Diabetic gastroparesis is a late complication of long-standing uncontrolled diabetes. Pathogenesis is complex as it involves hyperglycemia, vagus neuropathy, and inflammation. Gastroparesis leads to gastric outlet obstruction, delayed gastric emptying, and gastroesophageal reflux. Symptoms are nausea, vomiting, reflux, bloating, weight loss, and improper gastrointestinal absorption.
In this article, the authors provide an in-depth analysis and review of the literature on diabetic gastroparesis. They discuss in detail the pathogenesis, structural anomalies, the role of hyperglycemia, neuropathy, inflammation, and symptoms. They also discuss thoroughly various diagnostic testing, current medications available, and potential future drugs.
Diabetic gastroparesis requires a multidisciplinary approach, including a nutritionist, primary care physician, endocrinologist, gastroenterologist, and surgeon. Tight control of hyperglycemia is paramount in preventing gastroparesis in the first place as well as halting its progression.
This review covers the epidemiology, pathophysiology, clinical features, diagnosis, and management of diabetic gastroparesis, and more broadly diabetic gastroenteropathy, which encompasses all the gastrointestinal manifestations of diabetes mellitus.
Up to 50% of patients with type 1 and type 2 DM and suboptimal glycemic control have delayed gastric emptying (GE), which can be documented with scintigraphy, 13C breath tests, or a wireless motility capsule; the remainder have normal or rapid GE.
Many patients with delayed GE are asymptomatic; others have dyspepsia (i.e., mild to moderate indigestion, with or without a mild delay in GE) or gastroparesis, which is a syndrome characterized by moderate to severe upper gastrointestinal symptoms and delayed GE that suggest, but are not accompanied by, gastric outlet obstruction.
Gastroparesis can markedly impair quality of life, and up to 50% of patients have significant anxiety and/or depression. Often the distinction between dyspepsia and gastroparesis is based on clinical judgement rather than established criteria. The following are implicated in the pathogenesis of delayed GE.
- Autonomic neuropathy,
- Enteric neuromuscular inflammation and injury
Alternatively, there are limited data to suggest that delayed GE may affect glycemic control. The management of diabetic gastroparesis is guided by the severity of symptoms, the magnitude of delayed GE, and the nutritional status.
- Initial options include dietary modifications, supplemental oral nutrition, and antiemetic and prokinetic medications.
- Patients with more severe symptoms may require a venting gastrostomy or jejunostomy and/or gastric electrical stimulation.
- Promising newer therapeutic approaches include ghrelin receptor agonists and selective 5-hydroxytryptamine receptor agonists.
More from the publication:
The enteric nervous system contains 100 million neurons. It is organized in distinct ganglionated plexi, that is, the myenteric plexus, which regulates motility, and the submucous plexus, which primarily regulates absorption and secretion. The interstitial cells of Cajal (ICCs) serve as pacemakers and also convey messages from nerve to smooth muscle. DM can affect not only the gut’s autonomic and enteric nervous system but also the somatic nerve supply (e.g., pudendal nerves). Derangements of the extrinsic nerves at any level may alter GI motility and secretion.
Autonomic neuropathy has been implicated as the major mechanism for DM gastroenteropathy. More recently, there is emerging evidence for disturbances in the enteric nervous system (i.e., enteric neurons and ICCs) and smooth muscle myopathy.
In humans, most attention has centered on delayed GE and its relationship to acute hyperglycemia and autonomic neuropathy, which is often associated with other complications (i.e., peripheral neuropathy, retinopathy, and nephropathy). Delayed GE may result from reduced antral contractility, which impairs the ability of the antrum to triturate or grind food into smaller particles that can be emptied from the stomach, and/or pylorospasm, hindering GE. Both disturbances (i.e., antral hypomotility and pylorospasm) may result from a vagal neuropathy or enteric neuromuscular dysfunction.
There is a bidirectional relationship between glycemic control and GE in DM, that is, hyperglycemia can delay GE wheras GE disturbances affect glycemic control (and perhaps variability). The effects of hyperglycemia on GE may be influenced by the duration of hyperglycemia. Hence, it is useful to characterize glycemic exposure as follows: immediate (i.e., fasting glucose before the study), recent (i.e., HbA1c before the GE study), and remote (e.g., HbA1c 20 years ago).
