Metformin: A Candidate Drug for Renal Diseases

Abstract

Over the past decades metformin has been the optimal first-line treatment for type 2 diabetes mellitus (T2DM). Only in the last few years, it has become increasingly clear that metformin exerts benign pleiotropic actions beyond its prescribed use and ongoing investigations focus on a putative beneficial impact of metformin on the kidney. Both acute kidney injury (AKI) and chronic kidney disease (CKD), two major renal health issues, often result in the need for renal replacement therapy (dialysis or transplantation) with a high socio-economic impact for the patients. Unfortunately, to date, effective treatment directly targeting the kidney is lacking. Metformin has been shown to exert beneficial effects on the kidney in various clinical trials and experimental studies performed in divergent rodent models representing different types of renal diseases going from AKI to CKD. Despite growing evidence on metformin as a candidate drug for renal diseases, in-depth research is imperative to unravel the molecular signaling pathways responsible for metformin's renoprotective actions. This review will discuss the current state-of-the-art literature on clinical and preclinical data, and put forward potential cellular mechanisms and molecular pathways by which metformin ameliorates AKI/CKD.

Keywords: AMP-activated protein kinase pathway; acute kidney injury; chronic kidney disease; lactic acidosis; metformin; renoprotection; type 2 diabetes mellitus.

Figure 1

Five stages of chronic kidney disease based on the estimated glomerular filtration rate (eGFR) (mL/min per 1.73 m²).

Figure 2

Association between the biochemistry of lactate production and metformin use. Glycolysis is the metabolic pathway that converts glucose into pyruvate in the cytoplasm. Pyruvate is the only precursor of lactate. (1) When oxygen is available, pyruvate enters the mitochondria, and is converted to Acetyl CoA and oxidized in the Krebs cycle, delivering nicotinamide adenine dinucleotide (NADH), flavin adenine dinucleotide (FADH2), and adenosine triphosphate (ATP). NADH and FADH2 feed the electron transport chain in the inner mitochondrial membrane to eventually generate the bulk of ATP by chemiosmosis. (2) Under anaerobic conditions, pyruvate is reduced to lactate. However, in the liver and kidney, lactate can be converted to pyruvate again by the Cori cycle. (3) Pyruvate, the first designated substrate of the gluconeogenic pathway, can be used to generate glucose. Metformin inhibits gluconeogenesis, leading to pyruvate accumulation and subsequent increased lactate production. It also inhibits the electron transport chain, resulting in elevated levels of NADH, a reduced Krebs cycle flow and, hence, further contributing to increased pyruvate levels. Figure was produced using Servier Medical Art: https://smart.servier.com/ (accessed on 25 October 2018).

Figure 3

Potential underlying molecular mechanisms of metformin’s renoprotection. Metformin is transported into the renal tubular cells mainly through the plasma membrane transporter OCT2. Inside the renal cell metformin activates AMPK via two separate mechanisms, i.e., the inhibition of the mitochondrial respiratory chain complex 1, and subsequent increase in AMP/ATP and ADP/ATP ratio, and/or the direct activation of AMPK. AMPK has pleiotropic downstream signaling pathways involved in divergent cellular processes, such as autophagy, fatty acid oxidation, inflammation, fibrosis, oxidative stress, and reactive oxygen species (ROS) in renal cells and FGF23 production in bone cells, which have been shown to protect the kidney against AKI and CKD. Further, MATE1 and MATE2 contribute to the renal excretion of metformin. ACC, acetyl-CoA carboxylase; AKI, acute kidney injury; AMPK, AMP-activated protein kinase; CKD, chronic kidney disease; FGF23, fibroblast growth factor 23; MATE1, multidrug and toxin extrusion 1; MATE2, multidrug and toxin extrusion 2; mTOR, mammalian target of rapamycin; NADPH, nicotinamide adenine dinucleotide phosphate; NFκB, nuclear factor kappa B; OCT2, organic cation transporter 2; ROS, reactive oxygen species; TGF-β1, transforming growth factor β1; ULK1, uncoordinated-51 like kinase 1. Figure was produced using Servier Medical Art: https://smart.servier.com/ (accessed on 2 November 2018).