SHIPping out Diabetes-Metformin, an Old Friend Among New SHIP2 Inhibitors

Overview

Journal Acta Physiol (Oxf)

Specialty Physiology

Date 2019 Jul 26

PMID 31342643

Citations 6

Authors

Sanna Lehtonen

Affiliations

Soon will be listed here.

Abstract

SHIP2 (Src homology 2 domain-containing inositol 5'-phosphatase 2) belongs to the family of 5'-phosphatases. It regulates the phosphoinositide 3-kinase (PI3K)-mediated insulin signalling cascade by dephosphorylating the 5'-position of PtdIns(3,4,5)P3 to generate PtdIns(3,4)P2, suppressing the activity of the pathway. SHIP2 mouse models and genetic studies in human propose that increased expression or activity of SHIP2 contributes to the pathogenesis of the metabolic syndrome, hypertension and type 2 diabetes. This has raised great interest to identify SHIP2 inhibitors that could be used to design new treatments for metabolic diseases. This review summarizes the central mechanisms associated with the development of diabetic kidney disease, including the role of insulin resistance, and then moves on to describe the function of SHIP2 as a regulator of metabolism in mouse models. Finally, the identification of SHIP2 inhibitors and their effects on metabolic processes in vitro and in vivo are outlined. One of the newly identified SHIP2 inhibitors is metformin, the first-line medication prescribed to patients with type 2 diabetes, further boosting the attraction of SHIP2 as a treatment target to ameliorate metabolic disorders.

Citing Articles

Metformin's Effects on Cognitive Function from a Biovariance Perspective: A Narrative Review.

Chele D, Sirbu C, Mitrica M, Toma M, Vasiliu O, Sirbu A Int J Mol Sci. 2025; 26(4).

PMID: 40004246 PMC: 11855408. DOI: 10.3390/ijms26041783.

Discovery of aurones bearing two amine functionalities as SHIP2 inhibitors with insulin-sensitizing effect in rat myotubes.

Lim P, Yap B, Tay Y, Hanapi N, Yusof S, Lee C RSC Med Chem. 2024; 15(6):2179-2195.

PMID: 38911152 PMC: 11187551. DOI: 10.1039/d3md00360d.

Ebselen enhances insulin sensitivity and decreases oxidative stress by inhibiting SHIP2 and protects from inflammation in diabetic mice.

Polianskyte-Prause Z, Tolvanen T, Lindfors S, Kon K, Hautala L, Wang H Int J Biol Sci. 2022; 18(5):1852-1864.

PMID: 35342343 PMC: 8935241. DOI: 10.7150/ijbs.66314.

Targeting SHIP1 and SHIP2 in Cancer.

Pedicone C, Meyer S, Chisholm J, Kerr W Cancers (Basel). 2021; 13(4).

PMID: 33672717 PMC: 7924360. DOI: 10.3390/cancers13040890.

Metformin Protects against Podocyte Injury in Diabetic Kidney Disease.

Lehtonen S Pharmaceuticals (Basel). 2020; 13(12).

PMID: 33321755 PMC: 7764076. DOI: 10.3390/ph13120452.

References

Vandeput F, Combettes L, Mills S, Backers K, Wohlkonig A, Parys J . Biphenyl 2,3',4,5',6-pentakisphosphate, a novel inositol polyphosphate surrogate, modulates Ca2+ responses in rat hepatocytes. FASEB J. 2007; 21(7):1481-91. DOI: 10.1096/fj.06-7691com. View

Lenoir O, Jasiek M, Henique C, Guyonnet L, Hartleben B, Bork T . Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis. Autophagy. 2015; 11(7):1130-45. PMC: 4590611. DOI: 10.1080/15548627.2015.1049799. View

Fuhler G, Brooks R, Toms B, Iyer S, Gengo E, Park M . Therapeutic potential of SH2 domain-containing inositol-5'-phosphatase 1 (SHIP1) and SHIP2 inhibition in cancer. Mol Med. 2011; 18:65-75. PMC: 3269644. DOI: 10.2119/molmed.2011.00178. View

Kerr W . Inhibitor and activator: dual functions for SHIP in immunity and cancer. Ann N Y Acad Sci. 2010; 1217:1-17. PMC: 4515353. DOI: 10.1111/j.1749-6632.2010.05869.x. View

Wasik A, Lehtonen S . Glucose Transporters in Diabetic Kidney Disease-Friends or Foes?. Front Endocrinol (Lausanne). 2018; 9:155. PMC: 5900043. DOI: 10.3389/fendo.2018.00155. View

