Targeting oxygen-sensing prolyl hydroxylase for metformin-associated lactic acidosis treatment

Tomoko Toramaru, Tomohiro Suhara, Noriyo Hayakawa, Takashi Nakamura, Akiko Kubo, Shizuka Minamishima, Kyoji Yamaguchi, Takako Hishiki, Hiroshi Morisaki, Makoto Suematsu, Yoji Andrew Minamishima

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 languageEnglish
Article numbere00248-17
JournalMolecular and Cellular Biology
Volume37
Issue number16
DOIs
Publication statusPublished - 2017 Aug 1

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Prolyl Hydroxylases
Lactic Acidosis
Metformin
Oxygen
Prolyl-Hydroxylase Inhibitors
Lactic Acid
Gluconeogenesis
Therapeutics
Kidney
Liver
Glycolysis
Intraperitoneal Injections
Chronic Renal Insufficiency
Type 2 Diabetes Mellitus
Transcription Factors
Gene Expression

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 journalArticle

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