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Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion

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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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.

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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.

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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.

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Correspondence to Mark O Huising.

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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

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