Undercover Toxic Ménage à Trois of Amylin, Copper (II) and Metformin in Human Embryonic Kidney Cells.

Terenzio Congiu,Giuseppina Pichiri,Mariusz Jaremko,Joanna I Lachowicz,Monica Piras,Mawadda Alghrably,Marco Piludu,Pierpaolo Coni,Lukasz Jaremko,Gavino Faa,Abdul-Hamid Emwas

doi:10.3390/pharmaceutics13060830

Abstract

In recent decades, type 2 diabetes complications have been correlated with amylin aggregation, copper homeostasis and metformin side effects. However, each factor was analyzed separately, and only in some rare cases copper/amylin or copper/metformin complexes were considered. We demonstrate for the first time that binary metformin/amylin and tertiary copper (II)/amylin/metformin complexes of high cellular toxicity are formed and lead to the formation of aggregated multi-level lamellar structures on the cell membrane. Considering the increased concentration of amylin, copper (II) and metformin in kidneys of T2DM patients, our findings on the toxicity of amylin and its adducts may be correlated with diabetic nephropathy development.

Highlights

Diabetic nephropathy (DN) has one of the highest incidences among the different complications of type 2 diabetes mellitus (T2DM), and in 1997 it accounted for 40% of all new end-stage renal disease (ESRD) cases in the United States, with the cost for treatment of USD 15.6 billion [1]
The solution containing 1:2 metal:metformin molar ration has the shape of Electron paramagnetic resonance (EPR) signals similar to that reported for the Cu(metformin)2 complex [5], while the equimolar solution has slightly higher g value and different shape
Metformin interactions with metal ions are well ascertained, up to now there have been no studies on the possible interactions of metformin with amylin and copper ions

Summary

Introduction

Diabetic nephropathy (DN) has one of the highest incidences among the different complications of type 2 diabetes mellitus (T2DM), and in 1997 it accounted for 40% of all new end-stage renal disease (ESRD) cases in the United States, with the cost for treatment of USD 15.6 billion [1]. Metformin is the first drug of choice for the treatment of T2DM and is used by at least 120 million people worldwide [3], reaching a market size of USD. It was shown that metformin alone [7,8] or in the complex with copper (II) [9,10] can bind to DNA and could exert its anti-tumor activity [11,12]

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