ABSTRACT
Gastrointestinal disorders are common in patients with diabetes mellitus and can be linked to diabetes itself, its complications, or medications used to treat it. These disorders include gastroesophageal reflux, gastroparesis, enteropathy manifesting clinically with constipation or diarrhea, and metabolic dysfunction–associated steatotic liver disease. Timely diagnosis and management of these disorders can improve patients’ quality of life. The authors provide clinically practical advice on when and how to screen for common diabetes-related gastrointestinal disorders and review the management of these disorders in the primary care setting.
Diabetes mellitus affects an increasingly large number of patients and can cause a wide range of gastrointestinal pathologies.
The most prevalent gastrointestinal disorders linked to diabetes are gastroparesis and metabolic dysfunction– associated steatotic liver disease, with both having a prevalence up to 70%.
The pathophysiology of diabetes mellitus–associated gastrointestinal complications is generally related to poor glycemic control and can be prevented with intense glycemic control.
Approximately 500 million people worldwide are living with diabetes, and this number is expected to grow to 700 million by 2045.1 Diabetes mellitus is linked to a wide range of gastrointestinal pathology. Gastrointestinal disorders associated with diabetes mellitus include gastroesophageal reflux disease, gastroparesis, small intestinal bacterial overgrowth, metabolic dysfunction–associated steatotic liver disease (MASLD), and acute pancreatitis.1 Diabetic neuropathy plays a large role in the pathogenesis of these disorders, from initial blunting of symptoms to eventual dysmotility that can occur across the entire gastrointestinal tract.
Patients with diabetes and coexisting gastrointestinal issues generally first seek care in the primary care setting due to symptoms such as reflux, nausea, vomiting, bloating, diarrhea, and constipation. Awareness of the protean effects of diabetes and diabetes medications on the gastrointestinal system is important, as appropriate and timely diagnosis of gastrointestinal disorders can improve quality of life for these patients.
This review addresses the epidemiology and pathophysiology of diabetes-related disorders affecting the esophagus, stomach, small and large intestine, liver, and pancreas. Included is discussion of medications that could be implicated, practical advice on when and how to screen, management and referral recommendations, and data to support recommended interventions.
GASTROESOPHAGEAL REFLUX
Individuals with diabetes mellitus are more predisposed to developing retrograde movement of acid from the stomach into the esophagus compared with those without diabetes.2 Proposed mechanisms for abnormal gastroesophageal reflux include delayed gastric emptying and impaired esophageal motility due to neuropathy caused by diabetes.3 In addition, it is hypothesized that autonomic neuropathy due to acute or chronic hyperglycemia can increase the frequency of transient relaxation of the lower esophageal sphincter, ie, relaxation without a swallow, which can lead to gastroesophageal reflux disease.2
The exact prevalence of gastroesophageal reflux disease in patients with diabetes mellitus is unclear; however, one study reported that 25% of patients with type 2 diabetes mellitus had heartburn and chest discomfort after eating, consistent with gastroesophageal reflux disease.4 In this study, reflux symptoms occurred more often in those with poorer glycemic control, as reflected by the presence of diabetes complications including retinopathy, nephropathy, or neuropathy.
Screening and management
Gastroesophageal reflux disease should be considered when patients present with typical symptoms such as substernal burning (“heartburn”), pain in the middle of the stomach, or regurgitation along with the need for over-the-counter antacids to resolve these symptoms. The GerdQ questionnaire, a 6-item diagnostic tool developed using data from primary care patients with upper gastrointestinal symptoms, can be used before making a gastroenterology referral (Table 1).5 Patients with a score of 8 or higher (indicating a high likelihood of gastroesophageal reflux disease) who do not have any alarm features (weight loss, dysphagia, bleeding [hematemesis, melena], vomiting, anemia) should undergo an 8-week trial of empiric treatment with a proton pump inhibitor, as recommended by the current American College of Gastroenterology guideline.6
GerdQ: Gastroesophageal reflux disease self-assessment
Gastroenterology referral is indicated for patients who have alarm symptoms, patients whose symptoms do not respond to proton pump inhibitor therapy, or patients whose symptoms return after proton pump inhibitors are discontinued (Figure 1).
Algorithm for assessment of gastroesophageal reflux disease (GERD) symptoms.
