Low Vitamin D Levels in Patients with Symptoms of Gastroparesis: Relationships with Nausea and Vomiting, Gastric Emptying and Gastric Myoelectrical Activity.

Patients with gastroparesis (Gp) often have diets deficient in calories, electrolytes, and vitamins. Vitamin D levels have been reported to be low in some patients with Gp but has not been systematically studied. AIMS: To determine vitamin D levels and relationships among symptoms, gastric emptying and gastric myoelectrical activity (GMA) in patients with symptoms of Gp. METHODS: 25-hydroxy-vitamin D was measured in patients at enrollment in the Gastroparesis Clinical Consortium Registry. Gastroparesis Cardinal Symptoms Index (GCSI), gastric emptying, and GMA before and after water load satiety test (WLST) were measured. GMA, expressed as percentage distribution of activity in normal and dysrhythmic ranges, was recorded using electrogastrography. RESULTS: Overall, vitamin D levels were low (< 30 ng/ml) in 288 of 513 (56.1%) patients with symptoms of Gp (206 of 376 (54.8%) patients with delayed gastric emptying (Gp) and 82 of 137 (59.9%) patients with symptoms of Gp and normal gastric emptying). Low vitamin D levels were associated with increased nausea and vomiting (P < 0.0001), but not with fullness or bloating subscores. Low vitamin D levels in patients with Gp were associated with greater meal retention at four hours (36% retention) compared with Gp patients with normal vitamin D levels (31% retention; P = 0.05). Low vitamin D in patients with normal gastric emptying was associated with decreased normal 3 cpm GMA before (P = 0.001) and increased tachygastria after WLST (P = 0.01). CONCLUSIONS: Low vitamin D levels are present in half the patients with symptoms of gastroparesis and are associated with nausea and vomiting and gastric neuromuscular dysfunction.

Pathophysiology of Gastroparesis Syndromes Includes Anatomic and Physiologic Abnormalities.

BACKGROUND: Factors underlying gastroparesis are not well defined. AIMS: We hypothesized that multiple systems may be involved in patients with gastroparesis symptoms and performed a comparative physiologic study. METHODS: We studied 43 consecutive eligible patients with gastroparetic symptoms categorized by GI symptoms, metabolic status, illness quantification, and gastric physiology. Patients were evaluated by two methods in each of five core areas: inflammatory, autonomic, enteric, electrophysiologic, and hormonal with abnormalities examined by correlations. RESULTS: Patients had similar GI symptoms regardless of baseline gastric emptying or diabetic/idiopathic status, and all patients demonstrated abnormalities in each of the 5 areas studied. Nearly all patients presented with elevated markers of serum TNFα (88%) and serum IL-6 (91%); elevated cutaneous electrogastrogram frequency (95%); and interstitial cells of Cajal count abnormalities (inner: 97%, outer: 100%). Measures of inflammation correlated with a number of autonomic, enteric anatomy, electrophysiologic and hormonal abnormalities. CONCLUSIONS: We conclude that patients with the symptoms of gastroparesis have multiple abnormalities, when studied by traditional, as well as newer, diagnostic assessments. Inflammation appears to be a fundamental abnormality that affects other organ systems in symptomatic patients. Future work on gastroparetic syndromes and their treatment may benefit from a focus on the diffuse nature of their illness, diverse pathophysiologic mechanisms involved, especially the possible causes of underlying inflammation and disordered hormonal status. TRAIL REGISTRY: This study is registered with Clinicaltrials.gov under study # NCT03178370 https://clinicaltrials.gov/ct2/show/NCT03178370 .

Diabetic Gastroparesis and Glycaemic Control.

