Title:Molecular Mechanism of Metformin Associated Lactic Acidosis (MALA)- an In Silico Exploration
Volume: 16
Issue: 3
Author(s): Siddiqur Rahman, Tamim Ahsan, Riajul Hossain, Tasnim Ahmed and Abu Ashfaqur Sajib*
Affiliation:
- Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka-1000,Bangladesh
Keywords:
Organic cation transporter, metformin, metformin associated lactic acidosis, type 2 diabetes, electron
transport system, Complex I.
Abstract: Background: Metformin is recommended in most clinical guidelines as a firstline
oral anti-hyperglycemic drug to treat type 2 diabetes. Despite its effectiveness as an
anti-hyperglycemic agent, certain genetic variants and conditions may cause metformin
accumulation in the body and lead to lactic acidosis- a condition commonly known as
Metformin Associated Lactic Acidosis (MALA). Though the incidence of MALA is relatively
rare, it is potentially fatal with a mortality rate of 30 to 50%. The mechanism of
MALA is not well defined yet.
Method: In this study, we explored the molecular mechanism of MALA following an in
silico approach. We applied structure modeling and molecular docking tools to predict interactions
of metformin with different human Organic Cation Transporters (OCTs) as well
as the Complex I of the mitochondrial Electron Transport System (ETS).
Results: Molecular docking analyses suggest potential interactions of metformin with the
core subunits of the human ETS Complex I that are essential for its function. In silico
analyses suggest that metformin can bind to the pores of 8 different OCTs, which are expressed
in different organs.
Conclusion: Based on these predicted interactions and organ specific gene expression data
in the databases, we present here a model to explain the molecular mechanism of MALA.
