Clinical Implication and Pathophysiology of Metabolic Factors in Gastrointestinal Disease
Date Issued
2014
Date
2014
Author(s)
Tseng, Ping-Huei
Abstract
Background and objective Metabolic syndrome, especially diabetes mellitus (DM) and obesity, has been associated a myriad of gastrointestinal (GI) complications, including gastroesophageal reflux disease (GERD), gastroparesis, constipation and diarrhea. The pathogenesis of GI complications in patients with metabolic derangement is complex and multi-factorial. Epidemiological studies have shown a close relationship between obesity and GERD-related complications. 18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) assesses not only anatomical structures, but also the degree of local glucose metabolism and provides us a unique opportunity to explore the complex relationship of GERD, esophageal inflammation and obesity. With the integrated approaches with both clinical and animal studies, we aim to investigate the clinical implication and underlying pathophysiology of metabolic factors of the various GI diseases. Materials and methods First, we analyzed the prevalence and severity of GI symptoms and endoscopic findings in diabetic subjects from a general population undergoing upper endoscopy/colonoscopy as part of a medical examination at the National Taiwan University Hospital. Second, we studied 458 subjects who underwent both an upper gastrointestinal endoscopy and FDG PET/CT during health check-ups. GERD symptoms were evaluated with Reflux Disease Questionnaire. Inflammatory activity, represented by standardized uptake values (SUVmax) of FDG at pre-determined locations of esophagus, stomach and duodenum, were compared. Third, to establish normal oatmeal-based gastric emptying scintigraphy reference values and test its correlation with gastroparesis symptoms in the Chinese population, we prospectively enrolled 60 healthy volunteers and 60 symptomatic patients (30 functional dyspepsia and 30 diabetes patients with gastroparesis symptoms). All participants were evaluated using the Gastroparesis Cardinal Symptom Index. Finally, we established the solid gastric emptying measurement with “beads method” in murine models of type 2 DM, C57BLKS/J db/db mice. We investigated the effect of glycemic control with insulin and GLP-1 analogue treatment on the gastric emptying of db/db mice.. Results In the first part, among the 7770 study subjects, 722 (9.3%) were diagnosed with DM. The overall prevalence of GI symptoms was lower in DM subjects (30.3% vs. 35.4%, P = 0.006). In contrast, the prevalence of erosive esophagitis, Barrett’s esophagus, peptic ulcer disease, gastric neoplasms, and colonic neoplasms were higher in diabetic subjects. Higher HbA1c levels were associated with a decrease of GI symptoms and an increase of endoscopic abnormalities. Second, subjects with erosive esophagitis on endoscopy had significantly higher SUVmax at esophagus, but not in stomach or duodenum. The severity of erosive esophagitis correlated with SUVmax and subjects with Barrett’s esophagus had the highest SUVmax at middle esophagus and esophagogastric junction. Heartburn positively correlated with higher SUVmax at middle esophagus. Using multivariate regression analyses, age, total cholesterol level, alcohol drinking, subcutaneous adipose tissue, BMI and waist circumference were independently associated with higher SUVmax at respective esophageal locations. Third, all participants finished the oatmeal-based test meal and tolerated the scintigraphy procedure well. All gastric emptying parameters were not significantly affected by age or gender. Waist circumference inversely correlated with gastric retention at 1 h. There were 4 (13.3%) diabetic patients found to have delayed emptying and 3 patients (10%) found to have rapid emptying, respectively. Gastric emptying parameters correlated best with vomiting severity in diabetic patients. For the animal studies, body weight (36.5 ± 3.2 vs. 21.5 ± 1.5 gm，P < 0.001) and fasting blood glucose (388 ± 49 vs. 131 ± 14 mg/dL，P < 0.001) were significantly higher in db/db mice than in db/m mice of the same age of 8 weeks. Solid gastric emptying measured with beads method was also faster in the db/db group (80 ± 18 vs. 48 ± 16 %，P = 0.018). Gastric emptying was slower in db/db mice of 12 and 16 weeks of age, while treatment with insulin or liraglutide accelerated the gastric emptying. Conclusion In conclusion, the present study shows that DM and higher levels of HbA1c are associated with lower prevalence of GI symptoms but higher prevalence of endoscopic abnormalities. Esophageal inflammation demonstrated by FDG PET/CT correlates with endoscopic findings and symptomatology of GERD. Obesity markers, both visceral and general, are independent determinants of esophageal inflammation. Furthermore, we established normal values of a simplified oatmeal-based gastric emptying scintigraphy and observe good correlation with various gastroparesis symptoms in the Chinese population. Finally, our animal model of measuring solid gastric emptying in db/db mice may be applied to further studies and may help to clarify the temporal relationship between metabolic factors and autonomic neuropathy in GI motility disorders.
Subjects
metabolic syndrome
diabetes mellitus
gastroesophageal reflux disease
gastroparesis
functional dyspepsia
autonomic neuropathy
FDG PET/CT
gastric emptying scintigraphy
db/db mice
SDGs
Type
thesis