The cardinal symptoms of gastroparesis include early satiety, postprandial fullness, nausea, vomiting, bloating, upper abdominal pain, and weight loss. In the NIDDK Gastroparesis Registry, symptoms begin at a later age in patients with type 2 DM (49 ± 11 years) than in patients with type 1 DM (34 ± 10 years) or idiopathic gastroparesis (36 ± 15 years).
In ∼50% of patients with gastroparesis (both idiopathic and diabetic), the symptoms began acutely. Approximately 19% of patients with idiopathic and 14% each with type 1 and type 2 DM had features of an infectious prodrome. In almost half of the patients, the symptoms waxed and waned over time; ∼33% of patients with idiopathic and diabetic gastroparesis had periodic exacerbations and 10% had a cyclical pattern.
The average duration of symptoms prior to diagnosis of gastroparesis was 6 years in type 1 DM and 4 years in type 2 DM. The evaluation was generally prompted by vomiting in diabetic gastroparesis and abdominal pain in idiopathic gastroparesis. In this and another study, retching and vomiting were more severe in diabetic than in idiopathic gastroparesis. In contrast, patients with idiopathic gastroparesis had more severe early satiety and postprandial fullness.
Among patients with gastroparesis, caloric intake is typically reduced, causing significant weight loss. In the NIDDK consortium registry, patients with diabetic gastroparesis consumed, on average, ∼1280 kcal daily. Approximately 60% of patients with diabetic gastroparesis consumed a calorie-deficient diet (i.e., an intake of <60% of the estimated total energy requirements) and half reported weight loss.
Among patients with DM and upper GI symptoms, a diagnosis of gastroparesis is established by documenting delayed GE and excluding gastric outlet obstruction, preferably with endoscopy. It is necessary to assess GE because symptoms alone cannot predict whether patients have normal, rapid, or delayed GE.
Medications that may delay (e.g., opioid analgesics, anticholinergic agents, GLP-1 analogs, and pramlintide) or accelerate (e.g., metoclopramide, domperidone, and erythromycin) GE should be discontinued before the test; for most medications, 48-72 hours is sufficient. Although guidelines recommend that the GE should not be assessed during severe hyperglycemia (blood glucose ≥275 mg/dL), there is limited evidence that the fasting blood glucose prior to the GE study is associated with delayed GE. Indeed, hyperglycemia was associated with faster GE in patients with poorly controlled type 2 DM.
GE can be evaluated with scintigraphy, which is the criterion standard test, GEBT, or with wireless capsule motility. The assessment of GE with ultrasound and MRI is limited to research studies. Typically, the GE of solids is evaluated with a meal containing eggs labeled with 99mTc sulfur colloid; images are acquired at baseline and 1, 2, and 4 hours. Postprandial scans at 1 and 2 hours can identify accelerated GE, whereas scans at 2 and 4 hours identify delayed GE.
There are two commonly used meals, with normal or low fat content, which in turn influences the normal values of GE. The regular fat meal (296 kcal, 31% protein, 32% carbohydrate, and 37% fat) consists of two scrambled eggs, one slice of whole wheat bread, and one glass of skim milk. GE is faster in men than in women; sex-appropriate normal values are available for this meal. At 4 hours, >23% retention (or <76% emptying) in men and >24% retention in women reflects delayed GE.
By definition, the symptoms of gastroparesis are similar to those of benign or malignant gastric outlet obstruction, which can be readily excluded with an upper endoscopy. Gastroparesis can be readily differentiated from most other organic causes of upper GI symptoms (e.g., acute cholecystitis)
The goals of therapy are to reduce symptom burden, to ensure adequate nutritional intake and, to improve quality of care. We recommend a stepwise approach that initially incorporates safe and less invasive interventions, reserving more invasive options for patients in whom the initial therapies are ineffective. Although there is evidence to support many of the individual steps, the efficacy of this stepwise approach has not been evaluated in clinical trials.
Antiemetics are used as first-line therapy, often before the diagnosis is established. Dietary modification utilizing a low-fat, low-fiber small-particle diet is beneficial but infrequently followed. When necessary, improving glycemic control is desirable, but there is little evidence to suggest that it improves GE.
In the United States, metoclopramide and erythromycin are the only FDA-approved medications that can accelerate GE. Although these drugs improve symptoms and facilitate increased nutritional intake, their use is associated with adverse effects. Administration of these medications in suspension, where available, rather than tablet form may reduce the risk of erratic pharmacokinetic profiles secondary to delayed GE by virtue of the differing GE profiles of liquids, solids, and large particles. Ghrelin and 5-hydroxytryptophan receptor agonists, which are in advanced clinical trials, appear to be promising options.
