Diabetic gastroparesis (Gp) is commonly thought to occur primarily in patients with type 1 diabetes mellitus (T1DM) along with other end-organ complications of diabetes including peripheral neuropathy, nephropathy, and retinopathy (1). Taken together, these 3 complications are termed “diabetic triopathy.” Gp is also recognized in patients with type 2 diabetes mellitus (T2DM) who are more prevalent than patients with T1DM. In a single center study, manifestations of diabetic triopathy (peripheral neuropathy, nephropathy, and retinopathy) were uncommon in diabetic patients (both T1DM and T2DM) with upper gastrointestinal (UGI) symptoms (2).
Gastric emptying (GE) in response to eating is a regulated process involving gastric accommodation, antral contractility, and pyloric relaxation (3). Gastric accommodation is, in part, a vagally mediated reflex occurring with meal ingestion. Up to half of patients with Gp have decreased gastric accommodation in response to satiety testing (4,5).
Diabetic Gp is associated with loss of interstitial cells of Cajals (ICCs), reduction of nerves, and inflammatory infiltrate (6). Vagal dysfunction has been shown in diabetic Gp by abnormal pancreatic polypeptide test (7). Vagal dysfunction can also be detected using autonomic function tests and on electrocardiograms by lack of R-R respiratory variation (8). In the Diabetes Control and Complications Trial, delayed GE was associated with greater HgbA1c, longer duration of diabetes, lower R-R variability, nephropathy, retinopathy, and greater gastrointestinal symptoms (9).
This study aims to determine the prevalence of diabetic complications (retinopathy, nephropathy, and peripheral neuropathy) in diabetic patients with symptoms of Gp, assessing whether there are differences between T1DM and T2DM and between delayed and normal GE. This will address whether delayed GE correlates with other diabetic end-organ damage.
The National Institute of Health Gastroparesis Clinical Research Consortium Gastroparesis Registry 2 (ClinicalTrials.gov Identifier: National Clinical Trial: NCT01696747) was implemented as an observational study of patients with symptoms of Gp (4). Entry criteria were aged 18 years or older with at least 12-week duration of symptoms, GE scintigraphy (GES), and without structural abnormalities on upper endoscopy. Patients were enrolled at 7 centers from September 2012 to March 2018. Patients with delayed GE and those with normal emptying were enrolled. Informed consent was obtained before screening participants for enrollment into the study. Patients could have had a previous upper endoscopy, blood work, or GE test for clinical purposes before signing the consent form. Patients underwent history and physical examination, GES, autonomic function testing, electrogastrography (EGG) with water load testing, and questionnaires assessing symptoms. Peripheral neuropathy was assessed by history and questionnaire; nephropathy by history and blood measurements of creatinine (Cr); retinopathy by history; autonomic dysfunction by autonomic function testing, vagal dysfunction by water load satiety test (WLST), and enteric ICC dysfunction by EGG. This study evaluated patients with diabetes, either T1DM or T2DM, as defined by the patient and physician.
During interviews with the subjects, study physicians or coordinators completed case report forms capturing Gp disease onset, symptoms, disease profile, associated medical and surgical conditions, including diabetes, and therapies (10). Patients were asked questions to help differentiate T1DM from T2DM (age at the onset of diabetes, weight at the time of diagnosis of diabetes, initial treatment of diabetes, current treatment of diabetes, and previous episodes of diabetic ketoacidosis). Patients were asked about complications of diabetes including retinopathy, previous laser eye treatment, nephropathy, and peripheral neuropathy. Laboratory measures included complete metabolic panel, complete blood count, HbA1c, erythrocyte sedimentation rate, C-reactive protein, and vitamin B12 level.
Patients filled out Patient Assessment of Upper Gastrointestinal Symptoms questionnaire assessing symptoms of Gp, dyspepsia, and gastroesophageal reflux disease (11) which includes symptoms of Gastroparesis Cardinal Symptom Index (GCSI) (12).
Neuropathy Total Symptom Score-6 (NTSS-6) questionnaire (13) was used to evaluate the frequency and intensity of neuropathy sensory symptoms of diabetic peripheral neuropathy. NTSS-6 score of >6 suggests diabetic peripheral neuropathy.
Disease-specific quality of life was assessed using Patient Assessment of Upper Gastrointestinal Disorders Quality of Life (14). The Medical Outcomes Study 36-Item Short-Form Health Survey version 2 (SF-36v2) assessed overall physical and mental health (15). Depression was assessed with Beck Depression Index (16) and anxiety with State-Trait Anxiety Inventory (17).
GES was performed using a low-fat egg white meal with 4-hour imaging after meal ingestion (18,19). Diabetic patients had glucose levels checked to ensure it is <270 mg/dL. Gastric retention of technetium-99 m >60% at 2 hours and/or >10% at 4 hours was considered evidence of delayed GE of solids.
EGG with water load testing.
EGG with WLST of noncaloric liquid water, a standardized test to induce gastric distension and gastric responses (20), was performed. After overnight fast and checking blood glucose at <270 gm/dL, the subjects underwent cutaneous EGG (3CPM Company, Towson, MD) (20,21) with 15 minutes of baseline EGG recording, followed by water load test, ingesting water until they achieved the sensation of “completely full” during a 5-minute period (20). The volume of ingested water was recorded (normal >238 mL (21). EGG was recorded for another 30 minutes.
The percentage distribution of gastric myoelectric activity power in 4 frequency ranges, normal (2.5–3.5 cpm), tachygastria (3.5–10 cpm), bradygastria (1–2.5 cpm), and duodenal respiration (10–15 cpm), was averaged for time 0 (before meal ingestion) and 10-minute periods after water load.
Autonomic function testing.
Autonomic function testing was performed using ANX 3.0 autonomic monitoring system (ANSAR Medical Technologies, Philadelphia, PA) (22,23), measuring both branches of cardiovagal autonomic nervous system using simultaneous spectral analysis of heart rate variability (HRV) and respiratory activity. The 15-minute recording includes 5 minutes of rest, 1 minute of deep breathing (parasympathetic challenge), 1 minute of short Valsalva maneuvers (sympathetic challenge), followed by rapid stand and then 5 minutes of standing quietly (sympathetic and parasympathetic challenge). Each challenge is separated by a 1-minute period of return to baseline. HRV and respiratory activity were measured concurrently with analyses performed independently and simultaneously to compute parasympathetic and sympathetic activity. HRV was computed measuring beat to beat R-R intervals, whereas respiratory activity was recorded using impedance plethysmography.
Baseline patient characteristics were compared by the presence of T1DM vs T2DM, the presence of delayed GE vs not delayed, the presence of peripheral neuropathy or not, the presence of retinopathy or not, and the presence of nephropathy or not. Data are presented as means (SD) for normally distributed variables, median (interquartile range) for variables with non-normal distributions, or n (%) for categorical measures. P values were determined by 2-sample t tests for normally distributed continuous measures, Wilcoxon rank-sum test for skewed continuous measures, and Fisher's exact test for categorical measures (24). We compared baseline characteristics by increasing the degrees of gastric retention at 4 hours (≤10%, >10% to ≤25%, >25% to ≤40%, and >40%) and by the number of triopathies present (0, 1, 2, and 3), with trend P values presented. A multivariable logistic regression model for outcome of delayed GE (yes/no) assessed independent associations of diabetic complications, adjusting for diabetes type (T1DM vs T2DM), diabetes duration, gender, and age. Two-sided P values were considered statistically significant if P < 0.05. Analyses were performed using SAS software (version 9.4; SAS Institute, Cary, NC) and Stata (Release 15.1; Stata Corporation, College Station, TX) (25,26).
There were 158 diabetic patients in GpR2. Five patients had previous fundoplication, and 20 patients had diabetes develop after Gp diagnosis; these patients were excluded from the analysis, leaving a total of 133 patients with symptoms of Gp after development of their diabetes.
