Bace2 is a β cell-enriched protease that regulates pancreatic β cell function and mass

Cell Metab. 2011 Sep 7;14(3):365-77. doi: 10.1016/j.cmet.2011.06.018.

Abstract

Decreased β cell mass and function are hallmarks of type 2 diabetes. Here we identified, through a siRNA screen, beta site amyloid precursor protein cleaving enzyme 2 (Bace2) as the sheddase of the proproliferative plasma membrane protein Tmem27 in murine and human β cells. Mice with functionally inactive Bace2 and insulin-resistant mice treated with a newly identified Bace2 inhibitor both display augmented β cell mass and improved control of glucose homeostasis due to increased insulin levels. These results implicate Bace2 in the control of β cell maintenance and provide a rational strategy to inhibit this protease for the expansion of functional pancreatic β cell mass.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases* / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases* / genetics
  • Amyloid Precursor Protein Secretases* / metabolism
  • Animals
  • Aspartic Acid Endopeptidases* / antagonists & inhibitors
  • Aspartic Acid Endopeptidases* / genetics
  • Aspartic Acid Endopeptidases* / metabolism
  • Blood Glucose / analysis
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gene Silencing / drug effects
  • Humans
  • Insulin / metabolism*
  • Insulin / pharmacology
  • Insulin Resistance
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Molecular Sequence Data
  • Plasmids
  • RNA, Small Interfering / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics*
  • Species Specificity
  • Substrate Specificity
  • Transfection

Substances

  • Bace2 protein, mouse
  • Blood Glucose
  • Enzyme Inhibitors
  • Insulin
  • Membrane Glycoproteins
  • RNA, Small Interfering
  • Tmem27 protein, mouse
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases