Open AccessRole of prolyl hydroxylase domain proteins in the regulation of insulin secretion
Author(s) -
Huang Mei,
Paglialunga Sabina,
Wong Julia M.K.,
Hoang Monica,
Pillai Renjitha,
Joseph Jamie W.
Publication year - 2016
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12722
Subject(s) - gene knockdown , secretion , insulin , hydroxylation , biology , cytosol , biochemistry , endocrinology , enzyme , medicine , microbiology and biotechnology , gene
Type 2 diabetes is associated with impaired nutrient‐regulated anaplerosis and insulin secretion in pancreatic β ‐cells. One key anaplerotic substrate that may be involved in regulating insulin release is α ‐ketoglutarate ( α KG). Since prolyl hydroxylase domain proteins ( PHD s) can metabolize cytosolic α KG, we sought to explore the role of this enzyme in the regulation of β ‐cell function. The oxygen‐sensing PHD s regulate the stability of hypoxia‐inducible factor 1 α (HIF1 α ) as well as other proline‐containing proteins by catalyzing the hydroxylation of proline residues. This reaction is dependent on sufficient levels of oxygen, iron, and α KG. In the present study, we utilized both pharmacological and genetic approaches to assess the impact of inhibiting PHD activity on β ‐cell function. We demonstrate that ethyl‐3,4‐dihydroxybenzoate ( EDHB ), a PHD inhibitor, significantly blunted glucose‐stimulated insulin secretion ( GSIS ) from 832/13 clonal cells, rat, and human islets. EDHB reduced glucose utilization, ATP / ADP ratio, and key TCA cycle intermediates such as pyruvate, citrate, fumarate, and malate. si RNA ‐mediated knockdown of PHD 1 and PHD 3 inhibited GSIS , whereas si RNA ‐mediated knockdown of PHD 2 had no effect on GSIS . Taken together, the current results demonstrate an important role for PHD s as mediators of islet insulin secretion.