Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion

Nature Medicine volume 21, pages 769–776 (2015)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Ucn3 is a paracrine factor expressed by mouse beta cells.
Figure 2: Ucn3-null islets are deficient in delta cell number and somatostatin secretion.
Figure 3: Endogenous Ucn3 promotes somatostatin-mediated negative feedback.
Figure 4: Ucn3 marks mature beta cells and aggravates hyperglycemia.
Figure 5: UCN3 is lost from the beta cells of individuals with type 2 diabetes and pre-diabetic macaques.
Figure 6: Ucn3 promotes somatostatin secretion from delta cells in an incretin-like fashion.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Referenced accessions

Gene Expression Omnibus

References

  1. Lin, H.V. & Accili, D. Hormonal regulation of hepatic glucose production in health and disease. Cell Metab. 14, 9–19 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Leto, D. & Saltiel, A.R. Regulation of glucose transport by insulin: traffic control of GLUT4. Nat. Rev. Mol. Cell Biol. 13, 383–396 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Ramnanan, C.J., Edgerton, D.S., Kraft, G. & Cherrington, A.D. Physiologic action of glucagon on liver glucose metabolism. Diabetes Obes. Metab. 13 (suppl. 1), 118–125 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang, Q. et al. Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes. Cell Metab. 18, 871–882 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Taborsky, G.J. Jr., Smith, P.H. & Porte, D. Jr. Interaction of somatostatin with the A and B cells of the endocrine pancreas. Metabolism 27, 1299–1302 (1978).

    Article  CAS  PubMed  Google Scholar 

  6. Caicedo, A. Paracrine and autocrine interactions in the human islet: more than meets the eye. Semin. Cell Dev. Biol. 24, 11–21 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Patel, Y.C. Somatostatin and its receptor family. Front. Neuroendocrinol. 20, 157–198 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Salehi, A., Qader, S.S., Grapengiesser, E. & Hellman, B. Pulses of somatostatin release are slightly delayed compared with insulin and antisynchronous to glucagon. Regul. Pept. 144, 43–49 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Schuit, F.C., Derde, M.P. & Pipeleers, D.G. Sensitivity of rat pancreatic A and B cells to somatostatin. Diabetologia 32, 207–212 (1989).

    Article  CAS  PubMed  Google Scholar 

  10. Unger, R.H. & Cherrington, A.D. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J. Clin. Invest. 122, 4–12 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Braun, M. et al. Somatostatin release, electrical activity, membrane currents and exocytosis in human pancreatic delta cells. Diabetologia 52, 1566–1578 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Barden, N., Alvarado-Urbina, G., Cote, J.P. & Dupont, A. Cyclic AMP-dependent stimulation of somatostatin secretion by isolated rat islets of Langerhans. Biochem. Biophys. Res. Commun. 71, 840–844 (1976).

    Article  CAS  PubMed  Google Scholar 

  13. Ipp, E. et al. Release of immunoreactive somatostatin from the pancreas in response to glucose, amino acids, pancreozymin-cholecystokinin, and tolbutamide. J. Clin. Invest. 60, 760–765 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schauder, P. et al. Somatostatin and insulin release from isolated rat pancreatic islets stimulated by glucose. FEBS Lett. 68, 225–227 (1976).

    Article  CAS  PubMed  Google Scholar 

  15. Patton, G.S. et al. Pancreatic immunoreactive somatostatin release. Proc. Natl. Acad. Sci. USA 74, 2140–2143 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hauge-Evans, A.C. et al. Somatostatin secreted by islet delta-cells fulfills multiple roles as a paracrine regulator of islet function. Diabetes 58, 403–411 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Göpel, S.O., Kanno, T., Barg, S. & Rorsman, P. Patch-clamp characterisation of somatostatin-secreting -cells in intact mouse pancreatic islets. J. Physiol. (Lond.) 528, 497–507 (2000).

    Article  Google Scholar 

  18. Vieira, E., Salehi, A. & Gylfe, E. Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells. Diabetologia 50, 370–379 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Li, C. et al. Urocortin III is expressed in pancreatic beta-cells and stimulates insulin and glucagon secretion. Endocrinology 144, 3216–3224 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. van der Meulen, T. et al. Urocortin 3 marks mature human primary and embryonic stem cell-derived pancreatic alpha and beta cells. PLoS ONE 7, e52181 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Benner, C. et al. The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression. BMC Genomics 15, 620 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Huising, M.O. & Vale, W.W. Corticotropin-releasing hormone and urocortins: binding proteins and receptors. in Encyclopedia of Neuroscience (ed. Squire, L.R.) 231–237 (Academic Press, Oxford, 2009).

  23. Hsu, S.Y. & Hsueh, A.J. Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nat. Med. 7, 605–611 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Lewis, K. et al. Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proc. Natl. Acad. Sci. USA 98, 7570–7575 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. van der Meulen, T. & Huising, M.O. Maturation of stem cell-derived beta cells guided by the expression of urocortin 3. Rev. Diabet. Stud. 11, 115–132 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Blum, B. et al. Functional beta-cell maturation is marked by an increased glucose threshold and by expression of urocortin 3. Nat. Biotechnol. 30, 261–264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Li, C., Chen, P., Vaughan, J., Lee, K.F. & Vale, W. Urocortin 3 regulates glucose-stimulated insulin secretion and energy homeostasis. Proc. Natl. Acad. Sci. USA 104, 4206–4211 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Huising, M.O. et al. Glucocorticoids differentially regulate the expression of CRFR1 and CRFR2α in MIN6 insulinoma cells and rodent islets. Endocrinology 152, 138–150 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Zhang, J., McKenna, L.B., Bogue, C.W. & Kaestner, K.H. The diabetes gene Hhex maintains delta cell differentiation and islet function. Genes Dev. 28, 829–834 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Artner, I. et al. MafA and MafB regulate genes critical to beta-cells in a unique temporal manner. Diabetes 59, 2530–2539 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bale, T.L. et al. Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nat. Genet. 24, 410–414 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Rivier, J. et al. Potent and long-acting corticotropin releasing factor (CRF) receptor 2 selective peptide competitive antagonists. J. Med. Chem. 45, 4737–4747 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Rorsman, P. & Braun, M. Regulation of insulin secretion in human pancreatic islets. Annu. Rev. Physiol. 75, 155–179 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Rozzo, A., Meneghel-Rozzo, T., Delakorda, S.L., Yang, S.B. & Rupnik, M. Exocytosis of insulin: in vivo maturation of mouse endocrine pancreas. Ann. NY Acad. Sci. 1152, 53–62 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Nygaard, E.B., Moller, C.L., Kievit, P., Grove, K.L. & Andersen, B. Increased fibroblast growth factor 21 expression in high-fat diet-sensitive non-human primates (Macaca mulatta). Int. J. Obes. (Lond) 38, 183–191 (2014).

    Article  CAS  Google Scholar 

  36. Yang, Y.H. et al. Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate beta cell apoptosis signalling via dependence receptors. Diabetologia 54, 828–842 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Rodriguez-Diaz, R. et al. Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans. Nat. Med. 17, 888–892 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Xu, E. et al. Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system. Cell Metab. 3, 47–58 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Yang, Y.H., Manning Fox, J.E., Zhang, K.L., MacDonald, P.E. & Johnson, J.D. Intraislet SLIT-ROBO signaling is required for beta-cell survival and potentiates insulin secretion. Proc. Natl. Acad. Sci. USA 110, 16480–16485 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Ohtani, O., Ushiki, T., Kanazawa, H. & Fujita, T. Microcirculation of the pancreas in the rat and rabbit with special reference to the insulo-acinar portal system and emissary vein of the islet. Arch. Histol. Jpn. 49, 45–60 (1986).

    Article  CAS  PubMed  Google Scholar 

  41. Liu, Y.M., Guth, P.H., Kaneko, K., Livingston, E.H. & Brunicardi, F.C. Dynamic in vivo observation of rat islet microcirculation. Pancreas 8, 15–21 (1993).

    Article  CAS  PubMed  Google Scholar 

  42. Murakami, T. et al. The insulo-acinar portal and insulo-venous drainage systems in the pancreas of the mouse, dog, monkey and certain other animals: a scanning electron microscopic study of corrosion casts. Arch. Histol. Cytol. 56, 127–147 (1993).

