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Cited by 86Gastrointestinal motility and disordersMicroRNA in disease regulationPancreatic function and diabetes

miR-10b-5p Rescues Diabetes and Gastrointestinal Dysmotility

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Singh, Rajan, Ha, Se Eun, Wei, Lai, Jin, Byungchang, Zogg, Hannah, Poudrier, Sandra M., Jorgensen, Brian G., Park, Chanjae +11 more·2021·Gastroenterology
DOI 10.1053/j.gastro.2020.12.062PMC PMC8532043
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Abstract

Background & aims Interstitial cells of Cajal (ICCs) and pancreatic β cells require receptor tyrosine kinase (KIT) to develop and function properly. Degeneration of ICCs is linked to diabetic gastroparesis. The mechanisms linking diabetes and gastroparesis are unclear, but may involve microRNA (miRNA)-mediated post-transcriptional gene silencing in KIT+ cells. Methods We performed miRNA-sequencing analysis from isolated ICCs in diabetic mice and plasma from patients with idiopathic and diabetic gastroparesis. miR-10b-5p target genes were identified and validated in mouse and human cell lines. For loss-of-function studies, we used KIT+ cell-restricted mir-10b knockout mice and KIT+ cell depletion mice. For gain-of-function studies, a synthetic miR-10b-5p mimic was injected in multiple diabetic mouse models. We compared the efficacy of miR-10b-5p mimic treatment vs antidiabetic and prokinetic medicines. Results miR-10b-5p is highly expressed in ICCs from healthy mice, but drastically depleted in ICCs from diabetic mice. A conditional knockout of mir-10b in KIT+ cells or depletion of KIT+ cells in mice leads to degeneration of β cells and ICCs, resulting in diabetes and gastroparesis. miR-10b-5p targets the transcription factor Krüppel-like factor 11 (KLF11), which negatively regulates KIT expression. The miR-10b-5p mimic or Klf11 small interfering RNAs injected into mir-10b knockout mice, diet-induced diabetic mice, and TALLYHO polygenic diabetic mice rescue the diabetes and gastroparesis phenotype for an extended period of time. Furthermore, the miR-10b-5p mimic is more effective in improving glucose homoeostasis and gastrointestinal motility compared with common antidiabetic and prokinetic medications. Conclusions miR-10b-5p is a key regulator in diabetes and gastrointestinal dysmotility via the KLF11-KIT pathway. Restoration of miR-10b-5p may provide therapeutic benefits for these disorders.

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  • In pre-clinical studies, modulation of the SCF/c-KIT pathway has been shown to promote ICC survival, reduce apoptosis, and improve gastric motor function.

    “In pre-clinic studies, modulation of the SCF/c-KIT pathway, has been shown to promote ICC survival, reduce apoptosis, and improve gastric motor function [174, 175].”

    From Diabetic gastroparesis: pathophysiology and impact on insulin timing choices (2026) · cites this paper as [175]

    The Introduction and Results (page unavailable) report that miR-10b-5p regulates KIT, that its loss is associated with ICC degeneration, and that mimic treatment restores KIT expression and improves GI motility in diabetic mice. The Discussion (page unavailable) says SCF and KIT signaling are required for ICC growth and function. The copy does not show that the intervention reduced ICC apoptosis or directly modulated SCF. (LLM, conf=0.86)

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  • ICC survival and network integrity depend on tightly regulated signaling pathways, particularly the SCF/c-KIT signal, which regulates ICC proliferation and function.

    “ICC survival and network integrity depend on tightly regulated signaling pathways, particularly the SCF/c-KIT signal, which regulates ICC proliferation and function [56, 174, 175].”

    From Diabetic gastroparesis: pathophysiology and impact on insulin timing choices (2026) · cites this paper as [175]

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Authors
Singh, R., Ha, S. E., Wei, L., Jin, B., Zogg, H., Poudrier, S. M., Jorgensen, B. G., Park, C., Ronkon, C. F., Bartlett, A., Cho, S., Morales, A., Chung, Y. H., Lee, M. Y., Park, J. K., Gottfried-Blackmore, A., Nguyen, L., Sanders, K. M., & Ro, S.
Affiliations
  • University of Nevada, Reno (US)
  • Wonkwang University (KR)
  • Stanford Medicine (US)
Corresponding author
Ro, Seungil
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2021-04
Volume
160
Issue
5
Pages
1662-1678.e18
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2020.12.062
PMC
PMC8532043
OpenAlex
W3120915673
Cited by
86
References
4
Citations by year
2026: 16 · 2025: 13 · 2024: 23 · 2023: 15 · 2022: 11 · 2021: 8
FWCI
13.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK091725, DK094886, DK103055, P01 DK41315)
Topics
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
miR-10b-5p, diabetic gastroparesis, gastrointestinal motility disorders, interstitial cells of Cajal, pancreatic beta cells, KIT receptor tyrosine kinase, KLF11, microRNA, post-transcriptional regulation, glucose homeostasis, diet-induced diabetes
MeSH terms
Adult, Aged, Animals, Blood Glucose, Diabetes Mellitus, Disease Models, Animal, Female, Gastric Emptying, Gastrointestinal Transit, Humans, Male, Mice, Inbred C57BL, Middle Aged, Repressor Proteins, Mice, Knockout, Gastroparesis, Proto-Oncogene Proteins c-kit, MicroRNAs, NIH 3T3 Cells, Insulin-Secreting Cells, Apoptosis Regulatory Proteins, Mice, Young Adult, Interstitial Cells of Cajal, HEK293 Cells

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