During the last half of the period for these GES studies, patients who were noted to have either normal or delayed gastric emptying while also having an elevated glycemic excursion were recommended to return for an additional liquid glucose GES study. Seven of these patients had type 2 diabetes and 2 had no diabetes. This second study was performed at the option of the referring doctor, although performance of both solid and liquid gastric-emptying studies in the same patient is a common practice in some nuclear medicine clinics. During this time, 9 patients with normal or delayed gastric emptying also in addition to abnormally elevated glycemic excursions were referred back for a follow-up liquid glucose carbohydrate gastric-emptying study. The liquid glucose meal was composed of 50 g of glucose in 450 mL of water (200 kcal, 0.62 molar) containing 1 mCi 99mTc-SC. Normal gastric-emptying rates for this liquid glucose meal protocol were previously described in prior studies published by our group.7,12,14 Comparisons of the standardized egg-white GES to the liquid glucose GES results in each of these 9 patients were analyzed using normal gastric-emptying parameters for each meal. Means and SDs of GES, along with normal parameters, were plotted for each study. Postprandial glycemic excursions were also compared between the standardized solid meal and the liquid glucose meal and statistically analyzed using paired t testing.
The results are shown in Figure 8. Of the 197 consecutive patients referred for gastrointestinal symptoms, 112 had diabetes and 75 had no diabetes. One hundred five patients had normal solid gastric emptying, 54 patients had delayed solid emptying at 4 hours, 13 patients had initially delayed solid emptying 1 or 2 hours with normal solid emptying at 4 hours, and 25 patients had rapid solid emptying based on the classification for solid gastric emptying of standardized solid egg-white meal (Table 1).1 One hundred one of the 197 patients had elevated glycemic excursions. Of these patients, 70.5% had diabetes and 29.3% had no diabetes (Table 2). There were 105 patients with normal gastric emptying, with 58 of these patients having elevated postprandial glycemic excursions, 47 having normal glycemic excursions, and none having minimal glycemic excursions. Of the 54 patients with delayed gastric emptying (at 4 hours), 26 had elevated glycemic excursions, 16 had normal glycemic excursions, and 12 patients had diminished glycemic excursions (Fig. 8). There were 13 patients with initially delayed gastric emptying at 1 or 2 hours but normal gastric emptying at 4 hours, with 2 patients having elevated glycemic excursions, 11 having normal glycemic excursions, and none having diminished glycemic excursions. A majority of the 25 patients (15 patients) with rapid solid gastric emptying had abnormally elevated glycemic excursions, whereas 8 had normal glycemic excursions, and 2 patients had diminished glycemic excursions.
Forty-seven of the 197 patients had normal solid gastric emptying and normal glycemic excursions. A typical patient with normal gastric-emptying study and normal postprandial glycemic excursion is shown in Figure 1. Fifty-four patients had delayed GES results. Nearly 50% (26/54) of these patients with delayed GES also had elevated postprandial glucose excursions. An example of a patient with this pattern is shown in Figure 2. Thirteen of the 197 patients had initially delayed gastric emptying (at 1 and/or 2 hours but normal gastric emptying at 4 hours), with a typical patient shown in Figure 3. In contrast, Figure 4A shows an example of a patient with a normal solid gastric-emptying rate but an abnormally elevated glycemic excursion, which was further assessed with a liquid glucose gastric-emptying study. This patient, 1 of the 9 who returned for dual assessments of GES techniques (Fig. 4B), demonstrated an abnormally rapid GES, which would have been undetected using standard protocols for GES. These data support the likely association of elevated solid meal glycemic excursions within the first hour with rapid emptying of the nonlabeled carbohydrate–containing components contained in the solid meal. An example of a patient with delayed solid emptying and an abnormally diminished glycemic excursion is shown in Figure 5. This pattern is most likely associated with delayed gastric emptying of the carbohydrate meal components as well as the protein meal component that would be expected with a vagal neuropathy. Lastly, 25 of the 197 patients had rapid solid gastric emptying. An example of a patient with rapid solid gastric emptying is shown in Figure 6. Only 2 of the 197 patients had abnormally rapid solid gastric emptying and an abnormally diminished glycemic excursion as shown in Figure 7. This pattern is consistent with patients who have malabsorption of the carbohydrate portion of the standardized meal. Interestingly, both of these patients complained of significant bloating and diarrhea.
