Gastric symptoms of diabetes are often a long-standing complication of uncontrolled diabetes mellitus (DM) which highly affect the patient's quality of life. ^{1 , 2} Delayed gastric emptying (DGE) without obstruction in diabetes gastroparesis (DG) is caused by disorder in the neuromuscular function of the stomach which can be a result of various processes: idiopathic, DM-associated gastroparesis, or as an adverse effect of medical intervention such as surgical gastric resection. ^{3 , 4} Diabetic gastroparesis is shown by gastrointestinal symptoms such as nausea, vomiting, postprandial fullness, bloating, and early satiety. ^{4 , 5} Hyperglycemia, oxidative stress, neuropathy, and inflammation in diabetic patients are associated with the pathophysiology of DG. ^{3 , 5}

A study in general practice from the United Kingdom revealed that the prevalence of gastroparesis per 100,000 persons was 13.8 in 2016. DM is the second most common etiology after idiopathic. ⁶ Different from that record, a study in the United States in 2018 found DM as the primary cause of gastroparesis, with as high as 57.4% of the patients having DM. The overall number is also higher, reaching 267.7 per 100,000 persons, although the prevalence of patients with definite delayed emptying reported from scintigraphy is lower, with only 21.5 per 100,000 persons. ⁷ It is estimated that the prevalence of this disorder to be 9.6 per 100,000 person in men and 37.8 per 100.000 in women. ⁸ Depression and anxiety are common in patients with gastroparesis; thus, their quality of life is significantly impaired. ^{5 , 9} Aside from the quality of life, evaluation of delayed emptying is also essential to analyze absorption and consequently regulation of blood glucose in DM. ^{1 , 5}

The gold standard for diagnosis of DG is with gastric emptying scintigraphy (GES) examination. ⁴ However, the application of this method is still limited in many countries due to the limited availability of examination equipment, relatively expensive cost, and long hours of the examination. ^{10 , 11} Radiation exposure is also a concern in itself. ¹² Other recommended alternatives such as 13C-octanoic acid breath test, wireless motility capsules, and electrogastrography (EGG) are even less available. In contrast, ultrasonography (USG) is readily available in most hospitals worldwide. USG examination is a non-invasive, affordable, and relatively easy-to-perform test. It can measure emptying time, intra-gastric volume, and antral cross-sectional area (CSA). ⁸ It is also known to be used by anesthesiologists to determine the volume and content of the stomach for perioperative point-of-care tests. ^{13 – 15} The broad availability, safety from radiation exposure, and affordable tools could make ultrasound a suitable candidate for an alternative gastric emptying examination ^{16 – 18} and its accuracy compared to the gold standard needs further investigation. The potential USG use on DG screening remains a question. The objective of this study is to ¹ evaluate USG findings of  gastric changes found in DM and DG. ²

This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-2020 guideline. ^{19 , 64} Prior to this publication, the study protocol had already been registered to the PROSPERO database ( CRD42022328695 (10/05/2022)). ²⁰

The search strategy described in Figure 1 resulted in 136 articles from database screening, four studies from manual screening, and three from citation screening. After evaluation of titles and abstracts, 43 articles were selected for full-text evaluation. The review yielded 25 case-control studies. Article appraisal graded 18 articles as good, four as fair, and two as poor ( Extended data¸supplemenent 1 ⁶⁴ ). All studies were included in the study to minimize the risk of publication bias.

All studies reported gastric changes found in people with diabetes with various degrees. The gastric antral area, emptying time, and antral contractility were found to be worse in DM and DG populations. Changes in antral contraction were found to be insignificant in diabetes but less in the DG population. With a total of 25 studies included, 715 samples of DM were included in this study. Further result are elaborated in Table 2.

Diabetes with and without gastroparesis results in changes in gastric physiological conditions that can be examined via ultrasonography. In our study, 11 case-controls demonstrated changes in gastric antral CSA, ^{17 , 23 – 26 , 28 – 33} indicating there is a possible structural change leading to a wider antral area (SMD 1.25 cm ² in fasting state and 3.70 cm ² in postprandial) compared to the HC. Total GET ^{16 , 18 , 30 , 34 – 37} and GE50 ^{12 , 26 , 34 , 38 , 39} were also assessed, and all studies reported longer emptying time in DM and DG groups (SMD to healthy control of GET in DG at 75.44-min, DM st 35.54-min; GE50 15.75-min in DM and 7.46-min in DG; and reduced GER SMD -31.95% in DG and -16.14% in DM). Reduced gastric motility ^{17 , 27 , 40 – 42} was also found in DG (SMD to control at -1.47 contraction).