PURPOSE OF REVIEW: Gastroparesis is an important complication of diabetes that may have a major impact on the quality of life as a result of upper gastrointestinal symptoms and impaired glycaemic control. Current management strategies include optimising blood glucose control, dietary modifications and supportive nutrition. Pharmacologic approaches with drugs that have prokinetic and/or antiemetic effects are also used widely; however, current available treatments have major limitations. There is increasing recognition that the rate of gastric emptying (GE) is a key determinant of the glycaemic response to a meal. RECENT FINDINGS: There is ongoing uncertainty regarding the impact of longstanding hyperglycaemia on GE, which requires clarification. New diagnostic techniques have been developed to better characterise the mechanisms underlying gastroparesis in individual patients, and these have the potential to lead to more personalised therapy. Management of gastroparesis is complex and suboptimal; novel approaches are desirable. This review summarises recent advances in the understanding of diabetic gastroparesis, with an emphasis on the current therapies that influence GE, and the bidirectional relationship between glycaemic control and GE.

Effects of Motilin Receptor Agonists and Ghrelin in Human motilin receptor Transgenic Mice.

Gastrointestinal motility is regulated by neural factors and humoral factors. Both motilin and ghrelin improve gastrointestinal motility, but many issues remain unclear. We prepared human motilin receptor transgenic (Tg) mice and performed experiments evaluating the effects of motilin, erythromycin (EM), and ghrelin. EM and ghrelin promoted gastric emptying (GE) when administered either peripherally or centrally to Tg mice. Atropine (a muscarinic receptor antagonist) counteracted GE induced by centrally administered EM, but not that induced by peripherally administered EM. The administration of EM in this model promoted the effect of mosapride (a selective serotonin 5-hydroxytryptamine 4 (5-HT4) receptor agonist), and improved loperamide (a µ-opioid receptor agonist)-induced gastroparesis. The level of acyl-ghrelin was significantly attenuated by EM administration. Thus, we have established an animal model appropriate for the evaluation of motilin receptor agonists. These data and the model are expected to facilitate the identification of novel compounds with clinical potential for relieving symptoms of dyspepsia and gastroparesis.

Is There a Role for Enterohormones in the Gastroparesis of Critically Ill Patients?

OBJECTIVES: Delayed gastric emptying occurs in critically ill patients and impairs the delivery, digestion, and absorption of enteral feeding. A pathophysiologic role of the enterohormones peptide YY and ghrelin is supported by preclinical data. To compare the circulating plasma levels of peptide YY and ghrelin in control subjects and in critically ill patients, during feeding and fasting, and to search for a correlation with gastric emptying. DESIGN: A prospective observational trial. SETTINGS: Mixed ICU of an academic hospital. SUBJECTS: Healthy volunteers and patients expected to stay in ICU for at least 3 days in whom enteral nutrition was indicated. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma peptide YY and ghrelin (enzyme-linked immunosorbent assay) were measured once in 10 fasting volunteers (controls) and daily from admission until day 5 of the ICU stay in 30 critically ill patients (median [interquartile range] age 63 [57-67] yr, median [interquartile range] Acute Physiology and Chronic Health Evaluation II score 21 [14-24]). Eight patients could not be fed (fasting group). In fed patients, 13 never had a gastric residual volume higher than 250 mL (low gastric residual volume group), in contrast to the high gastric residual volume group (n = 9). The plasma levels of peptide YY did not differ between patients (6.4 [0-18.1] pg/mL) and controls (4.8 [0.3-17.7] pg/mL). Ghrelin levels were lower in patients than in control (213 [54.4-522.7] vs 1,435 [1,321.9-1,869.3] pg/mL; p < 0.05). Plasma peptide YY or ghrelin did not differ between fasting and fed patients or between the high and low gastric residual volume groups. CONCLUSIONS: In critically ill patients, plasma concentration of ghrelin significantly differs from that of controls, irrespective of the feeding status. No correlation was found between the temporal profile of ghrelin or peptide YY plasma concentration with bedside functional assessment of gastric emptying.

Yield of Endoscopy in Pediatric Gastroparesis.

