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
  • 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: [email protected].
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.

Products