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Cited by 239Gastrointestinal motility and disordersHeme Oxygenase-1 and Carbon MonoxideCongenital gastrointestinal and neural anomalies

Heme Oxygenase-1 Protects Interstitial Cells of Cajal From Oxidative Stress and Reverses Diabetic Gastroparesis

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Choi, Kyoung Moo, Gibbons, Simon J., Nguyen, Tien V., Stoltz, Gary J., Lurken, Matthew S., Ordog, Tamas, Szurszewski, Joseph H., Farrugia, Gianrico·2008·Gastroenterology
DOI 10.1053/j.gastro.2008.09.003PMC PMC2796242
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Abstract

Background & aims Diabetic gastroparesis (delayed gastric emptying) is a well-recognized complication of diabetes that causes considerable morbidity and makes glucose control difficult. Interstitial cells of Cajal, which express the receptor tyrosine kinase Kit, are required for normal gastric emptying. We proposed that Kit expression is lost during diabetic gastroparesis due to increased levels of oxidative stress caused by low levels of heme oxygenase-1 (HO-1), an important cytoprotective molecule against oxidative injury. Methods Gastric emptying was measured in nonobese diabetic mice and correlated with levels of HO-1 expression and activity. Endogenous HO-1 activity was increased by administration of hemin and inhibited by chromium mesoporphyrin. Results In early stages of diabetes, HO-1 was up-regulated in gastric macrophages and remained up-regulated in all mice that were resistant to development of delayed gastric emptying. In contrast, HO-1 did not remain up-regulated in all the mice that developed delayed gastric emptying; expression of Kit and neuronal nitric oxide synthase decreased markedly in these mice. Loss of HO-1 up-regulation increased levels of reactive oxygen species. Induction of HO-1 by hemin decreased reactive oxygen species, rapidly restored Kit and neuronal nitric oxide synthase expression, and completely normalized gastric emptying in all mice. Inhibition of HO-1 activity in mice with normal gastric emptying caused a loss of Kit expression and development of diabetic gastroparesis. Conclusions Induction of the HO-1 pathway prevents and reverses cellular changes that lead to development of gastrointestinal complications of diabetes. Reagents that induce this pathway might therefore be developed as therapeutics.

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  • In diabetes, insulin and IGF-1 deficiency causes muscle atrophy and reduced SCF production, leading to ICC depletion and impaired neuromuscular transmission.

    “In diabetes, insulin and IGF-1 deficiency causes muscle atrophy and reduced SCF production, leading to ICC depletion and impaired neuromuscular transmission [52–60].”

    From Diabetic gastroparesis: pathophysiology and impact on insulin timing choices (2026) · cites this paper as [57]

    The introductory passage (page unavailable) reports ICC loss in diabetic gastroparesis, says stem cell factor is required for ICC survival, and explains ICC’s role in signaling to smooth muscle. The paper does not state that insulin and IGF-1 deficiency causes muscle atrophy or reduced stem cell factor production, nor does it establish that proposed causal chain; its Discussion instead focuses on oxidative stress and HO1. (LLM, conf=0.83)

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  • Reduced expression of the enzyme HO-1 promotes ICC loss and the development of gastroparesis.

    “also the enzyme HO-1 reduced expression promotes ICC loss and the development of gastroparesis [57].”

    From Diabetic gastroparesis: pathophysiology and impact on insulin timing choices (2026) · cites this paper as [57]

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Authors
Choi, K. M., Gibbons, S. J., Nguyen, T. V., Stoltz, G. J., Lurken, M. S., Ordog, T., Szurszewski, J. H., & Farrugia, G.
Affiliations
Mayo Clinic (US)
Corresponding author
Farrugia, Gianrico
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2008-12
Volume
135
Issue
6
Pages
2055-2064.e2
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2008.09.003
PMC
PMC2796242
OpenAlex
W2085743669
Cited by
239
References
1
Citations by year
2026: 7 · 2025: 9 · 2024: 5 · 2023: 16 · 2022: 8 · 2021: 16 · 2020: 13 · 2019: 11 · 2018: 20 · 2017: 16 · 2016: 14 · 2015: 12 · 2014: 21 · 2013: 19 · 2012: 11
FWCI
12.76
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (DK57061, DK-68055, P01DK068055, R01DK057061)
Topics
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
  • Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
Keywords
heme oxygenase-1, diabetic gastroparesis, interstitial cells of Cajal, KIT receptor, oxidative stress, delayed gastric emptying, hemin, chromium mesoporphyrin, neuronal nitric oxide synthase, reactive oxygen species, NOD mice, gastrointestinal complications of diabetes
MeSH terms
Animals, Diabetes Mellitus, Experimental, Female, Follow-Up Studies, Gastric Emptying, Gastric Mucosa, Immunohistochemistry, Blotting, Western, Mice, Inbred NOD, Oxidative Stress, Disease Progression, Gastroparesis, Mice, Heme Oxygenase-1

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