    Article  CAS  PubMed  Google Scholar 

  43. Bonner-Weir, S. & Orci, L. New perspectives on the microvasculature of the islets of Langerhans in the rat. Diabetes 31, 883–889 (1982).

    Article  CAS  PubMed  Google Scholar 

  44. Stagner, J.I., Samols, E. & Bonner-Weir, S. beta-alpha-delta pancreatic islet cellular perfusion in dogs. Diabetes 37, 1715–1721 (1988).

    Article  CAS  PubMed  Google Scholar 

  45. Samols, E. & Stagner, J.I. Islet somatostatin–microvascular, paracrine, and pulsatile regulation. Metabolism 39, 55–60 (1990).

    Article  CAS  PubMed  Google Scholar 

  46. Nyman, L.R. et al. Real-time, multidimensional in vivo imaging used to investigate blood flow in mouse pancreatic islets. J. Clin. Invest. 118, 3790–3797 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Benninger, R.K., Zhang, M., Head, W.S., Satin, L.S. & Piston, D.W. Gap junction coupling and calcium waves in the pancreatic islet. Biophys. J. 95, 5048–5061 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ravier, M.A. et al. Loss of connexin36 channels alters beta-cell coupling, islet synchronization of glucose-induced Ca2+ and insulin oscillations, and basal insulin release. Diabetes 54, 1798–1807 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Head, W.S. et al. Connexin-36 gap junctions regulate in vivo first- and second-phase insulin secretion dynamics and glucose tolerance in the conscious mouse. Diabetes 61, 1700–1707 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jørgensen, M.C. et al. An illustrated review of early pancreas development in the mouse. Endocr. Rev. 28, 685–705 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Herrera, P.L. et al. Embryogenesis of the murine endocrine pancreas; early expression of pancreatic polypeptide gene. Development 113, 1257–1265 (1991).

    CAS  PubMed  Google Scholar 

  52. Gromada, J., Franklin, I. & Wollheim, C.B. Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr. Rev. 28, 84–116 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Unger, R.H. & Orci, L. Paracrinology of islets and the paracrinopathy of diabetes. Proc. Natl. Acad. Sci. USA 107, 16009–16012 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Huising, M.O. et al. CRFR1 is expressed on pancreatic beta cells, promotes beta cell proliferation, and potentiates insulin secretion in a glucose-dependent manner. Proc. Natl. Acad. Sci. USA 107, 912–917 (2010).

    Article  PubMed  Google Scholar 

  55. Huising, M.O. et al. Residues of corticotropin releasing factor-binding protein (CRF-BP) that selectively abrogate binding to CRF but not to urocortin 1. J. Biol. Chem. 283, 8902–8912 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Asfari, M. et al. Establishment of 2-mercaptoethanol-dependent differentiated insulin-secreting cell lines. Endocrinology 130, 167–178 (1992).

    Article  CAS  PubMed  Google Scholar 

  57. Taniguchi, H. et al. A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron 71, 995–1013 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Herrera, P.L. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 127, 2317–2322 (2000).

    CAS  PubMed  Google Scholar 

  59. Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Reubi, J.C. et al. SST3-selective potent peptidic somatostatin receptor antagonists. Proc. Natl. Acad. Sci. USA 97, 13973–13978 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cescato, R. et al. Design and in vitro characterization of highly sst2-selective somatostatin antagonists suitable for radiotargeting. J. Med. Chem. 51, 4030–4037 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

    Article  CAS  PubMed  Google Scholar 

  63. Quinlan, A.R. & Hall, I.M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Anders, S. & Huber, W. Differential expression analysis for sequence count data. Genome Biol. 11, R106 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

  66. Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Brazeau, P. et al. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179, 77–79 (1973).

    Article  CAS  PubMed  Google Scholar 

  68. Vale, W., Rivier, J., Ling, N. & Brown, M. Biologic and immunologic activities and applications of somatostatin analogs. Metabolism 27, 1391–1401 (1978).

    Article  CAS  PubMed  Google Scholar 

  69. Vaughan, J.M. et al. Detection and purification of inhibin using antisera generated against synthetic peptide fragments. Methods Enzymol. 168, 588–617 (1989).

