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 2

Intracellular delivery of metabolic coupling intermediates reveals a role for isocitrate-derived NADPH in the control of β cell exocytosis.

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Intracellular delivery of metabolic coupling intermediates reveals a rol...
(A) Illustration of the whole-cell patch-clamp for intracellular delivery of molecules prior to (~3 minutes) stimulation of exocytosis by membrane depolarization. (B–E) The total exocytotic response of human β cells following acute glucose (10 mM) pretreatment, as in Figure 1A, or upon infusion of (B) 100 μM isocitrate (n = 42, 15, 59 cells; 7 donors), (C) 100 μM α-KG (n = 20, 24, 26 cells; 3 donors), (D) comparing infusion of either 100 μM isocitrate or α-KG in the same donors (n = 28, 36, 35 cells; 4 donors), or (E) upon infusion of 100 μM phosphoenolpyruvate (PEP) (n = 28, 20, 35 cells; 4 donors). (F) The amplification of exocytosis from 1 mM (n = 33 cells; 4 donors) to 10 mM glucose (n = 15 cells; 3 donors) is replicated by direct intracellular dialysis of NADPH (in a 10:1 molar ratio with NADP+, n = 34 cells, 4 donors compared with a ratio of 1:10, n = 31 cells, 4 donors). (G) As in F, without cAMP and with low (0.3 mM) ATP (n = 20, 24, 22, 23, 31 cells; 3 donors). (H) As in F, but with infusion of NADH (in a 10:1 molar ratio with NAD+, n = 20, 24, 31 cells, 3 donors). n values correspond to graph bars from left to right, respectively. Data are mean ± SEM and were compared with ANOVA followed by Bonferroni post-test. **P < 0.01, ***P < 0.001 compared with the 1 mM glucose condition, unless indicated otherwise.