title: Attenuation of high sucrose diet-induced insulin resistance in ABC transporter deficientwhitemutant of Drosophila melanogaster.
abstract: Exposure to high sugar diet (HSD) is an experimental model of insulin resistance (IR) and type 2 diabetes (T2D) in mammals and insects. In Drosophila, HSD-induced IR delays emergence of pupae from larvae and eclosion of imago from pupae. Understanding of mechanisms of IR/T2D is essential for refining T2D prevention and treatment strategies. Dysregulation of tryptophan (Trp)-kynurenine (Kyn) pathway was suggested as one of the mechanisms of IR/T2D development. Rate-limiting enzyme of Trp-Kyn pathway in Drosophila is Trp 2,3-dioxygenase (TDO), an evolutionary conserved ortholog of human TDO. We previously reported attenuation of HSD-induced IR invermilionmutants with inactive TDO. Conversion of Trp to Kyn is regulated not only by TDO activity but by intracellular Trp transport via ATP-binding cassette (ABC) transporter encoded by white gene in Drosophila. In order to evaluate the possible impact of deficient intracellular Trp transport on the inducement of IR by HSD, we compared the effect of HSD on pre-imago development in wild type flies, Canton-Special (C-S), and C-S flies containingwhitegene,white(C-S). Presence ofwhitegene attenuated (by 50%) HSD-induced delay of pupae emergence from larvae and female and male imago eclosion from pupae. Present study together with our earlier report reveals that both decreased TDO activity (due tovermiliongene mutation) or deficient Trp transport into cell without affecting TDO levels (due towhitegene mutation) attenuate HSD-induced development of IR in Drosophila model of T2D. Our data provide further support for hypothesis that dysregulation of Trp-Kyn pathway is one of the pathophysiological mechanisms and potential target for early diagnosis, prevention and treatment of IR/T2D.
authors.affiliation: Department of Genetics and Cytology, V.N. Karazin Kharkiv National University, Ukraine.
authors.forename: Valeriya
authors.initials: V
authors.lastname: Navrotskaya
authors.affiliation: Psychiatry and Inflammation Program, Department of Psychiatry, Tufts University/Tufts Medical Center, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Oxenkrug
authors.affiliation: Department of Genetics and Cytology, V.N. Karazin Kharkiv National University, Ukraine.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Vorobyova
authors.affiliation: Psychiatry and Inflammation Program, Department of Psychiatry, Tufts University/Tufts Medical Center, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Summergrad
keywords: ABC-transporter; drosophila; high sugar diet; insulin resistance; kynurenine; obesity; tryptophan; type 2 diabetes; white mutants