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Simultaneous Blood Glucose Monitoring During Gastric-Emptying Scintigraphy May Identify Unsuspected Abnormalities

McWhorter, Nathan, E., DO*; Abazid, Leen, MD; Gorzell, Brandon, C., BS; Lynch, Jane, L., MD§; Salman, Umber, A., MD; Metter, Darlene, F., MD; Phillips, William, T., MD

doi: 10.1097/RLU.0000000000002084
Original Articles

Purpose A retrospective study of 197 patients was performed to evaluate utility of simultaneous fingerstick glucose monitoring during standardized solid meal gastric-emptying scintigraphy (GES). We hypothesized the unlabeled carbohydrate components of the standardized meal often empty at different rates than the labeled egg protein component and that simultaneous glucose monitoring may identify rapid carbohydrate gastric emptying.

Methods Patients were classified as normal, rapid, or delayed gastric emptying from the standardized solid egg meal GES criteria. Further subcategorization was made based on postprandial glycemic excursions above baseline at 30/60 minutes and was delineated as elevated (>75 mg/>85 mg/dL), normal, or diminished (<30 mg/dL) glucose excursion.

Results Of the 197 patients, solid gastric-emptying rates for 105 were normal, delayed in 54, and rapid in 25 patients, and 13 patients had initially delayed emptying 1 or 2 hours with normal emptying by 4 hours. Of the 105 patients with normal gastric emptying, 58 had elevated, 47 normal, and none had diminished glucose excursions. Of the 54 patients with delayed gastric emptying, 26 had elevated, 16 had normal, and 12 had diminished glucose excursions. Nine patients with normal or delayed gastric emptying but elevated glycemic excursions returned for a liquid glucose GES. In contrast to their standardized GES results, all 9 had rapid emptying with elevated glycemic excursions.

Conclusions Simultaneous blood glucose monitoring with standardized GES protocols may provide a marker for contradictory findings of rapid gastric emptying of the unlabeled carbohydrate component in the standardized meal and may contribute to unexplained postprandial gastrointestinal symptoms. 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.

From the *Department of Nuclear Medicine, Brooke Army Medical Center, Fort Sam Houston; †Nuclear Medicine Section, Department of Radiology, University of Texas Health Science Center; ‡Nuclear Medicine Section, University Hospital, San Antonio; and §Department of Pediatric Endocrinology, University of Texas Health Science Center at San Antonio, San Antonio, TX.

Received for publication February 8, 2018; revision accepted March 4, 2018.

Conflicts of interest and sources of funding: none declared.

Correspondence to: William T. Phillips, MD, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78209. E-mail: phillips@uthscsa.edu.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

The standardized solid radiolabeled egg-white gastric-emptying study has been widely adopted for assessment of gastric-emptying abnormalities. The standardization of gastric-emptying studies alleviated the considerable confusion of study interpretation posed by a wide variety of clinical gastric-emptying meals and thereby facilitated a true comparison between patients in different institutions and on repeat study.1 In the standardized gastric-emptying meal, egg white is radiolabeled with 99mTc–sulfur colloid (SC) and combined with 2 pieces of toast and strawberry jam. However, the majority of the meal's kilocalorie content is contained in the high-carbohydrate toast and jam (76% of the total kilocalorie meal content); these high-carbohydrate components are not radiolabeled. Hence, the meal's carbohydrate impact on gastric-emptying rate is not assessed, which may be significant, because prior studies have reported that different meal components can frequently empty at different rates.2 In a comparative study, a radiolabeled high-carbohydrate component of a mixed nutrient meal emptied 30 minutes more rapidly than the radiolabeled hamburger/protein component.2 Differences in the gastric-emptying rates of various meal components are understandable considering that carbohydrates have very different digestive mechanisms compared with protein. For instance, while in the mouth, bread particles are well degraded by hydrolysis, which may accelerate their gastric emptying.3 There is also evidence that carbohydrates, proteins, and fats stimulate different incretin hormones that play important roles to regulate gastric emptying, raising the possibility that patients may have gastric-emptying variations related to isolated macronutrients.4 For example, carbohydrates stimulate glucagon-like peptide-1 secretion in the small intestine, a major moderator of the gastric emptying of carbohydrates, whereas protein gastric emptying is moderated via intestinal secretion of peptide YY.4

The most commonly used meals in clinical gastric-emptying scintigraphy (GES) radiolabel only the protein component of a mixed meal,1,5,6 and thus, carbohydrate gastric-emptying differences may remain undetected. We hypothesize that the unlabeled carbohydrate component of the standardized egg meal often empties more rapidly than the radiolabeled protein component, and this rapid carbohydrate emptying may lead to variable gastric-emptying effects not detected with current imaging methods. Abnormally rapid carbohydrate emptying may be an unidentified cause of postprandial gastrointestinal symptoms.

