Abstract
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.
| Original language | English |
|---|---|
| Article number | e00248-17 |
| Journal | Molecular and Cellular Biology |
| Volume | 37 |
| Issue number | 16 |
| DOIs | |
| Publication status | Published - 2017 Aug 1 |
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Keywords
- CKD
- Cori cycle
- Gluconeogenesis
- HIF
- Hypoxia
- Lactic acidosis
- MALA
- Metformin
- PHD
- Prolyl hydroxylase
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Cite this
Targeting oxygen-sensing prolyl hydroxylase for metformin-associated lactic acidosis treatment. / Toramaru, Tomoko; Suhara, Tomohiro; Hayakawa, Noriyo; Nakamura, Takashi; Kubo, Akiko; Minamishima, Shizuka; Yamaguchi, Kyoji; Hishiki, Takako; Morisaki, Hiroshi; Suematsu, Makoto; Minamishima, Yoji Andrew.
In: Molecular and Cellular Biology, Vol. 37, No. 16, e00248-17, 01.08.2017.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Targeting oxygen-sensing prolyl hydroxylase for metformin-associated lactic acidosis treatment
AU - 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
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 -