title: Suppression of insulin production and secretion by a decretin hormone.
abstract: Decretins, hormones induced by fasting that suppress insulin production and secretion, have been postulated from classical human metabolic studies. From genetic screens, we identified Drosophila Limostatin (Lst), a peptide hormone that suppresses insulin secretion. Lst is induced by nutrient restriction in gut-associated endocrine cells. limostatin deficiency led to hyperinsulinemia, hypoglycemia, and excess adiposity. A conserved 15-residue polypeptide encoded by limostatin suppressed secretion by insulin-producing cells. Targeted knockdown of CG9918, a Drosophila ortholog of Neuromedin U receptors (NMURs), in insulin-producing cells phenocopied limostatin deficiency and attenuated insulin suppression by purified Lst, suggesting CG9918 encodes an Lst receptor. NMUR1 is expressed in islet β cells, and purified NMU suppresses insulin secretion from human islets. A human mutant NMU variant that co-segregates with familial early-onset obesity and hyperinsulinemia fails to suppress insulin secretion. We propose Lst as an index member of an ancient hormone class called decretins, which suppress insulin output.
authors: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Neuroscience Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Ronald W
authors: RW
authors: Alfa
authors: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Sangbin
authors: S
authors: Park
authors: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Kathleen-Rose
authors: KR
authors: Skelly
authors: Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Gregory
authors: G
authors: Poffenberger
authors: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Nimit
authors: N
authors: Jain
authors: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Xueying
authors: X
authors: Gu
authors: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Lutz
authors: L
authors: Kockel
authors: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Jing
authors: J
authors: Wang
authors: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Yinghua
authors: Y
authors: Liu
authors: Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA.
authors: Alvin C
authors: AC
authors: Powers
authors: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine (Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: seungkim@stanford.edu.
authors: Seung K
authors: SK
authors: Kim
mesh_terms: D000328:Adult; D000818:Animals; D002675:Child, Preschool; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D055098:Endocrine Cells / Q000378:metabolism; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000096:biosynthesis* / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008875:Middle Aged; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D036361:Peptide Hormones / Q000378:metabolism*; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D055815:Young Adult
chemical_list: D029721:Drosophila Proteins; D006728:Hormones; D007328:Insulin; C000605942:Lst protein, Drosophila; D009479:Neuropeptides; D036361:Peptide Hormones; D017981:Receptors, Neurotransmitter; C082444:neuromedin U receptor; C056900:neuromedin U
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