OBJECTIVES: The aim of the study was to quantify the diagnostic yield of upper endoscopy in children with gastroparesis and to develop a clinical model for gastroparesis using common symptoms and screening blood tests. METHODS: We retrospectively reviewed charts of 196 patients of age 4 to 18 years evaluated for gastroparesis between 2009 and 2013. All patients completed a standard solid-phase gastric emptying scan and upper endoscopy within a 12-month period. We analyzed gross and histologic endoscopy findings. Symptom-based data were collected on dyspeptic symptoms and classic "red-flag" symptoms. RESULTS: Seventy patients with gastroparesis and 126 controls were included. Clinically significant endoscopic findings were noted in 35% of controls (44/126) and 43% of gastroparetics (30/70), P = 0.345. Concordance between gross and histologic findings was low at 50%. Histologic findings included gastritis 60% (17/28), esophagitis 39% (11/28), and duodenitis 7% (2/28). In univariate and multivariate analyses, there was no meaningful correlation between symptoms and/or screening laboratory values and diagnosis of gastroparesis. CONCLUSIONS: Clinically significant endoscopy findings were common in both controls and gastroparetics. As more than one-third of patients had findings on endoscopy, we conclude that upper endoscopy remains an important part of the evaluation process of patients with dyspeptic symptoms and suspected gastroparesis. As gross abnormalities were frequently not present with histologic changes, routine biopsy is required. There was no association between studied symptoms and the presence of gastroparesis. A comprehensive evaluation of children with dyspeptic symptoms requires endoscopy with biopsy and solid-phase gastric emptying scan to determine the underlying diagnosis.

Gastroparesis - a novel cause of persistent thyroid stimulating hormone elevation in hypothyroidism.

Hypothyroidism is easily treated by levothyroxine therapy which has an 80 percent absorption rate, mostly in the jejunum. The replacement dose of daily levothyroxine is usually calculated at 1.6 mcg/kg body weight per day. We report a 77-year-old man who required supraphysiologic thyroxine replacement (>2.7 mcg/ kg/day) to treat his hypothyroidism. The patient was referred for persistent thyroid stimulating hormone (TSH) elevation (40 mcIU/ml) while on 175 mcg of levothyroxine. Patient was compliant with medication. Medical history included diabetes mellitus type 2, cerebrovascular accident, depression, hypertension, hyperlipidemia, atherosclerotic cardiovascular disease, vitamin B12 deficiency, Addison's disease, as well as a colostomy secondary to diverticulitis. He was taking aspirin, carvedilol, cholecalciferol, finasteride, fluoxetine, furosemide, ketoconazole, levothyroxine, prednisone, and albuterol/ipratropium inhaler. His height was 180.3 cm; weight, 107 kg. Thyroid was impalpable, and he was clinically euthyroid. Despite discontinuation of iron and statin which are known to interfere with thyroxine absorption and crushing of thyroxine tablets to enhance absorption, his TSH remained elevated. Celiac disease and Helicobacter pylori infection were ruled out with serological testing. There was no proteinuria and anti-parietal cell antibody was positive. Gastroparesis was confirmed by gastric emptying study. He continued to require increasing doses of thyroxine with increment to 300 mcg daily. To our knowledge, this is the first documented association between gastroparesis and thyroxine malabsorption. We recommend that gastroparesis be considered in any patient with persistent TSH elevation despite usual thyroxine doses.

Comparative analysis of bilirubin in correlation to albumin between nephrotic syndrome patients and postoperative gastroparesis syndrome patients.

This study aimed to disclose the potential causality of low bilirubin in patients with nephrotic syndrome (NS). Correlation analysis was carried out on total bilirubin (TBIL) to serum albumin (ALB), urine protein (Upr), and urinary microalbumin/creatinine (Umalb/cr) for three groups in a case-control study. P < 0.001 was observed for TBIL, ALB, Umalb/cr, and Upr between the NS and chronic nephritis (CN) groups, and P values of 0.0001, 1.000, 0.0001, and 0.0001 were observed for TBIL, ALB, Umalb/cr, and Upr, respectively, between the postoperative gastroparesis (PGS) and CN groups. The values of r and P in correlation to TBIL were 0.549 and 0.000 for ALB, -0.405 and 0.000 for Umalb/cr, and -0.448 and 0.000 for Upr in the NS group; -0.007 and 0.959 for ALB, 0.213 and 0.091 for Umalb/cr, and -0.082 and 0.519 for Upr in the PGS group; and 0.509 and 0.000 for ALB, -0.431 and 0.000 for Umalb/cr, and -0.362 and 0.002 for Upr in the CN group. A probable causality is implied between the low level of blood bilirubin and its loss in urine in NS patients. This conclusion may provide a theoretical basis for the feasibility of therapies against oxidative stress in NS patients.

