Measurement of gastric emptying in diabetes.

Journal of Diabetes and Its Complications xxx (2014) xxx–xxx

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Measurement of gastric emptying in diabetes Liza K. Phillips a, b, c, Chris K. Rayner a, b, d, Karen L. Jones a, b, Michael Horowitz a, b, c,⁎ a

Discipline of Medicine, The University of Adelaide, Australia NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Australia c Endocrine and Metabolic Unit, Royal Adelaide Hospital, Australia d Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Australia b

a r t i c l e

i n f o

Article history: Received 26 May 2014 Accepted 10 June 2014 Available online xxxx Keywords: Gastric emptying Gastroparesis Postprandial glycemia Scintigraphy Glucose homeostasis Type 2 diabetes

a b s t r a c t There has been a substantial evolution of concepts related to disordered gastric emptying in diabetes. While the traditional focus has hitherto related to the pathophysiology and management of upper gastrointestinal symptoms associated with gastroparesis, it is now apparent that the rate of gastric emptying is central to the regulation of postprandial glycemia. This recognition has stimulated the development of dietary and pharmacologic approaches to optimize glycemic control, at least in part, by slowing gastric emptying. With the increased clinical interest in this area, it has proved necessary to expand the traditional indications for gastric emptying studies, and consider the relative strengths and limitations of available techniques. Scintigraphy remains the ‘gold standard’ for the measurement of gastric emptying, however, there is a lack of standardization of the technique, and the optimal test meal for the evaluation of gastrointestinal symptoms may be discordant from that which is optimal to assess impaired glycemic control. The stable isotope breath test provides an alternative to scintigraphy and can be performed in an office-based setting. The effect of glucagon-like peptide-1 (GLP-1) and its agonists to reduce postprandial glycemia is dependent on the baseline rate of gastric emptying, as well as the magnitude of slowing. Because the effect of exogenous GLP-1 to slow gastric emptying is subject to tachyphylaxis with sustained receptor exposure, ‘short acting’ or ‘prandial’ GLP-1 agonists primarily target postprandial glycemia through slowing of gastric emptying, while ‘long acting’ or ‘non-prandial’ agents lower fasting glucose primarily through insulinotropic and glucagonostatic mechanisms. Accordingly, the indications for the therapeutic use of these different agents are likely to vary according to baseline gastric emptying rate and glycemic profiles. Crown Copyright © 2014 Published by Elsevier Inc. All rights reserved.

1. Introduction

‘We need to learn to measure what we value, not value what we can easily measure’ [Marcus Aurelius AD 121-180] Traditionally, issues related to disordered gastric emptying in diabetes lay primarily within the domain of the gastroenterologist, with a particular focus on the management of upper gastrointestinal symptoms. More recently there has been a paradigm shift to the domain of the diabetologist, stimulated by the recognition of the pivotal role of gastric emptying as a determinant of glycemia and, consequently, as a therapeutic target to optimize postprandial Conflict of Interest Statement: None of the authors have a conflict of interest. ⁎ Corresponding author at: Centre of Research Excellence (CRE) in Translating Nutritional Science to Good Health, Discipline of Medicine, The University of Adelaide, Level 6 Eleanor Harrald Building, Royal Adelaide Hospital, Frome Road, S.A. 5005. E-mail address: [email protected] (M. Horowitz).

glycemic control in diabetes. The substantial evolution of concepts related to gastric emptying in diabetes has also dictated the need for reassessment of the indications for, and methods of, assessment of gastric emptying. This review focuses on the inter-relationship between gastric emptying and glycemia, the techniques that can be used to measure gastric emptying, with particular reference to scintigraphy, and the clinical indications for measurement (Fig. 1). 2. Evolution of concepts relating to diabetic gastroparesis Gastroparesis, when defined as delayed gastric emptying occurring in the absence of mechanical obstruction (Camilleri, 2007), is likely to affect 30%–50% (Chang, Rayner, Jones, & Horowitz, 2010; Marathe, Rayner, Jones, & Horowitz, 2013) of patients with longstanding type 1 or type 2 diabetes, although there have not been any true population-based studies. Clinical features of gastroparesis include nausea, vomiting, bloating, abdominal pain and malnutrition, with additional implications for oral drug absorption in general, and specific issues related to matching glucose-lowering therapy with oral intake. Accordingly, disordered gastric emptying should be

http://dx.doi.org/10.1016/j.jdiacomp.2014.06.005 1056-8727/Crown Copyright © 2014 Published by Elsevier Inc. All rights reserved.

Please cite this article as: Phillips, L.K., et al., Measurement of gastric emptying in diabetes, Journal of Diabetes and Its Complications (2014), http://dx.doi.org/10.1016/j.jdiacomp.2014.06.005

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L.K. Phillips et al. / Journal of Diabetes and Its Complications xxx (2014) xxx–xxx

considered in patients with substantial fluctuations in blood glucose i.e. hyperglycemia that is difficult to manage, in addition to unexplained hypoglycemia (Horowitz, Jones, Rayner, & Read, 2006; Lysy, Israeli, Strauss-Liviatan, & Goldin, 2006). It has been suggested that the diagnosis of gastroparesis requires the presence of gastrointestinal symptoms (Abell et al., 2008; Parkman, Hasler, & Fisher, 2004), however, given the clinical relevance of disordered gastric emptying to glycemic control in diabetes, this stipulation seems inappropriate. Furthermore, the relationship between symptoms and the rate of gastric emptying is weak (Bharucha, Camilleri, Forstrom, & Zinsmeister, 2009; Horowitz et al., 1991; Jones et al., 2001; Samsom et al., 2003), and the magnitude of delay in gastric emptying in those with symptoms is often modest or non-existent (Rayner, Samsom, Jones, & Horowitz, 2001; Samsom et al., 2003). Indeed, gastric emptying is abnormally rapid in a sub-set of patients with diabetes (Ariga et al., 2008; Bharucha et al., 2009; Schwartz, Green, Guan, McMahan, & Phillips, 1996), and symptoms in these patients may be indistinguishable from those in patients with gastroparesis. It has been suggested that the absence of symptoms in patients with markedly disordered gastric emptying may reflect an afferent nerve defect (Stevens, Jones, Rayner, & Horowitz, 2013). It is currently uncertain whether a patient who has significant symptoms consistent with gastroparesis, but in whom gastric emptying is ‘normal’, can be, in the absence of other pathology, considered to have ‘disordered gastric emptying’. There is evidence of visceral hypersensitivity in patients with symptoms in the absence of abnormalities of gastric emptying (Kumar, Attaluri, Hashmi, Schulze, & Rao, 2008; Rayner et al., 2000), and acute hyperglycemia may magnify gastrointestinal sensations (Rayner et al., 2001). However, it is also probable that the sensitivity of current techniques in identifying abnormalities in gastrointestinal motor and sensory function is less than optimal. Gastric emptying of ingested nutrients is modulated through a complex interplay between the extrinsic and enteric nervous systems, smooth muscle cells, immune cells, and the so-called interstitial cells of Cajal (ICC), the ‘pace-makers’ of the stomach. A balance between excitatory (e.g. acetylcholine and substance P) and inhibitory,

