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Keywords:

  • diabetes mellitus;
  • gastric emptying;
  • glucose;
  • glycemic control;
  • radiopaque markers;
  • scintigraphy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References

Background  Scintigraphy, the gold standard to measure gastric emptying, is expensive and not widely available. Therefore, we compared emptying of radiopaque markers (ROM) from the stomach, by use of fluoroscopy, with scintigraphy in patients with insulin-treated diabetes.

Methods  On the same day we measured gastric emptying of 20 ROM using fluoroscopy and scintigraphic emptying of a standard solid meal. The subjects also completed a validated gastrointestinal (GI) symptom questionnaire.

Key Results  We included 115 patients with insulin-treated diabetes (median age 53, range 21–69 years; 59 women). A moderately strong correlation was demonstrated between scintigraphic (% retained at 2 h) and ROM emptying (markers retained at 6 h) (r = 0.47; P < 0.0001). Eighty-three patients had delayed gastric emptying with scintigraphy, whereas only 29 patients had delayed emptying of ROM. Of the 29 patients with delayed emptying of ROM, 28 also had delayed scintigraphic emptying. The sensitivity and specificity of the ROM test was 34% and 97%, respectively. Significant correlations were only noted between scintigraphic gastric emptying and GI symptom severity, with the strongest correlations for fullness/early satiety (r = 0.34; P < 0.001) and nausea/vomiting (r = 0.30; P < 0.001).

Conclusions & Inferences  A gastric emptying test with ROM is a widely available screening method to detect delayed gastric emptying in patients with diabetes, where a positive result seems reliable. However, a normal ROM test does not exclude delayed gastric emptying, and if the clinical suspicion of gastroparesis remains, scintigraphy should be performed. Results from scintigraphy also correlate with GI symptom severity, which ROM test did not.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References

Gastroparesis is defined as delayed gastric emptying in the absence of an obstruction to outflow from the stomach and the most common cause is diabetes mellitus.1 Unfortunately, treatment options are limited and the pathogenesis of this disabling condition is still not well understood.1,2 It was originally described in the 1950s by Kassander, who coined the term ‘gastroparesis diabeticorum’.3 However, it has since then become apparent that many patients with diabetes have symptomatic gastroparesis and that it occurs in both diabetes type 1 and type 2.4 The prevalence of delayed gastric emptying in unselected patients with diabetes is not well known, but in studies of outpatients with long-standing diabetes 30–65% of subjects may suffer from gastroparesis.4,5 Diabetes per se is associated with an increased prevalence of gastrointestinal (GI) symptoms6 that decrease the quality of life.7 Although GI symptoms in general occur frequently in diabetic subjects, the severity of symptoms are only weakly predictive of delayed gastric emptying.5 Among upper GI symptoms in patients with diabetes, the most convincing evidence for an association with delayed gastric emptying has been reported for abdominal bloating and postprandial fullness.5

Delayed gastric emptying in diabetes is not only of potential relevance for GI symptoms, but may also influence drug absorption8 and glycemic control,9 including hypoglycemia in insulin-treated patients.10,11 Therefore, given the well-known importance of achieving good metabolic control to prevent diabetic complications,12 normalization or improvement of gastric emptying in patients with diabetic gastroparesis seems to be an integral part of the management strategy in these patients.13,14

As it seems to be clinically important to diagnose delayed gastric emptying in patients with diabetes, a widely available and cheap diagnostic method with high specificity and sensitivity is needed. To date, gastric scintigraphy of digestible solids is the gold standard to measure gastric emptying,15,16 however, it is expensive and not widely available. Emptying of radiopaque markers (ROM) (indigestible solids) from the stomach using fluoroscopy is an easy and inexpensive method, available at all hospitals.17 In our previous study, we found a significant correlation between gastric emptying of ROM with gastric scintigraphy in healthy subjects and in a small group of subjects with insulin-dependent diabetes.17 A better correlation between symptoms and disturbed gastric emptying in diabetes have been suggested with ROM emptying than with scintigraphy,18 but there are also studies with conflicting results.19 However, the previous studies were limited by small sample sizes and poor characterization of GI symptoms.

Therefore, in this study, we aimed to evaluate the correlation between emptying of ROM from the stomach using fluoroscopy, and gastric scintigraphy, in a larger group of patients with insulin-treated diabetes to define a potential role for ROM emptying in the management of patients with diabetes and clinical suspicion of delayed gastric emptying. We also wanted to assess the association between different GI symptoms, ROM emptying, and scintigraphic solid gastric emptying.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References

