We'd like to understand how you use our websites in order to improve them. Register your interest. Diabetic gastropathy is a term that encompassesa number of neuromuscular dysfunctions of the stomach,including abnormalities of gastric contractility, tone,and myoelectrical activity in patients with diabetes. These abnormalities range fromtachygastrias to antral hypomotility and frankgastroparesis. Diabetic gastropathies may be acutelyproduced during hyperglycemia. Symptoms of chronicdiabetic gastropathy include chronic nausea, vague epigastricdiscomfort, postprandial fullness, early satiety, andvomiting.
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Diabetic gastroparesis DGP is a gastric complication of diabetes mellitus that causes nausea, vomiting, early satiety, bloating and abdominal pain, in addition to significant morbidity. Original and review articles were reviewed through PubMed, including relevant guidelines from the European and American Neurogastroenterology Societies. Diagnosis of DGP requires endoscopy and measurement of gastric emptying.
Management requires prokinetic therapy, usually in addition to antinausea or other medications. The pathogenesis of DGP is poorly understood.
Management strategies are highly variable. Prokinetic and neuromodulatory medications are in human clinical trials specifically for gastroparesis. Further understanding of the molecular pathology leading to DGP is required to potentially arrest the development of this serious diabetic complication. Evaluation of novel agents for use in DGP is sorely needed.
Gastroparesis is a serious complication of diabetes mellitus DM , defined as a delay in gastric emptying without any mechanical obstruction in the stomach. Other non-diabetic causes of gastroparesis are surgery, neurologic disorders, medication and idiopathic causes; 1 however, the outcomes for those with diabetic gastroparesis DGP are worse.
In recent years, we have gained much insight into the pathophysiology of DGP, in addition to increased awareness of the disorder. However, different pathophysiologic mechanisms and variable response to treatments make it still difficult to optimize therapy. Population-based data on DGP are limited. In case series from tertiary care centers, delayed gastric emptying is reported in one-third of diabetic patients with an equal prevalence in type 1 and type 2 diabetes.
The disease affects females more than males in an approximate ratio and typically presents in the fourth or fifth decades in the type 1 diabetic population.
The hospitalization rate increased fairly dramatically after the year , for reasons that are not clear; however, both the removal of the prokinetic agent cisapride from the market and approval of gastric electrical stimulation which requires hospitalization for implantation occurred around that time. Gastric motility is regulated by a complex interplay between smooth muscle cells, interstitial cells of Cajal ICC , enteric nerves and the vagus nerve Fig.
The functional components of the stomach are divided into a proximal part fundus and a distal part corpus and antrum. When food is ingested, peristaltic propulsions of the esophagus bring the bolus into the fundus that then relaxes to accommodate the bolus. This accommodation is necessary to create a reservoir for the ingested food. Initial accommodation occurs in response to the presence of caloric food in the fundus, whereas increased filling will distend mechanosensitive tension receptors and lead to further accommodation of the proximal stomach.
Both these reflexes are mediated through the vagus nerve. Gastric function in the normal A and gastroparetic state B. Numerous coordinated processes are required for normal gastric function, which require an intact ENS. In DGP, one or more of these processes may be disrupted, ultimately leading to delayed gastric emptying and symptom generation. Once the meal is ingested, pacemaker cells of the ICC network will initiate contractions by triggering rhythmical electrical activity that is propagated along the stomach.
These cells are located at the border of fundus and corpus on the large curvature. The slow waves, with a frequency of three per minute, will induce peristaltic propulsions of the muscle layer and push the food from the proximal to the distal stomach. In the antrum, the rhythmic contractions grind the solid food into smaller pieces against a closed pyloric sphincter. Once the food particles are small enough, typically 1—2 mm, food will be emptied out of the stomach via an antro-duodenal reflex into the duodenum for digestion and absorption.
Emptying rate is highly controlled to ensure nutrients are received into the duodenum at an ideal size and rate to optimize absorption. Thus liquids with a low caloric content are emptied faster less than 1 h than liquid meals with a high caloric content 1—2 h. Similarly, emptying of solids takes longer 3—4 h because they are retained in the stomach until they are adequately processed.
Gastroparesis is defined by delayed gastric emptying in the absence of any mechanical obstruction. It is associated with symptoms of early satiety, nausea, bloating and vomiting. Delayed emptying can be the result of the pyloric contractions and antral hypomotility induced by the hyperglycemic state.
It is unclear however whether chronically elevated blood glucose has effects of similar magnitude on gastric emptying. As with other diabetic complications, strict blood glucose control is the best prevention. Unfortunately, once gastric function is excessively compromised, ongoing strict control may become difficult. Vagal dysfunction has also been postulated to play a role in DGP.