neurotransmitters (e.g. nitric oxide) is required for normal gastrointestinal motility (Kashyap & Farrugia, 2010). The pathogenesis of disordered gastric emptying in diabetes has long been attributed to irreversible vagal neuropathy (Camilleri, 2007), however it is clear that the underlying pathophysiology is multi-factorial, with both ‘reversible’ and ‘irreversible’ components. Recent reports from the Gastroparesis Clinical Research Consortium have provided important insights into the pathophysiological cellular changes in diabetic gastroparesis (Grover et al., 2011, 2012). This group examined the cellular changes in 40 patients with gastroparesis (diabetic n = 20, idiopathic n = 20) and matched controls. Full thickness gastric biopsies were obtained at the time of placement of a gastric stimulator for those with gastroparesis, and at the time of duodenal switch gastric bypass surgery in controls — an inherent limitation is that the disease group in these studies represents those with severe and debilitating gastroparesis, while those in the control group were likely to be morbidly obese. Pathologic abnormalities were observed in 83% of biopsies from those with gastroparesis, and an increase in immunoreactivity was evident in patients with diabetic gastroparesis—compared with controls, these patients demonstrated a 25% increase in the expression of CD45, a general cell marker for immune infiltrate, within the myenteric plexus. A central finding was loss of the ICC (Grover et al., 2011), confirming findings from earlier, smaller studies (Forster et al., 2005; He et al., 2001). Moreover, in patients with diabetes gastric emptying was slower when the loss of the ICC was greater, and the latter correlated directly with the loss of enteric nerves, supporting the functional significance of this finding (Grover et al., 2012). In contrast, ICC, and enteric nerve, loss did not correlate with symptom severity. Further work is required to explore the cellular mechanisms underlying the attrition of ICC in diabetic gastroparesis. Neuronal nitric oxide synthase (nNOS), which is responsible for the synthesis of nitric oxide, has an important, potentially reversible, role (He et al., 2001; Watkins et al., 2000), while the signaling molecule, carbon monoxide, has emerged as an important neuro-protective defense and modulator of gastrointestinal function, with the potential to be a therapeutic target in gastroparesis

GLP-1 = glucagon like peptide-1 ---- inhibitory effect

Hunger Food in take

Gastric emptying

Glucose

GLP-1

β–cell: amylin GLP-1

α-cell: glucagon β–cell: insulin

Fig. 1. Effects of amylin and GLP-1 on glucose homeostasis. The rate of gastric emptying following a meal is a critical determinant of postprandial glycemia. Ingested nutrients stimulate the release of GLP-1, which slows gastric emptying, promotes satiation and release of insulin, while inhibiting glucagon secretion. Amylin is co-secreted with insulin from pancreatic β cells and acts to slow gastric emptying and promote satiation.



(Gibbons, Verhulst, Bharucha, & Farrugia, 2013). Importantly, given the heterogeneous abnormalities in severe diabetic gastroparesis, multi-faceted management approaches are likely to be required. It has been established for some time that the rate of gastric emptying is a major determinant of the initial (from ~ 15–60 min) glycemic response to an oral glucose load in health (Corvilain et al., 1995; Horowitz, Edelbroek, Wishart, & Straathof, 1993, Horowitz, Cunningham, Wishart, Jones, & Read, 1996; O'Donovan et al., 2005; Schwartz, McMahan, Green, & Phillips, 1995) and in type 2 diabetes (Jones et al., 1995; Stevens et al., 2011). The clinical relevance of this is highlighted by the recognition that, in patients with an HbA1c of less than ~ 7.5%, including those on basal insulin, postprandial, rather than pre-prandial glycemia usually makes a greater contribution to overall glycemic control, as measured by HbA1c (Monnier, Lapinski, & Colette, 2003; Riddle, Umpierrez, DiGenio, Zhou, & Rosenstock, 2011). Moreover, postprandial hyperglycemia is emerging as an independent cardiovascular risk factor (Cavalot et al., 2006; Chiasson et al., 2003). It is now evident that there is a complex, interdependent, relationship between gastric emptying and glycemia (Marathe et al., 2013). The rate of gastric emptying determines postprandial glucose excursions, while conversely, the prevailing blood glucose concentration influences gastric emptying: insulin-induced hypoglycemia is associated with an acceleration of emptying (Russo et al., 2005), while emptying is slowed during acute hyperglycemia (Fraser et al., 1990), and even changes in blood glucose within the physiological range have an impact (Schvarcz et al., 1997). The introduction of pharmacological treatments that target gastric emptying for therapeutic effect, including pramlintide and glucagon-like peptide-1 (GLP-1) agonists, has further emphasized the importance of gastric emptying in glycemic control and, as will be discussed, consideration of gastric emptying is relevant in patients treated with these agents. 3. Inter-relationship between gastric emptying and glycemia The complex interplay between the gut and glycemia needs to be recognized when considering the role of the gastrointestinal tract in glucose homeostasis (Fig. 1). 3.1. Determinants of postprandial glycemia The factors influencing postprandial glycemia are numerous and include pre-prandial glucose concentrations, meal composition, the rate of gastric emptying, small intestinal function (glucose absorption, incretin hormone release), secretion of insulin and glucagon, and hepatic and peripheral glucose disposal. However, gastric emptying accounts for approximately 35% of the variance in the initial rise in postprandial blood glucose in health (Horowitz et al., 1993) and type 2 diabetes (Jones et al., 1996), and accordingly, even modest alterations in the rate of gastric emptying (Gonlachanvit et al., 2003) or rate of glucose entry into the duodenum (Ma et al., 2012; O'Donovan et al., 2004; Pilichiewicz et al., 2007) have a substantial impact on resultant blood glucose excursions. Exposure of the small and large intestine to nutrients promotes the release of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) from L cells in the distal ileum and colon, and K cells in the duodenum and jejunum, respectively (Baggio & Drucker, 2007). In addition to glucose-dependent insulin secretion, GLP-1 inhibits the release of glucagon, slows gastric emptying, and promotes satiation (Baggio & Drucker, 2007). Incretin-based therapies have focused on GLP-1, as, unlike GIP, GLP-1 retains much of its insulinotropic effect in type 2 diabetes. 3.2. Impact of gastric emptying on glycemia and incretin hormones In health, gastric emptying proceeds at an overall rate of 1–4 kcal/min (Brener, Hendrix, & McHugh, 1983), and is predominantly pulsatile,

