TY - JOUR
T1 - Targeting oxygen-sensing prolyl hydroxylase for metformin-associated lactic acidosis treatment
AU - Oyaizu-Toramaru, Tomoko
AU - Suhara, Tomohiro
AU - Hayakawa, Noriyo
AU - Nakamura, Takashi
AU - Kubo, Akiko
AU - Minamishima, Shizuka
AU - Yamaguchi, Kyoji
AU - Hishiki, Takako
AU - Morisaki, Hiroshi
AU - Suematsu, Makoto
AU - Minamishima, Yoji Andrew
N1 - Funding Information:
We thank the members of Grant-in-Aid for Scientific Research on Innovative Areas "Oxygen Biology: a New Criterion For Integrated Understanding of Life" (26111006) from The Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, and the members of Keiichi I. Nakayama's laboratory for valuable feedback. The PHD inhibitor REC2923 was kindly provided by Daiichi Sankyo Co. Ltd. Y.A.M. is supported in part by Grant-in-Aid for Scientific Research (B) (23310136 and 16H04723), Grant-in-Aid for Exploratory Research (20593966), and Grant-in-Aid for Scientific Research on Innovative Areas "Oxygen Biology: a New Criterion for Integrated Understanding of Life" (26111006) from The Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. T.S. is supported in part by a research grant from the Mitsukoshi Health and Welfare Foundation, Japan. S.M. is supported in part by a Grant-in-Aid for Exploratory Research (20622088) and Grant-in-Aid for Scientific Research (C) (17K11060) from MEXT, Japan. We declare that we have no conflict of interests.
Publisher Copyright:
© 2017 American Society for Microbiology.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Metformin is one of the most widely used therapeutics for type 2 diabetes mellitus and also has anticancer and antiaging properties. However, it is known to induce metformin-associated lactic acidosis (MALA), a severe medical condition with poor prognosis, especially in individuals with renal dysfunction. Inhibition of prolyl hydroxylase (PHD) is known to activate the transcription factor hypoxiainducible factor (HIF) that increases lactate efflux as a result of enhanced glycolysis, but it also enhances gluconeogenesis from lactate in the liver that contributes to reducing circulating lactate levels. Here, we investigated the outcome of pharmaceutical inhibition of PHD in mice with MALA induced through the administration of metformin per os and an intraperitoneal injection of lactic acid. We found that the PHD inhibitors significantly increased the expression levels of genes involved in gluconeogenesis in the liver and the kidney and significantly improved the survival of mice with MALA. Furthermore, the PHD inhibitor also improved the rate of survival of MALA induced in mice with chronic kidney disease (CKD). Thus, PHD represents a new therapeutic target for MALA, which is a critical complication of metformin therapy.
AB - Metformin is one of the most widely used therapeutics for type 2 diabetes mellitus and also has anticancer and antiaging properties. However, it is known to induce metformin-associated lactic acidosis (MALA), a severe medical condition with poor prognosis, especially in individuals with renal dysfunction. Inhibition of prolyl hydroxylase (PHD) is known to activate the transcription factor hypoxiainducible factor (HIF) that increases lactate efflux as a result of enhanced glycolysis, but it also enhances gluconeogenesis from lactate in the liver that contributes to reducing circulating lactate levels. Here, we investigated the outcome of pharmaceutical inhibition of PHD in mice with MALA induced through the administration of metformin per os and an intraperitoneal injection of lactic acid. We found that the PHD inhibitors significantly increased the expression levels of genes involved in gluconeogenesis in the liver and the kidney and significantly improved the survival of mice with MALA. Furthermore, the PHD inhibitor also improved the rate of survival of MALA induced in mice with chronic kidney disease (CKD). Thus, PHD represents a new therapeutic target for MALA, which is a critical complication of metformin therapy.
KW - CKD
KW - Cori cycle
KW - Gluconeogenesis
KW - HIF
KW - Hypoxia
KW - Lactic acidosis
KW - MALA
KW - Metformin
KW - PHD
KW - Prolyl hydroxylase
UR - http://www.scopus.com/inward/record.url?scp=85026372515&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85026372515&partnerID=8YFLogxK
U2 - 10.1128/MCB.00248-17
DO - 10.1128/MCB.00248-17
M3 - Article
C2 - 28606929
AN - SCOPUS:85026372515
VL - 37
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
SN - 0270-7306
IS - 16
M1 - e00248-17
ER -