When food is ingested and gastric accommodation is impaired, patients may experience symptoms such as early satiation, fullness and discomfort. Animal and human data suggest that vagal neuropathy can lead to reduction in pyloric relaxation, impaired antral contraction and disturbed antropyloric coordination. A major component of the ENS is the myenteric plexus, a network of nerves that is layered between the longitudinal and circular muscle layer of the gut and coordinates gastric motor function.
The myenteric plexus comprises excitatory cholinergic and purinergic and inhibitory nitrergic and purinergic motor neurons, as well as primary afferent neurons and several classes of interneurons. The excitatory motor neurons induce muscle contractions via release of neurotransmitters such as acetylcholine and substance P, whereas the inhibitory neurons will relax the muscle tissue via release of nitric oxide and also ATP and vasoactive intestinal peptide.
Pathologic changes in these pathways, especially the nitergic nerves, will affect motor control and may contribute to problems such as delayed emptying, impaired accommodation and gastric dysrhythmia. Evidence for a role of nitrergic nerves was already obtained in early studies that demonstrated that nNOS knockout mice developed a dilated stomach with hypertrophy of the circular muscle layer.
In other animal experiments, decreased expression of nNOS by disease or pharmacologic interference with nitric oxide synthase is also able to induce impaired gastric emptying. Several mechanisms have been proposed to underlie the decreased nNOS expression. Non-obese diabetic NOD mice showed a reversible loss of gastric nNOS expression, suggesting that down-regulation of nNOS without loss of nitrergic neurons occurs in the diabetic state.
These data show a biphasic loss of the nitrergic component that could be induced by accumulation of toxic components or increased oxidative stress seen in animal models and patients with diabetes. Loss of ICC has been reported in animal models and diabetic patients with gastroparesis.
NOD mice and STZ-induced rats show a loss of ICC in both corpus and antrum, and this could contribute to the delay in gastric emptying in these animals. Recent data from the Gastroparesis Clinical Research Consortium in the USA, which collected data from a large cohort of gastroparesis patients, have correlated the cellular changes in gastric surgical full-thickness biopsies to patient symptoms and gastric emptying rate.
Although similar changes were also observed in idiopathic gastroparesis patients, a significant correlation was lacking in this group; this may reflect the fact that idiopathic gastroparesis is likely a much more heterogenous disorder than DGP, with a less well understood pathophysiology and may include patients with severe functional dyspepsia.
In contrast to previous animal and human data, nNOS expression was not significantly decreased in diabetic and idiopathic gastroparesis patients in that study. It should be noted that the full-thickness biopsies were taken from patients who were undergoing placement of a gastric neurostimulator and, thus, may represent a subgroup that is not representative of the general population with DGP. Oxidative stress is also a plausible etiologic factor underlying loss of nitrergic function because it is well known that diabetes induces a high oxidative stress state that can target various tissues.
Oxidative stress can be caused by increased reactive oxygen species and loss of antioxidant protection such as heme-oxygenase-1 HO-1 that is up-regulated during oxidative stress. HO-1 is an enzyme that catalyzes the degradation of heme into several products of which carbon monoxide CO and biliverdin are suggested to have antioxidative effects.
Increased oxidative stress in NOD mice due to loss of macrophage HO-1, which normally protects against free radicals in the ENS, was associated with loss of ICC and induced a delay in gastric emptying. Onset of delayed gastric emptying, as the diabetes progressed, was associated with the loss of a subset of HO-1 positive macrophages.
Induction of HO-1 reversed the delay in gastric emptying. Because most of the histological changes described in DGP are only present in the myenteric plexus or muscularis layers of the stomach, full-thickness samples of the stomach as opposed to mucosal biopsies taken at endoscopy are required for analysis. Full-thickness gastric biopsies in gastroparesis have been proposed as a potential diagnostic tool for clinical use, and classifications of morphologic abnormalities have been proposed.
Furthermore, issues with optimal sampling and normative data remain to be clarified. Although most reports have used samples taken laparoscopically, less invasive percutaneous endoscopic approaches have been described. DGP can cause a wide variety of symptoms. As the degree of dysfunction worsens, symptoms become more common. Gastric stasis will typically cause nausea, vomiting and dyspeptic symptoms including early satiety, fullness or postprandial discomfort and bloating in addition to anorexia.
The vomiting may occur at any time. Typically, patients report vomiting in the morning of undigested food they ate the previous day. As these symptoms progress, weight loss and nutritional compromise commonly occur. For reasons that are unclear, symptom occurrence in some patients may have a cyclical nature, where they manifest as acute episodes or attacks or vomiting that prevents any oral intake and typically requires hospitalization.
These attacks may be interspersed with periods of respite or at least improved symptoms lasting weeks or months. Although some patients may be able to identify triggers for their symptoms such as certain foods , unfortunately most do not.