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rather than continuous, with frequent retrograde flow (Stevens et al., 2013). The significant inter-individual variation in gastric emptying observed in health (Horowitz et al., 1991) is even greater in those with diabetes, because of the high prevalence of delayed (Horowitz, Su, Rayner, & Jones, 2001) and, in a sub-set of patients, rapid (Phillips, Schwartz, & McMahan, 1992; Schwartz et al., 1996), gastric emptying. Intra-individual rates of emptying, however, are remarkably stable over time (Chang et al., 2012; Collins, Horowitz, Cook, Harding, & Shearman, 1983). We recently reported a longitudinal evaluation of gastric emptying in an unselected group (n = 13) of subjects with predominantly type 1 diabetes (Chang et al., 2012). Gastric emptying was reevaluated at 24.7 ± 1.5 years following the baseline scintigraphic study. There was remarkably little change in individual solid or liquid gastric emptying, or upper gastrointestinal symptoms, over time, in keeping with previous work (Jones et al., 2002). Although cardiovascular autonomic function predictably declined over time, there was an improvement in glycemic control, which may have mitigated potential deterioration in gastric emptying. It has been clearly established that the rate of gastric emptying of oral glucose has a significant impact on both the early and overall (e.g. AUC) glycemic response (Corvilain et al., 1995; Horowitz et al., 1993, 1996; Jones et al., 1995; O'Donovan et al., 2005; Schwartz et al., 1995; Stevens et al., 2011). However, there is less information about the relationship of the magnitude of slowing of gastric emptying to the subsequent reductions in peak and overall postprandial glycemia. However, following a solid, carbohydrate-containing, meal, much of the variability in postprandial glycemic response to differing carbohydrates can be attributed to differences in gastric emptying (Benini et al., 1995; Mourot et al., 1988; Rayner et al., 2001). Although gastric emptying can be manipulated pharmacologically, the rate of emptying is not constant and is highly variable between individuals. Direct infusion into the small intestine is a useful model, permitting precise titration of entry rate and site of nutrient exposure. In a series of studies, our group has recently explored the relationship between rate and site of glucose entry to the small intestine in health and type 2 diabetes. Minor variations of carbohydrate entry into the small intestine were shown to have large effects on glycemia (Ma et al., 2012; O'Donovan et al., 2004; Pilichiewicz et al., 2007; Trahair et al., 2012). Importantly, there is a non-linear relationship between the rate of entry of glucose and glycemic response in health (Trahair et al., 2012) and type 2 diabetes (Ma et al., 2012). Accordingly, in health and type 2 diabetes, an infusion rate of 1-kcal/min results in lower (and minimal) glycemic excursion, when compared with higher rates (2–4 kcal/min). However, among the higher infusion rates, there was no difference in the glycemic response in health, and only a modest difference in patients with diet-controlled type 2 diabetes, which was attributable to a higher insulin response to the greater glucose load (Ma et al., 2012; Trahair et al., 2012). The latter can be accounted for by a much greater incretin release, particularly for GLP1. More recently, we have demonstrated that in both health and type 2 diabetes, the magnitude of the incretin effect is substantially greater when glucose in infused intraduodenally at 4 kcal/min when compared to 2 kcal/min (Marathe et al., 2014). It is, therefore, critical that the rate of gastric emptying is considered when evaluating the incretin response, although this has not generally been recognized. Overall, it is evident that the impact of modulating gastric emptying on glycemia in type 2 diabetes is dependent on: i) the baseline rate of gastric emptying (Deane et al., 2010) (i.e. if baseline emptying is already relatively slow, there is less capacity for further slowing with a consequently reduced impact on glycemia), ii) the small intestinal carbohydrate load which impacts on the length and region of small intestinal exposed and iii) the incretin response, which appears to be greater at higher rates of carbohydrate entry into the small intestine. In terms of manipulating gastric emptying from a therapeutic perspective in type 2 patients who are not managed with insulin, slowing gastric emptying to a rate of approximately 1 kcal/min is likely to be


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the most effective goal. While pharmacological acceleration of gastric emptying will be associated with a greater incretin response, this will also be associated with greater glycemia. Recent work has highlighted the therapeutic potential of augmenting release of the incretins, particularly, GLP-1, through targeted intestinal exposure to nutrients (e.g. lauric acid) (Ma et al., 2013) or bile acid (taurocholic acid) (Wu et al., 2013). 3.3. Impact of glycemia on gastric emptying Teleologically, the acceleration of gastric emptying in the setting of hypoglycemia (Russo et al., 2005), and slowing of gastric emptying associated with acute hyperglycemia (Fraser et al., 1990), may represent an adaptive response aimed at correcting the respective underlying glycemic abnormality. Importantly, it has also been shown that even within the physiological range, the blood glucose concentration affects gastric emptying, which is slower at a glucose concentration of 8 mmol/L compared with 4 mmol/L (Schvarcz et al., 1997). This effect of acute glycemia on gastric emptying may be greater in normal subjects than in those with type 1 diabetes, but is clinically significant in both groups: at glucose concentrations of 8 mmol/L vs. 4 mmol/L, the retention of solids in the stomach at 100 min was reduced by 53% and 26% in health and in type 1 diabetes, respectively, while the 50% emptying (T50) for liquids was reduced by 78% and 29%. The specific mechanisms by which acute hyperglycemia delays gastric emptying are unclear, however, the pancreatic β-cell hormone human islet amyloid polypeptide (co-secreted with insulin), ghrelin (release of which is inhibited by hyperglycemia), nitric oxide (Kuo et al., 2009) and direct hypothalamic stimulation may all play a role through activation of parasympathetic pathways (Vinik, Nakave, & Chuecos Mdel, 2008). There is limited evidence that improved chronic glycemic control may normalize gastric emptying (Camilleri, Parkman, Shafi, Abell, & Gerson, 2013), but further work is needed to delineate the relative contributions of acute versus chronic glycemia on gastric emptying. 4. Measurement of gastric emptying Traditionally, the indications for gastric emptying studies focused on the investigation of upper gastrointestinal symptoms. The appreciation of the pivotal role of gastric emptying in glycemia and the emergence of diabetic therapies that modulate gastric emptying have seen an appropriate expansion of clinical and research interest in gastric emptying and, therefore, its measurement. Scintigraphy is the most widely accepted method for measuring gastric emptying (Camilleri, 2007; Shin & Camilleri, 2013) and represents the ‘gold standard’. Other modalities are available, however, and the relative advantages and disadvantages of each available technique are summarized in Table 1. The optimal technique and test meal may depend on the indication for measurement. 4.1. Scintigraphy Scintigraphy allows direct physiological measurement of gastric emptying, and intragastric distribution of the ingested meal can also be quantified (Camilleri, 2007; Shin & Camilleri, 2013). This technique requires access to a gamma camera and involves radiation exposure, and is, therefore, contraindicated in pregnancy, and a relative contraindication in children. Despite the long-term adoption of scintigraphy as a diagnostic tool, there is a lack of standardization of the technique e.g. meal composition and volume, posture of subjects, frequency and duration of data acquisition and parameters used to quantify gastric emptying. A consensus report from the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine in 2008 (Abell et al., 2008) proposed a standardized