One hundred thirty-three diabetic patients (59 with T1DM and 74 with T2DM and 103 with delayed GE and 30 without delayed) with symptoms of Gp were studied (Table 1). Average age was 48.3 years, with 76% being female participants. Average body mass index was 30.8 kg/m2.
The duration of diabetes averaged 17.6 years, being greater in T1DM than in T2DM (22.2 vs 15.5 years; P < 0.001). The duration from diabetes diagnosis to the onset of Gp symptoms was 12.0 years, being longer for T1DM than for T2DM (13.8 vs 11.7; P = 0.03). At enrollment into registry, the duration of Gp symptoms averaged 3.8 years, being longer in T1DM than in T2DM (4.7 vs 3.1 years; P = 0.003). GCSI total score averaged 2.6 and was greater in T1DM than in T2DM (2.8 vs 2.4; P = 0.04) along with higher bloating subscore (3.0 vs 2.4; P = 0.04). HgbA1c averaged 8.3%, which was greater in T1DM than in T2DM (8.8% vs 8.0%; P = 0.01).
In these diabetic patients with symptoms of Gp, history of retinopathy occurred in 30%, nephropathy in 14%, and peripheral neuropathy in 45% (Table 1). The presence of retinopathy (37% vs 24%; P = 0.13), nephropathy (19% vs 11%; P = 0.22), and peripheral neuropathy (53% vs 39%; P = 0.16) was not significantly higher in T1DM than in T2DM. Mean number of complications making up triopathies (retinopathy, nephropathy, and peripheral neuropathy) was greater in T1DM than in T2DM (1.1 vs 0.7; P = 0.04). Triopathies (a combination of retinopathy, nephropathy, and peripheral neuropathy) were seen in 10% of T1DM and 3% of T2DM (P = 0.04). At least one of the individual triopathies was seen in 56% of the diabetic patients in this study (64% for T1DM and 49% for T2DM; P = 0.05). For delayed vs not delayed emptying, 61% of patients with delayed GE have at least one of the individual triopathies, whereas 37% of patients without delay have one of the individual triopathies (P = 0.02).
Average score of the NTSS-6 for diabetic peripheral neuropathy was similar in both patients with T1DM and T2DM (7.8 vs 7.8; P = 0.99). There was also similar percentages of patients with NTSS-6 score of >6 (48% vs 49%; P = 1.00).
Table 2 shows the characteristics of patients by increasing number of complications making up triopathies present. Increasing number of triopathies in these diabetic patients was associated with higher prevalence of T1DM compared with T2DM (P = 0.046).
Overall, 103 diabetic patients had delayed GE (48 patients with T1DM and 55 with T2DM) and 30 had nondelayed GE (11 patients with T1DM and 19 with T2DM) (Table 3). Three of 30 patients with nondelayed GE had rapid GE and 27 had normal GE.
Diabetic patients with delayed GE had higher prevalence of retinopathy (36% vs 10%; P = 0.006) and higher proportion of peripheral neuropathy (50% vs 30%; P = 0.06) (Table 3). The number of diabetic complications was greater in delayed GE than in normal GE (1.0 vs 0.5; P = 0.009). Increasing number of triopathies present was associated with increased gastric retention at 2 hours (P = 0.005) and 4 hours (P = 0.008). Of note, 39% of the diabetic patients with delayed GE did not have any complications of diabetes.
Supplemental Table 1 (see Supplementary Digital Content 1, http://links.lww.com/AJG/B295) divides the patients by T1DM vs T2DM and then by the presence of delayed or normal GE. For both T1DM and T2DM, the presence of delayed GE was associated with an increase in the prevalence of retinopathy (P = 0.02) and an increase in the number of complications that make up the triopathies (P = 0.02)
Table 4 shows diabetic patients by increasing degrees of gastric retention at 4 hours. As gastric retention at 4 hours increased, the proportion of patients with retinopathy and peripheral neuropathy increased (P for trend = 0.002 and 0.02, respectively) and the mean number of triopathies increased (P for trend = 0.001).