A validated score for measuring DGP symptoms has been developed for use in research settings. Abdominal pain is also a significant component of DGP symptomatology that is under-recognized. Similar to other forms of neuropathic pain, the symptoms are often chronic and respond poorly to current therapies. In general, diabetic enteropathy occurs in parallel with other forms of diabetic neuropathy, whether peripheral, autonomic or both. Although the degree and extent of symptoms patients experience from diabetic neuropathy is highly variable, it is unusual for patients to develop DGP without some symptoms of other forms of diabetic neuropathy.
With the unpredictability of gastric emptying, many patients experience difficulty controlling their blood glucose. Insulin dosing is ideally given before eating so that peak insulin action matches postprandial glucose increases.
If emptying is delayed or the patient vomits and the glucose peak does not happen adequately, then the risk of hypoglycemia is high. This risk will often lead patients to dose insulin mid-meal or even after the meal, leading to further poor blood glucose control. DGP may frequently be associated with other manifestations of diabetic enteropathy elsewhere in the gastrointestinal tract.
This disorder is well recognized, but poorly understood. Unfortunately, typical prokinetic treatment used for DGP may exacerbate diarrhea in this situation. Finally, gastroesophageal reflux may occur commonly with DGP, due to poor gastric emptying, and constipation is also prevalent in a large subgroup of diabetic patients. The diagnosis of gastroparesis is made based on a typical clinical history, exclusion of gastric outlet or other gastrointestinal GI obstruction, and confirmation of delayed gastric emptying.
Other disorders that may mimic DGP include rumination syndrome, cyclic vomiting syndrome, bulimia nervosa or superior mesenteric artery syndrome. Similarly, although DGP may develop shortly after diagnosis of DM, patients will generally have a longer history of the disease 10 years or longer. Exclusion of gastroduodenal obstruction, such as by gastric cancer or peptic ulcer disease, requires endoscopy.
Significant amounts of retained food or gastric bezoars in a patient known to be fasting overnight are also highly suggestive of DGP. Cross-sectional imaging or abdominal ultrasound is helpful to rule out more distal obstruction or external compression of the GI tract and to rule out other causes of chronic upper GI tract symptoms such as gallstones. Assessment of gastric emptying may be completed using a number of validated tests such as scintigraphy, 13 C breath testing or wireless motility capsule WMC.
Although other methods for characterization of gastric function have been described including antroduodenal manometry, ultrasound, MRI, gastric barostat and electrogastrography , these either have not been validated or are not generally available outside of research centers. Scintigraphy requires technetium labeling of a standardized test meal eggs, bread and jam that is then eaten by the patient.
Pathophysiology and Management of Diabetic Gastropathy: A Guide for Endocrinologists
Diabetic gastropathy is a term that encompasses a number of neuromuscular dysfunctions of the stomach, including abnormalities of gastric contractility, tone, and myoelectrical activity in patients with diabetes. These abnormalities range from tachygastrias to antral hypomotility and frank gastroparesis. Diabetic gastropathies may be acutely produced during hyperglycemia. Symptoms of chronic diabetic gastropathy include chronic nausea, vague epigastric discomfort, postprandial fullness, early satiety, and vomiting.
Diabetic gastroparesis DGP is a gastric complication of diabetes mellitus that causes nausea, vomiting, early satiety, bloating and abdominal pain, in addition to significant morbidity. Original and review articles were reviewed through PubMed, including relevant guidelines from the European and American Neurogastroenterology Societies. Diagnosis of DGP requires endoscopy and measurement of gastric emptying. Management requires prokinetic therapy, usually in addition to antinausea or other medications.
Delayed gastric emptying, or gastroparesis, represents the far end of the spectrum of dysmotility disorders collectively referred to as diabetic gastropathy or the diabetic stomach. The diabetic stomach is a manifestation of diabetic autonomic neuropathy. It is characterized by potentially debilitating gastrointestinal symptoms and can also interfere with glucoregulation by contributing to a vicious cycle of delayed emptying of food or oral medications. The result may be late glycemic peaks followed by hyperglycemia and further delays in gastric emptying, or by hypoglycemia secondary to retention of food in the stomach. The goal of treatment of diabetic gastropathy is not only to prevent morbidity by controlling gastrointestinal manifestations, but also to enhance glucoregulation and, thus, better control the basic diabetic process.
Diabetic gastropathy, presenting as nausea, vomiting, bloating, and pain, has been considered synonymous with gastroparesis as many patients exhibit delayed gastric emptying. Yet, emptying rates correlate poorly with symptoms and improvements on therapy do not associate with normalized emptying. Thus, other factors are pathogenic of gastropathic symptoms in diabetes. Dysfunctional visceral afferent transmission purportedly underlies symptoms in functional bowel disorders. Recent studies have shown that hyperalgesia is present in some diabetics with nausea and bloating.