Antral area and antral dilation were found to be wider in both fasting and postprandial states than HC in our study. Undeland et al. (1996) ³¹ reported the loss of parasympathetic innervation presented by the loss of vagal tone and the finding of wider fasting and postprandial antral area. Further study by the same author ³³ reported that loss of vagal tone is associated with the antral area and intragastric meal distribution. The mechanism might be related to vagal nerve function to stimulate gastric acid secretion to prepare the stomach for digestion. In DM and DG, acid secretion was found to be lower ⁴³ with slower emptying of gastric juice, ²⁹ which may be resulted from vagal neuropathy. ^{31 , 33} Autonomic neuropathy due to vagal impairment also causes loss of gastric tone ³² ; consequently, wider dilation before and after the food filling can be seen in DM.

Prolonged emptying time in DM is often associated with two mechanisms; hyperglycemic condition and the presence of autonomic neuropathy. ⁵ The first mechanism is a hyperglycemic condition. Moldovan et al. (2005) ³⁰ discovered that HbA1c level and fasting glucose are highly significant with DGE. Maheshwari et al. (2021) ⁴⁴ stated the prevalence of DGE to be around 30–50% in DM patients. In acute hyperglycemia, disturbance of the physiologic gastric emptying phase is associated with prolonged gastric emptying. Gastric emptying of solids is divided into two phases; the lag phase (movement of meals from the fundus to antrum) and the post-lag phase (the process of meal passing the pylorus), which involves actions of the pyloric, antral, and proximal gastric section. Conditions of hyperglycemia can stimulate pyloric contraction, disrupt antral wave, and reduce proximal gastric tone, causing a longer lag phase and slower post-lag emptying rate. ⁴⁵ Chronic hyperglycemia can also cause prolonged gastric emptying. In the normal state, blood glucose and incretin secretion depend on carbohydrate exposure in the small intestines. However, constant hyperglycemia in poorly controlled DM can induce glucagon like peptide-1 (GLP1) and gastric inhibitory polypeptide (GIP) production, which stimulate insulin production, resulting in a constantly high level of GLP1. ⁴⁶ GLP1 slows gastric emptying rate. ^{47 , 48} Furthermore, the hormonal by-product from incretin secretion, amylin, induces vagal response and further decreases the gastric emptying rate in both DM and DG population. ⁴⁹ Therefore, both acute and chronic conditions may lead to prolonged gastric emptying in DM.

The second mechanism that often-prolonged gastric emptying shown in DM is neuropathy. ⁵ The gastric area receives innervation from celiac ganglia and vagal nerve, which regulate gastric motility. ⁵⁰ Diabetes causes neuropathy that reduces antral contraction, causing less contraction and resulting in slower food digestion in the stomach and, eventually, longer emptying time. ⁵ A study by Kawagishi et al. ⁴⁰ and Vogelberg et al. ^{38 , 41} finds that autonomic neuropathy is associated with reduced antral contraction. The prevalence of neuropathy in DM with DGE from the studies varies, ranging from 39%–75%, indicating a possible correlation to DGE. Seven studies ^{25 , 30 , 33 , 40 , 51 , 52} found a significant relation in DGE to autonomic neuropathy (AN) in DM. However, Pfaffenbach et al. (1994) ³⁶ and Zhou et al. (2019) ⁵³ found no significant difference in DGE in DM with AN or without AN. These findings are congruent to the theory of prolonged GET due to neuropathy.

Gastric half emptying time in diabetic patients showed an interesting result. The finding showed SMD to HC of 15.75-min in DM and 7.46-min in DG, with longer GE50 in DM, contrary to the definition of DG itself, which is an established diagnosis after findings of definite prolonged gastric emptying with the absence of structural obstruction. ⁵⁴ The longer GE50 in DM is because studies included in the meta-analysis in DG used a liquid test-meal, ^{12 , 39} while all samples in DM were measured with a solid test-meal, which requires a longer time to digest. ^{26 , 34 , 38} Therefore, a slower half-emptying time was found in the solid meal test in DM compared to liquid test in DG populations.

The method for ultrasonography assessment of gastric emptying varies across all studies. To the best of our knowledge, a protocol for gastric emptying measurement has not yet been established, especially in DG. The fasting time varies for every study, with the shortest overnight fasting (6~8 hours) ^{31 , 33} and the longest at 16 hours. ³⁴ The meal sets to evaluate postprandial gastric changes in both liquid and solid meal test were also very diverse. Various liquid meals were used in the liquid meal test, including water, ⁵¹ consommé, ^{27 , 42} meat soup, ^{1 , 26 , 31 , 32} soluble dietary fiber liquid, ⁵⁵ and commercial meal soup. ^{1 , 33} For meal test, a variation on solid meal test includes World Instant Gastrointestinal Ultrasound Contrast, ^{12 , 56} test meal with different calorie content (280–650kcal), ^{30 , 35 , 36 , 38 , 41 , 57} rice pudding, ^{15 , 28 , 29 , 52 , 58} minced beef meat, ¹⁰ gastro-enteric ultrasound developer meal, ³⁷ and semi-solid paste. ⁵⁹ An established protocol for meal-set and fasting time is necessary to reduce the risk of bias in the gastric emptying study.