    Article  CAS  PubMed  Google Scholar 

  70. Padmanabhan, K., Eddy, W.F. & Crowley, J.C. A novel algorithm for optimal image thresholding of biological data. J. Neurosci. Methods 193, 380–384 (2010).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We dedicate this work to the memory of Wylie W. Vale (W.W.V.), who co-discovered both somatostatin (in 1973) and urocortin 3 (in 2001) and who would have been delighted by their participation in the same feedback loop. We acquired images at the Waitt Advanced Biophotonics Center at the Salk Institute and at the Veterinary Medicine Advanced Imaging Facility and Plant Biology core facilities at University of California Davis. We acknowledge N. Justice (University of Texas Health Science Center, Houston, Texas, USA) for generating the BAC construct used to generate the Crhr2α−mCherry−Cre reporter line. We acknowledge J. Vaughan for iodination of tracers and H. Park, K. Tigyi and S. Dólleman for their excellent assistance with various aspects of these studies. We thank R. Yang and K. Nakamura at Dexcom Inc. for their assistance in unblinding CGM data at the conclusion of the CGM experiment. We performed this research with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative Type 1 diabetes research project sponsored by the Juvenile Diabetes Research Foundation (JDRF). We obtained human islets through the integrated islet distribution program (IIDP). M.O.H. is the recipient of a Career Development Award of the JDRF. These studies were supported by grants 17−2012−424 and 2−2013−54 from the JDRF (to M.O.H.), P01−DK026741 from the US National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (to W.W.V.) and the Clayton Medical Research Foundation, Inc. (to M.O.H. and W.W.V.) The nonhuman primate studies at the Oregon National Primate Research Center (ONPRC) Obese Resource were funded by US National Institutes of Health/Office of the Director grant P51 OD011092 (to K.L.G.). We first reported these findings at the Emerging Concepts and Targets in Islet Biology meeting in Keystone, Colorado on April 8, 2014 and the 73rd and 74th Scientific Sessions of the American Diabetes Association in Chicago on June 23, 2013 and San Francisco on June 16, 2014, respectively.

Author information

Authors and Affiliations

  1. Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, California, USA

    Talitha van der Meulen, Anna E Hunter, Christopher Cowing-Zitron & Mark O Huising

  2. Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California, USA

    Talitha van der Meulen, Cynthia J Donaldson, Elena Cáceres, Anna E Hunter & Mark O Huising

  3. Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA

    Lynley D Pound & Kevin L Grove

  4. Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, La Jolla, California, USA

    Michael W Adams

  5. Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA

    Andreas Zembrzycki

  6. Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, Davis, California, USA.,

    Mark O Huising

Authors
  1. Talitha van der Meulen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cynthia J Donaldson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elena Cáceres
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna E Hunter
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christopher Cowing-Zitron
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lynley D Pound
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael W Adams
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andreas Zembrzycki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kevin L Grove
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mark O Huising
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.v.d.M. and M.O.H. validated the mouse models generated over the course of this study and designed all mouse experiments. T.v.d.M., E.C., A.E.H., A.Z. and M.O.H. performed mouse experiments. T.v.d.M., C.J.D., A.E.H. and M.O.H. performed many islet isolations. C.J.D. performed all insulin and somatostatin hormone measurements and coordinated the receipt of human islets. E.C. and M.O.H. designed, performed and analyzed the continuous glucose monitoring experiment. C.C.-Z. and M.O.H. performed bioinformatics analyses. T.v.d.M. and M.O.H. conducted immunolabeling and acquired all images. M.W.A. performed super-resolution structured illumination microscopy and supported image acquisition and analysis. L.D.P. and K.L.G. designed and conducted the nonhuman primate studies and provided the histological material used in this study. M.O.H. conceived the study, was responsible for its overall design and planning and wrote the article together with T.v.d.M.

Corresponding author

Correspondence to Mark O Huising.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 & Supplementary Tables 1–5 (PDF 13484 kb)

Supplementary Video 1 (MOV 10531 kb)

Source data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

van der Meulen, T., Donaldson, C., Cáceres, E. et al. Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion. Nat Med 21, 769–776 (2015). https://doi.org/10.1038/nm.3872

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3872

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing