Claudia Miele 1, Gregory Alexander Raciti, Angela Cassese, Chiara Romano, Ferdinando Giacco, Francesco Oriente, Flora Paturzo, Francesco Andreozzi, Assunta Zabatta, Giancarlo Troncone, Fatima Bosch, Anna Pujol, Hervé Chneiweiss, Pietro Formisano, Francesco Beguinot
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The phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (ped/pea-15) gene is overexpressed in human diabetes and causes this abnormality in mice. Transgenic mice with beta-cell-specific overexpression of ped/pea-15 (beta-tg) exhibited decreased glucose tolerance but were not insulin resistant. However, they showed impaired insulin response to hyperglycemia. Islets from the beta-tg also exhibited little response to glucose. mRNAs encoding the Sur1 and Kir6.2 potassium channel subunits and their upstream regulator Foxa2 were specifically reduced in these islets. Overexpression of PED/PEA-15 inhibited the induction of the atypical protein kinase C (PKC)-zeta by glucose in mouse islets and in beta-cells of the MIN-6 and INS-1 lines. Rescue of PKC-zeta activity elicited recovery of the expression of the Sur1, Kir6.2, and Foxa2 genes and of glucose-induced insulin secretion in PED/PEA-15-overexpressing beta-cells. Islets from ped/pea-15-null mice exhibited a twofold increased activation of PKC-zeta by glucose; increased abundance of the Sur1, Kir6.2, and Foxa2 mRNAs; and enhanced glucose effect on insulin secretion. In conclusion, PED/PEA-15 is an endogenous regulator of glucose-induced insulin secretion, which restrains potassium channel expression in pancreatic beta-cells. Overexpression of PED/PEA-15 dysregulates beta-cell function and is sufficient to impair glucose tolerance in mice.
PED/PEA-15 inhibits hydrogen peroxide-induced apoptosis in Ins-1E pancreatic beta-cells via PLD-1.
Fiory F, Parrillo L, Raciti GA, Zatterale F, Nigro C, Mirra P, Falco R, Ulianich L, Di Jeso B, Formisano P, Miele C, Beguinot F.PLoS One. 2014 Dec 9;9(12):e113655. doi: 10.1371/journal.pone.0113655. eCollection 2014.PMID: 25489735 Free PMC article.
Cassese A, Raciti GA, Fiory F, Nigro C, Ulianich L, Castanò I, D'Esposito V, Terracciano D, Pastore L, Formisano P, Beguinot F, Miele C.PLoS One. 2013 Apr 9;8(4):e60555. doi: 10.1371/journal.pone.0060555. Print 2013.PMID: 23585839 Free PMC article.
Vigliotta G, Miele C, Santopietro S, Portella G, Perfetti A, Maitan MA, Cassese A, Oriente F, Trencia A, Fiory F, Romano C, Tiveron C, Tatangelo L, Troncone G, Formisano P, Beguinot F.Mol Cell Biol. 2004 Jun;24(11):5005-15. doi: 10.1128/MCB.24.11.5005-5015.2004.PMID: 15143191 Free PMC article.
Diverse roles of K(ATP) channels learned from Kir6.2 genetically engineered mice.
Seino S, Iwanaga T, Nagashima K, Miki T.Diabetes. 2000 Mar;49(3):311-8. doi: 10.2337/diabetes.49.3.311.PMID: 10868950 Review.
Targetting PED/PEA-15 for diabetes treatment.
Fiory F, Spinelli R, Raciti GA, Parrillo L, D'esposito V, Formisano P, Miele C, Beguinot F.Expert Opin Ther Targets. 2017 Jun;21(6):571-581. doi: 10.1080/14728222.2017.1317749. Epub 2017 Apr 21.PMID: 28395542 Review.
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Bosi E, Marselli L, De Luca C, Suleiman M, Tesi M, Ibberson M, Eizirik DL, Cnop M, Marchetti P.NAR Genom Bioinform. 2020 Nov 20;2(4):lqaa097. doi: 10.1093/nargab/lqaa097. eCollection 2020 Dec.PMID: 33575641 Free PMC article.
Parkinson-like phenotype in insulin-resistant PED/PEA-15 transgenic mice.
Perruolo G, Viggiano D, Fiory F, Cassese A, Nigro C, Liotti A, Miele C, Beguinot F, Formisano P.Sci Rep. 2016 Jul 18;6:29967. doi: 10.1038/srep29967.PMID: 27426254 Free PMC article.
Parrillo L, Costa V, Raciti GA, Longo M, Spinelli R, Esposito R, Nigro C, Vastolo V, Desiderio A, Zatterale F, Ciccodicola A, Formisano P, Miele C, Beguinot F.Int J Obes (Lond). 2016 Jun;40(6):929-37. doi: 10.1038/ijo.2016.36. Epub 2016 Mar 16.PMID: 26980478
PED/PEA-15 inhibits hydrogen peroxide-induced apoptosis in Ins-1E pancreatic beta-cells via PLD-1.
Fiory F, Parrillo L, Raciti GA, Zatterale F, Nigro C, Mirra P, Falco R, Ulianich L, Di Jeso B, Formisano P, Miele C, Beguinot F.PLoS One. 2014 Dec 9;9(12):e113655. doi: 10.1371/journal.pone.0113655. eCollection 2014.PMID: 25489735 Free PMC article.
Greig FH, Nixon GF.
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