Prognosis of diabetic gastroparesis--a 25-year evaluation.

AIM: To evaluate the prognosis of diabetic gastroparesis. METHODS: Eighty-six patients with diabetes had measurements of gastric emptying of a mixed meal using a dual isotope test of solid and liquid meal components, mean blood glucose levels, HbA1c , upper gastrointestinal symptoms and autonomic nerve function performed in 1984-1989. These patients were followed up in 2011, after a mean period of ~25 years. RESULTS: Of the 86 patients, gastric emptying of solid (the percentage remaining in the stomach at 100 min) was delayed in 35 (41%), and of liquid (the time taken for 50% of the liquid to empty) was delayed in 38 (44%). In 2011, 53 patients were known to be alive, 29 had died and four were lost to follow-up. In those who had died, both age at baseline (P < 0.001) and the score for autonomic nerve dysfunction (P < 0.001) were greater than those who were alive, while there was no difference in emptying of either the solid or liquid between the two groups. When patients with delayed gastric emptying were divided according to the median value ('delayed' and 'markedly delayed'), mortality tended to be greater in the 'markedly delayed' group for both solids (P = 0.12) and liquids (P = 0.09). Of the 82 patients who could be followed up, 23 of the 35 (66%) with delayed gastric emptying of solid and 25 of 38 (66%) with delayed gastric emptying of liquid were alive. After adjustment for age and autonomic dysfunction, there was no association between gastric emptying of either solid or liquid and death. CONCLUSIONS: Over a period of ~25 years, diabetic gastroparesis is apparently not usually associated with a poor prognosis, or increased mortality. ABBREVIATIONS: T100 min, the percentage remaining in the stomach at 100 mins; T50%, the time taken for 50% of the liquid to empty.

Gastric dysmotility and low serum vitamin D levels in patients with gastroparesis.

Nutritional abnormalities are common in patients with gastroparesis (Gp), a disorder that may affect gastric motility and may delay emptying. The aim of this work was to identify relationships between serum nutrition markers including 25-OH vitamin D and gastric motility measures in Gp patients. We enrolled 59 consecutive gastric motility clinic patients (48 females, 11 males; mean age 44 years; 42 idiopathic; 17 diabetes mellitus) with Gp symptoms. The 25-OH vitamin D levels, for most patients slightly above the lower limit of normal (96.98 nmol/l ± 60.99), were lowest in diabetic range (DM) (75.68 nmol/l ± 34.22) vs. idiopathic (ID) (105.03 nmol/l ± 67.08) gastroparesis patients. First hour GET: one unit increase in 25-OH vitamin D level was associated 0.11% improvement (95% CI -0.22, 0.01 p=0.056) in gastric motility in all patients; this association, although marked in ID Gp patients, (-0.13, CI -0.25, -0.01 p=0.034), was not seen in DM Gp, (0.2, CI -0.45, 0.87, p=0.525). Fourth hour GET: Every unit increase of 25-OH vitamin D was associated with significant improvement in all patients, ( 0.11% CI -0.23, 0.01, p=0.053), and some weak improvement in ID group, (0.11% -0.24, 0.01, p=0.076) and absent in patients with DM (0.03, CI -0.66, 0.72, p=0.932). It is concluded that 25-OH vitamin D levels may influence gastric emptying. Underlying mechanisms for this observation might include the impact of 25-OH vitamin D on the health of the enteric nervous system. 25-OH vitamin D contributions to enteric nerve functions should be explored, particularly where autonomic nervous system comorbidities exist.