approach to gastric emptying scintigraphy, aspects of which are discussed in further detail below. 4.2. Factors to consider during measurement with scintigraphy A number of factors warrant consideration with the scintigraphic technique, however, it should be noted that many of these (e.g. test meal, glycemia) also apply to other methodologies. 4.2.1. Symptoms The recent consensus guidelines do not stipulate that symptoms be documented during the testing procedure, though it is acknowledged that this is routinely undertaken in research settings (Abell et al., 2008). Brief, validated questionnaires are available, and reproducibility of reported symptoms may be an important outcome measure in many patients (Camilleri et al., 2013). However, as discussed, the requirement for the presence of gastrointestinal symptoms for the diagnosis of diabetic gastroparesis is inappropriate given the other important manifestations of slowed gastric emptying. 4.2.2. Test meal and timing of imaging The rate of gastric emptying varies substantially according to meal composition; liquid is more rapidly emptied when compared with solid components. Low-nutrient liquids, such as water, do not induce small intestinal feedback to slow gastric emptying and, therefore, should not be used. However, it is likely that high-nutrient liquid, or semi-solid, meals are not inferior to solid test meals in the measurement of gastric emptying. The relationship between solid and liquid gastric emptying in diabetes is relatively weak (Horowitz et al., 1991; Jones et al., 1995), and, therefore, evaluation of nutrient liquid, as well as solid, emptying increases the sensitivity of scintigraphy (Sachdeva et al., 2011); in addition, if carbohydrate is included in the meal, the relationship between glycemia and gastric emptying can be determined. Digestible components of a meal empty more rapidly compared with indigestible residue, while the gastric emptying of fat is usually slower than that of protein and carbohydrate. In general, solid components of a meal empty in an overall linear fashion following a lag phase of 20–40 min (Stevens et al., 2013). In contrast, liquids do not have a significant lag phase; low-nutrient liquids empty in a monoexponential fashion; highnutrient liquids, however, empty at a linear rate (Stevens et al., 2013). The rate of solid emptying is influenced by the volume and nutritional composition of co-ingested liquid: liquids are preferentially emptied, and nutrient containing liquids delay the emptying of solid components of a test meal (Stevens et al., 2013). Accordingly, following ingestion of a mixed solid and liquid test meal, approximately 80% of the liquid component empties prior to the commencement of solid emptying (Stevens et al., 2013). Current meals used by various institutions include ground beef and chicken liver, egg white, whole egg, oatmeal and pancakes, with or without liquid elements. The consensus statement from the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine, recommends a low-fat, egg-white meal: a technetium (Tc)-99 m sulfur colloid radiolabeled meal containing the equivalent of two large eggs (Eggbeaters, ConAgra Foods Inc., Omaha, NE, USA), two slices of bread and strawberry jam (30 g) with water (120 mL) (Abell et al., 2008). This meal compromises 255 kcal (72% carbohydrate, 24% protein, 2% fat and 2% fiber) and has the largest published normative database available (Tougas et al., 2000). There are, however, limitations with the use of this meal. Although the meal is generally administered with a patient’s usual diabetic medications, it represents a moderate glycemic load, so consideration of the effects of any hyperglycemia is required. Furthermore, this test meal is low in fat, which may not be physiologically relevant for evaluation of delayed emptying in some patients. The test meal is given with water, partly in order to limit the possibilities of nausea and vomiting in symptomatic



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Table 1 Measurement approaches for gastric emptying. Test

Advantages

Limitations

Scintigraphy

‘Gold standard’ technique for measurement of gastric emptying Direct measurement of gastric emptying Intragastric distribution can be determined, to characterize fundal and antral function Acceptable alternative to scintigraphy particularly when need to avoid radiation exposure (e.g. pregnancy, breastfeeding, children) No radiation exposure Non-invasive Cheaper than scintigraphy May be an acceptable alternative to scintigraphy Non-invasive No requirement for radiation 3D ultrasonography provides information on intragastric distribution and meal volume

Radiation exposure Access to Nuclear Medicine facility

Breath testing 13 C-octanoic acid 13 C Spirulina platensis

Ultrasonography

Acetaminophen or paracetamol absorption

Non-invasive

Wireless motility capsule

Correlates with scintigraphy No radiation exposure Correlates well with scintigraphy Can differentiate between solid and liquid (cf ultrasonography) Greater degree of functional information obtained that can help differentiate between neuropathic and non-neuropathic causes of gastroparesis

MRI

Gastroduodenal manometry

patients, but in some cases – and certainly in the research setting – the inclusion of a carbohydrate-containing drink is useful to quantify glycemic response and the relationship with gastric emptying. There are also obvious limitations for those with egg allergy and celiac disease, although food intolerance can pose an issue for many of the alternative test meals too. Imaging is suggested at 0, 1, 2, and 4 h after ingestion of the ‘standard’ meal, with emphasis on the 4 h value. However optimal imaging following other test meals may differ from these guidelines. As rapid gastric emptying may present with symptoms similar to those of delayed gastric emptying (Lin, Van Citters, Zhao, & Waxman, 1999; Schwartz et al., 1996), earlier time points such as 15 and 30 min may need to be considered (Abell et al., 2008); further work in defining rapid gastric emptying is required.

