A novel mechanism of metformin through iron chelation

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08884
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Kobe University
• Principal Investigator: Sugawara Kenji 神戸大学, 医学部附属病院, 特定助教 (70645217)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: メトホルミン / キレート作用 / 糖尿病

Outline of Final Research Achievements

The purpose of this study was to investigate whether the chelating property of metformin is involved in the pharmacological effects of the drug. Utilizing HepG2 cells, we examined the effect of cell permeable copper-chelating agent , ammonium tetrathiomolybdate (TM), on phosphorylation of AMPK (adenosine monophosphate-activated protein kinase). The results showed that at concentrations of 0.01 mM and 0.1 mM, TM enhanced AMPK phosphorylation similar to metformin. Furthermore, administration of TM to obese diabetic KK-Ay mice via drinking water for four weeks resulted in improvements in blood glucose levels and weight loss effects. Based on these findings, it is indicated that at least in part, the pharmacological effects of metformin are mediated through its copper chelation property.

Free Research Field

糖尿病学

Academic Significance and Societal Importance of the Research Achievements

メトホルミンは60年以上に亘って使用されている薬剤であるが、その詳細な作用メカニズムは不明な点が多い。本研究でメトホルミンの新たな作用機序が明らかになれば、糖尿病診療における臨床上の大きな進歩となる。また、本成果は生体の金属動態の破綻が糖尿病病態に寄与する可能性を示すことになるため、新たな糖尿病病態の解明に大きく貢献する。さらに、本成果は生体内の金属自体が糖尿病治療の標的となることを示すことから、「キレート能を有する新たな糖尿病治療薬の開発」に繋がる可能性もあり、本研究の意義と波及効果は大きい。