title: 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.
authors.affiliation: 1] Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, California, USA. [2] Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Talitha
authors.initials: T
authors.lastname: van der Meulen
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Donaldson
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Cáceres
authors.affiliation: 1] Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, California, USA. [2] Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Hunter
authors.affiliation: Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, California, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Cowing-Zitron
authors.affiliation: Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health &Science University, Beaverton, Oregon, USA.
authors.forename: Lynley D
authors.initials: LD
authors.lastname: Pound
authors.affiliation: Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Adams
authors.affiliation: Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Andreas
authors.identifier: 0000000184684195
authors.initials: A
authors.lastname: Zembrzycki
authors.affiliation: Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health &Science University, Beaverton, Oregon, USA.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Grove
authors.affiliation: 1] Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, California, USA. [2] Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California, USA. [3] Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, Davis, California, USA.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Huising
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D002675:Child, Preschool; D003920:Diabetes Mellitus / Q000235:genetics / Q000473:pathology; D025461:Feedback, Physiological; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000473:pathology; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008251:Macaca; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008954:Models, Biological; D019899:Paracrine Communication; D013004:Somatostatin / Q000378:metabolism*; D014019:Tissue Donors; D059467:Transcriptome / Q000235:genetics; D054832:Urocortins / Q000172:deficiency / Q000378:metabolism*; D055815:Young Adult
chemical_list: D007328:Insulin; D054832:Urocortins; D013004:Somatostatin