Table 5 divides the patients by the presence of retinopathy. The presence of retinopathy was associated with greater duration of diabetes (23.7 vs 15.5 years; P < 0.001) and the duration between diabetes diagnosis and the onset of Gp symptoms (16.1 vs 11.0 years; P < 0.001). The presence of retinopathy was associated with increased gastric retention at 2 and 4 hours (P = 0.02 and 0.03, respectively). The presence of retinopathy was associated with the presence of neuropathy and nephropathy and higher NTSS-6 scores.
Table 6 describes the patients by the presence of nephropathy. The presence of nephropathy was associated with longer duration of diabetes (24.2 vs 17.1 years; P = 0.01) but not the duration of Gp symptoms (4.3 vs 3.8; P = 0.40). Nephropathy was associated with the presence of retinopathy (68% vs 24%; P < 0.001). Mean Cr was higher in patients with nephropathy than in those without nephropathy (1.7 vs 0.8 mg/dL; P < 0.001). Cr of the patients with delayed GE was not significantly different from that of the patients with normal GE (1.0 vs 0.9; P = 0.17).
Table 7 divides the patients by the presence or absence of peripheral neuropathy. The presence of peripheral neuropathy was associated with greater duration of diabetes (20.9 vs 15.8 years; P = 0.005) and the duration between diabetes diagnosis and the onset of Gp symptoms (13.7 vs 11.4 years; P = 0.006). NTSS-6 score was greater in patients with peripheral neuropathy by patient report (12.7 vs 3.7; P < 0.001) as well as the percentage of patients with NTSS-6 score of >6 (80% vs 23%; P < 0.001). The presence of peripheral neuropathy was associated with increased gastric retention at 2 hours (63.4% vs 54.2%, P = 0.04) and at 4 hours (38.4 vs 27.6; P = 0.07), and with the number of patients with Gp (85% vs 71%; P = 0.06).
Water load satiety testing
The volume ingested during WLST was similar in patients with T1DM and T2DM (Table 1), between those with delayed and normal GE (Table 3), between those with and without retinopathy (Table 5), between those with and without nephropathy (Table 6), and between those with and without peripheral neuropathy (Table 7).
EGG was assessed in fasting period and after the WLST (see Table 2, Supplementary Digital Content 1, http://links.lww.com/AJG/B295). Patients with delayed GE had higher baseline tachygastria and less bradygastria than patients with normal GE. There were no EGG changes when patients were compared by presence or absence of retinopathy, nephropathy, peripheral neuropathy.
Autonomic function testing
Compared with patients with T2DM, patients with T1DM had lower resting parasympathetic activity (P = 0.04) (see Table 3, Supplementary Digital Content, http://links.lww.com/AJG/B295). Challenge, but not resting parasympathetic excess, was more prevalent in patients with delayed GE (34% vs 10%; P = 0.02). As the percentage of retention at 4 hours increased, there was a significantly greater percentage of patients with challenge parasympathetic excess (Table 4). Autonomic dysfunction was not associated with the number of triopathies or the type of diabetic complication, although patients with peripheral neuropathy had lower resting parasympathetic activity (0.3 vs 0.6; P = 0.05).
Multivariable logistic regression was performed for the independent factors associated with delayed GE (Table 8). The presence of retinopathy was significantly associated with delayed GE (odds ratio = 4.3; 95% confidence interval: 1.1–16.0; P = 0.03), controlling for diabetes type, duration, gender, and age.
This study demonstrates that in diabetic patients with symptoms of Gp, delayed GE was associated with the presence of retinopathy and the total number of diabetic complications. The presence of diabetic complications should raise awareness for Gp in diabetic patients either with T1DM or T2DM. Contrarily, Gp can occur without complications as most of the diabetic patients with Gp did not have a triopathy and 36% of diabetic patients with delayed GE had no complications.
Our study shows expected differences between patients with T1DM and T2DM. The duration of diabetes was greater in T1DM than in T2DM, and HgbA1c was greater in T1DM than in T2DM. The duration from diabetes diagnosis to the onset of Gp symptoms and the duration of Gp symptoms were also longer in T1DM than in T2DM. Although gastric retention during GES was not significantly different, the GCSI total score was greater in T1DM than in T2DM. Our previous studies have shown that gastric retention was greater in T1DM compared with idiopathic Gp (27). A subsequent study showed that baseline symptoms were similar in patients with T1DM and T2DM, even though patients with T1DM had worse GE delays and higher HbA1c (28). Similar to our study, Chedid et al. also found that symptomatic patients with T1DM had longer duration of disease before gastric motility evaluation than patients with T2DM; however, duration and glycemic control based on the most recent HbA1c in the past year were not significantly associated with abnormal gastric motor functions (2).
Defining, diagnosing, and treating diabetic Gp can be a challenge (29). Up to 75% of diabetic patients may experience gastrointestinal symptoms to some degree (30). Some patients with symptoms of Gp can have normal GE (31). Hyperglycemia may affect GE results; hyperglycemia can delay GE (32). Diabetic Gp patients have increased mortality compared with other diabetic patients, and this might reflect their associated complications from diabetes or associated comorbidities, such as cardiovascular disease (33-35).
Our study showed that diabetic patients with delayed GE had increased prevalence of retinopathy and number of diabetic complications compared with diabetic patients with normal GE. Increasing number of triopathies present was associated with increased gastric retention at 2 and 4 hours. In a study from Denmark, patients with T1DM having symptoms of Gp had more retinopathy, peripheral polyneuropathy, and nephropathy (36). In the Diabetes Control and Complications Trial trial, delayed GE was associated with greater baseline HbA1c, duration of diabetes, lower R-R variability during deep breathing, severe nephropathy, and a greater symptoms score; in multivariable analysis, retinopathy was the only DM complication associated with delayed GE (9).
Of the diabetic patients with delayed GE, retinopathy occurred in 36%, nephropathy in 16%, and peripheral neuropathy in 50%, with triopathy (all 3 together) in 7%. Interestingly, 36% of diabetic patients with delayed GE had no complications. Thus, although the presence of diabetic complications should raise awareness for pursuing Gp in either T1DM or T2DM, diabetic Gp frequently occurs without other diabetic complications. Manifestations of diabetic triopathy (peripheral neuropathy, nephropathy, and retinopathy) were also uncommon in a Mayo Clinic study assessing UGI symptoms and gastric motor function in diabetic patients (2).
Our study also shows that Gp symptoms can occur in diabetic patients without delayed GE. This is pointed out in a previous article of our GpC (31). GE looks at overall GE. Abnormalities in fundic accommodation, gastric dysrhythmias, and other abnormalities may contribute to the genesis of Gp symptoms in some individuals.
This study used water load as an indirect assessment of gastric accommodation, a reflex that is, in part, vagally mediated. Volumes of water ingested were similar between patients with T1DM and T2DM, between patients with delayed and normal GE, and between those with and without peripheral neuropathy, retinopathy, or nephropathy. Studies from the Mayo Clinic showed that abnormal gastric accommodation was present in 39% of patients with diabetes with UGI symptoms, whereas 28% had normal GE and accommodation (2).
EGG was used as an indirect measure of ICC function (20,37). Patients with delayed GE had higher baseline tachygastria and less bradygastria than patients with normal GE. Other studies have also suggested that EGG abnormalities are present in patients with delayed GE (38). Specifically, patients with Gp often have gastric dysrhythmias and a lack of increase in amplitude or power of the EGG signal with ingestion (38). In patients with Gp, a variety of gastric dysrhythmias, including tachygastrias, have been recorded when ICCs were depleted (39). There were no EGG differences when patients were compared by the presence or absence of retinopathy, nephropathy, or peripheral neuropathy.
Using autonomic function testing, challenge parasympathetic excess, but not resting parasympathetic excess, was more prevalent in diabetic patients with delayed GE but not associated with the number of triopathies or the type of diabetic complication. Challenge parasympathetic excess is an abnormality of the parasympathetic nervous system associated with standing or Valsalva (22,23). In other studies, vagal cholinergics were found to be affected to a greater degree in diabetic compared with idiopathic Gp (33). This agrees with studies showing abnormal pancreatic polypeptide tests suggesting vagal dysfunction in diabetic Gp but not in idiopathic Gp (7).
