Dual Role of Nitric Oxide in Pancreatic β-Cells

Kaneko, Yukiko; Ishikawa, Tomohisa

doi:10.1254/jphs.13r10cp

Cited by 39 publications

(19 citation statements)

References 51 publications

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“…As secretory cells, neurons share their transport and secretory machinery with β-cells, suggesting that these genes play a role in the insulin secretion process. Among the genes identified, several are implicated in insulin secretion and/or β-cell survival: Chl1 (cell adhesion molecule L1-like), whose silencing has previously been shown to reduce glucose-induced insulin secretion in INS1 cells [30] and is down regulated in islets from Type 2 diabetic subjects [31]; Nos1 (neuronal nitric oxyde synthase), implicated in insulin secretion and β-cell survival [32]; Adcyap1r1 (adenylate cyclase activating polypeptide 1 receptor 1), encoding the PAC1 receptor of the pituitary adenylate cyclase activating polypeptide (PACAP) neuroendocrine factor [33] and Cplx1 (complexin 1) [34]. None of several key β-cell signature genes involved in the regulation of Ins expression and β-cell identity ( Figure 4C), or of the "disallowed" β-cell gene family ( Figure 4D) [3], were affected by Stard10 deletion.…”

Section: Altered Expression Of Genes Controlling Ca 2+ Fluxes Exocytmentioning

confidence: 99%

The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis

Carrat

Haythorne

Tomás

et al. 2020

Preprint

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AbstractObjectiveRisk alleles for type 2 diabetes at the STARD10 locus are associated with lowered STARD10 expression in the β-cell, impaired glucose-induced insulin secretion and decreased circulating proinsulin:insulin ratios. Although likely to serve as a mediator of intracellular lipid transfer, the identity of the transported lipids, and thus the pathways through which STARD10 regulates β-cell function, are not understood. The aim of this study was to identify the lipids transported and affected by STARD10 in the β-cell and its effect on proinsulin processing and insulin granule biogenesis and maturation.MethodsWe used isolated islets from mice deleted selectively in the β-cell for Stard10 (βStarD10KO) and performed electron microscopy, pulse-chase, RNA sequencing and lipidomic analyses. Proteomic analysis of STARD10 binding partners was executed in INS1 (832/13) cell line. X-ray crystallography followed by molecular docking and lipid overlay assay were performed on purified STARD10 protein.ResultsβStarD10KO islets had a sharply altered dense core granule appearance, with a dramatic increase in the number of “rod-like” dense cores. Correspondingly, basal secretion of proinsulin was increased. Amongst the differentially expressed genes in βStarD10KO islets, expression of the phosphoinositide binding proteins Pirt and Synaptotagmin 1 were decreased while lipidomic analysis demonstrated changes in phosphatidyl inositol levels. The inositol lipid kinase PIP4K2C was also identified as a STARD10 binding partner. STARD10 bound to inositides phosphorylated at the 3’ position and solution of the crystal structure of STARD10 to 2.3 Å resolution revealed a binding pocket capable of accommodating polyphosphoinositides.ConclusionOur data indicate that STARD10 binds to, and may transport, phosphatidylinositides, influencing membrane lipid composition, insulin granule biosynthesis and insulin processing.

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Section: Altered Expression Of Genes Controlling Ca 2+ Fluxes Exocytmentioning

confidence: 99%

The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis

Carrat

Haythorne

Tomás

et al. 2020

Preprint

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“…differentiation [ 4 ], survival vs . apoptosis [ 5 ], and neuroprotection vs . neurodegeneration [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

SCF-KIT signaling induces endothelin-3 synthesis and secretion: Thereby activates and regulates endothelin-B-receptor for generating temporally- and spatially-precise nitric oxide to modulate SCF- and or KIT-expressing cell functions