The response of symptoms to proton pump inhibitor therapy depends on the degree of glycemic control. Further, a case-control study found that obesity concurrent with diabetes mellitus was associated with failure of proton pump inhibitor therapy.7 Improving glycemic control can alleviate symptoms, increase responsiveness to therapy, and reduce the need for future nonessential endoscopic screening.
Increased risk for esophageal carcinoma
Long-standing gastroesophageal reflux disease can lead to development of Barrett esophagus and predispose patients to esophageal adenocarcinoma. In a case-control study of male veterans undergoing routine colorectal cancer screening, 821 participants were recruited for additional upper endoscopy. Among these, 70 (8.5%) were diagnosed with Barrett esophagus, of whom 15 (21%) had preexisting diabetes.8 In a meta-analysis of observational studies, diabetes mellitus was associated with an increased risk of esophageal carcinoma (relative risk 2.72, 95% confidence interval 1.01–4.46).9 In a Veterans Affairs database study, 30.8% of patients with esophageal carcinoma had concomitant diabetes mellitus, and logistic regression showed an association between diabetes and risk of esophageal cancer (odds ratio 2.23, 95% confidence interval 1.75–2.82).10
Although diabetes mellitus is a modest risk factor for esophageal carcinoma, current evidence does not support screening for esophageal carcinoma. In patients with diabetes mellitus and known gastroesophageal reflux disease, we recommend counseling on lifestyle modifications with weight loss and smoking cessation to ameliorate preventable risk factors associated with esophageal adenocarcinoma.
GASTROPARESIS
Gastroparesis is defined as delayed gastric emptying without mechanical obstruction. The pathogenesis of gastroparesis in patients with diabetes remains poorly understood, but it is accepted that hyperglycemia plays a role. Hyperglycemia reduces the number of “pacemaker” interstitial cells of Cajal in gastrointestinal smooth muscle, leading to improper synchronization of smooth muscle in the stomach.11
The overall prevalence of gastroparesis in patients with diabetes is 9.3%.12 In a population-based cohort study, the 10-year cumulative incidence of gastroparesis was 5.2% in patients with type 1 diabetes and 1.0% in those with type 2 diabetes.13 Bytzer et al14 found coexisting peripheral neuropathy to be significantly associated with the development of gastroparesis. Analysis of data from the Diabetes Control and Complications Trial–Epidemiology of Diabetes Interventions and Complications study showed that gastroparesis occurs in patients who have had type 1 diabetes mellitus for at least 10 years.15
Screening and management
Primary care clinicians can screen for gastroparesis in patients with diabetes mellitus by asking about symptoms of nausea, satiety, and bloating. If these symptoms are present, a thorough medication reconciliation can be helpful. Many medications are known to reduce gastrointestinal motility (Table 2), including glucagon-like peptide (GLP) 1 receptor agonists used to treat type 2 diabetes (more on these medications below). Patients whose symptoms persist for at least 1 month after medication reconciliation should be referred to gastroenterology for esophagogastroduodenoscopy to rule out mechanical obstruction.
Medications that can cause gastrointestinal complications in patients with diabetes
Primary care clinicians can educate patients on how to intensify glycemic control and modify their diet around small-particle, low-fat food, both of which can decrease the risk of gastroparesis.16 However, achieving glycemic control in patients who have developed gastroparesis is challenging. Symptoms interfere with regular meals, and patients may withhold insulin to avoid hypoglycemia.