Subjects

Patients with insulin-treated diabetes and GI symptoms and/or poor glycemic control leading to a clinical suspicion of gastroparesis were recruited from hospital and primary care outpatient clinics in the western region of Sweden during the period of August 2007–November 2011. Study inclusion was based on the occurrence of GI symptoms. To include patients with a wide range of GI symptom severity, we also included a proportion of insulin-treated diabetes patients with mild GI symptoms and minor clinical suspicion of gastroparesis, who participated in a questionnaire study on GI symptoms in diabetes (manuscript in preparation). Exclusion criteria were as follows: previous GI surgery except appendectomy, severe psychiatric disease, sequelae after cerebrovascular disease, untreated disease with a potential impact on gastric emptying, or GI symptoms, such as endocrinology diseases e.g., hypothyroidism. An upper GI endoscopy had recently been performed in the majority of the patients as part of the clinical management as decided by the treating physician. Clinical characteristics of the subjects were obtained from chart review, and this was also the case for the most recent glycosylated hemoglobin (HbA1c) values (converted to the Diabetes Control and Complications Trial (DCCT) standard levels using the formula: HbA1c (DCCT) = [0.923 × HbA1c (MonoS) + 1.345; R= 0.998]20) and glomerular filtration rate (GFR). Drugs known to promote or inhibit gastric emptying, including GLP-1 agonists, were not allowed before (48 h) or during the investigation.

This study was approved by the Radiation Safety Committee at Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, and Regional Ethical Review Board at the University of Gothenburg, Gothenburg, Sweden. Each participant was informed about the study and gave written informed consent.

The test meal

The test meal consisted of an omelet and a glass of water of 150 g. The omelet was made from 111 g egg, 100 g milk (3% fat), 15 g wheat flour, 5 g margarine, salt, and pepper. The nutrient content was 310 kcal, 19 g protein (25 energy %), 18 g fat (52 energy %), and 17 g carbohydrates (23 energy %), as calculated from the Database Swedish National Food Composition Tables, (The National Food Agency, Uppsala, Sweden), using the computer program Dietist XP version 3.2, (Diet and Nutrition Data, Bromma, Sweden). The omelet was cooked in a microwave oven at 1000 W for 2 min. After stirred, the omelet was cooked in the microwave oven for another 1 min.21 15 MBq of the tracer 99mTc (LyoMAA kit; Medical, Petten, Holland) was added to the study meal to determine scintigraphic emptying. The albumen binds to the protein during cooking.22 Twenty spheric ROM (density 1.27 g cm−3 and 4 mm diameter; Leewood AB, France) were served at the same time as the test meal.23,24

Gastric emptying

Gastric emptying were measured using gamma cameras (MAXI II General Electric; Hermes Nuclear Diagnostic AB, Milwaukee, WI, USA) and fluoroscopy equipment (Exposcop 7000 Compact; Ziehm GmbH, Nürenberg, Germany). The gamma cameras registered the gamma radiation from 99mTc in anterior and posterior views of the stomach every 5th minute up to 3 h after meal ingestion. Each monitored value is an average for the measurement during 3 min. Data were collected in dynamic mode using a computerized system. Nationwide reference values for solid gastric emptying have been established in a study of 160 healthy subjects (69 men, 91 women) (mean ± 2 SD). For men, the normal range for retention of the radioactivity in the stomach at 120 min after the finished meal (R120) was 0–51%, for women < 50 years old, 9–66% and for women >50 years old 0–55%.15

The reference values for gastric emptying of 20 ROM were based on 131 healthy subjects (57 men, 74 women)23,24 and the 95th percentile for numbers of retained ROM at 6 h was used as the upper reference value: males >0 ROM retained, females >6 ROM retained. For exploratory reasons alternative definitions of abnormal emptying of ROM were used: ROM retained at 5 h: males >3 ROM retained and females >16 ROM retained; and mean retention of ROM 4–6 h24: males >26%, females >63%.

Glycemic control

Plasma glucose samples were taken before and after finishing the meal and at 15 min intervals during the first hour of the test and every 30 min from 1–6 h. The samples were immediately analyzed in an automated plasma glucose analyzer by a glucose oxidase method (Merck, Darmstadt, Germany) using HemoCue1 NAD-NADH (HemoCue AB, Ängelholm, Sweden). Patients who had plasma glucose <4 mmol L−1 during the test were given glucose supplementation (tablets).

Severity of GI symptoms

The subjects were asked to complete the validated questionnaire, Patient Assessment of Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM) evaluating symptom severity during the past 2 weeks. The 20-item PAGI-SYM includes six subscales: heartburn/regurgitation, fullness/early satiety, nausea/vomiting, bloating, upper abdominal pain, and lower abdominal pain analyzed in a 6-point Likert scale ranging from 0 (no symptoms) to 5 (very severe symptoms). This instrument has undergone thorough validation procedure and has been found to be valid, reliable and responsive to changes in patients with upper GI disorders.25,26 Furthermore, a subset of this scale, the nine-item Gastroparesis Cardinal Symptom Index (GCSI), consisting of the three subscales fullness/early satiety, nausea/vomiting and bloating, has been validated in patients with gastroparesis.27