Assumes normal small bowel absorption and normal liver and pulmonary function

Operator dependent Obesity and/or bowel gas may limit imaging Requires geometric assumptions of shape of stomach Generally only measures liquid GE 3D ultrasonography requires greater expertise cf 2D Validated for liquid emptying only Repeated blood sampling Does not directly measure gastric emptying High cost and limited availability Long duration for image capture and interpretation Does not measure gastric emptying directly Only measures lumen occlusive contractions Invasive, expensive Limited availability

should be taken (Abell et al., 2008), which is appropriate. However, guidelines should also stipulate that GLP-1 agonists and pramlintide need to be withheld for testing of gastric emptying, and alternative strategies for managing glycemia implemented. Documentation of blood glucose concentrations during testing is an appropriate reporting requirement and should aim to capture peak glycemia and potential postprandial hypoglycemia — this could be achieved, for example, by documenting blood glucose concentrations every 30 min for the first 2 h, and hourly thereafter. The consensus guidelines do not have a current stipulation for measurement, or documentation, of blood glucose concentrations, however their suggestion of measurements at 2 and 4 h, again needs further refinement (Abell et al., 2008).

4.3. Breath testing 4.2.3. Glycemia Given the increasing understanding of the influence of glycemia on gastric emptying (Fraser et al., 1990; Horowitz et al., 2002; Schvarcz et al., 1997), it seems clear that blood glucose concentrations should be documented prior to its measurement. Recent guidelines suggest that the test meal should be given when the blood glucose is b 275 mg/dL (15.3 mmol/L) (Camilleri et al., 2013). However, gastric emptying tests undertaken at this level of glycemia are likely to result in a number of false positives due to the slowing of gastric emptying observed in the setting of acute hyperglycemia, as discussed. It would seem reasonable to lower the blood glucose concentrations to ≤ 180 mg/dL (10 mmol/L), and preferably below 155 mg/dL (8 mmol/L), prior to testing. It is suggested that half the usual dose of insulin should be administered with the test meal (Abell et al., 2008); however, given the known relationship between gastric emptying and glycemia, this point warrants refinement e.g. if the test meal contains a substantial portion of high glycemic index carbohydrate, then short-acting insulin is likely to be required, and basal insulin, if this is the ‘usual’ insulin, is not an appropriate substitute. Although oral hypoglycemic agents are not formally addressed in the consensus guidelines, the accompanying patient information in the appendix suggests that oral hypoglycemic drugs

Breath tests represent an alternative approach, particularly when scintigraphy is not feasible (Shin & Camilleri, 2013), and are based on the incorporation of 13C-labeled substrates into a solid meal. The most commonly used substrate is 13C-octanoic acid, but 13C Spirulina platensis has also been employed. The stable 13C isotope is emptied from the stomach following the trituration and liquefaction of the solid component of the test meal, and is transported to the liver via the portal vein, where it is oxidized to 13C02. End-tidal breath samples are collected and 13C content measured using isotope ratio mass spectrometry (Shin & Camilleri, 2013); estimation of gastric emptying is obtained following mathematical modeling (Shin & Camilleri, 2013). The technique is non-invasive and does not expose the patient to radiation and, therefore, is an option in pregnant or lactating women, and in children. Furthermore, breath tests are cheaper than scintigraphy, and as samples can be sent to a central laboratory, may be undertaken in an office-based setting (Shin & Camilleri, 2013), or in patients who cannot be easily transported within the hospital setting e.g. Intensive Care Unit. Breath testing does assume normal small intestinal, hepatic and pulmonary function, and testing in populations outside of this range (e.g. small intestinal malabsorption, pulmonary or liver disease), may be inaccurate (Shin & Camilleri, 2013). The technique has been shown to be reproducible and has been validated


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in a diabetic cohort with a reported sensitivity and specificity between 75%–86% and 80%–86%, respectively (Viramontes et al., 2001; Ziegler et al., 1996), although reproducibility remains to be demonstrated in populations with markedly delayed gastric emptying (Shin & Camilleri, 2013).

4.7. MRI Repeated transaxial abdominal scans at 15 min intervals can be used to assess gastric emptying (Parkman et al., 2004). This noninvasive test avoids radiation exposure, but requires availability of expensive equipment and expertise, and image capture and interpretation are slow. It is, therefore, largely reserved for research purposes.

4.4. Wireless motility capsule (‘SmartPill’) The wireless motility capsule (WMC) or ‘SmartPill’ is ingested following a test meal, and transmits information regarding pH, pressure and temperature to an external recorder (Shin & Camilleri, 2013). Gastric emptying is inferred from a rapid drop in pH, so proton pump inhibitors and H2 receptor antagonists should ideally be ceased prior to testing, however, it does appear that in many cases a pH change can still be detected when these common medications are continued (Shin & Camilleri, 2013). Although this technique involves no radiation exposure, is relatively safe and demonstrates a moderate correlation with gastric emptying of a solid meal measured by scintigraphy (r = 0.606) (Cassilly et al., 2008), the WMC does not directly measure physiological gastric emptying of a meal. Rather, it assesses emptying of indigestible solids which occurs with ‘phase 3’ activity; the latter may be disrupted by acute hyperglycemia, or impaired in diabetes, and further validation is required before it can be considered a true alternative to scintigraphy (Camilleri et al., 2013).

4.5. Ultrasonography Ultrasonography can be undertaken using a 2D or 3D technique. Advantages of this non-invasive technique include lack of radiation exposure and information on intragastric meal distribution and volume. To date, ultrasonography has primarily been validated for both low and high-nutrient liquid gastric emptying (Shin & Camilleri, 2013), however, it also enables assessment of gastric distension, nonlumen occlusive antral contractility, and transpyloric flow (Chang, Rayner, Jones, & Horowitz, 2011). The technique is operatordependent and more difficult in obesity (Parkman et al., 2004). Measurements of antral area are utilized to derive gastric emptying in 2D sonography; the 3D technique is more accurate when compared with 2D sonography, but requires additional equipment and expertise. Sonography has been validated against scintigraphy in both healthy subjects and in those with diabetes (Chang et al., 2011), but is generally reserved for the research setting because of the expertise required.

4.6. Acetaminophen/paracetamol absorption This is an older test of gastric emptying, and with the advent of breath tests, has largely been superseded. The technique is based on the premise that the rate-limiting step of paracetamol absorption is gastric emptying, because paracetamol is not absorbed from the stomach and is rapidly absorbed from the small intestine — this is also the case with other solutes, including alcohol. However, there are a number of factors unrelated to gastric emptying that impact on paracetamol concentrations, including variations in first pass hepatic metabolism, volume of distribution, and elimination of paracetamol. In addition, the rate of gastric emptying of a solid meal per se is not measured with this test, and results correlate primarily with emptying of the liquid phase. Although algorithms have been formulated to adjust for inter- and intra-individual differences in paracetamol pharmacokinetics, in general, there is only a modest correlation between scintigraphy and paracetamol absorption tests, and the technique cannot be recommended as an alternative to scintigraphy or breath tests.

