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 8

Pancreatic islet–specific knockout of Senp1 blunts insulin secretion due to an impaired amplification of exocytosis.

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Pancreatic islet–specific knockout of Senp1 blunts insulin secretion due...
(A) Immunostaining of pSENP1-WT and pSENP1-KO mouse pancreatic sections for insulin (green), glucagon (red), and nuclei (blue) revealed no difference in islet architecture (see also Supplemental Figure 3B; n = 4 mice of each genotype). (B) Perifusion profile of the secretory response to glucose (16.7 mM) and KCl (30 mM) of pSENP1-WT and pSENP1-KO islets (n = 4 mice of each genotype). (C) With KATP channels held open with diazoxide, the secretory response of pSENP1-WT islets (n = 4 mice) to KCl (30 mM) at 16.7 mM (circles) versus 2.8 mM (squares) glucose is blunted in pSENP1-KO islets (n = 4 mice). (D) Action potential firing is moderately altered in pSENP1-KO β cells (n = 17, 19 cells; 3 and 4 mice of each genotype; see also Supplemental Figure 6, A–C), (E) although islet intracellular Ca2+ responses were unchanged (n = 4 mice of each genotype). (F) The glucose-dependent amplification of exocytosis is lost in pSENP1-KO β cells, and is rescued by reintroduction of cSENP1 (4 μg/ml; n = 28, 33, 42, 32, 37, 39 cells; 4 mice of each genotype). (G) GSH (10 μM) is unable to amplify exocytosis in pSENP1-KO β cells (n = 37, 39, 57, 51, 32, 49 cells; 5 mice of each genotype). (H) Proposed pathway linking mitochondrial export of (iso)citrate, glutathione biosynthesis (blue), and glutathione reduction (orange) pathways to the amplification of insulin exocytosis (yellow). Data are mean ± SEM and were compared with ANOVA followed by Bonferroni post-test (B, C, F, and G) or by 2-tailed Student’s t test (D and E). *P < 0.05, ***P < 0.001. Scale bar: 100 μm (A). n values correspond to graph bars from left to right, respectively.