The overall objectives of this proposal (Project 3 of PPG) are to understand the mechanisms of and to develop novel management approaches for gastric emptying (GE) disturbances (i.e., delayed GE or gastroparesis and rapid GE) in idiopathic disorders and diabetes mellitus (DM). Delayed GE is attributed to autonomic dysfunctions, hyperglycemia, and an enteropathy. Exciting preliminary data (Project 1) indicate that failure to upregulate heme oxygenase-1 (HO-1) in response to hyperglycemia-induced oxidative stress causes delayed GE in non-obese diabetic (NOD) mice. HO-1 degrades heme to generate carbon monoxide, which has cytoprotective effects and sustains interstitial cells of Cajal. Hemin increased HO-1 expression in NOD mice. While improved glycemic control reduces the microvascular complications of DM, its effects on GE have not been studied. Although acute hyperglycemia delays GE, our preliminary data suggest that improving glycemic control for 12h or 6 mo does not improve GE in DM with delayed GE. Finally, our preliminary data suggest that nutrient-induced entero-gastric feedback mechanisms mediated by gut peptides (CCK and GLP-1), normally responsible for regulating GE are impaired in patients with rapid GE. Our CENTRAL HYPOTHESIS is that delayed or accelerated GE, due to DM or related disorders, are attributable to vagal neuropathy, hyperglycemia, enteric neuropathy, and/or disordered enterogastric reflexes. Our proposal has three SPECIFIC AIMS. FIRST, we will test the hypothesis that compared to placebo, hemin will increase HO-1 activity and GE in patients with DM and delayed GE. SECOND, we will test the hypothesis that neither acute (12h) nor medium-term (i.e., 6 month) improvements in glycemic control will improve gastric emptying in DM. THIRD, we will test the hypothesis that idiopathic rapid GE results from disordered enterogastric feedback mechanisms (i.e., reduced enteric hormonal release and/or end-organ effects) and increased gastric motility and is associated with impaired glucose tolerance.

Public Health Relevance

Delayed gastric emptying, or gastroparesis, and rapid gastric emptying are poorly understood conditions, which cause indigestion, affect glycemic control in DM, and cannot be not effectively managed by available therapies. This proposal will use state-of-the-art approaches to evaluate gastrointestinal motor activity, entero-gastric reflexes, autonomic functions, and imaging techniques to address the mechanisms and develop novel therapeutic strategies for gastric motor disturbances in idiopathic disorders and DM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK068055-10
Application #
8685962
Study Section
Special Emphasis Panel (ZDK1-GRB-9)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
10
Fiscal Year
2014
Total Cost
$424,958
Indirect Cost
$155,389
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Loavenbruck, A; Iturrino, J; Singer, W et al. (2015) Disturbances of gastrointestinal transit and autonomic functions in postural orthostatic tachycardia syndrome. Neurogastroenterol Motil 27:92-8
Bharucha, Adil E; Kudva, Yogish; Basu, Ananda et al. (2015) Relationship between glycemic control and gastric emptying in poorly controlled type 2 diabetes. Clin Gastroenterol Hepatol 13:466-476.e1
Bharucha, Adil E; Fidler, Jeff L; Huprich, James E et al. (2014) A prospective randomized controlled study of erythromycin on gastric and small intestinal distention: implications for MR enterography. Eur J Radiol 83:2001-6
Bharucha, Adil E; Choi, Kyoung Moo; Saw, Jessica J et al. (2014) Effects of aspirin & simvastatin and aspirin, simvastatin, & lipoic acid on heme oxygenase-1 in healthy human subjects. Neurogastroenterol Motil 26:1437-42
Wada, Naoki; Singer, Wolfgang; Gehrking, Tonette L et al. (2014) Comparison of baroreflex sensitivity with a fall and rise in blood pressure induced by the Valsalva manoeuvre. Clin Sci (Lond) 127:307-13
Farrugia, Gianrico; Szurszewski, Joseph H (2014) Carbon monoxide, hydrogen sulfide, and nitric oxide as signaling molecules in the gastrointestinal tract. Gastroenterology 147:303-13
Clardy, Stacey L; Lucchinetti, Claudia F; Krecke, Karl N et al. (2014) Hydrocephalus in neuromyelitis optica. Neurology 82:1841-3
Kolar, G J; Camilleri, M; Burton, D et al. (2014) Prevalence of colonic motor or evacuation disorders in patients presenting with chronic nausea and vomiting evaluated by a single gastroenterologist in a tertiary referral practice. Neurogastroenterol Motil 26:131-8
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
Wada, Naoki; Singer, Wolfgang; Gehrking, Tonette L et al. (2014) Determination of vagal baroreflex sensitivity in normal subjects. Muscle Nerve 50:535-40

Showing the most recent 10 out of 83 publications