Role of prolyl hydroxylase domain proteins in the regulation of insulin secretion

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 (αKG). Since prolyl hydroxylase domain proteins (PHDs) can metabolize cytosolic...

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Main Authors:	Huang, Mei, Paglialunga, Sabina, Wong, Julia M.‐K., Hoang, Monica, Pillai, Renjitha, Joseph, Jamie W.
Format:	Online
Language:	English
Published:	John Wiley and Sons Inc. 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823601/

id	pubmed-4823601
recordtype	oai_dc
spelling	pubmed-48236012016-04-18 Role of prolyl hydroxylase domain proteins in the regulation of insulin secretion Huang, Mei Paglialunga, Sabina Wong, Julia M.‐K. Hoang, Monica Pillai, Renjitha Joseph, Jamie W. Original Research 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 (αKG). Since prolyl hydroxylase domain proteins (PHDs) can metabolize cytosolic αKG, we sought to explore the role of this enzyme in the regulation of β‐cell function. The oxygen‐sensing PHDs regulate the stability of hypoxia‐inducible factor 1α (HIF1α) 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 αKG. 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. siRNA‐mediated knockdown of PHD1 and PHD3 inhibited GSIS, whereas siRNA‐mediated knockdown of PHD2 had no effect on GSIS. Taken together, the current results demonstrate an important role for PHDs as mediators of islet insulin secretion. John Wiley and Sons Inc. 2016-03-20 /pmc/articles/PMC4823601/ /pubmed/26997627 http://dx.doi.org/10.14814/phy2.12722 Text en © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Huang, Mei Paglialunga, Sabina Wong, Julia M.‐K. Hoang, Monica Pillai, Renjitha Joseph, Jamie W.
spellingShingle	Huang, Mei Paglialunga, Sabina Wong, Julia M.‐K. Hoang, Monica Pillai, Renjitha Joseph, Jamie W. Role of prolyl hydroxylase domain proteins in the regulation of insulin secretion
author_facet	Huang, Mei Paglialunga, Sabina Wong, Julia M.‐K. Hoang, Monica Pillai, Renjitha Joseph, Jamie W.
author_sort	Huang, Mei
title	Role of prolyl hydroxylase domain proteins in the regulation of insulin secretion
title_short	Role of prolyl hydroxylase domain proteins in the regulation of insulin secretion
title_full	Role of prolyl hydroxylase domain proteins in the regulation of insulin secretion
title_fullStr	Role of prolyl hydroxylase domain proteins in the regulation of insulin secretion
title_full_unstemmed	Role of prolyl hydroxylase domain proteins in the regulation of insulin secretion
title_sort	role of prolyl hydroxylase domain proteins in the regulation of insulin secretion
description	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 (αKG). Since prolyl hydroxylase domain proteins (PHDs) can metabolize cytosolic αKG, we sought to explore the role of this enzyme in the regulation of β‐cell function. The oxygen‐sensing PHDs regulate the stability of hypoxia‐inducible factor 1α (HIF1α) 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 αKG. 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. siRNA‐mediated knockdown of PHD1 and PHD3 inhibited GSIS, whereas siRNA‐mediated knockdown of PHD2 had no effect on GSIS. Taken together, the current results demonstrate an important role for PHDs as mediators of islet insulin secretion.
publisher	John Wiley and Sons Inc.
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823601/
_version_	1613563359973605376

Role of prolyl hydroxylase domain proteins in the regulation of insulin secretion

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