Whether there is a biologic mechanistic explanation for the specific association between delayed GE and retinopathy but not with the peripheral neuropathy or nephropathy is not clear. Neurologic damage has been thought to be the most important contributor to gastric dysfunction in diabetic patients. Gp is associated with vagal neuropathy and abnormalities in the enteric nervous system: loss of neuronal nitric oxide synthase, loss of ICC, and an immune infiltrate (23,24). Microvascular complications are thought to relate to neuropathy, retinopathy, and kidney disease in diabetic patients. Our current Gastroparesis Clinical Research Consortium studies are looking at genetic factors and proteomics associated with Gp.
This study has strengths but also limitations. The patients enrolled were from several medical centers using consensus GE tests and validated questionnaires. There might be a bias in more severely affected diabetic patients are seen in the tertiary academic medical center. This study used patients' reports about their diabetic complications. Patients did not undergo fundoscopic examination for the detection of retinopathy, electromyographic studies for peripheral neuropathy, or urine collection for proteinuria or Cr clearance. Patients' knowledge of their complications coincided with other objective tests. The presence of peripheral neuropathy was associated with higher scores on NTSS-6 questionnaire. Patients' knowledge of having nephropathy was associated with a higher Cr level. The presence of retinopathy was associated with previous laser eye treatments. The study used a number of questionnaires; there may be recall bias in filling these out that pertain to past experiences.
In summary, this study demonstrates that in diabetic patients with symptoms of Gp, delayed GE was associated with the presence of retinopathy and the total number of diabetic complications in patients with either T1DM or T2DM. There are 3 important take-home messages from this study. First, delayed GE occurs in both patients with T1DM and T2DM. Second, the presence of diabetic complications should raise awareness for pursuing Gp in diabetic patients with either T1DM or T2DM. Third, diabetic Gp can occur without other diabetic complications.
CONFLICTS OF INTEREST
Guarantor of the article: Henry P. Parkman, MD.
Specific author contributions: H.P.P.: study conceptualization, patient recruitment, data interpretation, and writing manuscript. L.A.W.: statistical analysis, data interpretation, and writing manuscript. G.F.: study conceptualization and revising manuscript. K.L.K., W.L.H., L.A.N., T.L.A., W.J.S.: study conceptualization, patient recruitment, and revising manuscript. J.C., B.K.: patient recruitment and revising manuscript. R.W.M., I.S.: study conceptualization, patient recruitment, and revising manuscript. M.G., L.M.: study conceptualization and revising manuscript. J.T.: study conceptualization, statistical analysis, data interpretation, and revising manuscript. F.A.H.: study conceptualization and revising manuscript. P.J.P.: study conceptualization, patient recruitment, and revising manuscript.
Financial support: The National Institute of Health/NIDDK Gastroparesis Clinical Research Consortium is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK073975 [Parkman], U01DK073983 [Pasricha], U01DK074007 [Abell], U01DK073974 [Koch], U01DK074035 [McCallum], U01DK112193 [Kuo], and U01DK074008 [Tonascia]).
Potential competing interests: None to report.
WHAT IS KNOWN
- ✓ Gp occurs more often in T1DM than in T2DM.
- ✓ Other diabetic end-organ complications include peripheral neuropathy, nephropathy, and retinopathy (together termed triopathy).
- ✓ How delayed GE associates with other end-organ complications in T1DM and T2DM is not clear.
WHAT IS NEW HERE
- ✓ In diabetic patients with symptoms of Gp, delayed GE was associated with the presence of retinopathy and the total number of diabetic complications. Only 10% of patients with T1DM and 3% of those with T2DM having Gp had triopathy of complications.
- ✓ Thirty-nine percent of diabetic patients with delayed GE did not have other diabetic complications.
- ✓ The presence of diabetic complications should raise awareness for Gp in either patients with T1DM or T2DM. However, Gp can still occur without other diabetic complications.