Study protocol

The subjects came to the hospital after an overnight fast (10 h) at 8 am in the morning. Alcohol containing beverages were not allowed 24 h before the test and drugs with an effect on GI motility were not allowed within 48 h before the test. Smoking was prohibited during the test. On the same day we measured solid gastric emptying using scintigraphy of a standard meal and emptying of non-digestible solids by adding 20 spheric ROM to the meal and used fluoroscopy to follow the emptying. Before the test, the patients also completed PAGI-SYM.25

Plasma glucose had to be ≤ 10 mmol L−1 immediately before the test because of the known adverse effects of hyperglycemia on gastric emptying.28 After the subjects had taken their ordinary dose of insulin for breakfast adjusted to the carbohydrate content of the test meal (units insulin g−1 carbohydrates), they ingested the test meal and 20 spheric ROM within 10 min. One third of the omelet was eaten and then 10 ROM were given. The next third of the omelet was then eaten and the remaining 10 ROM were swallowed and finally the last third of the omelet was consumed. The subjects ingested the meal in a sitting position and remained in a sitting position during the whole scintigraphic study (3 h).

Immediately after the end of the scintigraphic study, the subject was transported in a wheelchair to the fluoroscopy equipment for assessment of emptying of the ROM. The number of ROM in the stomach was counted using fluoroscopy at 3, 4, 5, and 6 h after meal intake, unless all markers had left the stomach. Since indigestible solids or ROM are emptied with a time delay of 1.5–2 h relative to digestible solids,17 we focused on the time period 4–6 h after meal intake to test for delayed gastric emptying of ROM.

Statistical analysis

Results are presented as median and range. Statistical evaluations were performed using the statistical software package IBM SPSS/PC statistics 19 (Chicago, IL, USA). Median and range were compared between two groups using the Mann–Whitney U-test, whereas nominal data were compared by use of the Pearson’s Chi-squared test. Correlations were calculated using Spearman’s correlation coefficients. We also estimated the sensitivity, specificity, and positive and negative predictive value of ROM emptying to diagnose gastroparesis, using gastric scintigraphy as the gold standard. For these analyses, different definitions of abnormal ROM emptying were used. Two-tailed P values <0.05 were accepted as statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References

Subjects

We included 115 subjects with insulin-treated diabetes (56 men, 59 women, age 53, 21–69 year (median, range), and all patients completed the investigation. Of these, 72 were referred to our unit for evaluation of suspected gastroparesis, and 43 were recruited from a trial assessing GI symptoms in patients with diabetes. On clinical grounds, the principal investigator (EO) suspected that 99 of the patients suffered from delayed gastric emptying. Seventy-eight subjects had type 1 diabetes, 31 type 2 diabetes, one Maturity Onset Diabetes in Young (MODY) diabetes, three Latent Autoimmune Diabetes in the Adult (LADA) diabetes, and two subjects had secondary diabetes (caused of pancreatitis and corticosteroid medication, respectively). For the analyses, the subjects were grouped in two main groups, type 1 and 2 diabetes, where LADA and secondary diabetes caused of pancreatitis were included in type 1 diabetes and MODY and secondary diabetes caused of cortisone in type 2 diabetes. All participants except one were of European origin. The clinical characteristics of the subjects are shown in Table 1, divided into type 1 and type 2 diabetes.

Table 1. Characteristics of the subjects with type 1α and type 2γ diabetes
 Type 1 diabetes, n = 82Type 2 diabetes, n = 33
MedianRangeMedianRange
  1. GFR, glomular filtration rate; HbA1c, glycosylated hemoglobin.

  2. α Type 1 diabetes: type 1 diabetes, LADA = Latent Autoimmune Diabetes in the Adult and secondary (pancreatitis) diabetes.

  3. γType 2 diabetes: type 2 diabetes, MODY = Maturity Onset Diabetes in Young diabetes and secondary (cortisone) diabetes.

  4. *P = 0.034, **P = 0.006, ***P = 0.001, ****P < 0.0001.

Age, years50***21–6963***27–69
Weight, kg77.1***48.7–124.592.4***56.5–114.5
BMI kg m−226.0****18.4–38.031.0****18.6–40.9
Duration of diabetes, years30****2–6317****2–40
Insulin treated, years30****2–638****1–24
U insulin kg−1 body weight0.5**0.1–1.30.8**0.1–3.1
Number of injections, n4*1–84*1–6
HbA1c, %7.9 ns4.2–10.17.8 ns5.7–12.1
HbA1c 5 years ago, %8.1 ns5.7–12.08.2 ns5.8–11.7
Creatinine, μmol L−172 ns51–14081 ns47–174
GFR, mL min−1 1.73 m−288.5 ns40–14186 ns34–144