In summary, 9 patients with either normal or delayed gastric emptying who were also having elevated postprandial glucose excursions during the first hour were referred back for further assessment using liquid glucose GES to investigate our concerns that an elevated glycemic excursions may lead to otherwise undetected rapid rates of isolated carbohydrate gastric emptying. Comparison of the average glycemic excursions between the 2 meals is shown in Figure 9A. All 9 of these patients were found to have rapid liquid glucose carbohydrate gastric emptying with abnormally elevated postprandial blood glycemic excursions, which were not significantly different between the glucose and the solid meal, (P = 0.3 at 30 minutes, P = 0.19 at 1 hour, and P = 0.73 at 2 hours) as shown in Figure 9A. Average gastric emptying of the solid meal in the 9 patients was within normal limits as shown in Figure 9B. Abnormally rapid average gastric emptying of the liquid glucose meal for these same 9 patients is shown in Figure 9C. Note the exponential pattern of emptying of the liquid glucose meal, similar to the exponential pattern expected in gastric emptying of water, even though this liquid glucose meal has been previously reported to empty in a linear fashion in normal, nonsymptomatic subjects.14
The association between gastric-emptying abnormalities and patient's gastrointestinal symptoms remains suboptimally understood, and it is well known that gastric-emptying studies have not always correlated well with patient symptoms.15–18 Based on our current study, it is likely that at least 1 factor underlying the poor correlation between gastric symptoms and the rate of gastric emptying may be related to unrecognized abnormal gastric emptying of unlabeled meal components. Our study suggests that a significant number of patients with normal or delayed gastric emptying of the solid egg-white meal component may have rapid emptying of the carbohydrate meal components. Eighty-six of 172 patients with normal or delayed solid gastric emptying also had an abnormally elevated postprandial glycemic excursion. Surprisingly, 26 of the 54 patients with delayed solid emptying were also shown to have an abnormally elevated glycemic excursion consistent with these patients having rapid carbohydrate emptying during the first hour of the study, which was then followed by delayed emptying of the radiolabeled solid egg-white meal component.
In this study, it was an unexpected result to find that more than 50% of all the patients had an abnormally elevated glycemic excursion with the standardized egg-white, bread, and jam meal. Although it is possible that some of these patients have severe insulin resistance as a cause of their elevated postprandial glycemic excursions, prior studies have shown that high glycemic excursions within the first hour are commonly associated with rapid gastric emptying of carbohydrate meal components.8,12 Rapid gastric emptying of carbohydrates has been previously reported to be common in diabetic patients,12,19–21 and this may explain the high percentage of patients with elevated glycemic excursions in our study because the majority of our patients had diabetes (Table 2). In this study, almost 30% of the nondiabetic subjects also had elevated glycemic excursions. These nondiabetic patients are likely at increased risk of developing diabetes as several studies have suggested that nondiabetic patients with rapid gastric emptying and elevated postprandial glycemic excursions are at increased risk of developing diabetes.11,12 These nondiabetic subjects may have metabolic syndrome as prior studies by our group have shown that patients with markers of metabolic syndrome have more rapid gastric emptying.7,22
It may be expected that the different meal components could potentially empty at different rates, knowing that fats, proteins, and carbohydrates are digested by different enzymes, and their rate of gastric emptying is controlled by different incretin hormones secreted from small intestine incretin cells.2 Carbohydrates are typically digested and triturated into liquid form more rapidly than proteins.17 The antropyloric contractions in conjunction with partial opening and closing of the pylorus result in a “sieving effect” in which small particles continuously flow from the stomach to the duodenum, whereas the larger particles are retropelled and retained in the stomach for further digestion.3 As previously discussed, it is also true that different meal macronutrients are under different hormonal controls.4
