Pathophysiology of Diabetic Gastroparesis

Aims To perform an exploratory cohort study including 26 type 1 diabetes (DM1) patients aged 18-85 years with gastroparesis and 26 comparable DM1 diabetes patients without gastroparesis, investigating nerve fibre density and length in the mucosal and submucosal layer of the stomach (fundus, and antrum). A variety of molecular, biochemical and cellular experimental procedures will be performed on bloodsamples and tissue biopsies collected during gastroscopy exploring the pathophysiology of gastroparesis. In addition, we will compare differences in, measures of glucose metabolism in the two patient groups through bloodsamples.

Hypotheses

1. Nerve fibre morphology in the stomach is different in type 1 diabetes patients with diabetic gastroparesis compared to diabetes patient without gastroparesis and associated with differences in glucose metabolism and the severity of autonomic and peripheral neuropathy.

2. Patients with gastroparesis show loss of interstitial cells of Cajal (ICC) in the gastric body, antrum and fundus and have marked morphological changes indicative of injuries.

3. Macrophages are thought to play a central role in diabetic gastroparesis, in which a loss of anti-inflammatory heme-oxygenase-1 (HO-1) positive macrophages leads to decreased protection against oxidative stress, resulting in damage to ICCs.

4. In gastroparesis there is increased presence of fibrosis in the stroma and alteration in inflammatory cells.

5. Patients with gastroparesis may have decreased levels of neurotransmitters such as NO and substance P.

6. Gastroparesis may cause pathological alterations of enteric glial and ganglion cells and the cytoplasm of smooth muscle cells.

7. Patients with gastroparesis have lower pyloric distensibility.

8. Examining transcriptional changes in between groups will reveal new genes associated with disease development. Newly developed in vitro models make it possible to explore and correlate molecular biochemical and cellular factors to disease development and progression.

Study Design All participants will be type 1 diabetes patients attending treatment at Steno Diabetes Center Copenhagen (SDCC) or type 1 diabetes patients referred from other treatment facilities. Patients will fill out the Gastroparesis Cardinal Symptom Index (GCSI) questionnaire and be asked if they have been diagnosed with gastroparesis. Patients with known gastroparesis or with a GCSI score ≥ 1.9 without known gastroparesis will be subject to a technetium scintigraphy. Patients without established gastroparesis and a GCSI score < 1.9 will also undergo technetium scintigraphy. A gastric content above 10%, 4 hours after meal ingestion will be considered the diagnostic threshold for gastroparesis Patients with gastroparesis will be considered as cases and patients without gastroparesis as control. All patients will have a gastroscopy to rule out other causes to gastro-intestinal symptoms. During gastroscopy, 8 biopsies will be obtained and endo-flip will be used to measure distesibility in pylorus. Tissue specimens and blood samples will be collected and used in various research-based analyses to understand the pathophysiology.