Prolonged treatment with transcutaneous electrical nerve stimulation (TENS) modulates neuro-gastric motility and plasma levels of vasoactive intestinal peptide (VIP), motilin and interleukin-6 (IL-6) in systemic sclerosis.

PURPOSE: We assessed the effects of transcutaneous electrical nerve stimulation (TENS) on neurogastric functioning in scleroderma patients. METHODS: Seventeen SSc patients underwent 30 min TENS treatment >10Hz at GI acupuncture points PC6 and ST36, once (acute TENS) and then after two weeks of TENS sessions for 30 min twice daily (prolonged TENS). Data collected at Visits 1 and 2 included gastric myoelectrical activity (GMA) by surface electrogastrography (EGG), heart rate variability (HRV) by surface electrocardiography (EKG), GI specific symptoms and health related SF-36 questionnaires. Plasma VIP, motilin and IL-6 levels were determined. Statistical analyses were performed by Student's t-test, Spearman Rank and p-values <0.05 were considered significant. RESULTS: 1. Only after prolonged TENS, the percentages of normal slow waves and average slow wave coupling (especially channels 1, 2 reflecting gastric pacemaker and corpus regions) were significantly increased; 2. the percentage of normal slow waves was significantly correlated to sympathovagal balance; 3. Mean plasma VIP and motilin levels were significantly decreased after acute TENS, (vs. baseline), generally maintained in the prolonged TENS intervals. Compared to baseline, mean plasma IL-6 levels were significantly increased after acute TENS, but significantly decreased after prolonged TENS. 4. After prolonged TENS, the frequency of awakening due to abdominal pain and abdominal bloating were significantly and modestly decreased, respectively. CONCLUSIONS: In SSc patients, two weeks of daily TENS improved patient GMA scores, lowered plasma VIP, motilin and IL-6 levels and improved association between GMA and sympathovagal balance. This supports the therapeutic potential of prolonged TENS to enhance gastric myoelectrical functioning in SSc.

Identification of domperidone metabolites in plasma and urine of gastroparesis patients with LC-ESI-MS/MS.

Domperidone is a prokinetic agent used to treat gastroparesis. Previous studies reported oxidative metabolites of domperidone, detected by radiometric high-performance liquid chromatography or single quadrupole mass spectrometric techniques. Our aim was to identify domperidone Phase I and Phase II metabolites using liquid chromatography combined with electrospray ionization-enabled tandem mass spectrometry. Domperidone metabolites were identified in the plasma and urine of 11 gastroparesis patients currently being treated with domperidone. In addition, oxidative and conjugative metabolites of domperidone were characterized in human liver subcellular fractions. Seven metabolites were detected in vivo. Domperidone was metabolized to two mono-hydroxylated metabolites (M1 and M2), a de-alkylated metabolite (M5) and a di-hydroxylated metabolite (M7). The mono-hydroxylated metabolites were further glucuronidated to M8, M9 and sulfated to M11. To the best of our knowledge, M7, M8, M9 and M11 have not been reported previously. Five additional metabolites were identified in vitro in human subcellular fractions which comprise two additional mono-hydroxylated metabolites (M3 and M4), an alcohol metabolite (M6) possibly formed from an aldehyde intermediate, and other conjugative metabolites (M10 and M12). M6, M10 and M12 have not been characterized previously. In total, 12 domperidone metabolites including 7 new metabolites were identified in the present study. These results allow a better understanding of domperidone disposition in humans.

Diabetic gastroparesis-backwards and forwards.

Diabetic gastroparesis was once thought to be rare, associated with a poor prognosis, and to affect only patients with type 1 diabetes and irreversible autonomic neuropathy. A landmark study conducted by Horowitz et al. and published in JGH in 1986 paved the way for further studies to examine the pathophysiology, natural history and prognosis of diabetic gastroparesis, as well as its optimal management. This review summarizes the developments in knowledge gained over the last ∼25 years that have led to understanding about normal and disordered gastric emptying in diabetes, with a particular emphasis on the inter-relationship between the rate of gastric emptying and the regulation of blood glucose.