Based on the observations in this study, it appears that the majority of patients would benefit from having an isolated carbohydrate meal GES in addition to the standardized solid egg-white meal GES for a more comprehensive characterization of their gastric emptying. Alternatively, it may be possible to develop a dual-isotope–radiolabeled meal protocol enabling the carbohydrate and protein components of the meal to be tracked separately during the same meal. Dual-isotope gastric-emptying studies have already been described using 99mTc-SC to label minced beef and 113mIn-DTPA or 67Ga-EDTA to label 10% dextrose.16
Simultaneous blood glucose monitoring during the gastric-emptying study appears to be a valuable addition to the standardized GES protocol. It is inexpensive and relatively easy to perform. Monitoring postprandial glycemic excursion appears to provide a useful indicator for the emptying of the unlabeled carbohydrate component in the standardized meal. All 9 patients who returned for liquid glucose GES had abnormally elevated carbohydrate gastric emptying. As shown in this study, glucose monitoring during the standardized solid egg-white meal gastric-emptying study can screen patients for rapid gastric emptying of unlabeled carbohydrate meal components. Postprandial glucose levels can also clarify a neuropathic pattern of gastric emptying in which an abnormally diminished glycemic excursion is consistent with both the carbohydrate meal component and the radiolabeled egg white having delayed gastric emptying as would be expected for gastroparesis due to vagal neuropathy. The early postprandial symptoms noted in many of the patients with elevated glycemic excursions are similar to symptoms observed in patients with functional dyspepsia. The global prevalence of functional dyspepsia is between 5% and 11%, with medical costs associated with this condition in excess of $18 billion per year,23,24 yet its pathophysiology remains poorly understood.25 The cause and mechanisms of functional dyspepsia are controversial. Although functional dyspepsia has previously been assumed to be associated with delayed gastric emptying,26 promotility agents have not been very effective for its treatment.23,25 Several studies over the last decade have reported that functional dyspepsia can be associated with rapid gastric emptying.15,27,28
Gastric-emptying studies determined to be delayed may in fact have a rapid emptying carbohydrate component contributing to the patient's symptoms, thus obscuring the clinical picture and suboptimizing clinical management. These patients may have a “feedback gastroparesis” caused by elevated glucose levels leading to a delayed emptying of the radiolabeled solid meal component. This feedback gastroparesis is possible because blood glucose is an important regulator of gastric emptying.16,29–31 Schvarcz et al31 performed a study in which induced hyperglycemia with an intravenous glucose clamp was associated with significantly delayed gastric emptying. The high number of patients in this study with elevated postprandial glycemic excursion while also having delayed solid gastric emptying may provide some clues to the confusion and controversy surrounding the causes of gastroparesis.32 In our study, patients with delayed solid gastric emptying were twice as likely to have elevated glycemic excursions in the first hour as to have diminished glycemic excursions.
The monitoring of glucose during the standardized gastric-emptying study can provide valuable information for assessing each patient and developing a patient management plan. The additional insights provided by fingerstick glucose monitoring are inexpensive, easy to perform and may provide for new approaches to management of patient’s gastrointestinal symptoms.
The authors thank Johnathan Sumner for his excellent help with the graphic table, Sarah K. Flores for her assistance with the graphic programming, and Robert Martinez for his support of the nuclear medicine image acquisitions. The authors also thank Dr Ralph Blumhardt for his reading of the article and providing valuable feedback.
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Keywords:Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
diabetes; functional dyspepsia; gastric-emptying scintigraphy; gastroparesis; glycemic excursions; postprandial glucose