To address this challenge, investigators have explored the use of continuous subcutaneous insulin infusion therapy in patients with diabetic gastroparesis. In a small UK trial of patients with type 1 diabetes, continuous subcutaneous insulin infusions were shown to be effective in reducing blood glucose variability as well as reducing hospitalizations for gastroparesis.17 In an open-label pilot study, continuous subcutaneous insulin infusions along with continuous glucose monitoring safely reduced patients’ time in hypoglycemia and improved hemoglobin A1c and gastroparesis symptoms.18
GLP-1 receptor agonists and gastric motility
It is well known that GLP-1 receptor agonists can cause delayed gastric emptying and gastroparesis, and that they are associated with other gastrointestinal complications such as nausea and vomiting, constipation, cholelithiasis, and cholecystitis. These complications are related to the effect of GLP-1 receptor agonists on gastrointestinal motility. In the primary care setting, starting a GLP-1 receptor agonist at a high dose or escalating a dose too quickly can lead to complications. It is recommended that clinicians start patients at the lowest dose and discontinue treatment if symptoms of gastroparesis occur.19
SMALL INTESTINAL BACTERIAL OVERGROWTH
Small intestinal bacterial overgrowth is an alteration in the quantity and type of bacteria in the small intestine. Recent data indicate that a normal gut microbiome consists primarily of Firmicutes, Bacteroides, and Actinobacteria, which respectively make up 60% to 80%, 20% to 30%, and 10% of the gut microbiota.20 However, in several clinical trials the ratio of Firmicutes to Bacteroides was found to be much lower in patients with diabetes mellitus.21
Diabetes mellitus causes decreased motility of the small intestine, enabling bacterial stasis, dysbiosis, and subsequent overgrowth. These changes can increase bacterial byproducts such as ammonia, fatty acids, and toxins that can damage the gut lining, ultimately decreasing normal absorption of carbohydrates and fat.22 The clinical effects are abdominal bloating, discomfort, and diarrhea.
In a small prospective study, small intestinal bacterial overgrowth was diagnosed in 43% (15 or 35) of patients with type 1 or type 2 diabetes mellitus who had chronic diarrhea.23 The prevalence of small intestinal bacterial overgrowth does not differ significantly in patients with type 2 diabetes vs type 1 diabetes mellitus.24
Screening and management
Primary care clinicians should refer patients to gastroenterology to screen for small intestinal bacterial overgrowth when they have unexplained chronic diarrhea, bloating, or signs and symptoms of persistent, significant unintentional weight loss and malnutrition.22
Addressing any underlying disease or condition is a key component of treating small intestinal bacterial overgrowth. In patients with long-standing type 1 diabetes mellitus, proper glycemic control can improve gastrointestinal symptoms caused by small intestinal bacterial overgrowth.25 We can hypothesize that better glycemic control also can improve symptoms in patients with type 2 diabetes.
Primary care clinicians can also suggest that patients try a low FODMAP (fermentable oligo-, di-, monosaccharides and polyols) diet to relieve symptoms, but data remain inconclusive for this modality.26
LARGE INTESTINE: DIARRHEA AND CONSTIPATION
Cohort studies have found that chronic constipation affects between 15% and 25% of patients with diabetes mellitus, and constipation seems to be significantly more common in patients with autonomic neuropathy than in those without neuropathy.27 Diabetic neuropathy can lead to impaired rectal sensation, and can also affect the function of the anal sphincters and the rectum, hindering the passage of stool.27 Further, about 20% of patients with diabetes complain of diarrhea and fecal incontinence.28
Management
Notably, there are no published data on diagnostic testing in patients with diabetes who present with clinical symptoms of diarrhea or constipation, nor are there algorithms for screening these patients.
Artificial sweeteners that patients may use as alternatives to sugar are commonly associated with diarrhea, so clinicians should ask patients if these are a regular part of their diet.
GLP-1 receptor agonists and metformin are notably associated with gastrointestinal adverse effects, including diarrhea, nausea, indigestion, vomiting, and constipation. Patients’ medications should be reviewed. If a patient’s gastrointestinal symptoms are attributable to medications, clinicians can switch to agents from a different drug class, but switching to an alternative formulation also may be effective. For example, a large meta-analysis found that the extended-release formulation of metformin was associated with reduced bloating, vomiting, and abdominal pain compared with the immediate-release formulation.29 In a prospective cohort study in Italy of patients who were intolerant to immediate-release metformin, 88% of patients reported improvement in diarrhea after taking extended-release metformin.30
METABOLIC DYSFUNCTION–ASSOCIATED STEATOTIC LIVER DISEASE
MASLD is characterized by fat accumulation in the liver that is not linked to alcohol consumption or other toxins. MASLD is common in patients with type 2 diabetes; its prevalence can be as high as 69.5% in this population.31
Type 2 diabetes contributes to MASLD by promoting accumulation of fat in the liver. Hyperglycemia and insulin resistance cause the liver to synthesize more glucose, providing substrates for hepatic lipogenesis, which exceeds lipolysis.32 The result is an increase in hepatic free fatty acids, which are toxic to hepatocytes. This process correlates with higher levels of insulin and insulin resistance, which drives the synthesis of free fatty acids.
