? Diabetic gastropathy, presenting as nausea, vomiting, bloating, and pain, has been considered synonymous with gastroparesis as many patients exhibit delayed gastric emptying. Yet, emptying rates correlate poorly with symptoms and improvements on therapy do not associate with normalized emptying. Thus, other factors are pathogenic of gastropathic symptoms in diabetes. Dysfunctional visceral afferent transmission purportedly underlies symptoms in functional bowel disorders. Recent studies have shown that hyperalgesia is present in some diabetics with nausea and bloating. We hypothesize: (1) altered gastric sensation is prevalent in diabetic gastropathy and correlates with symptoms, (2) sensory abnormalities relate to other diabetic neuropathies, (3) altered sensation parallels the natural history of gastropathy, and (4) responses to therapy relate to improved afferent function. We propose 2 multicenter protocols to be conducted by the Gastroparesis Clinical Research Consortium. Diabetics with >6 months of nausea, vomiting, bloating, early satiety, or discomfort will be recruited. The first protocol will relate gastric sensory and accommodation defects, measured by satiety and barostat tests, to specific gastropathy symptoms, diabetic complications, psychosocial parameters, quality of life measures, gastric emptying, and measures of peripheral and autonomic neuropathy. These studies will quantify the prevalence of afferent dysfunction in diabetic gastropathy and assess its potential pathogenic role in symptom development in this condition. The second protocol will follow diabetics with gastropathy longitudinally. Serial satiety, barostat, and gastric, emptying tests will be correlated with clinical parameters and measures of peripheral and autonomic neuropathy to compare when abnormal gastric sensory vs. motor function develop in the natural history of diabetes. Subsets of patients in this longitudinal study will enroll in treatment trials. Satiety, accommodation, perception, and emptying will be quantified before and at 12 weeks of double-blind therapy with the pure prokinetic drug erythromycin vs. placebo. In separate individuals, gastric testing will be performed before and 24 weeks after implantation of the gastric stimulator (Enterra)-which has little prokinetic action. Double-blind testing will occur in sham-stimulation controlled fashion with the device turned OFF in half of patients 4 weeks before testing. Gastric function improvements with each therapy will be correlated with symptom reductions to test if therapies that selectively target motor dysfunction or heightened visceral sensation produce greater benefits. Lay description: Nausea, vomiting and bloating are prevalent in patients with long-standing diabetes and markedly impair quality of life. These studies will provide insight into symptom pathogenesis in diabetic gastropathy and will direct future research into therapies that correct visceral sensory rather than motor defects in this condition ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK073985-03
Application #
7430416
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (O1))
Program Officer
Hamilton, Frank A
Project Start
2006-04-15
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
3
Fiscal Year
2008
Total Cost
$353,277
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Hasler, W L; May, K P; Wilson, L A et al. (2018) Relating gastric scintigraphy and symptoms to motility capsule transit and pressure findings in suspected gastroparesis. Neurogastroenterol Motil 30:
Parkman, H P; Hallinan, E K; Hasler, W L et al. (2017) Early satiety and postprandial fullness in gastroparesis correlate with gastroparesis severity, gastric emptying, and water load testing. Neurogastroenterol Motil 29:
Grover, M; Bernard, C E; Pasricha, P J et al. (2017) Diabetic and idiopathic gastroparesis is associated with loss of CD206-positive macrophages in the gastric antrum. Neurogastroenterol Motil 29:
Koch, K L; Hasler, W L; Yates, K P et al. (2016) Baseline features and differences in 48 week clinical outcomes in patients with gastroparesis and type 1 vs type 2 diabetes. Neurogastroenterol Motil 28:1001-15
Hasler, William L (2016) Newest Drugs for Chronic Unexplained Nausea and Vomiting. Curr Treat Options Gastroenterol 14:371-385
Parkman, H P; Hallinan, E K; Hasler, W L et al. (2016) Nausea and vomiting in gastroparesis: similarities and differences in idiopathic and diabetic gastroparesis. Neurogastroenterol Motil 28:1902-1914
Pasricha, Pankaj J; Yates, Katherine P; Nguyen, Linda et al. (2015) Outcomes and Factors Associated With Reduced Symptoms in Patients With Gastroparesis. Gastroenterology 149:1762-1774.e4
Bernard, C E; Gibbons, S J; Mann, I S et al. (2014) Association of low numbers of CD206-positive cells with loss of ICC in the gastric body of patients with diabetic gastroparesis. Neurogastroenterol Motil 26:1275-84
Iorio, Raffaele; Lucchinetti, Claudia F; Lennon, Vanda A et al. (2013) Intractable nausea and vomiting from autoantibodies against a brain water channel. Clin Gastroenterol Hepatol 11:240-5
Hasler, William L (2013) Pathology of emesis: its autonomic basis. Handb Clin Neurol 117:337-52

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