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Cited by 256Pancreatic function and diabetesNeuropeptides and Animal PhysiologyDiabetes Treatment and Management

Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion

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van der Meulen, Talitha, Donaldson, Cynthia J, Cáceres, Elena, Hunter, Anna E, Cowing-Zitron, Christopher, Pound, Lynley D, Adams, Michael W, Zembrzycki, Andreas +2 more·2015·Nature Medicine
DOI 10.1038/nm.3872PMC PMC4496282
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Abstract

The peptide hormone urocortin3 (Ucn3) is abundantly expressed by mature beta cells, yet its physiological role is unknown. Here we demonstrate that Ucn3 is stored and co-released with insulin and potentiates glucose-stimulated somatostatin secretion via cognate receptors on delta cells. Further, we found that islets lacking endogenous Ucn3 have fewer delta cells, reduced somatostatin content, impaired somatostatin secretion, and exaggerated insulin release, and that these defects are rectified by treatment with synthetic Ucn3 in vitro. Our observations indicate that the paracrine actions of Ucn3 activate a negative feedback loop that promotes somatostatin release to ensure the timely reduction of insulin secretion upon normalization of plasma glucose. Moreover, Ucn3 is markedly depleted from beta cells in mouse and macaque models of diabetes and in human diabetic islets. This suggests that Ucn3 is a key contributor to stable glycemic control, whose reduction during diabetes aggravates glycemic volatility and contributes to the pathophysiology of this disease.

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Authors
van der Meulen, T., Donaldson, C. J., Cáceres, E., Hunter, A. E., Cowing-Zitron, C., Pound, L. D., Adams, M. W., Zembrzycki, A., Grove, K. L., & Huising, M. O.
Affiliations
  • Salk Institute for Biological Studies (US)
  • University of California, Davis (US)
  • Oregon National Primate Research Center (US)
Corresponding author
Huising, Mark O
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2015-06-15
Volume
21
Issue
7
Pages
769-776
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.3872
PMC
PMC4496282
OpenAlex
W1940160448
Cited by
256
References
6
Citations by year
2026: 19 · 2025: 16 · 2024: 25 · 2023: 19 · 2022: 29 · 2021: 41 · 2020: 26 · 2019: 25 · 2018: 16 · 2017: 20 · 2016: 15 · 2015: 5
FWCI
18.82
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (P51OD011092)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P01DK026741)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
somatostatin, insulin secretion, pancreatic beta cells, delta cells, negative feedback loop, glucose-stimulated secretion, paracrine signaling, islets, diabetes mellitus, glycemic control, glucocorticoid receptor
MeSH terms
Insulin Secretion, Adolescent, Adult, Aged, Animals, Child, Child, Preschool, Diabetes Mellitus, Female, Gene Expression Regulation, Humans, Hyperglycemia, Infant, Infant, Newborn, Insulin, Macaca, Male, Mice, Inbred C57BL, Middle Aged, Models, Biological, Somatostatin, Tissue Donors, Paracrine Communication, Feedback, Physiological, Insulin-Secreting Cells, Urocortins, Young Adult, HEK293 Cells, Transcriptome

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