et al. 2017

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We demonstrate that SCF-KIT signaling induces synthesis and secretion of endothelin-3 (ET3) in human umbilical vein endothelial cells and melanoma cells in vitro, gastrointestinal stromal tumors, human sun-exposed skin, and myenteric plexus of human colon post-fasting in vivo. This is the first report of a physiological mechanism of ET3 induction. Integrating our finding with supporting data from literature leads us to discover a previously unreported pathway of nitric oxide (NO) generation derived from physiological endothelial NO synthase (eNOS) or neuronal NOS (nNOS) activation (referred to as the KIT-ET3-NO pathway). It involves: (1) SCF-expressing cells communicate with neighboring KIT-expressing cells directly or indirectly (cleaved soluble SCF). (2) SCF-KIT signaling induces timely local ET3 synthesis and secretion. (3) ET3 binds to ETBR on both sides of intercellular space. (4) ET3-binding-initiated-ETBR activation increases cytosolic Ca2+, activates cell-specific eNOS or nNOS. (5) Temporally- and spatially-precise NO generation. NO diffuses into neighboring cells, thus acts in both SCF- and KIT-expressing cells. (6) NO modulates diverse cell-specific functions by NO/cGMP pathway, controlling transcriptional factors, or other mechanisms. We demonstrate the critical physiological role of the KIT-ET3-NO pathway in fulfilling high demand (exceeding basal level) of endothelium-dependent NO generation for coping with atherosclerosis, pregnancy, and aging. The KIT-ET3-NO pathway most likely also play critical roles in other cell functions that involve dual requirement of SCF-KIT signaling and NO. New strategies (e.g. enhancing the KIT-ET3-NO pathway) to harness the benefit of endogenous eNOS and nNOS activation and precise NO generation for correcting pathophysiology and restoring functions warrant investigation.

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“…Nitric oxide (NO), a major factor in the regulation of vascular function, is believed to also exert a significant role in the maintenance of glucose homeostasis, by contributing to modulation of peripheral insulin sensitivity [3], [4] and possibly insulin secretion [5], [6]. Both arterial hypertension and insulin resistance have been documented in either endothelial NO synthase (eNOS) null mice [7], [8], [9] or mice with partial deletion of the eNOS gene when challenged with a nutritional stress such as high fat diet (HFD) [10].…”

Section: Introductionmentioning

confidence: 99%

Partial Deletion of eNOS Gene Causes Hyperinsulinemic State, Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet

et al. 2014

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Abnormalities in eNOS gene, possibly interacting with high fat diet (HFD), affect peripheral vascular function and glucose metabolism. The relative role of eNOS gene, HFD and metabolic derangement on coronary function has not been fully elucidated. We test whether eNOS gene deficiency per se or in association with HFD modulates coronary function through mechanisms involving molecular pathways related to insulin signaling. Wild type (WT), eNOS−/− and eNOS+/− mice were studied. WT and eNOS+/− mice were fed with either standard or HF diet for 16 weeks and compared with standard diet fed eNOS−/−. Glucose and insulin tolerance tests were performed during the last week of diet. Coronary resistance (CR) was measured at baseline and during infusions of acetylcholine (Ach) or sodium-nitroprusside (SNP) to evaluate endothelium-dependent or independent vasodilation, in the Langendorff isolated hearts. Cardiac expression of Akt and ERK genes as evaluation of two major insulin-regulated signaling pathways involved in the control of vascular tone were assessed by western blot. HFD-fed mice developed an overt diabetic state. Conversely, chow-fed genetically modified mice (in particular eNOS−/−) showed a metabolic pattern characterized by normoglycemia and hyperinsulinemia with a limited degree of insulin resistance. CR was significantly higher in animals with eNOS gene deletions than in WT, independently of diet. Percent decrease in CR, during Ach infusion, was significantly lower in both eNOS−/− and eNOS+/− mice than in WT, independently of diet. SNP reduced CR in all groups except eNOS−/−. The cardiac ERK1-2/Akt ratio, increased in animals with eNOS gene deletions compared with WT, independently of diet. These results suggest that the eNOS genetic deficiency, associated or not with HFD, has a relevant effect on coronary vascular function, possibly mediated by increase in blood insulin levels and unbalance in insulin-dependent signaling in coronary vessels, consistent with a shift towards a vasoconstrictive pattern.

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Dual Role of Nitric Oxide in Pancreatic β-Cells

Cited by 39 publications

References 51 publications

The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis

The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis

SCF-KIT signaling induces endothelin-3 synthesis and secretion: Thereby activates and regulates endothelin-B-receptor for generating temporally- and spatially-precise nitric oxide to modulate SCF- and or KIT-expressing cell functions

Partial Deletion of eNOS Gene Causes Hyperinsulinemic State, Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet

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