4.8. Gastroduodenal manometry Manometry is primarily a research tool used to investigate both gastric and small intestinal motor function, rather than measuring gastric emptying directly. In the clinical setting, it may be used to differentiate between neuropathic and myopathic processes affecting the gastrointestinal tract (Parkman et al., 2004). 5. Indications for measurement of gastric emptying The traditional indications for measurement of gastric emptying in diabetes, after mucosal lesions and gastric outlet obstruction have been excluded by endoscopy, include symptoms such as nausea, vomiting, bloating, abdominal pain and malnutrition. This is complicated by the observation that although gastrointestinal symptoms are more common in diabetes than in the non-diabetic population, symptoms are not strongly predictive of gastric emptying (Chang et al., 2011). However, given the relationship between glycemia and gastric emptying, consideration should also be given to gastric emptying studies in the setting of ‘difficult-to-control’ glycemia. Other situations in which gastric emptying studies may be considered are outlined below and summarized in Table 2, however this is an evolving area, and more research is required. 5.1. Postprandial hypoglycemia That a mismatch between the action of exogenous insulin and gastric emptying of a meal is a cause of ‘unexplained’ postprandial hypoglycemia was suggested by Kassander in 1958 (Kassander, 1958). Indeed, a high proportion of patients with insulin-treated diabetes who experience hypoglycemia in the early postprandial period have gastroparesis, and gastric emptying studies should be considered in such patients (Lysy et al., 2006). Rapid gastric emptying is a complication of gastrectomy (full or partial) associated with a drainage procedure and gastric bypass surgery for obesity, and can manifest as early satiation, postprandial hypoglycemia and diarrhea (Hasler, 2002; Playford et al., 2013). However, more rapid gastric emptying may also occur in those with normal gastrointestinal anatomy (Playford et al., 2013), and is known to affect a subset of patients with type 2 diabetes (Lin et al., 1999; Schwartz et al., 1996). 5.2. Optimization of treatment approaches Consideration to gastric emptying is intuitively important in patients on prandial insulin, where nutrient and treatment delivery need to be matched to avoid hypoglycemia. In this setting, the important issue is that of predictability in order to match the availability of insulin to intake. Similarly, if employing the Dose Adjustment for Normal Eating (DAFNE) (Pieber et al., 1995) approach to dietetic management of diabetes, knowledge of gastric emptying would be useful to be able to ‘time’ calculated insulin doses appropriately. However, in other patients, particularly in type 2 diabetes which is characterized by a delay in insulin release and insulin resistance, slowing of gastric emptying may be a logical treatment approach, as illustrated by the efficacy of pramlintide and GLP-1 agonists (discussed in more detail below).


L.K. Phillips et al. / Journal of Diabetes and Its Complications xxx (2014) xxx–xxx Table 2 Indications for measurement of gastric emptying in type 2 diabetes. Traditional indications: i) postprandial nausea, vomiting, fullness, abdominal pain ii) malnutrition iii) intractable gastroesophageal reflux Indications based on relationship between gastric emptying and glycemia: i) difficult to control glycemia ii) recurrent, or postprandial hypoglycemia Indications with specific regard to treatments targeting gastric emptying (e.g. ‘short-acting’ GLP-1 agonists, pramlintide, acarbose) in clinical research studies: i) gastric emptying measurements used to develop patient predictors of response: a) baseline gastric emptying b) gastric emptying rates on treatment, and relationship to clinical response to therapy ii) longitudinal follow up in an epidemiologic cohort to establish long-term pattern of gastric emptying in type 2 diabetes — the natural history of gastric emptying in type 2 diabetes is of significance when considering long-term treatment with an agent targeting gastric emptying

5.3. Therapeutics in which glucose lowering mediated through gastric emptying 5.3.1. Amylin analogues — pramlintide Amylin is co-secreted with insulin from the pancreatic β cell and modifies postprandial glycemia though inhibition of gastric emptying (Samsom et al., 2000); a single dose of pramlintide, a synthetic analogue of amylin, delays the gastric half-emptying time in patients with type 1 diabetes by ~ 50% (Kong et al., 1997, 1998). In addition, amylin inhibits postprandial glucagon secretion (Grunberger, 2013) and promotes satiation (Grunberger, 2013). Pramlintide was given FDA approval in 2005 for type 1 and type 2 diabetes, to improve postprandial glycemic control, in conjunction with prandial insulin treatment. There is currently inadequate information as to whether the baseline rate of gastric emptying predicts an individual patient’s response, however, in theory it seems reasonable to consider measuring gastric emptying in patients prior to commencing therapy, as pramlintide is unlikely to offer full therapeutic potential in those with slow gastric emptying at baseline. Further information in this area is required. 5.3.2. GLP-1 agonists GLP-1 agonists include ‘short-acting’ agents, comprising exenatide twice daily (exenatide BID), and lixisenatide (given daily) (Meier, 2012), and ‘long-acting’ agents, liraglutide (given daily), albiglutide (given weekly) and exenatide long-acting release (exenatide LAR, given weekly). These agents are resistant to dipeptidyl-peptidase-4 (DPP-4), the protease responsible for the short half-life (approximately 2–4 min) of GLP-1 in-vivo (Baggio & Drucker, 2007), and are administered parenterally. The GLP-1 agonists promote weight loss, and, as their insulinotropic action is glucose-dependent, carry a low risk of hypoglycemia when used in isolation, or with non-insulinsecretagogue treatment. The varying duration of action of available GLP-1 agonists translates into important pharmacodynamic differences within this therapeutic class. Comparisons of GLP-1 agonists in clinical trials demonstrate that the ‘short-acting’ agonists target postprandial glycemia, primarily through inhibition of gastric emptying (Owens, Monnier, & Bolli, 2013). In contrast, use of the ‘long-acting’ GLP-1 agonists appears to be associated with tachyphylaxis of the initial effect to slow gastric emptying (this phenomenon has clearly been demonstrated in relation to sustained exposure to exogenous GLP-1) (Nauck, Kemmeries, Holst, & Meier, 2011; Umapathysivam et al.,