Gastric emptying – scintigraphy vs ROM emptying

All subjects completed the gastric emptying tests and tolerated the test meal well. The plasma glucose level was 8.3, 4.0–10.0 (median, range) mmol L−1 at the beginning of the test meal. During the test, the lowest plasma glucose value was 3.0 mmol L−1 and the highest value 17.2 mmol L−1. Ten subjects needed supplementation of glucose during the study, depending on plasma glucose below 4 mmol L−1. The plasma glucose level during the first 3 h of the test was 8.5, 4.7–13.1 (median, range) mmol L−1 and during the entire test (6 h) 8.3, 4.7–13.1 mmol L−1. Compared with baseline, the plasma glucose level was higher 1 h after meal intake [8.7 (3.3–12.6) mmol L−1; P < 0.0001], but did not differ significantly from baseline values at 2 [8.4 (3.6–14.9) mmol L−1; P = 0.98], 3 [7.9 (3.0–16.0) mmol L−1; P = 0.35], or 4 h after meal intake [7.4 (3.6–16.5) mmol L−1; P = 0.07]. However, the plasma glucose levels were significantly lower than before meal intake at 5 [7.1 (3.0–12.7) mmol L−1: P = 0.02] and 6 h after meal intake [7.3 (4.1–12.5) mmol L−1; P = 0.04]. This pattern was seen in both patients with and without delayed gastric emptying (data not shown).A statistically significant association was noted between mean plasma glucose levels 0–3 h and number of ROM remaining in the stomach at 6 h (r = 0.24; P = 0.009), whereas no association could be seen with retention of digestible solids (scintigraphy) at 3 h (r = 0.15; P = 0.1) or between mean plasma glucose levels 0–6 h and ROM remaining in the stomach at 6 h (r = 0.17; P = 0.07).

A moderate relationship between retention of digestible (gastric scintigraphy) solids at 1, 2, and 3 h and indigestible solids (ROM emptying) at 3, 4, 5, and 6 h was demonstrated with Spearman’s correlation coefficients between 0.41 and 0.54 (P < 0.0001) (Fig. 1 and Table 2).

image

Figure 1.  Association between retention of the radioactivity in the stomach at 120 min (R_120) and number of radiopaque markers (ROM) at 6 h (ROM_6) after meal intake in 115 diabetic subjects (r = 0.47; P < 0.0001).

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Table 2. Correlation coefficients between gastric scintigraphy and emptying of radiopaque markers (ROM)
 Scint Ret 1 hScint Ret 2 hScint Ret 3 h
  1. Spearman′s correlation coefficients: all P < 0.0001.

ROM Ret 3 h0.420.450.41
ROM Ret 4 h0.540.490.48
ROM Ret 5 h0.440.450.48
ROM Ret 6 h0.410.470.52
ROM Ret 4–6 h0.530.520.52

Eighty-three (72%) patients had delayed gastric emptying rate with the scintigraphic technique (delayed emptying at 2 h),15 whereas 29 (25%) patients had delayed emptying of ROM (delayed emptying at 6 h).23,24 Of the 29 patients with delayed emptying of ROM, 28 also had delayed scintigraphic emptying, whereas 55 of the patients with a normal ROM test (total 86 patients) had delayed gastric emptying with scintigraphy, indicating poor sensitivity (34%) and negative predictive value (36%) of ROM emptying, but high specificity and positive predictive value (both 97%) (Table 3) to diagnose gastroparesis, with emptying of digestible solids assessed with scintigraphy being the gold standard. As can be seen in Table 3, using alternative definitions of abnormal ROM emptying did not improve these results, except for ‘abnormal retention of ROM at 5 and/or 6h’, where a higher sensitivity was obtained (40%), but at the expense of reduced specificity (94%). Duration of diabetes, type of diabetes, age, or HbA1c did not differ significantly between patients with normal and delayed gastric emptying, irrespective of which method we used for definition of delayed gastric emptying (data not shown).

Table 3. Sensitivity, specificity, and negative and positive predictive value of radiopaque markers (ROM) emptying to diagnose gastroparesis, using gastric scintigraphy (retention at 2 h) as the gold standard
SCINT_Ret2h
 PositiveNegativeTotal
ROM_Ret6h
 Positive28129
 Negative553186
 Total8332115
 Sensitivity  34%
 Specificity  97%
 Positive Predictive value  97%
 Negative Predictive value  36%
ROM_MeanRet 4–6h
 Positive26935
 Negative572380
 Total8332115
 Sensitivity  32%
 Specificity  72%
 Positive Predictive value  75%
 Negative Predictive value  29%
ROM_Ret5h
 Positive24226
 Negative593089
 Total8332115
 Sensitivity  29%
 Specificity  94%
 Positive Predictive value  93%
 Negative Predictive value  34%
ROM_Ret5and/or6h
 Positive33235
 Negative503080
 Total8332115
 Sensitivity  40%
 Specificity  94%
 Positive Predictive value  95%
 Negative Predictive value  38%