Plasma endocannabinoids and cannabimimetic fatty acid derivatives are altered in gastroparesis: A sex- and subtype-dependent observation.

BACKGROUND: Gastroparesis (GP) is a motility disorder of the stomach presenting with upper gastrointestinal symptoms in the setting of delayed gastric emptying. Endocannabinoids are involved in the regulation of GI function including motility. However, their role in the pathophysiology of GP has not been sufficiently investigated. Our goal was to compare the circulating levels of endocannabinoids and cannabimimetic fatty acid derivatives in GP versus control subjects. METHODS: The study compared plasma concentrations of endocannabinoids and their lipoamine and 2-acyl glycerol congeners, measured by high-pressure liquid chromatography/tandem mass spectrometry (HPLC-MS-MS), in adult patients with diabetic gastroparesis (DM-GP; n = 24; n = 16 female), idiopathic gastroparesis (ID-GP; n = 19; n = 11 female), diabetic patients without GP (DM; n = 19; n = 10 female), and healthy controls (HC; n = 18; n = 10 female). Data, presented as mean ± SEM, were analyzed with ANOVA (Sidak post hoc). KEY RESULTS: Endocannabinoids anandamide (AEA: 0.5 ± 0.1 nMol/L) and 2-arachidonoyl glycerol (2-AG: 2.6 ± 0.7 nMol/L) were significantly lower in female DM-GP patients vs. DM females (AEA: 2.5 ± 0.7 nMol/L and 2-AG: 9.4 ± 3.3 nMol/L). Other monoacylglycerols including 2-palmitoyl glycerol and 2-oleoyl glycerol were also lower in female DM-GP patients compared to DM females. No changes were observed in men. CONCLUSIONS & INFERENCES: Endocannabinoids and other fatty acid derivatives with cannabimimetic properties are reduced in female DM-GP patients. Since GP, particularly with diabetic etiology, is more prevalent among women and since cannabinoids are antiemetic, this decrease in levels may contribute to symptom development in these subjects. Targeting the endocannabinoid system may be a future therapeutic option in DM-GP patients.

Assessment of pyloric sphincter distensibility and pressure in patients with diabetic gastroparesis.

BACKGROUND: Recent studies have shown that pyloric distensibility is altered in 30-50% of gastroparetic patients but the number of diabetic patients included in prior reports has been small. The aim of the present study was to assess pyloric sphincter measurements in diabetic patients with gastroparesis and to determine whether diabetes characteristics were correlated to pyloric disfunction. METHODS: Pyloric distensibility and pressure were measured using EndoFLIP® system in 46 patients with diabetic gastroparesis (DGP) and compared with 21 healthy volunteers (HV), and 33 patients with idiopathic gastroparesis (IGP). Altered pyloric distensibility was defined as the measurement below 10 mm2 /mmHg at 40 ml of inflation. In diabetic patients, blood glucose, glycated hemoglobin, duration, complications, and treatments were collected. KEY RESULTS: Mean pyloric distensibility at 40 ml of inflation was lower in DGP and IGP groups with, respectively, 10.8 ± 0.9 mm2 /mmHg and 14.8 ± 2.2 mm2 /mmHg in comparison with the HV group (25.2 ± 2.3 mm2 /mmHg; p < 0.005). 56.5% of patients had a decreased pyloric distensibility in the DGP group, 51.5% of patients in the IGP group, and 10% of patients in the HV group. No correlation was found between pyloric sphincter measurements and diabetes characteristics, including blood glucose, glycated hemoglobin, diabetes mellitus type, neuropathy, or GLP1 agonists intake. CONCLUSION AND INTERFERENCES: Pyloric sphincter distensibility and pressure were altered both in diabetic and idiopathic gastroparesis. Pyloric sphincter distensibility was not correlated to diabetes parameters.