Screening and management
Primary care clinicians should screen patients for hepatic fibrosis, the most important determinant of liver and nonliver outcomes in patients with MASLD. The American Diabetes Association33 and American Association of Clinical Endocrinology,34 along with other professional societies, recommend screening for MASLD and metabolic dysfunction–associated steatohepatitis in patients with obesity and prediabetes or with type 2 diabetes mellitus, as the pretest probability of hepatic steatosis in these populations is 70% or higher. For high-risk patients older than 35, clinicians can start by calculating a fibrosis-4 score; this measure uses age, levels of aspartate and alanine transaminases, and platelet count to estimate the amount of liver scarring:33
Score less than 1.3: fibrosis can be reliably excluded
Score between 1.3 and 2.67: liver ultrasonography with transient elastography to determine liver stiffness is recommended
Score greater than 2.67: patient is at increased risk of advanced liver fibrosis and requires gastroenterology referral for further evaluation.35
Weight loss. Management of MASLD can be started in the primary care setting with a combination of lifestyle modification and weight management. Weight loss of at least 3% to 5% of total body weight can improve steatosis. Typically, more than 5% weight loss is needed to reverse steatohepatitis, and many studies suggest that more than 10% is needed to improve fibrosis, but responses can vary.36
Exercise has been shown to decrease insulin resistance, plasma aminotransferases, and steatosis. Aerobic activity and high-intensity activity potentially offer greater hepatic benefits than other types of exercise.37 Current guidelines recommend moderate-intensity exercise for at least 150 minutes per week or 75 minutes of vigorous-intensity activity per week with resistance training 2 to 3 times per week.38 Minimizing sedentary time with activities such as walking is also encouraged.
Dietary approaches. A diet incorporating high-fiber foods and unsaturated fats is generally recommended. Foods high in saturated fat and sugars such as sucrose or high-fructose corn syrup are associated with post-prandial hypertriglyceridemia, insulin resistance, and ultimately a higher risk for MASLD or metabolic dysfunction–associated steatohepatitis; these foods should be limited.39 It is best to avoid ultraprocessed foods and to reduce intake of saturated fats, simple sugars, and fructose.
No single nutritional approach has been found superior. Readily available nutritional approaches seem comparable in their ability to improve steatosis; these include low-fat and low-carbohydrate foods, Mediterranean dietary approaches to stop hypertension (the DASH [Dietary Approaches to Stop Hypertension] diet), high-protein foods, and intermittent fasting.
A pharmacologic approach to comorbid conditions such as type 2 diabetes mellitus with GLP-1 receptor agonists (ie, tirzepatide, semaglutide) can effectively reduce hemoglobin A1C levels, increase weight loss, and reduce liver fibrosis. Resmetirom and semaglutide are also approved by the US Food and Drug Administration for treatment of metabolic dysfunction– associated steatohepatitis and MASLD.40
GALLSTONE DISEASE AND ACUTE PANCREATITIS
Gallstone disease is the most common cause of acute pancreatitis, accounting for 20% to 70% of pancreatitis cases worldwide.41 Patients with diabetes have an increased incidence and prevalence of gallbladder disease,42 which increases their risk for developing gallstone-related acute pancreatitis. The pathophysiology of acute pancreatitis in patients with diabetes is poorly understood, but studies have shown that patients with type 2 diabetes mellitus have a 3-fold greater risk of pancreatitis compared with patients without type 2 diabetes mellitus.43
Recent trials have shown no increased risk of pancreatitis with GLP-1 receptor agonists compared with placebo.44 A systematic review and meta-analysis of long-term placebo-controlled, randomized controlled trials also demonstrated that treatment with a GLP-1 receptor agonist does not increase the risk of pancreatitis.45
Some patients may develop diabetes following an episode of acute pancreatitis, which is called type 3c diabetes mellitus, or pancreatogenic diabetes. The underlying pathophysiology is poorly understood. Recent systematic reviews and meta-analyses have shown that around 15% of patients develop diabetes within 1 year of an acute pancreatitis episode and the severity of the acute pancreatitis episode may impact the likelihood of developing diabetes in the future.46 There are no current guidelines on screening for diabetes after an episode of acute pancreatitis.
DISCLOSURES
The authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.
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