Gastric emptying – GI symptoms

Both upper and lower GI symptoms were commonly reported by the patients (Fig. 2), with the highest median (range) subscale scores for bloating 2.5 (0–5), fullness/early satiety and upper abdominal pain had both 2.0 (0–5) and the lowest scores for nausea/vomiting 0.67 (0–5), lower abdominal pain 1.0 (0–5), and heartburn/regurgitation 1.3 (0–4.9). The strongest correlations between gastric emptying and upper gastrointestinal symptoms were noted for scintigraphic emptying and nausea/vomiting (r = 0.30; P < 0.001) and postprandial fullness/early satiety (r = 0.34; P < 0.0001). No sum score was significantly associated with emptying of ROM (Table 4). When comparing patients with vs without gastroparesis no median subscale scores differed significantly between the groups irrespective of method used to determine gastric emptying (data not shown).

image

Figure 2.  Severity of GI symptoms in subjects with insulin-treated diabetes with and without gastroparesis. Distribution of PAGI-SYM summary scores (0–5); white represents the highest score (very severe symptoms), and with increasing darkness of the gray color the severity of the symptoms decreases (darkest gray color = no symptoms).

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Table 4. Spearman`s correlation coefficients between gastric emptying and gastrointestinal symptom, measured with PAGI-SYM
PAGI-SYM summary scoresGastric scintigraphy retention at 2 h Spearman′s correlations coefficient (r =)ROM at 6 h Spearman′s correlations coefficient
  1. ROM, radiopaque markers.

  2. PAGI-SYM = Patient Assessment of gastrointestinal Disorders-Symptom Severity Index.

  3. **P < 0.01, *P < 0.05.

Nausea/vomiting 0.30**0.13
Postprandial fullness/early satiety 0.34**0.05
Bloating 0.26**0.02
Upper abdominal pain 0.21*0.04
Lower abdominal pain 0.170.05
Heartburn/regurgitation 0.26**0.03

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References

In this study, we have demonstrated a moderate association between gastric emptying of digestible solids, measured with gastric scintigraphy, the current gold standard for measuring gastric emptying in clinical practice, and gastric emptying of indigestible solids, ROM indicating that these two methods reflect similar, but not identical, events, which is consistent with our previous smaller study.17 From a gastric physiological point of view, the methods are not measuring the same parameter and therefore cannot be expected to show exactly the same results. Moreover, emptying of ROM at 6 h demonstrated high specificity and positive predictive value (both 97%), but poor sensitivity and negative predictive value to diagnose gastroparesis, using gastric scintigraphy as the reference method. This implicates that one single plain abdominal x-ray obtained 6 h after ingestion of ROM can be used clinically as an easy, cheap and widely available screening method to diagnose diabetic gastroparesis. If the test shows delayed gastric emptying, no further test seems necessary, whereas a normal result does not exclude gastroparesis, and if the clinical suspicion of gastroparesis remains, a scintigraphic test should be advocated. Consistent with several previous studies, we also demonstrated modest associations between GI symptom severity and gastric emptying, indicating that other mechanisms are also involved in symptom perception in patients with diabetes.29–32

Indigestible ROM are easy to use and well established for evaluation of colonic transit time.16 Our and other groups have also used ROM in clinical studies of gastric emptying17–19,23 and transit through the small intestine.23 This technique has several advantages such as being inexpensive, widely available, easy to use and with an acceptable risk profile.17,23 However, as was demonstrated in this study, it cannot replace gastric scintigraphy, but rather serve as an initial screening tool for patients with clinical suspicion of diabetic gastroparesis. The fact that no/limited additional information was obtained by determining the number of ROM hourly 3–6 h after intake of the ROM compared with one single fluoroscopy investigation at 6 h in subjects with diabetic gastroparesis, further simplifies the procedure and reduces the already low radiation burden on the patient.23 However, it is not clear that this applies to other types of gastroparesis. In one of the pioneering studies, Feldman et al. compared gastric emptying of ROM (1 cm long and 2 mm wide) using fluoroscopy with emptying of isotope-labeled liquid and solid test meals and demonstrated slower gastric emptying of ROM compared with the test meal,18 which is consistent with the findings in this study. However, these authors also suggested that this method may be a more sensitive indicator of gastric motor dysfunction in diabetes, which we were unable to confirm. Several potential explanations behind this discrepancy are possible. Our normal material is much larger, taking the relatively large interindividual variation in GI transit (including gastric emptying) in healthy volunteers into account.23 Moreover, the size and density of the ROM used in the two studies are not identical, which may have influenced the results, even though the size of the ROM have a relatively modest impact on the emptying rate up to a particle size of 7 mm.17,33 Patient selection may also be of relevance for the discrepancy between the studies, where a larger proportion of subjects in the American study appeared to suffer from chronic nausea and vomiting (60%), whereas nausea and vomiting was the least prominent symptom among patients in our study.