Elevated Circulating Levels of Motilin are Associated with Diabetes in Individuals after Acute Pancreatitis.

AIM: The study aimed to investigate the associations between glycaemic control after acute pancreatitis and gastrointestinal motility, using plasma motilin concentration and gastroparesis cardinal symptom index score as proxies. METHODS: This cross-sectional study recruited a total of 93 individuals after acute pancreatitis. Gastroparesis cardinal index scores, demographic and anthropometric factors, as well as pancreatitis-related factors were analysed. Fasting venous blood was collected to measure motilin, glycated haemoglobin, and fasting blood glucose. Linear regression analyses were conducted to investigate the associations between glycaemic control and gastrointestinal motility in unadjusted and adjusted models. RESULTS: Motilin was significantly higher in individuals with diabetes across all adjusted models, with the highest ß-coefficient (95% confidence interval) of 588.89 (138.50, 1039.28); P=0.010. Fasting blood glucose was significantly associated with motilin across all models, with the highest ß-coefficient (95% confidence interval) of 156.30 (55.49, 257.10); P=0.002. Glycated haemoglobin was significantly associated with motilin in one adjusted model with ß-coefficient (95% confidence interval) of 18.78 (1.53, 36.02); P=0.033. Gastroparesis cardinal symptom index was not significantly associated with any measure of glycaemic control. CONCLUSIONS: Diabetes in individuals after acute pancreatitis appears to be characterised by elevated plasma motilin but not gastroparesis cardinal symptom index. The role of motilin in this setting warrants further investigations.

Gender-Related Differences in Gastroparesis.

Gastroparesis is a disorder where the stomach empties contents too slowly into the small intestine with associated symptoms of nausea, vomiting, postprandial fullness, bloating, early satiety and/or abdominal pain. It is a well-established fact that the female gender is more susceptible to developing gastroparesis compared to males, although the significance and rationale behind this gender inequality remains an unresolved mystery. Several hypotheses have been proposed including an intrinsically slower stomach in females, elevated levels of sex steroid hormones, loss of neuronal nitric oxide (nNOS) expression, and possibly due to altered serotonergic signaling. Recently, our group investigated gender-associated differences in the number of interstitial cells of Cajal in the antral and pyloric smooth muscle of diabetic patients with severe refractory gastroparesis and found there was no significant difference between the 2 genders. Targeting these gender-specific mechanisms may lead towards future therapeutic options that might alleviate and/or prevent gastroparesis. Furthermore, a better-understanding of the sex-related differences in gastroparesis can allow medical practitioners to better tailor treatment options for their patients. This article will attempt to explain why females are more vulnerable to developing gastroparesis by examining the pathogenesis and molecular basis of gender-related factors that have been identified to play a role in the gender disparity of this entity.

Preoperative Blood Glucose Level Predicts Postsurgical Gastroparesis Syndrome after Subtotal Gastrectomy: Development of an Individualized Usable Nomogram.

BACKGROUND: Postsurgical gastroparesis syndrome (PGS) after subtotal gastrectomy imposes significant social and economic burdens. We aimed to investigate the relationship between preoperative blood glucose level and PGS and develop a nomogram for individualized prediction. Patients and Methods. We retrospectively analyzed 633 patients with gastric cancer who underwent subtotal gastrectomy. Preoperative blood glucose levels were evaluated via receiver operating characteristic (ROC) curve analysis. Chi-squared tests and multivariable logistic regression analyses were used to develop a predictive model for PGS, presented as a nomogram, which was assessed for its clinical usefulness. RESULTS: Thirty-eight of 633 patients were diagnosed with PGS. Based on the ROC curve analysis, the preoperative blood glucose cutoff value for PGS was 6.25 mmol/L. The predictors of PGS included preoperative hyperglycemia (odds ratio (OR) 2.3, P = 0.03), body mass index (BMI; OR 0.21, P = 0.14 for BMI < 18.5 and OR 3.0, P = 0.004 for BMI > 24), and the anastomotic method (OR 7.3, P = 0.001 for Billroth II and OR 5.9, P = 0.15 for Roux-en-Y). The predictive model showed good discrimination ability, with a C-index of 0.710, and was clinically useful. CONCLUSIONS: Preoperative hyperglycemia effectively predicts PGS. We present a nomogram incorporating the preoperative blood glucose level, BMI, anastomotic method, and tumor size, for individualized prediction of PGS.

