Diabetic gastroparesis is one of most common gastrointestinal complications of diabetes and is associated with significant morbidity. In previous work, we determined that hallmarks of the disease are loss of heme oxygenase 1 (HOI), increased reactive oxygen species (ROS) and subsequent loss of interstitial cells of Cajal (ICC). In preliminary experiments for this proposal, we have made the following key observations. (1) Induction of HOI in the stomach occurs primarily in M2 macrophages in the stomach wall. (2) Tissue from patients with diabetes without gastroparesis contains H01 expressing macrophages. HOI expression is very low in tissue from patients with diabetic gastroparesis. (3) Addition of advanced glycation end products (AGE) or ROS to cultures result in loss of ICC. (4) Induction of HOI reverses molecular and electrophysiological changes associated with delayed gastric emptying. (5) Tachygastria is present in diabetic mice with delayed gastric emptying and is reversed with hemin treatment. (6) Inhaled CO reverses delayed gastric emptying. (7) Flow cytometry on tissue from diabetic mice with and without delayed gastric emptying allows us to determine numbers of cell, including ICC and M1 and M2 macrophages in the stomach. (8) The pyrimidine rich region in the promoter of the hmox-1 gene predicts delayed gastric emptying. Our overall hypothesis is that, in diabetes, damage to ICC and development of delayed gastric emptying is a result of an alteration in the balance between ICC loss factors such as ROS and AGE and the cytoprotective effects of induction of HOI in M2 macrophages. Induction of HOI, or use of the products of HOI activity, after development of delayed gastric emptying will re-establish the balance between survival factors and loss factors and restore normal gastric emptying. The overall hypothesis will be tested in two specific aims. SA 1 will determine the role of HOI in preventing the development of diabetic gastroparesis and SA 2 will determine the mechanisms that regulate HOI activity in diabetes. We will utilize a 13C octanoic acid gastric emptying test, electrophysiology, immunohlstochemistry, molecular biology techniques, flow cytometry, FACS and ICC cultures to address the specific aims. Successful completion of the proposed studies has both basic significance and clinical impact. Our work will shed light on basic mechanisms that underlie the cellular and molecular events linked to the development of diabetic gastroparesis. Our proposed work also goes further towards understanding and testing strategies to reverse or prevent diabetic gastroparesis that will be directly used by Project 3 to guide clinical trials.

Public Health Relevance

Our work is relevant at the basic science level and also at the therapeutic level. We will study the basic mechanisms that lead to the development of diabetic gastroparesis and we will test strategies to reverse diabetic gastroparesis, leading to clinical trials. Our work also has broad implications beyond the gastrointestinal tract as the studied pathways are applicable to any cell type and therefore the work has implications for increasing the understanding of other complications of diabetes and for developing treatment options.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK068055-09
Application #
8668487
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (J1))
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2013
Total Cost
$328,338
Indirect Cost
$120,136
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Cipriani, Gianluca; Gibbons, Simon J; Verhulst, Pieter-Jan et al. (2016) Diabetic Csf1(op/op) mice lacking macrophages are protected against the development of delayed gastric emptying. Cell Mol Gastroenterol Hepatol 2:40-47
Rajan, Elizabeth; Gostout, Christopher J; Wong Kee Song, Louis M et al. (2016) Innovative gastric endoscopic muscle biopsy to identify all cell types, including myenteric neurons and interstitial cells of Cajal in patients with idiopathic gastroparesis: a feasibility study (with video). Gastrointest Endosc 84:512-7
Cipriani, Gianluca; Gibbons, Simon J; Kashyap, Purna C et al. (2016) Intrinsic Gastrointestinal Macrophages: Their Phenotype and Role in Gastrointestinal Motility. Cell Mol Gastroenterol Hepatol 2:120-130.e1
Nelson, A D; Camilleri, M; Acosta, A et al. (2016) Effects of ghrelin receptor agonist, relamorelin, on gastric motor functions and satiation in healthy volunteers. Neurogastroenterol Motil 28:1705-1713
Wang, Zhiquan; Zhang, Honglian; Liu, Ji et al. (2016) USP51 deubiquitylates H2AK13,15ub and regulates DNA damage response. Genes Dev 30:946-59
Yan, Huihuang; Tian, Shulan; Slager, Susan L et al. (2016) Genome-Wide Epigenetic Studies in Human Disease: A Primer on -Omic Technologies. Am J Epidemiol 183:96-109
Choi, Kyoung Moo; Gibbons, Simon J; Sha, Lei et al. (2016) Interleukin 10 Restores Gastric Emptying, Electrical Activity, and Interstitial Cells of Cajal Networks in Diabetic Mice. Cell Mol Gastroenterol Hepatol 2:454-467
Eisenman, S T; Gibbons, S J; Verhulst, P-J et al. (2016) Tumor necrosis factor alpha derived from classically activated ""M1"" macrophages reduces interstitial cell of Cajal numbers. Neurogastroenterol Motil :
Bharucha, A E; Daley, S L; Low, P A et al. (2016) Effects of hemin on heme oxygenase-1, gastric emptying, and symptoms in diabetic gastroparesis. Neurogastroenterol Motil 28:1731-1740
Halland, Magnus; Bharucha, Adil E (2016) Relationship Between Control of Glycemia and Gastric Emptying Disturbances in Diabetes Mellitus. Clin Gastroenterol Hepatol 14:929-36

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