1. Parkman HP, Hasler WL, Fisher RS. American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology 2004;127:1592–622.
2. Chedid V, Brandler J, Vijayvargiya P, et al. Characterization of upper gastrointestinal symptoms, gastric motor functions and associations in patients with diabetes at a referral center. Am J Gastroenterol 2019;114:143–54.
3. Parkman HP, Jones MP. Tests of gastric neuromuscular function. Gastroenterology 2009;136:1526–43.
4. Parkman HP, Hallinan EK, Hasler WL, et al; NIDDK Gastroparesis Clinical Research Consortium (GpCRC). Early satiety and postprandial fullness in gastroparesis correlate with gastroparesis severity, gastric emptying, and water load testing. Neurogastroenterol Motil 2017;29. doi: 10.1111/nmo.12981.
5. Koch KL, Hasler WL, Van Natta M, et al. Satiety testing in diabetic gastroparesis: Effects of insulin pump therapy with continuous glucose monitoring on upper gastrointestinal symptoms and gastric myoelectrical activity. Gastroenterology 2017;152:S-–272.
6. Grover M, Farrugia G, Lurken MS, et al; NIDDK Gastroparesis Clinical Research Consortium. Cellular changes in diabetic and idiopathic gastroparesis. Gastroenterology 2011;140(5):1575–85.
7. Gaddipati KV, Simonian HP, Kresge KM, et al. Abnormal ghrelin and pancreatic polypeptide responses in gastroparesis. Dig Dis Sci 2006;51:1339–46.
8. Park SY, Acosta A, Camilleri M, et al. Gastric motor dysfunction in patients with functional gastroduodenal symptoms. Am J Gastroenterol 2017;112:1689–99.
9. Bharucha AE, Batey-Schaefer B, Cleary PA, et al. Delayed gastric emptying is associated with early and long-term hyperglycemia in type 1 diabetes mellitus. Gastroenterology 2015;149:330–9.
10. Abell TL, Bernstein VK, Cutts T, et al. Treatment of gastroparesis: A multidisciplinary clinical review. Neurogastroenterol Motil 2006;18:263–83.
11. Rentz AM, Kahrilas P, Stanghellini V, et al. Development and psychometric evaluation of the patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) in patients with upper gastrointestinal disorders. Qual Life Res 2004;13:1737–49.
12. Revicki DA, Rentz AM, Dubois D, et al. Development and validation of a patient-assessed gastroparesis symptom severity measure: The gastroparesis cardinal symptom index. Aliment Pharmacol Ther 2003;18:141–50.
13. Bastyr EJ III, Price KL, Bril V. MBBQ Study Group. Development and validity testing of the neuropathy total symptom score-6: Questionnaire for the study of sensory symptoms of diabetic peripheral neuropathy. Clin Ther 2005;27:1278–94.
14. de la Loge C, Trudeau E, Marquis P, et al. Cross-cultural development and validation of a patient self-administered questionnaire to assess quality of life in upper gastrointestinal disorders: The PAGI-QOL. Qual Life Res 2004;13:1751–62.
15. Ware JE, Kosinski M, Dewey JE. How to Score Version 2 of the SF-36® Health Survey. QualityMetric Incorporated: Lincoln, RI, 2000.
16. Beck AT, Steer RA, Ball R, et al. Comparison of Beck depression inventories -IA and -II in psychiatric outpatients. J Pers Assess 1996;67:588–97.
17. Spielberger C, Gorsuch R, Lushene R. Manual for the State-Trait Anxiety Inventory. Consulting Psychologists Press: Palo Alto, CA, 1970.
18. Tougas G, Eaker EY, Abell TL, et al. Assessment of gastric emptying using a low fat meal: Establishment of international control values. Am J Gastroenterol 2000;95:1456–62.
19. Abell TL, Camilleri M, Donohoe K, et al. Consensus recommendations for gastric emptying scintigraphy. Am J Gastro 2008;103:753–63.
