terms of our understanding of the impact of diabetes, and specifically, gastric emptying. Gastric emptying is the complex, co-ordinated process of delivering chyme from the stomach to the small intestine. The rate of gastric emptying exhibits a wide interindividual variation, usually ranging between 1 and 3 kcal/min in healthy people.24,25 This variation is even greater in people with diabetes, as a significant proportion have abnormally delayed emptying (gastroparesis) and a few have, paradoxically, rapid emptying.26,27 The rate of gastric emptying is particularly relevant as it is a major determinant of post-meal glucose levels in people with and without diabetes and may, hence, influence treatment regimens. The natural variation in gastric emptying is thought to account for at least 30% of the variance in the initial post-meal glucose response (0–30 minutes post-meal) in health.28
The relationship between the rate of gastric emptying and post-meal glucose levels is time-dependent and dependent on glucose tolerance status (Figure).26,27,29 There is a suggestion that in people requiring insulin who have gastroparesis, there is an increased propensity to hypoglycaemia in the initial postprandial period, a phenomenon termed ‘gastric hypoglycaemia’.30,31 A small study in patients with type 1 diabetes and gastroparesis revealed lower insulin requirements in the first 120 minutes post-meal to maintain euglycaemia, but a greater requirement between 180 and 240 minutes, reflecting a mismatch between insulin delivery and blood glucose excursions.32
Acute glycaemic changes also affect gastric emptying.33 Acute hyperglycaemia slows gastric emptying in a dose-dependent manner. Conversely, acute hypoglycaemia accelerates gastric emptying, also in a dose-dependent fashion, and almost certainly represents an important GI counter-regulatory response to hypoglycaemia.33,34 Nutritional interventions, such as a nutrient preload (e.g. a small meal of whey protein or olive oil before a main meal), can slow gastric emptying and, thereby, reduce post-meal glucose excursions. Pharmacological agents can modulate gastric emptying. For instance, when gastric emptying is slowed by agents such as morphine, or accelerated by prokinetic agents such as erythromycin, there is a corresponding decrease or increase in the post-meal glucose excursions, respectively.35,36
Gastroparesis
The term ‘gastroparesis diabeticorum’ was coined by Paul Kassander in 1958 when describing increased gastric retention of barium in people with diabetes treated with insulin, who were notably asymptomatic.37 Gastroparesis is defined as abnormally delayed gastric emptying in the absence of mechanical obstruction.38
Diabetes is thought to account for at least one-third of cases of chronic gastroparesis and is not limited to people with advanced, poorly controlled diabetes, as previously believed.39 Conventional risk factors for diabetic gastroparesis include a long duration of diabetes, presence of other microvascular complications, smoking, obesity and female sex.40 The exact prevalence of diabetic gastroparesis is not known, with studies showing wide variation; the Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications analysis reported a prevalence of 47%.41 It is not clear if the prevalence varies between type 1 and type 2 diabetes. Although some studies suggest gastroparesis is more common in type 2 diabetes, the USA-funded National Institutes of Health Gastroparesis Clinical Research Consortium reported a comparable prevalence, especially in longstanding and poorly controlled diabetes.42 However, significant gaps exist in the literature, with fewer studies in type 2 diabetes, particularly in those diagnosed in youth. US hospital data suggest that both hospitalisations and healthcare costs related to diabetic gastroparesis have been on the rise over the past two decades.43 In well-controlled type 1 diabetes, the prevalence of gastroparesis may be lower, attesting to the importance of glycaemic control.
Normal gastric emptying is a complex, co-ordinated process involving the autonomic nervous system (enteric and vagal), specialised interstitial cells of Cajal or gastric pacemaker cells, GI musculature, gut hormones and peptides (e.g. cholecystokinin [CCK] and glucagon-like peptide-1 [GLP-1]) and immune cells. This process is modulated by feedback from nutrient interactions in the small intestine.44 Impairments in any of these components may lead to gastroparesis. A characteristic feature is the loss of interstitial cells of Cajal, likely secondary to immunological changes, such as a shift from protective M2 to M1 macrophages and impaired regulation of haem oxygenase-1, leading to oxidative stress.45-47 There are significant knowledge gaps that represent an area of active research.
