Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells
Mourad Ferdaoussi, … , Christopher B. Newgard, Patrick E. MacDonald
Mourad Ferdaoussi, … , Christopher B. Newgard, Patrick E. MacDonald
Published September 21, 2015
Citation Information: J Clin Invest. 2015;125(10):3847-3860. https://doi.org/10.1172/JCI82498.
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Research Article Endocrinology

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

Mourad Ferdaoussi, Xiaoqing Dai, Mette V. Jensen, Runsheng Wang, Brett S. Peterson, Chao Huang, Olga Ilkayeva, Nancy Smith, Nathanael Miller, Catherine Hajmrle, Aliya F. Spigelman, Robert C. Wright, Gregory Plummer, Kunimasa Suzuki, James P. Mackay, Martijn van de Bunt, Anna L. Gloyn, Terence E. Ryan, Lisa D. Norquay, M. Julia Brosnan, Jeff K. Trimmer, Timothy P. Rolph, Richard G. Kibbey, Jocelyn E. Manning Fox, William F. Colmers, Orian S. Shirihai, P. Darrell Neufer, Edward T.H. Yeh, Christopher B. Newgard, Patrick E. MacDonald

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Figure 1

Glucose-dependent amplification of exocytosis in human β cells.

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Glucose-dependent amplification of exocytosis in human β cells. (A) Exoc...
(A) Exocytotic responses of single human β cells measured as increases in cell membrane capacitance by whole-cell patch clamp (at arrow) performed after acute pretreatment with 1 mM (gray trace) or 10 mM (black trace) glucose (representative of 280 and 311 cells from 50 donors). (B) Cumulative frequency distribution of the exocytotic response in β cells from 50 nondiabetic donors at 1 mM (n = 280 cells) and 10 mM glucose (n = 311 cells). (C) Representative voltage-activated Ca2+ currents from human β cells recorded at 1 mM and 10 mM glucose (representative of 72 and 79 cells from 14 donors). (D) The Ca2+ charge entry upon a single 500-ms depolarization to 0 mV at 1 mM (n = 72 cells; 14 donors) and 10 mM glucose (n = 79 cells; 14 donors). (E) The glucose concentration-response curve for amplification of the exocytotic response (black) of human β cells (n = 6 donors) is left-shifted compared with that for glucose-stimulated insulin secretion (gray) from intact human islets (n = 6 donors). Data are mean ± SEM and were compared by 2-tailed Student’s t test.