A potential drawback with our study is the fact that we did not measure retention of the test meal with scintigraphy at 4 h, which has shown to increase the detection rate of gastroparetic subjects.34 However, the nationwide reference value most widely used in Sweden is retention at 2 h and therefore we choose this time point as our main endpoint parameter,15 and logistic reasons related to the study forced us to move the patient from the nuclear medicine unit to the fluoroscopy unit after 3 h. However, since the majority of the subjects in this study already had abnormal scintigraphy at 2 h, the potential gain from adding a 4 h value is probably minor, and therefore unlikely to affect the main findings in our study. Another limitation with this study is that there was a dominance of patients with gastroparesis, making the reliability of the ROM test in patients with normal gastric scintigraphy less certain.

Several factors may influence gastric emptying and we tried as far as possible to control for these. The subjects remained sitting during the scintigraphic investigation and were transported sitting in a wheelchair to the fluoroscopy equipment, as gastric emptying has been found to increase during walking.35 It is well known that hyperglycemia decrease gastric emptying.28 Therefore, we aimed to start the test with an acceptable plasma glucose level and the upper limit was 10 mmol L−1 at the start of the test. Moreover, we could not find any strong association between the plasma glucose levels during the test and the gastric emptying, indicating that the variation in blood glucose levels between study subjects in our study had a minor impact on our findings. Furthermore, hyperglycemia is known to inhibit the antral component of the interdigestive phase III.36,37 However, this is probably also of minor relevance to the present results since also ROM are known to empty from the stomach before the reappearance of interdigestive motility after a meal.33 Furthermore, drugs with known effect on GI motility,38 smoking,39 and alcohol-containing beverages40 were not allowed during/before the test.

One of the main goals with our study was to assess the association between GI symptom severity and pattern and gastric emptying measured with the two different techniques. Consistent with previous studies, we found only a modest association between GI symptoms and gastric emptying.4,5 Several other mechanisms than delayed gastric emptying may be involved in symptom generation in patients with diabetes, such as visceral hypersensitivity,30 abnormal gastric compliance and accommodation,32 central nervous system abnormalities,31 psychological comorbidity,29 and effects of pharmacological agents.41 In our study, results from scintigraphy correlated with upper GI symptoms in subjects with insulin-treated diabetes, but not with ROM emptying. Therefore, it seems reasonable to maintain gastric scintigraphy as the gold standard to diagnose gastroparesis in diabetes until a technique that better explains symptom severity has been demonstrated.

During recent years other non-invasive measurements of gastric emptying have been developed such as transabdominal ultrasonography, magnetic resonance imaging, gastric emptying breath tests, and wireless pH and motility capsule (‘Smart Pill’).16 However, so far these techniques are not widely used in clinical practice, even though they all show adequate sensitivity and specificity to define patients with gastroparesis. Ultrasonography, even though widely available, has the disadvantage of being very operator dependent,16 and assessment of gastric emptying with magnetic resonance imaging has so far been limited by the specialized equipment and expense.42 Gastric emptying breath tests has mainly been used in clinical studies and in a few European centers, but is not available for clinical use in the US, even though the correlation with scintigraphy is good,16,43 and the wireless motility and pH capsule, Smart pill,44 has only recently become available in Europe.

In summary, even though this study has some limitations, a gastric emptying test with ROM using fluoroscopy seems to be a widely available and inexpensive screening method to detect delayed gastric emptying in diabetic subjects, where a positive result is reliable. However, it is important to state that a normal emptying of ROM does not exclude delayed scintigraphic gastric emptying, and in case of remaining clinical suspicion of gastroparesis, investigation with gastric scintigraphy should be performed. Results from scintigraphy also correlate modest with GI symptom severity, which ROM emptying did not. Maintaining gastric scintigraphy as the gold standard to diagnose gastroparesis in patients with diabetes mellitus, until a technique that better explains symptom severity has been demonstrated, seems reasonable.

Funding

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References

The research leading to these results has received funding from the European Community’s Seventh Framework Programme FP7/2007–2013 under grant agreement no. 223630. MS has received research support from the Swedish Medical Research Council (grants 13409, 21691 and 21692), The Marianne and Marcus Wallenberg Foundation, University of Gothenburg, Centre for Person-Centered Care (GPCC), Sahlgrenska Academy, and University of Gothenburg and by the Faculty of Medicine, University of Gothenburg. EAO has received research support from Swedish Nutrition Foundation, Lund, the Västra Götaland Region, Sahlgrenska University Hospital Foundations, the Diabetes Association in Gothenburg, and sponsorship for the cuvettes for analysis of plasma glucose from Hemocue AB, Ängelholm.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References

No other conflicts of interest relevant to this article were reported.