There is a poor correlation between upper GI symptoms and gastric motility.15 Therefore, a diagnosis of diabetic gastroparesis should not be made without a formal measurement of gastric emptying. Scintigraphy is considered the gold-standard technique for this measurement, as it can precisely measure the emptying of both solid and liquid components of a meal. The American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine have suggested a standardised meal for this test, comprising two egg whites, two slices of bread with jam (30 g) and water (120 mL).48 This meal contains 255 kilocalories with a macronutrient composition of 72% carbohydrates, 24% protein, 2% fat and 2% fibre. With this meal, gastroparesis is defined as an intragastric retention of more than 60% of the solid meal at two hours or more than 10% at four hours.49 The disadvantages of scintigraphy include the requirement for trained staff, cost and radiation exposure. Acceptable alternatives to scintigraphy include the 13C stable isotope breath test and ultrasonography.
Management of gastroparesis is often suboptimal. General dietary advice includes smaller, frequent meals with reduced particle size and avoidance of fibre and fat, although this is not based on rigorous clinical trial evidence.50,51 For people with symptomatic advanced gastroparesis, the diet should be formulated under the supervision of a trained and experienced dietitian. A thorough medication history should be performed, as many common medications, including some used for diabetes, can alter gastric and intestinal motility. There is some evidence to suggest that optimising glycaemic control is important. An uncontrolled UK-based study found that optimising glycaemic control with continuous subcutaneous insulin infusions in people with diabetic gastroparesis resulted in substantial reductions in hospitalisation, although this requires corroboration in other trials.52
Pharmacological therapy is currently the mainstay of treatment for gastroparesis (Table 1).53-74 However, the evidence is based primarily on relatively short-duration trials with few head-to-head comparisons, and current agents may have considerable adverse effect profiles. Commonly used prokinetic agents include metoclopramide, domperidone and erythromycin. These pharmacological agents are also susceptible to tachyphylaxis, i.e. diminution of response over time. Cisapride, a previously used prokinetic drug, has been withdrawn from the market because of concerns about cardiac arrhythmias. There have been few trials on the use of antiemetics such as ondansetron and aprepitant in people with severe gastroparesis.75,76 Agents in development include ghrelin agonists (e.g. relamorelin) and highly selective serotonin type 4 receptor agonists (e.g. velusetrag and prucalopride). In people with refractory gastroparesis, gastric electrical stimulation (via a device) has been used and has shown success in open-label trials.77,78 However, the results of blinded studies have not been as promising. Recent studies have explored potential surgical approaches including gastric peroral endoscopic myotomy and combined electrical stimulation and pyloroplasty, with both approaches requiring further evaluation.79-81
The intestines
Chronic constipation
Chronic constipation is common in people with diabetes, although the reported prevalence varies substantially. One cohort study found that up to 25% of people with type 2 diabetes experience chronic constipation, with a higher prevalence observed in those with known autonomic neuropathy.82,83 A large study in the USA involving 5620 women with type 2 diabetes found that those with chronic constipation had more than twice the risk of mortality, suggesting that constipation may be an important symptom in this patient population.84 The reasons for this are not clear, but it has been suggested that chronic constipation may be a symptom of diabetes complications, and longitudinal studies are needed to evaluate the temporal relationship between the onset of chronic constipation and other diabetes complications.
The pathophysiology of chronic constipation in diabetes is multifactorial, involving microvascular, neuropathic and myopathic changes.85 The diagnosis of intestinal involvement in diabetes is primarily based on the patient’s history and the exclusion of other likely aetiologies. It should be recognised that there is currently no universally accepted definition of chronic constipation. Clinical tools, such as the Bristol Stool Form Scale, are commonly used as a visual aid. The Rome IV classification is a symptom-based system for functional GI disorders, including chronic constipation, but it is currently considered a research tool and is not widely used in clinical practice.
Initial management involves lifestyle and dietary modifications. Recommendations include a high-fibre diet, increased water intake and increased physical activity (Flowchart 1). Pharmacological treatment is offered if the symptoms are not managed adequately with lifestyle changes. Treatment typically involves laxatives. The Rome IV criteria recommend a stepwise approach: initial treatment with a bulk-forming agent, followed by an osmotic laxative and then a stimulant laxative if needed.86,87 An overview of the key prokinetic and motility-enhancing agents utilised in the treatment of constipation is presented in Table 2.88-103 Drugs such as prucalopride, linaclotide and plecanatide have consistently demonstrated efficacy in increasing bowel movement frequency and alleviating symptoms.88,89,104-106 In contrast, newer agents, such as lubiprostone and elobixibat, act via alternative mechanisms with promising outcomes, specifically through the activation of chloride channel 2 and bile acid transporters.90-93 Among these agents, only prucalopride is currently available in Australia.