If these measures are insufficient, supplemental nutrition, preferably enteral, administered through a feeding jejunostomy often accompanied by a venting gastrostomy, should be considered. The evidence for more invasive options (i.e., GES, pyloromyotomy, and gastrectomy) is of low quality. These should be considered on a case-by-case basis, and only at specialist centers. In primarily uncontrolled studies, GES improved symptoms but not GE. Hence, the enthusiasm for GES varies considerably across centers. Endoscopic pyloromyotomy is the new kid on the block. Subtotal or total gastrectomy is rarely performed.
Primarily based on physiologic principles and supported by relatively small clinical trials, a low-fat, low-fiber, small-particle or liquid diet is recommended for gastroparesis. Patients should begin by restricting the ingestion of foods in the “difficult to digest” category, and expand, as necessary, to exclude foods in the moderate and easy to digest groups. Practical and specific dietary guidelines are provided elsewhere.
The symptoms of gastroparesis (e.g., nausea, vomiting, and erratic caloric intake) increase the challenge of balancing carbohydrate intake while avoiding hypoglycemia. However, as detailed in the section on the bidirectional relationship between glycemia and GE, there is limited evidence that delayed GE is associated with hypoglycemia in DM. To avoid the unpredictable hypoglycemic episodes associated with delayed GE, patients may be more comfortable with suboptimal glycemic control.
In type 2 DM, several medications, including newer agents (e.g., SGLT-2 inhibitors) to improve glucose control, are available and can be used alone or in combination. GLP-1 receptor agonists should be avoided because they delay GE. Conceivably, oral agents may be combined with CGM and insulin pumps even for type 2 DM.
Metoclopramide reduces emesis via central effects (i.e., at chemoreceptor trigger zone), which are attributable to antagonism of dopamine receptors, and peripheral effects, which are attributable to cholinergic agonism and increased foregut motility. The latter comprises increased lower esophageal sphincter and gastric fundus tone, gastric and duodenal motility with synchronized antroduodenal motility that accelerates GE. It can be administered via the oral (tablet and liquid), parenteral (218), rectal, or nasal routes.
Similar to metoclopramide, domperidone is a dopamine receptor antagonist. It is only available as an oral formulation and improves symptoms to a similar extent as metoclopramide. However, in contrast to metoclopramide, domperidone does not cross the blood–brain barrier. Hence, the risk of extrapyramidal adverse effects is extremely low.
Motilin is a 22–amino acid peptide hormone expressed throughout the gut. Motilin receptors, however, are predominantly located proximal to the ligament of Trietz. Stimulation initiates phases 2 and 3 interdigestive antral contractions that promote GE. Erythromycin, a macrolide antibiotic, which is available as oral (tablet and suspension) and IV formulations, acts as a motilin receptor agonist and stimulates gastric migrating motor complexes at doses substantially lower than those used for antibacterial effects.
Limited evidence suggests that a second macrolide antibiotic, azithromycin, may also improve the rate of GE. Relative to erythromycin, azithromycin has a longer half-life, fewer drug interactions, and fewer adverse effects. However, there are no reports regarding the effect of azithromycin on gastroparesis symptoms. Furthermore, similar to erythromycin, azithromycin use is associated with a risk of sudden cardiac death, particularly in those with underlying cardiac disease. A third compound, derived from macrolide antibiotics but with no antibiotic properties, increased GE but failed to reduce symptoms in patients with DM and upper GI symptoms.
Ghrelin is a natural ligand for the growth hormone secretagogue receptor expressed throughout the GI tract. At pharmacologic doses, ghrelin promotes gastric motility in healthy people and in idiopathic gastroparesis. Two ghrelin agonists (i.e., TZP-102 and relamorelin) have been assessed in diabetic gastroparesis.
Cisapride, which is a serotonin receptor agonist that improved the symptoms of gastroparesis, was withdrawn from the US market due to concerns regarding unexpected cardiac events. More recently, 5-HT(4) receptor agonists are being evaluated for treating gastroparesis. Reported in abstract form, prucalopride, which is currently used to treat constipation, improved the GE rate and symptoms of gastroparesis in a blinded crossover study.