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2014), and agents such as liraglutide and exenatide EQW primarily target fasting glycemia through insulinotropic and glucagonostatic mechanisms (Meier, 2012). The observations that i) co-administration of the prokinetic erythromycin reduces the ability of GLP-1 to lower postprandial glycemia (Meier, Kemmeries, Holst, & Nauck, 2005) and ii) postprandial insulin concentrations are dose-dependently reduced following administration of GLP-1 (Little et al., 2006), exenatide (Kolterman et al., 2003) and lixisenatide (Horowitz, Rayner, & Jones, 2013), despite improvement in glycemia, highlight the significance of the slowing of gastric emptying by ‘short-acting’ GLP-1 agonists. In addition, the magnitude of glucose lowering correlates with the degree of slowing of emptying (Linnebjerg et al., 2008), so that baseline gastric emptying is an important predictor of response (Deane et al., 2010). It follows, therefore, that the glucose-lowering potential of ‘short-acting’ GLP-1 agonists will be greatest in patients who have relatively normal or rapid emptying, while those with slow emptying are unlikely to experience substantial improvement in postprandial glycemia. Therefore, determination of the baseline gastric emptying rate prior to commencing therapy would seem helpful. Many clinical trials evaluating GLP-1 based treatments already include a ‘meal-test’, and the inclusion of a stable isotope would permit formal testing of this hypothesis. It is known that hyperglycemia attenuates the effect of prokinetic drugs on gastric emptying. 24 25 Whilst intuitively likely, it is unclear whether this phenomenon translates to medications that slow gastric emptying, such as the GLP-1 based therapies. This is an area that needs further exploration, particularly in light of the dependence of ‘short-acting’ GLP-1 agonists on gastric emptying for their effects to decrease postprandial glycemia. 5.3.3. Dipeptidyl-peptidase-4 (DPP-4) inhibitors Treatment with GLP-1 agonists induces supra-physiological concentrations of GLP-1. In contradistinction, the DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin and alogliptin) do not increase total GLP-1 concentrations above the physiological range, and their effect on gastric emptying appears minimal (Aulinger et al., 2014; Nonaka et al., 2013; Stevens et al., 2012; Vella et al., 2007). A recent study by our group did not identify any effect of sitaglitpin on gastric emptying (Stevens et al., 2012), however the rate of gastric emptying was an important determinant of glycemia in the presence of DPP4-inhibition. 5.3.4. Acarbose Acarbose, is an α-glucosidase and pancreatic α-amylase inhibitor — other drugs in this class are miglitol and voglibose. These agents target postprandial glycemia through the delay of carbohydrate absorption in the small intestine, slowing of gastric emptying, and stimulation of GLP-1 release (Enc et al., 2001). We have identified that although acarbose has a substantial effect on gastric emptying, with an approximate doubling of the percent of gastric meal retention at 3 h compared with control, effects on gastric emptying were not evident until 90 min following ingestion of a mixed-meal (Gentilcore et al., 2005). 5.4. Toward a personalized approach to therapy The information summarized above suggests that ‘short-acting’ GLP-1 agonists may be an appropriate ‘personalized’ treatment approach in patients with relatively well-controlled diabetes, in whom improved prandial control is desired. In this setting, the baseline gastric emptying rate would need be relatively preserved, and the patient willing to inject 1–2 times a day. Of note, exenatide administered twice daily offers postprandial control following breakfast and dinner, with a lesser effect on lunchtime glycemia (Meier, 2012), while lixisenatide given in the morning may have a lesser effect on post-dinner glycemic control. Patient sub-groups that may benefit from this approach include those with ‘early’ type 2


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diabetes, and type 2 diabetes on basal insulin. In contrast, in a patient with relatively delayed baseline gastric emptying, or in whom fasting glycemia is a particular target, a ‘long-acting’ agent is likely to be more appropriate. Furthermore, it is likely that ‘short-acting’ GLP-1 agonists would retain efficacy in the setting of progressive β cell failure, while a reduction in therapeutic effect would be anticipated with the use of ‘long-acting’ agents. The differences between therapeutic profiles of ‘short’ and ‘long’ acting GLP-1 agonists may also translate into differential adverse effect profiles. The rate of nausea and vomiting associated with initiation of GLP-1 agonists is somewhat greater for ‘short-acting’ GLP1 agonists than ‘long-acting’ GLP-1 agonists (approximately 20%–50% vs. 20%–40%, respectively) (Meier, 2012), and these symptoms appear less likely to resolve with ongoing use of the former (Meier, 2012). However, the upper gastrointestinal symptoms associated with GLP-1 agonists have largely been assessed by self-report, rather than with the use of validated instruments. Diarrhea is also associated with GLP1 agonist treatment, occurring in approximately 10%–20% of patients and appears to be more common in those on ‘long-acting’ GLP-1 agonists (Meier, 2012). There have been some case reports of the occurrence of pancreatitis associated with exenatide and other GLP-1 agonists, although an elevated risk for pancreatitis with GLP-1 agonists has not been evident in phase 2 and phase 3 clinical trials (Meier, 2012). Determination of any elevated risk of pancreatitis associated with treatment is complicated by the observation that baseline risk of this condition is elevated 2–3 fold in patients with type 2 diabetes (Noel, Braun, Patterson, & Bloomgren, 2009). There does not appear to be an increased risk of pancreatic cancer associated with the use of GLP-1 based therapy (Meier, 2012). The insulinotropic effects of GLP-1 are glucose-dependent, however, issues with hypoglycemia may arise when these agents are used in conjunction with insulin-secretagogue therapy, or insulin. We have recently demonstrated that acute administration of exogenous GLP-1 attenuates the acceleration of gastric emptying in healthy subjects following insulin-induced hypoglycemia (Plummer et al., 2014); problematic hypoglycemia is therefore a theoretical concern in patients treated with insulin or secretagogue therapy (Vinik et al., 2008), although, unlike type 1 diabetes, the majority of type 2 patients have an intact glucagon response to hypoglycemia. To date hypoglycemia has not been a substantial issue in clinical trials — post-marketing data with real life experience outside the clinical trial setting may provide more information on this issue. Although there has been a case-report of a recurrent gastric bezoar in a patient treated with GLP-1 agonist therapy (Ahmad & Swann, 2008), there have otherwise been minimal serious gastrointestinal safety concerns with any of the GLP-1 agonists to date. While it is likely that GLP-1 agonists will not slow gastric emptying significantly in patients with gastroparesis, this should be evaluated.