Author Contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References

EAO, SA, and MS designed the research study; EAO performed the research; EAO and MS analyzed the data and prepared the manuscript; HG and MI scintigraphic expertise; POS and HA expertise on ROMs emptying; EAO, SA, MS, and AMD provided funding. All co-authors revised critically the manuscript.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Funding
  8. Disclosure
  9. Author Contributions
  10. References
  • 1
    Abrahamsson H. Treatment options for patients with severe gastroparesis. Gut2007; 56: 87783.
  • 2
    Kashyap P, Farrugia G. Diabetic gastroparesis: what we have learned and had to unlearn in the past 5 years. Gut2010; 59: 171626.
  • 3
    Kassander P. Asymptomatic gastric retention in diabetics (gastroparesis diabeticorum). Ann Intern Med1958; 48: 797812.
  • 4
    Horowitz M, O’Donovan D, Jones KL, Feinle C, Rayner CK, Samsom M. Gastric emptying in diabetes: clinical significance and treatment. Diabet Med2002; 19: 17794.
  • 5
    Jones KL, Russo A, Stevens JE, Wishart JM, Berry MK, Horowitz M. Predictors of delayed gastric emptying in diabetes. Diabetes Care2001; 24: 12649.
  • 6
    Bytzer P, Talley NJ, Leemon M, Young LJ, Jones MP, Horowitz M. Prevalence of gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15,000 adults. Arch Intern Med2001; 161: 198996.
  • 7
    Talley NJ, Young L, Bytzer P et al. Impact of chronic gastrointestinal symptoms in diabetes mellitus on health-related quality of life. Am J Gastroenterol2001; 96: 716.
    Direct Link:
  • 8
    Hebbard GS, Sun WM, Bochner F, Horowitz M. Pharmacokinetic considerations in gastrointestinal motor disorders. Clin Pharmacokinet1995; 28: 4166.
  • 9
    Horowitz M, Edelbroek MA, Wishart JM, Straathof JW. Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects. Diabetologia1993; 36: 85762.
  • 10
    Horowitz M, Jones KL, Rayner CK, Read NW. ‘Gastric’ hypoglycaemia – an important concept in diabetes management. Neurogastroenterol Motil2006; 18: 4057.
  • 11
    Lysy J, Israeli E, Strauss-Liviatan N, Goldin E. Relationships between hypoglycaemia and gastric emptying abnormalities in insulin-treated diabetic patients. Neurogastroenterol Motil2006; 18: 43340.
  • 12
    The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med1993; 329: 97786.
  • 13
    Abell TL, Bernstein RK, Cutts T et al. Treatment of gastroparesis: a multidisciplinary clinical review. Neurogastroenterol Motil2006; 18: 26383.
  • 14
    Parkman HP, Yates KP, Hasler WL et al. Dietary intake and nutritional deficiencies in patients with diabetic or idiopathic gastroparesis. Gastroenterology2011; 141: 48698, 498 e481-487.
  • 15
    Gryback P, Hermansson G, Lyrenas E, Beckman KW, Jacobsson H, Hellstrom PM. Nationwide standardisation and evaluation of scintigraphic gastric emptying: reference values and comparisons between subgroups in a multicentre trial. Eur J Nucl Med2000; 27: 64755.
  • 16
    Rao SS, Camilleri M, Hasler WL et al. Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies. Neurogastroenterol Motil2011; 23: 823.
  • 17
    Stotzer PO, Fjalling M, Gretarsdottir J, Abrahamsson H. Assessment of gastric emptying: comparison of solid scintigraphic emptying and emptying of radiopaque markers in patients and healthy subjects. Dig Dis Sci1999; 44: 72934.
  • 18
    Feldman M, Smith HJ, Simon TR. Gastric emptying of solid radiopaque markers: studies in healthy subjects and diabetic patients. Gastroenterology1984; 87: 895902.
  • 19
    Caballero-Plasencia AM, Muros-Navarro MC, Martin-Ruiz JL et al. Gastroparesis of digestible and indigestible solids in patients with insulin-dependent diabetes mellitus or functional dyspepsia. Dig Dis Sci1994; 39: 140915.
  • 20
    Hoelzel W, Weykamp C, Jeppsson JO et al. IFCC reference system for measurement of hemoglobin A1c in human blood and the national standardization schemes in the United States, Japan, and Sweden: a method-comparison study. Clin Chem2004; 50: 16674.
  • 21
    Chaundhuri TK, Greenwald AJ, Heading RC, Chaudhuri TK. A new radioisotopic technic for the measurement of gastric emptying time of solid meal. Am J Gastroenterol1976; 65: 4651.
  • 22
    Hermansson G, Sivertsson R. Tc-labelled pancake for studies of gastric emptying of solids. Nucl Med Commun1991; 12: 97381.
