2. Academic Validation
  3. Suppression of insulin production and secretion by a decretin hormone

Suppression of insulin production and secretion by a decretin hormone

  • Cell Metab. 2015 Feb 3;21(2):323-334. doi: 10.1016/j.cmet.2015.01.006.
Ronald W Alfa 1,  Sangbin Park 2,  Kathleen-Rose Skelly 2,  Gregory Poffenberger 3,  Nimit Jain 4,  Xueying Gu 2,  Lutz Kockel 2,  Jing Wang 2,  Yinghua Liu 2,  Alvin C Powers 5,  Seung K Kim 6
Affiliations

Affiliations

  • 1 Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Neuroscience Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 2 Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 3 Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 4 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.
  • 5 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.
  • 6 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.
PMID: 25651184 DOI: 10.1016/j.cmet.2015.01.006
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.

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