This proposal (Project 3) continues to focus on understanding the prevalence and pathophysiology of gastric emptying disturbances, particularly the contribution of chronic hyperglycemia (Aim 1), the effects of modulating gastric emptying on glycemic control (Aim 2), and the contribution of small intestinal sensitivity to symptoms in diabetic gastroparesis (Aim 3). Delayed gastric emptying in diabetes mellitus (DM) is attributed to autonomic dysfunctions, hyperglycemia, loss of interstitial cells of Cajal (Project 1) and an enteropathy (Project 2). The Diabetes Control and Complications Trial and the ongoing Epidemiology of Diabetes Interventions and Complications (EDIC) Study, implicated chronic hyperglycemia in the pathogenesis of complications of type 1 DM (T1DM) other than delayed gastric emptying. However, the contribution of chronic hyperglycemia to delayed gastric emptying in DM is unclear. Our preliminary findings suggest that (i) chronic hyperglycemia is a significant risk factor for delayed gastric emptying in T1DM patients in the EDIC study, (ii) delayed gastric emptying is associated with poorer glycemic control, and (iii) diabetic gastroparesis is associated with increased sensitivity during duodenal nutrient infusion and increased epithelial permeability.
Our specific aims are to: (i) compare symptoms, the diabetic phenotype, chronic glycemic control, and epigenetic markers between T1DM patients with normal and delayed GE in the EDIC study, (ii) evaluate the effects of stimulating ghrelin receptors on gastric emptying, control of glycemia, and symptoms in patients with poorly-controlled DM, and (iii) investigate the pathophysiology of increased intestinal chemosensitivity, specifically vagal function, the small bowel epithelial barrier, and GLP-1 in DM. A multi-disciplinary collaborative team will apply innovative approaches to address these hypotheses in a highly refined manner. Each study is designed to understand the pathophysiology of symptoms and/or to improve patient care in humans.

Public Health Relevance

Many people have symptoms (abdominal discomfort, nausea, vomiting) due to diabetes mellitus or functional dyspepsia (indigestion). Our studies have the potential to refine diagnostic tests, uncover mechanisms, and identify new medications for these conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK068055-12
Application #
9109608
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
12
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Cipriani, Gianluca; Gibbons, Simon J; Miller, Katie E et al. (2018) Change in Populations of Macrophages Promotes Development of Delayed Gastric Emptying in Mice. Gastroenterology 154:2122-2136.e12
Desai, A; O'Connor, M; Neja, B et al. (2018) Reproducibility of gastric emptying assessed with scintigraphy in patients with upper GI symptoms. Neurogastroenterol Motil 30:e13365
Miller, K E; Bajzer, Ž; Hein, S S et al. (2018) High temporal resolution gastric emptying breath tests in mice. Neurogastroenterol Motil :e13333
Karakashev, Sergey; Zhu, Hengrui; Wu, Shuai et al. (2018) CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity. Nat Commun 9:631
Rajan, Elizabeth; Al-Bawardy, Badr; Gostout, Christopher J et al. (2018) Endoscopic muscle biopsy sampling of the duodenum and rectum: a pilot survival study in a porcine model to detect myenteric neurons. Gastrointest Endosc 87:600-606
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Gibbons, Simon J; Grover, Madhusudan; Choi, Kyoung Moo et al. (2017) Repeat polymorphisms in the Homo sapiens heme oxygenase-1 gene in diabetic and idiopathic gastroparesis. PLoS One 12:e0187772
Hayashi, Yujiro; Toyomasu, Yoshitaka; Saravanaperumal, Siva Arumugam et al. (2017) Hyperglycemia Increases Interstitial Cells of Cajal via MAPK1 and MAPK3 Signaling to ETV1 and KIT, Leading to Rapid Gastric Emptying. Gastroenterology 153:521-535.e20
Camilleri, Michael; McCallum, Richard W; Tack, Jan et al. (2017) Efficacy and Safety of Relamorelin in Diabetics With Symptoms of Gastroparesis: A Randomized, Placebo-Controlled Study. Gastroenterology 153:1240-1250.e2
Eisenman, S T; Gibbons, S J; Verhulst, P-J et al. (2017) Tumor necrosis factor alpha derived from classically activated ""M1"" macrophages reduces interstitial cell of Cajal numbers. Neurogastroenterol Motil 29:

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