Ishihara H, Sasaoka T, Ishiki M, Wada T, Hori H, Kagawa S . Membrane localization of Src homology 2-containing inositol 5'-phosphatase 2 via Shc association is required for the negative regulation of insulin signaling in Rat1 fibroblasts overexpressing insulin receptors. Mol Endocrinol. 2002; 16(10):2371-81. DOI: 10.1210/me.2002-0083. View

Anil Kumar P, Welsh G, Saleem M, Menon R . Molecular and cellular events mediating glomerular podocyte dysfunction and depletion in diabetes mellitus. Front Endocrinol (Lausanne). 2014; 5:151. PMC: 4174857. DOI: 10.3389/fendo.2014.00151. View

Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G . Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010; 120(7):2355-69. PMC: 2898585. DOI: 10.1172/JCI40671. View

Liu Q, Shalaby F, Jones J, Bouchard D, Dumont D . The SH2-containing inositol polyphosphate 5-phosphatase, ship, is expressed during hematopoiesis and spermatogenesis. Blood. 1998; 91(8):2753-9. View

10.

Suwa A, Kurama T, Yamamoto T, Sawada A, Shimokawa T, Aramori I . Glucose metabolism activation by SHIP2 inhibitors via up-regulation of GLUT1 gene in L6 myotubes. Eur J Pharmacol. 2010; 642(1-3):177-82. DOI: 10.1016/j.ejphar.2010.06.002. View

11.

Ichihara Y, Fujimura R, Tsuneki H, Wada T, Okamoto K, Gouda H . Rational design and synthesis of 4-substituted 2-pyridin-2-ylamides with inhibitory effects on SH2 domain-containing inositol 5'-phosphatase 2 (SHIP2). Eur J Med Chem. 2013; 62:649-60. DOI: 10.1016/j.ejmech.2013.01.014. View

12.

Elong Edimo W, Janssens V, Waelkens E, Erneux C . Reversible Ser/Thr SHIP phosphorylation: a new paradigm in phosphoinositide signalling?: Targeting of SHIP1/2 phosphatases may be controlled by phosphorylation on Ser and Thr residues. Bioessays. 2012; 34(8):634-42. DOI: 10.1002/bies.201100195. View

13.

Satchell S, Harper S, Tooke J, Kerjaschki D, Saleem M, Mathieson P . Human podocytes express angiopoietin 1, a potential regulator of glomerular vascular endothelial growth factor. J Am Soc Nephrol. 2002; 13(2):544-550. DOI: 10.1681/ASN.V132544. View

14.

Madhusudhan T, Wang H, Ghosh S, Dong W, Kumar V, Al-Dabet M . Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function. Blood. 2017; 130(12):1445-1455. PMC: 5734620. DOI: 10.1182/blood-2017-02-767921. View

15.

Schiffer M, Bitzer M, Roberts I, Kopp J, Ten Dijke P, Mundel P . Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest. 2001; 108(6):807-16. PMC: 200928. DOI: 10.1172/JCI12367. View

16.

Takeda T, Go W, ORLANDO R, Farquhar M . Expression of podocalyxin inhibits cell-cell adhesion and modifies junctional properties in Madin-Darby canine kidney cells. Mol Biol Cell. 2000; 11(9):3219-32. PMC: 14987. DOI: 10.1091/mbc.11.9.3219. View

17.

Ghosh S, Scozzaro S, Ramos A, Delcambre S, Chevalier C, Krejci P . Inhibition of SHIP2 activity inhibits cell migration and could prevent metastasis in breast cancer cells. J Cell Sci. 2018; 131(16). DOI: 10.1242/jcs.216408. View

18.

Weil E, Lemley K, Mason C, Yee B, Jones L, Blouch K . Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy. Kidney Int. 2012; 82(9):1010-7. PMC: 3472108. DOI: 10.1038/ki.2012.234. View

19.

Viernes D, Choi L, Kerr W, Chisholm J . Discovery and development of small molecule SHIP phosphatase modulators. Med Res Rev. 2013; 34(4):795-824. PMC: 4991215. DOI: 10.1002/med.21305. View

20.

Drapeau N, Lizotte F, Denhez B, Guay A, Kennedy C, Geraldes P . Expression of SHP-1 induced by hyperglycemia prevents insulin actions in podocytes. Am J Physiol Endocrinol Metab. 2013; 304(11):E1188-98. DOI: 10.1152/ajpendo.00560.2012. View