20. Koch KL, Hong SP, Xu L. Reproducibility of gastric myoelectrical activity and the water load test in patients with dysmotility-like dyspepsia symptoms and in control subjects. J Clin Gastroenterol 2000;31:125–9.
21. Koch KL. Electrogastrography for evaluation of patients with suspected gastroparesis. In: Parkman H, McCallum R (eds). Gastroparesis: Pathophysiology, Presentation, Diagnosis and Treatment. Springer: New York, NY, 2011, pp 153–61.
22. Colombo J, Shoemaker WC, Belzberg H, et al. Noninvasive monitoring of the autonomic nervous system and hemodynamics of patients with blunt and penetrating trauma. J Trauma 2008;65:1364–73.
23. Nguyen L, Wilson LA, Miriel L, et al. Autonomic function in gastroparesis and chronic unexplained nausea and vomiting: relationship with etiology, gastric emptying and symptom severity. Gastroenterology 2017;152:S-–276.
24. Agresti A. Categorical Data Analysis. John Wiley & Sons, Inc.: New York, NY, 1990.
25. SAS Institute, Inc. SAS software, version 9.3 of the SAS system for Windows. SAS Institute, Inc: Cary, NC, 2002–2010.
26. StataCorp. Stata Statistical Software: Release 12. College Station, TX: StataCorp LP: 2011.
27. Parkman HP, Yates K, Hasler WL, et al; National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium. Similarities and differences between diabetic and idiopathic gastroparesis. Clin Gastroenterol Hepatol 2011;9:1056–64.
28. Koch KL, Hasler WL, Yates KP, et al; NIDDK Gastroparesis Clinical Research Consortium (GpCRC). Baseline features and differences in 48 week clinical outcomes in patients with gastroparesis and type 1 vs type 2 diabetes. Neurogastroenterol Motil 2016;28:1001–15.
29. Angeli TR, O'Grady G. Challenges in defining, diagnosing, and treating diabetic gastroparesis. J Diabetes Complicat 2018;32:127–8.
30. Schvarcz E, Palmér M, Ingberg CM, et al. Increased prevalence of upper gastrointestinal symptoms in long-term type 1 diabetes mellitus. Diabet Med 1996;13:478–81.
31. Pasricha PJ, Colvin R, Yates K, et al. Characteristics of patients with chronic unexplained nausea and vomiting and normal gastric emptying. Clin Gastroenterol Hepatol 2011;9:567–76.
32. Kong MF, Horowitz M. Gastric emptying in diabetes mellitus: Relationship to blood-glucose control. Clin Geriatr Med 1999;15:321–38.
33. Mohammad MK, Pepper DJ, Kedar A, et al. Measures of autonomic dysfunction in diabetic and idiopathic gastroparesis. Gastroenterol Res 2016;9:65–9.
34. Hyett B, Martinez FJ, Gill BM, et al. Delayed radionucleotide gastric emptying studies predict morbidity in diabetics with symptoms of gastroparesis. Gastroenterology 2009;137:445–52.
35. Shada A, Nielsen A, Marowski S, et al. Wisconsin's enterra therapy experience: A multi-institutional review of gastric electrical stimulation for medically refractory gastroparesis. Surgery 2018;164(4):760–5.
36. Kofod-Andersen K, Tarnow L. Prevalence of gastroparesis-related symptoms in an unselected cohort of patients with Type I diabetes. J Diabetes Complications 2012;26:89–93.
37. O'Grady G, Wang TH, Du P, et al. Recent progress in gastric arrhythmia: Pathophysiology, clinical significance and future horizons. Clin Exp Pharmacol Physiol 2014;41:854–62.
38. Parkman HP, Hasler WL, Barnett JL, et al; American motility Society clinical GI motility testing task force. Electrogastrography: A document prepared by the gastric section of the American motility Society clinical GI motility testing task force. Neurogastroenterol Motil 2003;15:89–102.
39. O'Grady G, Angeli T, Du P, et al. Abnormal initiation and conduction of slow-wave activity in gastroparesis, defined by high-resolution electrical mapping. Gastroenterology 2012;143:589–98.