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Abstract

Metformin, the first-line drug to treat type 2 diabetes, inhibits mitochondrial glycerolphosphate dehydrogenase in the liver to suppress gluconeogenesis. The major adverse effects caused by metformin were lactic acidosis and gastrointestinal discomfort. Therefore, there is need to develop a strategy with excellent permeability and appropriate retention effects.In this study, we synthesized a simple and biocompatible PolyMetformin (denoted as PolyMet) through conjugation of PEI_1.8K with dicyandiamide, and then formed PolyMet-hyaluronic acid (HA) nanocomplexs by electrostatic self-assembly of the polycationic PolyMet and polyanionic hyaluronic acid (HA). Similar to metformin, the PolyMet-HA nanocomplexs could reduce the catalytic activity of the recombinant SHIP2 phosphatase domain in vitro. In SHIP2-overexpressing myotubes, PolyMet-HA nanocomplexes ameliorated glucose uptake by downregulating glucose transporter 4 endocytosis. PolyMet-HA nanocomplexes also could restore Akt signaling and protect the podocyte from apoptosis induced by SHIP2 overexpression. In essence, the PolyMet-HA nanocomplexes act similarly to metformin and increase glucose uptake, and maybe have a potential role in the treatment of type 2 diabetes.

Keywords

PolyMet-HA nanocomplexes SHIP2 glucose uptake diabetes Akt signaling

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References

Lehtonen

SHIPping out diabetes-Metformin, an old friend among new SHIP2 inhibitors. Acta Physiol (Oxf) 2020; 228: e13349.

Shaw

Sicree

Zimmet

PZ.

Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010; 87: 4–14.

Foretz

Guigas

Bertrand

, et al. Metformin: from mechanisms of action to therapies. Cell Metab 2014; 20: 953–966.

Hundal

Krssak

Dufour

, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 2000; 49: 2063–2069.

Chinnaiyan

Deivasigamani

Gadela

VR.

Combined synergetic potential of metformin loaded pectin-chitosan biohybrids nanoparticle for NIDDM. Int J Biol Macromol 2019; 125: 278–289.

Nankar

Prabhakar

Doble

Hybrid drug combination: combination of ferulic acid and metformin as anti-diabetic therapy. Phytomedicine 2017; 37: 10–13.

Patino-Herrera

Louvier-Hernandez

Escamilla-Silva

, et al. Prolonged release of metformin by SiO2 nanoparticles pellets for type II diabetes control. Eur J Pharm Sci 2019; 131: 1–8.

Vafayi

Gharibe

Investigation of in vitro drug release from porous hollow silica nanospheres prepared of ZnS@SiO2 core-shell. Bioinorg Chem Appl 2013; 2013: 541030.

Tolvanen

Dash

Polianskyte-Prause

, et al. Lack of CD2AP disrupts Glut4 trafficking and attenuates glucose uptake in podocytes. J Cell Sci 2015; 128: 4588–4600.

10.

Hyvonen

Saurus

Wasik

, et al. Lipid phosphatase SHIP2 downregulates insulin signalling in podocytes. Mol Cell Endocrinol 2010; 328: 70–79.

11.

Zhao

Wang

Guo

, et al. PolyMetformin combines carrier and anticancer activities for in vivo siRNA delivery. Nat Commun 2016; 7: 11822.

12.

Suwa

Yamamoto

Sawada

, et al. Discovery and functional characterization of a novel small molecule inhibitor of the intracellular phosphatase, SHIP2. Br J Pharmacol 2009; 158: 879–887.

13.

Repen

Schneider

Alexiev

Optimization of a malachite green assay for detection of ATP hydrolysis by solubilized membrane proteins. Anal Biochem 2012; 426: 103–105.

14.

Dobrovolskaia

MA.

Pre-clinical immunotoxicity studies of nanotechnology-formulated drugs: challenges, considerations and strategy. J Control Release 2015; 220: 571–583.

15.

Jose

Sundar

Anjali

, et al. Metformin-loaded BSA nanoparticles in cancer therapy: a new perspective for an old antidiabetic drug. Cell Biochem Biophys 2015; 71: 627–636.

16.

Kumar

Bhanjana

Verma

, et al. Metformin-loaded alginate nanoparticles as an effective antidiabetic agent for controlled drug release. J Pharm Pharmacol 2017; 69: 143–150.

17.

Yang

Zhang

Wang

, et al. Coencapsulation of epirubicin and metformin in PEGylated liposomes inhibits the recurrence of murine sarcoma S180 existing CD133+ cancer stem-like cells. Eur J Pharm Biopharm 2014; 88: 737–745.

18.

Hori

Sasaoka

Ishihara

, et al. Association of SH2-containing inositol phosphatase 2 with the insulin resistance of diabetic db/db mice. Diabetes 2002; 51: 2387–2394.

19.

Sasaoka

Hori

Wada

, et al. SH2-containing inositol phosphatase 2 negatively regulates insulin-induced glycogen synthesis in L6 myotubes. Diabetologia 2001; 44: 1258–1267.

20.

Wada

Sasaoka

Funaki

, et al. Overexpression of SH2-containing inositol phosphatase 2 results in negative regulation of insulin-induced metabolic actions in 3T3-L1 adipocytes via its 5'-phosphatase catalytic activity. Mol Cell Biol 2001; 21: 1633–1646.

21.

Polianskyte-Prause

Tolvanen

Lindfors

, et al. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity. Faseb J 2019; 33: 2858–2869.

22.

Rogacka

Piwkowska

Audzeyenka

, et al. Involvement of the AMPK-PTEN pathway in insulin resistance induced by high glucose in cultured rat podocytes. Int J Biochem Cell Biol 2014; 51: 120–130.

23.

Rogacka

Audzeyenka

Rychłowski

, et al. Metformin overcomes high glucose-induced insulin resistance of podocytes by pleiotropic effects on SIRT1 and AMPK. Biochim Biophys Acta Mol Basis Dis 2018; 1864: 115–125.

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PolyMet-HA nanocomplexs regulates glucose uptake by inhibiting SHIP2 activity

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