Predictors of gastric myoelectrical activity in type 2 diabetes mellitus.

BACKGROUND: Previous studies have clearly demonstrated the delayed gastric emptying of solid meals in diabetics, whereas their gastric myoelectrical activity, which primarily determines gastric motility, has not yet been fully confirmed. GOALS: This study aimed to clarify the characteristics and potential predictors of gastric myoelectrical activity in type 2 diabetics. STUDY: Twenty-eight diabetics and 18 healthy controls participated. Duodenal biopsy sample was used for reverse transcription-polymerase chain reaction to evaluate cholecystokinin and motilin mRNA contents. Electrogastrography was performed before and after the test meal, and was assessed in terms of dominant frequency; dominant frequency instability coefficient; and the percentage of bradygastria, normogastria, and tachygastria. RESULTS: Over the entire recording period, dominant frequency was significantly lower, and dominant frequency instability coefficient and the percentage of bradygastria were significantly higher in diabetics than in controls. In diabetics, the multiple regression analysis demonstrated that dominant frequency instability coefficient and the percentage of tachygastria in the fasting period were dependent on fasting plasma glucose level and HbA1c, respectively. Moreover, dominant frequency over the entire period and the postprandial percentage of bradygastria were significantly associated with body mass index; the fasting percentage of bradygastria and postprandial dominant frequency instability coefficient were associated with fasting serum leptin level; the postprandial percentage of bradygastria was also associated with cholecystokinin mRNA content. CONCLUSIONS: Gastric myoelectrical activity in type 2 diabetics is impaired on dominant frequency, dominant frequency instability coefficient, and the percentage of bradygastria and predicted by body mass index, fasting serum leptin level, and cholecystokinin mRNA content besides the glycemic status.

Gastroparesis is associated with oxytocin deficiency, oesophageal dysmotility with hyperCCKemia, and autonomic neuropathy with hypergastrinemia.

BACKGROUND: Gastrointestinal (GI) dysmotility and autonomic neuropathy are common problems among diabetics with largely unknown aetiology. Many peptides are involved in the autonomic nervous system regulating the GI tract. The aim of this study was to examine if concentrations of oxytocin, cholecystokinin (CCK), gastrin and vasopressin in plasma differ between diabetics with normal function and dysfunction in GI motility. METHODS: Nineteen patients with symptoms from the GI tract who had been examined with gastric emptying scintigraphy, oesophageal manometry, and deep-breathing test were included. They further received a fat-rich meal, after which blood samples were collected and plasma frozen until analysed for hormonal concentrations. RESULTS: There was an increase in postprandial oxytocin plasma concentration in the group with normal gastric emptying (p = 0.015) whereas subjects with delayed gastric emptying had no increased oxytocin secretion (p = 0.114). Both CCK and gastrin levels increased after the meal, with no differences between subjects with normal respective delayed gastric emptying. The concentration of vasopressin did not increase after the meal. In patients with oesophageal dysmotility the basal level of CCK tended to be higher (p = 0.051) and those with autonomic neuropathy had a higher area under the curve (AUC) of gastrin compared to normal subjects (p = 0.007). CONCLUSION: Reduced postprandial secretion of oxytocin was found in patients with delayed gastric emptying, CCK secretion was increased in patients with oesophageal dysmotility, and gastrin secretion was increased in patients with autonomic neuropathy. The findings suggest that disturbed peptide secretion may be part of the pathophysiology of digestive complications in diabetics.