Routine use of ultrasonography for gastric emptying has multiple benefits. A study by Stevens et al. (2011) ¹⁰ analyzed the difference in gastric emptying measurement using 2D-USG compared to the 3D-USG method and found no significant correlation in results from both examination methods. However, 3D-USG was found to be superior due to its significance and relatively good agreement limit when compared to the previous gold standard GES. ⁶⁰ Two studies ^{28 , 36} analyzed the inter-observer and intra-observer variability in USG to assess the reproducibility of USG and found the inter-observer standard measurement of error (SME) around 0.3%–10.9% and intra-observer SME around 3.6%–9.5%, indicating a good reproducibility for USG. GES and USG comparison shows a good correlation with a limit of agreement within 2SD ¹⁵ and no significant difference on result. ^{10 , 12} Bian et al. (2011) ²⁵ compared the octane breath test to USG and found a significantly similar result on variables. Another study by Jūngling et al. (2001) ⁵¹ used USG as the standard method to assess oatmeal test sensitivity and specificity. All results showed a favorable tendency on USG use for gastric emptying measurement except for one study by Maheshwari et al. (2021), ⁴⁴ which found poor concordance in gastric evaluation compared to endoscopy to examine residual gastric volume. However, the poor correlation needs further investigation as it might be resulted from other factors (i.e., poor measurement technique, suboptimal positioning, clinician's expertise, etc.). ⁴⁴ The capability of USG to assess real-time emptying and the gastric area remains superior for USG compared to GES. ^{28 , 29} Furthermore, Zhou et al. (2001), ⁶¹ Murray (2005), ⁵⁷ and Vogelberg (1988) ¹⁷ also highlight the possible use of USG to monitor gastric improvement after ghrelin, metoclopramide, and cisapride medication. Therefore, the use of USG in GES requires a standardized clinical trial or more extensive study to evaluate the extent of function and possible use of USG in gastric emptying assessment.

Abdominal symptoms were mostly complained by the patient with DM and DG with DGE. Chiu et al. (2014) ²⁶ reported that GI symptoms score in DM postprandial decrease less than HC. The top three most complained symptoms were abdominal distension (36.1%–54.7% prevalence), ^{23 , 26 , 30} postprandial fullness (19.4%–54.7%), ^{23 , 30} and dysphagia (38.9%). ³⁰ The food process in the stomach is complex and requires coordinated actions of all stomach regions. Starting from reservoir function of the fundus, peristaltic mix in the antrum, and lastly, gastric pylorus as the gate filters before the chyme enters duodenum. ² Other structures were also involved in the food process, including smooth muscles, vascular system, enteric and extrinsic autonomic nerve, and the interstitial cells of Cajal. ⁶² In diabetic patients, changes in gastric anatomy, ^{25 , 26} supporting structures ^{51 , 56 , 62} (i.e., autonomic innervation, vascular system), ⁶² impaired gastric content distribution, ³³ immunological changes, ⁶³ and systemic conditions (i.e., hyperglycemic state, hormone production) ⁴⁰ were found. These changes disrupt the physiological process of gastric digestion, leading to alteration of emptying time to the complaint of gastric symptoms. ⁶² Delays in gastric emptying in DM itself is a spectrum of gastric change, leading to gastroparesis.

There are some limitations in our study. We found that there are very limited data for ultrasonography measurement in a certain population (i.e., patient with marked gas retention, markedly obese due to inability to assess USG results objectively); some studies excluded obese ^{27 , 42} patients for better representation of the general population. Therefore, further evaluation of ultrasonography measurement in this population is needed. We included postprandial data for every various meal set for each study. A standardized protocol in solid or liquid food packages to evaluate gastric emptying must be established to ensure a correct assessment. Long examination hours for USG (range from 30 minute ³⁸ – 8 hours ⁵³ ) might not be viable for every situation. Therefore a further study to evaluate shorter analysis, or a standardized time for USG assessment is advised. We also acknowledge that there are potential publication bias in our study based on the Begg’s funnel plot assessment. Aside from the limitations, to the best of our knowledge, this is the first meta-analysis that evaluates the ultrasonography findings in DM and DG that includes various study designs with no language exclusion and included studies from all countries worldwide.

In conclusion, DM and DG could affect gastric anatomic and physiologic function, which results in prolonged emptying time and gastric symptoms. Wider antral area, longer gastric emptying time, longer half-emptying time, reduced gastric emptying rate, and less antral contraction were found in both populations. This study supports the use of ultrasonography for screening and diagnostic methods to treatment monitoring for DGE. However, these findings were based on observational studies, in which nonuniform definitions exist for several outcomes. Therefore, randomized controlled trials are advised for future studies.