A Novel Screening Approach of Down Syndrome Genes Identifies That RCAN1 Is Overexpressed in Type 2 Diabetic Islets and Causes ß-Cell Mitochondrial Dysfunction

Heshan Peiris, Michael Duffield, Joao Fadista, Claire Jessup, Amanda Genders, Sean McGee, Tertius Hough, Elizabeth Fisher, Victor Tybulewicz, Jorge Busciglio, Pinar Coskun, Ann Becker, Pavel Belichenko, William Mobley, Ross Laybutt, P Coates, Melanie Pritchard, Damien Keating

    Research output: Contribution to journalMeeting Abstractpeer-review

    Abstract

    Mitochondrial dysfunction is observed in human type 2 diabetes (T2D)β-cells and is central to β-cell dysfunction in this disease. Down syndrome(DS, Trisomy 21) also presents with β-cell mitochondrial dysfunction. By profiling the glycaemic status of different DS mouse lines, a shortlist of candidate genes contributing to hyper glycemia in some DS lines was generated. We then identified which of these have increased expression in a large cohort of control and T2D human islets. This approach identified a single candidate, RCAN1. Gene expression is increased in human (p < 0.01) T2Dislets and RCAN1 protein levels increase 3-fold in db/db mouse islets (p <0.01). Glucose-stimulated insulin secretion (GSIS) is reduced in mice overexpressing RCAN1. Mouse β-cells overexpressing RCAN1 display mitochondrial dysfunction exemplified by reduced mitochondrial respiration and low islet ATP. Insulin secretion in response to methyl succinate is lower whenRCAN1 is overexpressed (p < 0.01), indicating a defect downstream of complex II in the electron transport chain. In vitro GSIS is reduced by inhibition of the mitochondrial ATP translocator in WT islets, but inhibition has no effect when RCAN1 expression is increased. Thus, increased RCAN1 inhibits ATP translocation from the mitochondria. This lack of cytosolic ATP negatively affects multiple steps of the insulin secretion pathway by reducing glucose stimulated membrane depolarisation (p < 0.01) and lowering insulin exocytosis in response to a series of depolarising pulses (p < 0.05). Thus, amongst the ~5,000 gene expression changes identified in T2D β-cells, our novel screening approach identifies increased RCAN1 expression as a functionally relevant gene expression change that causes mitochondrial dysfunction inβ-cells.
    Original languageEnglish
    Article number339-OR
    Pages (from-to)A88
    Number of pages1
    JournalDiabetes
    Volume64
    Issue numberS1
    DOIs
    Publication statusPublished - Jun 2015
    EventAmerican Diabetes Association 75th Scientific Sessions - Boston, United States
    Duration: 5 Jun 20159 Jun 2015
    https://professional.diabetes.org/meeting/scientific-sessions/75th-scientific-sessions

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