Diabetic diarrhoea
Diabetic diarrhoea is characterised by chronic, watery, large-volume diarrhoea that is often painless with a predisposition to occur at night. The onset typically lasts for more than six weeks. It is non-bloody and often occurs in the setting of poorly controlled diabetes. The National Health and Nutrition Examination Survey data suggest that chronic diarrhoea is almost twice as common in people with type 1 and type 2 diabetes compared with nondiabetic controls (about 11% vs 6%).107 Diabetic diarrhoea is more commonly seen in women, with a 3:2 ratio.40,107
The pathophysiology of diabetic diarrhoea is complex and has conventionally been regarded as a manifestation of autonomic neuropathy.108 It is now understood that in addition to neuropathy of the enteric nervous system, the pathogenesis also involves a loss of interstitial cells of Cajal, enteric glial cell dysfunction, oxidative stress and inflammation.109
Enteric glial cells, specialised peripheral neuroglial cells located within the enteric nervous system, play a crucial role in regulating enteric neurons and maintaining the integrity and function of the enteric nervous system. They have been shown to have multiple pivotal roles including GI immune regulation, motility and maintaining the intestinal epithelial barrier, as well as being a conduit for the gut–brain axis. Enteric glial cell dysfunction has been reported in diabetes, and these impairments may play a significant role in the development of enteric neuropathy.48,109-111
The diagnosis of diabetic diarrhoea is essentially clinical and one of exclusion. As diarrhoea is generally more common in people with diabetes, other important causes should be excluded. The differential diagnosis includes chronic diarrhoea secondary to antidiabetic medications (e.g. metformin, GLP-1 receptor agonists, acarbose), dietary factors, largely non-nutritive sweeteners, malabsorption syndromes (e.g. coeliac disease, exocrine pancreatic insufficiency), small intestinal bacterial overgrowth, irritable bowel syndrome, inflammatory bowel disease and microscopic colitis.109
The management of diabetic diarrhoea includes general measures such as resolving fluid and electrolyte imbalances, optimising glycaemic control and consuming a low FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols) diet. 109 A number of pharmacological agents can be used, although high-quality evidence to support these therapies is currently lacking.109 These agents include loperamide (a mu-opioid receptor agonist), bile acid sequestrants (e.g. cholestyramine, colesevelam), clonidine, octreotide and ondansetron. A management approach is presented in Flowchart 2.
Faecal incontinence
Faecal incontinence is an important yet often overlooked complication of diabetes, with substantial implications for quality of life. It impacts around 18% of people with diabetes and exhibits a higher prevalence than in those without diabetes.111,112 Autonomic neuropathy, resulting from hyperglycaemia-induced damage to the enteric nervous system that governs the internal and external anal sphincters, is the primary attributable factor.3 Certain glucose-lowering medications, such as metformin, may exacerbate faecal incontinence in susceptible people. The considerable negative impact of faecal incontinence on quality of life, its social stigma and the lack of routine screening pose barriers to accurate and early diagnosis.113 Early diagnosis and targeted treatment strategies, including glycaemic optimisation, management of diarrhoea and constipation, review of medications and pelvic floor and sphincter training, are key for improving both symptom burden and overall quality of life.114
The gallbladder
A number of studies, but not all, suggest that there is an increased incidence of gallstones in people with diabetes. Major predisposing factors for cholelithiasis, such as obesity, dyslipidaemia (increased triglycerides) and intestinal dysmotility, are more common in people with type 2 diabetes.115-117 GLP-1 receptor agonists are also associated with an increased prevalence of gallbladder-related disorders.118,119
Delayed post-meal gallbladder emptying in diabetes is referred to as diabetic cholecystoparesis; although it is frequently cited as contributing to gallstone formation, this has not been demonstrated conclusively.120 A role of autonomic neuropathy in the development of diabetic cholecystoparesis has been suggested but not clearly established. Similar to the stomach, glucose clamp studies have shown that acute hyperglycaemia slows gallbladder emptying.121 It has been suggested that delayed gastric emptying may also correlate with delayed gallbladder emptying, although this needs to be conclusively demonstrated.122,123 It has been hypothesised that the increased prevalence of gallbladder disorders with GLP-1 receptor agonists is secondary to an increased gallbladder refilling time.124 A role for the gastroduodenal peptide CCK has also been suggested in the impaired motility of the gallbladder in people with diabetes, including reduced sensitivity of the gallbladder smooth muscle to plasma CCK and a reduction in CCK receptors in the gallbladder wall.125 There is some evidence to support a role for increased dopaminergic activity.125,126 Scintigraphy is generally used to measure gallbladder emptying.125