6. Recommendations: clinical vs. research settings Although there are preliminary data to support the concept of individualizing therapies based on known pharmacodynamics differences between different GLP-1 agonists, more information is required. In order to identify patient characteristics which will predict response with a particular agent, trials evaluating these therapies should measure and document gastric emptying at baseline, and again when stabilized on treatment. Furthermore, postprandial glycemic effects should be assessed routinely. There are also clear implications for the potential use of GLP-1 agonists in the management of type 1 diabetes, where slowing of gastric emptying in addition to glucagon suppression, may be useful. Gastric emptying in the research setting could be evaluated either with scintigraphy or with a validated breath test; the latter poses fewer logistical issues. Clinical practice can then follow from research data, with treatment indications based on sound evidence.

7. Conclusions Gastric emptying is a critical determinant of postprandial glycemia, and even modest alterations in the rate of carbohydrate entry into the small intestine may impact substantially on postprandial glucose excursions. Furthermore, acute blood glucose concentrations affect gastric motility, even within the physiological range. This complex, inter-dependent relationship is of increasing clinical relevance in the management of diabetes, given the emergence of agents that modulate gastric emptying for therapeutic effect. In particular, the ‘short-acting’ GLP-1 agonists have highlighted the importance of gastric emptying in the management of diabetes. The gold standard for measurement of gastric emptying is scintigraphy, however a number of other techniques are available. The breath test technique, in particular, holds promise as a validated alternative method applicable to widespread use in an officebased setting. The increased appreciation of the role of gastric emptying as a determinant of glycemia and a therapeutic target in diabetes demands a re-evaluation of the role of measurement of gastric emptying in diabetes. In addition to ‘traditional indications’, measurement of gastric emptying should be considered in patients with recurrent, unexplained hypoglycemia and difficult to control hyperglycemia. Although there is insufficient evidence to routinely recommend gastric emptying studies in all patients commencing GLP-1 agonists, there is evidence that selection of these agents could be ‘personalized’ according to baseline gastric emptying and glycemic profiles, although more information about potential predictors of treatment success is required. Acknowledgements Much of the authors’ work in this area has been funded the National Health Medical and Research Council of Australia. References Abell, T. L., Camilleri, M., Donohoe, K., Hasler, W. L., Lin, H. C., Maurer, A. H., et al. (2008). Consensus recommendations for gastric emptying scintigraphy: A joint report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Journal of Nuclear Medicine Technology, 36(1), 44–54 (PubMed PMID: 18287197. Epub 2008/02/22. Eng). Ahmad, S. R., & Swann, J. (2008). Exenatide and rare adverse events. New England Journal of Medicine, 358(18), 1970–1971 (discussion 1–2, PubMed PMID: 18456920). Ariga, H., Imai, K., Chen, C., Mantyh, C., Pappas, T. N., & Takahashi, T. (2008). Does ghrelin explain accelerated gastric emptying in the early stages of diabetes mellitus? American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 294(6), R1807–R1812 (PubMed PMID: 18385464). Aulinger, B. A., Bedorf, A., Kutscherauer, G., de Heer, J., Holst, J. J., Goke, B., et al. (2014). Defining the role of GLP-1 in the enteroinsulinar axis in type 2 diabetes using DPP-4 inhibition and GLP-1 receptor blockade. Diabetes, 63(3), 1079–1092 (PubMed PMID: 24296715). Baggio, L. L., & Drucker, D. J. (2007). Biology of incretins: GLP-1 and GIP. Gastroenterology, 132(6), 2131–2157 (PubMed PMID: 17498508. Epub 2007/05/ 15. Eng). Benini, L., Castellani, G., Brighenti, F., Heaton, K. W., Brentegani, M. T., Casiraghi, M. C., et al. (1995). Gastric emptying of a solid meal is accelerated by the removal of dietary fibre naturally present in food. Gut, 36(6), 825–830 (PubMed PMID: 7615267. Pubmed Central PMCID: 1382616). Bharucha, A. E., Camilleri, M., Forstrom, L. A., & Zinsmeister, A. R. (2009). Relationship between clinical features and gastric emptying disturbances in diabetes mellitus. Clinical Endocrinology, 70(3), 415–420 (PubMed PMID: 18727706. Pubmed Central PMCID: 3899345). Brener, W., Hendrix, T. R., & McHugh, P. R. (1983). Regulation of the gastric emptying of glucose. Gastroenterology, 85(1), 76–82 (PubMed PMID: 6852464). Camilleri, M. (2007). Clinical practice. Diabetic gastroparesis. New England Journal of Medicine, 356(8), 820–829 (PubMed PMID: 17314341). Camilleri, M., Parkman, H. P., Shafi, M. A., Abell, T. L., & Gerson, L. (2013). American College of G. clinical guideline: Management of gastroparesis. American Journal of Gastroenterology, 108(1), 18–37 (quiz 8. PubMed PMID: 23147521. Pubmed Central PMCID: 3722580. Epub 2012/11/14. eng). Cassilly, D., Kantor, S., Knight, L. C., Maurer, A. H., Fisher, R. S., Semler, J., et al. (2008). Gastric emptying of a non-digestible solid: Assessment with simultaneous SmartPill pH and pressure capsule, antroduodenal manometry, gastric emptying


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Measurement of gastric emptying by magnetic resonance imaging in humans.

Solid food label for measurement of gastric emptying.

Gastric emptying in newborns and young infants. Measurement of the rate of emptying using indium-113m-microcolloid.

Models of gastric emptying.

Continuous gastric pH monitoring in children: the effect of gastric emptying on the measurement of gastric acid secretion.

Letter: Gastric emptying in labour.

Gastric emptying tests in man.

Gastric emptying in coeliac disease.

Peripartum changes in gastric emptying.

Simultaneous measurement of antroduodenal motility, gastric emptying, and duodenogastric reflux in man.

Gastric emptying in infants and children: limited utility of 1-hour measurement.

Gastric emptying after gastric pull-up.

Postoperative gastric retention and delaying gastric emptying.

Cytomegalovirus infection and gastric emptying.

Measurement of gastric emptying time--a comparative study between nonisotopic aspiration method and new radioisotopic technique.

Gastric emptying, fibre, and absorption.

Delayed gastric emptying following gastrectomy.

Gastric emptying following Colles' fracture.

Serotonin, gastric emptying, and dyspepsia.

Gastric emptying of hypertonic glucose in diabetes mellitus and duodenal ulcer.

Serotonin, gastric emptying, and dyspepsia.

Relationship Between Control of Glycemia and Gastric Emptying Disturbances in Diabetes Mellitus.

Differing effects of liraglutide on gastric emptying in Japanese patients with type 2 diabetes.

Gastric emptying in patients with fundal gastritis and gastric cancer.