title: Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells.
abstract: Insulin secretion from β cells of the pancreatic islets of Langerhans controls metabolic homeostasis and is impaired in individuals with type 2 diabetes (T2D). Increases in blood glucose trigger insulin release by closing ATP-sensitive K+ channels, depolarizing β cells, and opening voltage-dependent Ca2+ channels to elicit insulin exocytosis. However, one or more additional pathway(s) amplify the secretory response, likely at the distal exocytotic site. The mitochondrial export of isocitrate and engagement with cytosolic isocitrate dehydrogenase (ICDc) may be one key pathway, but the mechanism linking this to insulin secretion and its role in T2D have not been defined. Here, we show that the ICDc-dependent generation of NADPH and subsequent glutathione (GSH) reduction contribute to the amplification of insulin exocytosis via sentrin/SUMO-specific protease-1 (SENP1). In human T2D and an in vitro model of human islet dysfunction, the glucose-dependent amplification of exocytosis was impaired and could be rescued by introduction of signaling intermediates from this pathway. Moreover, islet-specific Senp1 deletion in mice caused impaired glucose tolerance by reducing the amplification of insulin exocytosis. Together, our results identify a pathway that links glucose metabolism to the amplification of insulin secretion and demonstrate that restoration of this axis rescues β cell function in T2D.
authors.forename: Mourad
authors.initials: M
authors.lastname: Ferdaoussi
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Dai
authors.forename: Mette V
authors.initials: MV
authors.lastname: Jensen
authors.forename: Runsheng
authors.initials: R
authors.lastname: Wang
authors.forename: Brett S
authors.initials: BS
authors.lastname: Peterson
authors.forename: Chao
authors.initials: C
authors.lastname: Huang
authors.forename: Olga
authors.initials: O
authors.lastname: Ilkayeva
authors.forename: Nancy
authors.initials: N
authors.lastname: Smith
authors.forename: Nathanael
authors.initials: N
authors.lastname: Miller
authors.forename: Catherine
authors.initials: C
authors.lastname: Hajmrle
authors.forename: Aliya F
authors.initials: AF
authors.lastname: Spigelman
authors.forename: Robert C
authors.initials: RC
authors.lastname: Wright
authors.forename: Gregory
authors.initials: G
authors.lastname: Plummer
authors.forename: Kunimasa
authors.initials: K
authors.lastname: Suzuki
authors.forename: James P
authors.initials: JP
authors.lastname: Mackay
authors.forename: Martijn
authors.initials: M
authors.lastname: van de Bunt
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
authors.forename: Terence E
authors.initials: TE
authors.lastname: Ryan
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Norquay
authors.forename: M Julia
authors.initials: MJ
authors.lastname: Brosnan
authors.forename: Jeff K
authors.initials: JK
authors.lastname: Trimmer
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Rolph
authors.forename: Richard G
authors.initials: RG
authors.lastname: Kibbey
authors.forename: Jocelyn E
authors.initials: JE
authors.lastname: Manning Fox
authors.forename: William F
authors.initials: WF
authors.lastname: Colmers
authors.forename: Orian S
authors.initials: OS
authors.lastname: Shirihai
authors.forename: P Darrell
authors.initials: PD
authors.lastname: Neufer
authors.forename: Edward T H
authors.initials: ET
authors.lastname: Yeh
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.forename: Patrick E
authors.initials: PE
authors.lastname: MacDonald
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D002462:Cell Membrane / Q000378:metabolism; D003546:Cysteine Endopeptidases; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000503:physiopathology*; D010450:Endopeptidases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D055786:Gene Knockout Techniques; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism* / Q000503:physiopathology; D007521:Isocitrate Dehydrogenase / Q000502:physiology; D007523:Isocitrates / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D009249:NADP / Q000378:metabolism; D009928:Organ Specificity; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism; D015398:Signal Transduction; D058207:Sumoylation
chemical_list: D007328:Insulin; D007523:Isocitrates; D011993:Recombinant Fusion Proteins; D009249:NADP; C034219:isocitric acid; D007521:Isocitrate Dehydrogenase; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases; C501974:Senp1 protein, mouse; D005978:Glutathione; D005947:Glucose