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 6

Glucose-dependent amplification of exocytosis in human β cells is impaired in T2D and rescued by activating the isocitrate-to-SENP1 pathway.

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Glucose-dependent amplification of exocytosis in human β cells is impair...
(A) Cumulative frequency distribution of exocytotic responses from human β cells cultured under control conditions (BSA) or following 400 μM oleate/palmitate culture, after acute pretreatment with 1 or 10 mM glucose (n = 24, 56, 27, 65 cells; 6 donors). (B) Average exocytotic and (C) secretory responses of BSA-treated and oleate/palmitate-treated cells and islets (n = 5 donors), respectively. (D) Cumulative frequency distribution of exocytotic responses from human β cells from nondiabetic donors (ND, same as Figure 1B; n = 280, 311 cells; 50 donors) or donors with T2D (black lines; n = 116, 148 cells; 19 donors). (E) Average exocytotic and (F) secretory responses of nondiabetic and T2D cells and islets, respectively (for secretion, n = 28 nondiabetic and 12 donors with T2D). (G and H) Total exocytotic response of control treated (BSA) or oleate/palmitate-treated human β cells to glucose stimulation or infusion of (G) 100 μM isocitrate (n = 24, 12, 34, 26 cells; 3 donors) or (H) 4 μg/ml cSENP1 (n = 40, 37, 28, 41 cells; 5 donors). (I–L) Total exocytotic responses of β cells from donors with T2D following infusion of (I) 100 μM isocitrate (n = 25, 26, 47 cells; 4 donors), (J) NADPH (at 10:1 with NADP+; n = 47, 41, 63 cells; 5 donors), or (K) 10 μM GSH (n = 29, 39, 50 cells; 4 donors), or (L) upon transduction with Ad-GFP or Ad-GFP-SENP1 (n = 31, 35, 51 cells; 4 donors). Data are mean ± SEM and were compared with ANOVA followed by Bonferroni post-test. *P < 0.05, **P < 0.01, ***P < 0.001. n values correspond to graph bars from left to right, respectively.