Specific management options for diabetic cholecystoparesis are currently limited. The use of prokinetic agents in diabetic cholecystoparesis can be considered, but this is not supported by evidence-based guidelines. Agents that have some limited evidence in this regard include erythromycin, metoclopramide and levosulpiride (levosulpiride is not currently available in Australia).126-129
Gastrointestinal effects of antidiabetic medications
Diabetes itself can cause impaired GI function; however, commonly used antidiabetic medications are also associated with adverse GI effects. Up to 25% of people prescribed metformin, a biguanide and first-line oral agent for type 2 diabetes, report adverse GI effects, primarily diarrhoea and nausea.130,132 Although the precise mechanisms remain uncertain, effects on the liver and direct actions on the gut, including slowing of gastric emptying, have been proposed. Strategies to mitigate the adverse effects include initiating treatment at a low dose (e.g. 500 mg daily) and gradually uptitrating to 2 grams daily, avoiding consumption on an empty stomach and using slow-release or extended-release formulations. The evidence to support these approaches is not robust. Other oral agents, such as alpha-glucosidase inhibitors (e.g. acarbose), are known to induce GI symptoms by inducing malabsorption of carbohydrates, with substantial adverse GI effects including flatulence, diarrhoea and abdominal distension. Patients should be advised of these adverse effects prior to prescription.
GLP-1 receptor agonists, now established as an extremely potent therapy for managing type 2 diabetes and obesity, are based on gut-derived peptides, and have profound, albeit variable, effects to slow gastric emptying. Both short- and long-acting agents slow gastric emptying, with the effect likely being greater with short-acting agents. Data from large-scale cardiovascular outcome trials indicate up to 13% of people on GLP-1 receptor agonists discontinue these agents due to adverse GI effects. Nausea is the most common symptom, reported by about 25% of users, with vomiting and diarrhoea reported by about 10%.119,133 The adverse GI effects are thought to be both central (direct action on GLP-1 receptors in the area postrema in the brainstem) and local (direct effect on the intestines).
Several case reports describing GLP-1 receptor agonist-induced gastroparesis have been published recently, and there is increasing concern about their use in the perioperative period because of slowed gastric emptying and a consequently increased aspiration risk.132, 134-136 It is, therefore, important to ensure that all people with diabetes undergoing elective surgery, and specifically those requiring general anaesthesia or deep sedation, undergo preoperative evaluation if they are on GLP-1 receptor therapy, as recommendations regarding the cessation of these drugs are inconsistent and lack a sound evidence base. In 2023, the American Society of Anaesthesiologists published a statement that short-acting GLP-1 receptor agonists should be discontinued for one day, and long-acting GLP-1 receptor agonists for one week prior to elective procedures.137 Subsequently, several position statements have been published, with inconsistent recommendations.138
In 2025, a multidisciplinary consensus statement by the Society of Perioperative Assessment and Quality Improvement provided a more nuanced, individualised approach influenced by the presence of significant GI symptoms, other patient-related factors and the indication for GLP-1 receptor agonist use.139 Australian clinical practice guidelines recommend the continuation of these agents periprocedurally and do not suggest an adequate cessation period prior to planned procedures; the guidelines recommend checking for usage of GLP-1-based agents prior to an elective procedure, informing the patient of the benefits and risks of these agents, dietary modifications and fasting in the preceding 24 hours (including 24 hours of clear fluids prior and 6 hours of standard fasting) to reduce the risk of aspiration.140 GLP-1 receptor agonists can affect both small intestinal and colonic motility; these effects are poorly defined and their significance uncertain.141
Conclusion
Abnormalities along the entirety of the GI tract are observed commonly in type 1 and type 2 diabetes, although the prevalence can vary widely. Gastroparesis remains the most widely studied and clinically challenging manifestation, and treatment with currently available modalities can often be suboptimal. There is a bidirectional relationship between gastric emptying and postprandial glycaemia. Validated screening tools for quantifying GI symptoms need to be more widely used in clinical practice and research. Commonly used antidiabetic medications, such as metformin and GLP-1 receptor agonists, are often associated with GI adverse effects. ET
COMPETING INTERESTS: None.
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