  • 23
    Sadik R, Abrahamsson H, Stotzer PO. Gender differences in gut transit shown with a newly developed radiological procedure. Scand J Gastroenterol2003; 38: 3642.
  • 24
    Strid H, Simren M, Stotzer PO, Abrahamsson H, Bjornsson ES. Delay in gastric emptying in patients with chronic renal failure. Scand J Gastroenterol2004; 39: 51620.
  • 25
    Rentz AM, Kahrilas P, Stanghellini V et al. Development and psychometric evaluation of the patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) in patients with upper gastrointestinal disorders. Qual Life Res2004; 13: 173749.
  • 26
    Revicki DA, Rentz AM, Tack J et al. Responsiveness and interpretation of a symptom severity index specific to upper gastrointestinal disorders. Clin Gastroenterol Hepatol2004; 2: 76977.
  • 27
    Revicki DA, Rentz AM, Dubois D et al. Development and validation of a patient-assessed gastroparesis symptom severity measure: the Gastroparesis Cardinal Symptom Index. Aliment Pharmacol Ther2003; 18: 14150.
  • 28
    Schvarcz E, Palmer M, Aman J, Horowitz M, Stridsberg M, Berne C. Physiological hyperglycemia slows gastric emptying in normal subjects and patients with insulin-dependent diabetes mellitus. Gastroenterology1997; 113: 606.
  • 29
    de Kort S, Kruimel JW, Sels JP, Arts IC, Schaper NC, Masclee AA. Gastrointestinal symptoms in diabetes mellitus, and their relation to anxiety and depression. Diabetes Res Clin Pract2012; 96: 24855.
  • 30
    Frokjaer JB, Brock C, Brun J, et al.Esophageal distension parameters as potential biomarkers of impaired gastrointestinal function in diabetes patients. Neurogastroenterol Motil2012; 24: 1016e544.
  • 31
    Frokjaer JB, Egsgaard LL, Graversen C et al. Gastrointestinal symptoms in type-1 diabetes: is it all about brain plasticity?Eur J Pain2011; 15: 24957.
  • 32
    Samsom M, Salet GA, Roelofs JM, Akkermans LM, Vanberge-Henegouwen GP, Smout AJ. Compliance of the proximal stomach and dyspeptic symptoms in patients with type I diabetes mellitus. Dig Dis Sci1995; 40: 203742.
  • 33
    Stotzer PO, Abrahamsson H. Human postprandial gastric emptying of indigestible solids can occur unrelated to antral phase III. Neurogastroenterol Motil2000; 12: 4159.
  • 34
    Guo JP, Maurer AH, Fisher RS, Parkman HP. Extending gastric emptying scintigraphy from two to four hours detects more patients with gastroparesis. Dig Dis Sci2001; 46: 249.
  • 35
    Lipp RW, Schnedl WJ, Hammer HF, Kotanko P, Leb G, Krejs GJ. Effects of postprandial walking on delayed gastric emptying and intragastric meal distribution in longstanding diabetics. Am J Gastroenterol2000; 95: 41924.
    Direct Link:
  • 36
    Barnett JL, Owyang C. Serum glucose concentration as a modulator of interdigestive gastric motility. Gastroenterology1988; 94: 73944.
  • 37
    Bjornsson ES, Urbanavicius V, Eliasson B, Attvall S, Smith U, Abrahamsson H. Effects of hyperglycemia on interdigestive gastrointestinal motility in humans. Scand J Gastroenterol1994; 29: 1096104.
  • 38
    Hejazi RA, McCallum RW, Sarosiek I. Prokinetics in diabetic gastroparesis. Curr Gastroenterol Rep2012; 14: 297305.
  • 39
    Sanaka M, Anjiki H, Tsutsumi H et al. Effect of cigarette smoking on gastric emptying of solids in Japanese smokers: a crossover study using the 13C-octanoic acid breath test. J Gastroenterol2005; 40: 57882.
  • 40
    Franke A, Nakchbandi IA, Schneider A, Harder H, Singer MV. The effect of ethanol and alcoholic beverages on gastric emptying of solid meals in humans. Alcohol Alcohol2005; 40: 18793.
  • 41
    Bytzer P, Talley NJ, Jones MP, Horowitz M. Oral hypoglycaemic drugs and gastrointestinal symptoms in diabetes mellitus. Aliment Pharmacol Ther2001; 15: 13742.
  • 42
    de Zwart IM, de Roos A. MRI for the evaluation of gastric physiology. Eur Radiol2010; 20: 260916.
  • 43
    Lee JS, Camilleri M, Zinsmeister AR et al. Toward office-based measurement of gastric emptying in symptomatic diabetics using [13C]octanoic acid breath test. Am J Gastroenterol2000; 95: 275161.
    Direct Link:
  • 44
    Kuo B, McCallum RW, Koch KL et al. Comparison of gastric emptying of a nondigestible capsule to a radio-labelled meal in healthy and gastroparetic subjects. Aliment Pharmacol Ther2008; 27: 18696.