Synaptotagmin-7 as a positive regulator of glucose-induced glucagon-like peptide-1 secretion in mice

Diabetologia. 2011 Jul;54(7):1824-30. doi: 10.1007/s00125-011-2119-3. Epub 2011 Mar 22.

Abstract

Aims/hypothesis: Glucagon-like peptide-1 (GLP-1), a hormone with potent antihyperglycaemic effects, is produced and secreted from highly specialised gut endocrine L-cells. It regulates glucose homeostasis by promoting glucose-dependent insulin secretion, suppressing glucagon secretion and enhancing insulin sensitivity. Similar to islet alpha and beta cells, L-cells are electrically excitable, and express calcium channels and ATP-sensitive potassium channels. GLP-1 is also stored in secretory granules, the exocytosis of which is triggered by increased intracellular calcium levels. Although the calcium dependence of GLP-1 granule exocytosis is well established, the identities of calcium-sensing proteins in GLP-1 secretion remain elusive. Here we tested whether synaptotagmin-7, a calcium sensor in pancreatic alpha and beta cells, regulates GLP-1 secretion.

Methods: We studied GLP-1 secretion using synaptotagmin-7 knockout (KO) mice and GLUTag cells with lentiviral-mediated synaptotagmin-7 silencing.

Results: We found that synaptotagmin-7 was co-localised with GLP-1 in intestinal L-cells. GLP-1 secretion was impaired in synaptotagmin-7 KO mice when they were challenged by glucose ingestion. Lentiviral knockdown (KD) of synaptotagmin-7 in GLUTag cells led to similar reductions in GLP-1 secretion, as determined by biochemical assays and by membrane capacitance measurements. Calcium response was not altered in synaptotagmin-7 KD cells.

Conclusions/interpretation: These results demonstrate that synaptotagmin-7 functions as a positive regulator of GLP-1 secretion in intestinal L-cells and GLUTag cells, consistent with its proposed role as a calcium sensor in GLP-1 secretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Electrophysiology
  • Glucagon-Like Peptide 1 / metabolism*
  • Immunohistochemistry
  • Intestines / cytology*
  • Mice
  • Mice, Knockout
  • Polymerase Chain Reaction
  • RNA, Small Interfering / genetics
  • Synaptotagmins / genetics
  • Synaptotagmins / metabolism*

Substances

  • RNA, Small Interfering
  • Synaptotagmins
  • Glucagon-Like Peptide 1