In the current study, we postulate that serial blood glucose measurements during GES can be utilized as a surrogate marker for gastric-emptying patterns of the unlabeled carbohydrate components in the standardized radiolabeled egg-white meal. Multiple studies have reported the rate of carbohydrate gastric emptying is highly correlated with 30-minute and 1-hour postprandial glucose excursions above baseline.7–12 In a study of normal subjects, the postprandial glucose excursions were significantly correlated with gastric emptying at 30 minutes (R = −0.58, P < 0.05),8 and in another study, diabetic subjects had 1-hour blood glucose excursions that significantly correlated with gastric half-emptying times (R = −0.65, P = 0.0001).9 In a prior study by our group, all normal and diabetic patients with postprandial serum glucose excursions of greater than 75 mg/dL above their fasting baseline levels at 30 minutes were found to have abnormally rapid gastric emptying of a liquid carbohydrate meal composed of a flavored glucose solution having an osmolality (0.62 molar) similar to commercial juice and soda beverages. On the other hand, all subjects with normal gastric-emptying rates had glucose excursions of less than 60 mg/dL at 30 minutes and 1 hour.12

In this article, we retrospectively reviewed 197 consecutive patients referred to our clinic for a solid standardized radiolabeled egg-white, toast, and jam GES over a 2-year period who also had simultaneous fingerstick blood glucose measurements performed at each time point of acquisition of the gastric scintigraphy images (baseline, 0.5, 1, 2, and 4 hours) using methodology described in a consensus statement for the standardized egg-white meal by the nuclear medicine and gastroenterology societies.1

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METHODS

A retrospective analysis was performed on 197 consecutive patients referred for GES from January 1, 2015, to March 31, 2017, for evaluation of postprandial abdominal pain or other gastrointestinal symptoms such as vomiting and bloating. For comparative purposes, consecutive patients were excluded from this retrospective review if they did not complete consumption of 100% of the standardized solid radiolabeled egg-white meal. Approval to perform this retrospective review was given by the University of Texas Health Science Center at San Antonio Institutional Review Board and University Hospital, San Antonio, under protocol HSC-20140318H. All patients were given the standardized solid 99mTc-SC radiolabeled egg-white meal containing 120 g of egg white (61 kcal), 2 slices of white bread (120 kcal), and 30 g of strawberry jam (74 kcal, total kilocalorie content of 255 kcal) radiolabeled with 1 mCi 99mTc-SC with imaging performed according to the 2007 American College of Radiology/Society of Nuclear Medicine/Society for Pediatric Radiology Practice Guideline for the Performance of Gastrointestinal Scintigraphy based on international control values.6 Static 1-minute images were obtained in the anterior and posterior positions with regions of interest drawn around the stomach in the anterior and posterior positions, and geometric mean calculation of the percent retained in the stomach was performed. Importantly, on the first set of anterior and posterior images acquired immediately after meal consumption, a region of interest was drawn around both the stomach and the whole abdomen on both the anterior and posterior images to determine the amount of meal emptied during the time of meal consumption. In addition, all patients had blood glucose measurements performed by fingerstick glucometer prior to meal consumption and at 0.5, 1, 2, and 4 hours postmeal consumption. The collection of postprandial glucose measurements is a standard part of our clinical practice, which was suggested as a likely future addition to GES in the Joint Report of the Consensus Recommendations for Gastric Emptying.1,13 Blood glucose measurements were made immediately prior to acquisition of 1-minute planar anterior and posterior gastric scintigraphy.

Patients were classified as having normal, rapid, or delayed gastric emptying based on criteria specified in the standardized 99mTc-SC solid meal gastric-emptying protocol.1 According to this convention, “delayed” gastric emptying is defined as having more than 10% of the meal remaining in the stomach at 4 hours. Based on criteria for the standardized solid meal, patients were classified as having rapid solid gastric emptying if they emptied greater than 30% of the meal at 30 minutes and/or greater than 70% of the meal at 1 hour, delayed gastric emptying at 4 hours if they emptied less than 90% of the meal, and delayed emptying at 1 and 2 hours only if they emptied less than 10% of the meal. Patients were further subcategorized according to postprandial glycemic excursions above baseline at 30 minutes or 1 hour. A postprandial glucose was considered to be “elevated” if the glycemic excursion above baseline was greater than 75 mg/dL at 30 minutes or greater than 85 mg/dL at 1 hour. A postprandial glycemic excursion was considered “normal” if the elevation above the fasting baseline was greater than 30 mg/dL but less than 75 mg/dL at 30 minutes or greater than 30 mg/dL but less than 85 mg/dL at 1 hour. Patients were classified as having a “diminished” glycemic excursion if the serum glucose elevation at 30 minutes was less than 30 mg/dL above baseline glucose levels. These criteria for postprandial glycemic excursions were based on prior studies published by our group measuring both gastric emptying and postprandial glycemic excursions in diabetic and normal patients who were administered a liquid carbohydrate glucose meal.7,12,12 When classification was independently applied to the 197 GES results, all 3 readers were independently in agreement with the individual GES and glucose assessments. In addition, patient-specific symptoms were recorded before and during all imaging time points and ranked on a scale of 1 to 10, with 1 being mild nausea or discomfort and 10 being the most severe nausea or discomfort. These symptom patterns are depicted in the individual patient examples of Figures 1 to 7, but they have not been systematically analyzed in this article.

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

FIGURE 4

FIGURE 4

FIGURE 5

FIGURE 5

FIGURE 6

FIGURE 6

FIGURE 7

FIGURE 7

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.

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RESULTS

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.

FIGURE 8

FIGURE 8

TABLE 1

TABLE 1

TABLE 2

TABLE 2

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

FIGURE 9

FIGURE 9

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DISCUSSION

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.

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ACKNOWLEDGMENTS

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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REFERENCES

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Keywords:

diabetes; functional dyspepsia; gastric-emptying scintigraphy; gastroparesis; glycemic excursions; postprandial glucose

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