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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Child, Preschool
  • Drosophila
  • Drosophila Proteins / metabolism*
  • Endocrine Cells / metabolism
  • Hormones / metabolism*
  • Humans
  • Insulin / biosynthesis*
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / metabolism
  • Middle Aged
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Peptide Hormones / metabolism*
  • Receptors, Neurotransmitter / metabolism
  • Young Adult

Substances

  • Drosophila Proteins
  • Hormones
  • Insulin
  • Lst protein, Drosophila
  • Neuropeptides
  • Peptide Hormones
  • Receptors, Neurotransmitter
  • neuromedin U receptor
  • neuromedin U