Regulation of pancreatic β-cell survival by nitric oxide

Bedoya, Francisco J.; Salguero-Aranda, Carmen; Cahuana, Gladys M.; Tapia-Limonchi, Rafael; Soria, Bernat; Tejedo, Juan R.

doi:10.4161/isl.19822

Cited by 32 publications

(22 citation statements)

References 152 publications

(238 reference statements)

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“…Although the role of iNOS in ␤-cell death remains controversial (5,14), several studies have demonstrated that reduced iNOS expression or activity decreases cytokine-mediated cytotoxicity (2,8,32). Whether the protective effect of SUMOylation depends on reduced iNOS expression, however, has yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

SUMOylation protects against IL-1β-induced apoptosis in INS-1 832/13 cells and human islets

Hajmrle

Ferdaoussi

Plummer

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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tional modification by the small ubiquitin-like modifier (SUMO) peptides, known as SUMOylation, is reversed by the sentrin/SUMOspecific proteases (SENPs). While increased SUMOylation reduces ␤-cell exocytosis, insulin secretion, and responsiveness to GLP-1, the impact of SUMOylation on islet cell survival is unknown. Mouse islets, INS-1 832/13 cells, or human islets were transduced with adenoviruses to increase either SENP1 or SUMO1 or were transfected with siRNA duplexes to knockdown SENP1. We examined insulin secretion, intracellular Ca 2ϩ responses, induction of endoplasmic reticulum stress markers and inducible nitric oxide synthase (iNOS) expression, and apoptosis by TUNEL and caspase 3 cleavage. Surprisingly, upregulation of SENP1 reduces insulin secretion and impairs intracellular Ca 2ϩ handling. This secretory dysfunction is due to SENP1-induced cell death. Indeed, the detrimental effect of SENP1 on secretory function is diminished when two mediators of ␤-cell death, iNOS and NF-B, are pharmacologically inhibited. Conversely, enhanced SUMOylation protects against IL-1␤-induced cell death. This is associated with reduced iNOS expression, cleavage of caspase 3, and nuclear translocation of NF-B. Taken together, these findings identify SUMO1 as a novel antiapoptotic protein in islets and demonstrate that reduced viability accounts for impaired islet function following SENP1 up-regulation. islets of Langerhans; SUMOylation; inducible nitric oxide synthase; sentrin/SUMO-specific protease 1; SENP1 SMALL UBIQUITIN-RELATED MODIFIER (SUMO) peptides are involved in the posttranslational modification of numerous cellular proteins (19,20,26). SUMO modification, known as SUMOylation, occurs through a cascade of well-characterized enzymatic events that rely on the E2 conjugating enzyme Ubc9 (19,20,22). SUMOylation is made reversible by the sentrin/ SUMO-specific proteases (SENPs), which remove SUMO from target proteins (49). Due to the large number of SUMOylatable targets, the cellular outcomes of SUMO modification are diverse, ranging from the control of DNA repair to the regulation of transcription factors and plasma membrane proteins (9,10,20,28,39,42,44). SUMO1 modification has a negative impact on ␤-cell secretory function (35). Upregulation of SUMO1 decreases insulin gene expression (28, 44), glucagon-like peptide-1 (GLP-1) receptor signaling (42), and both glucose-and exendin-4-stimulated insulin secretion (10, 42), suggesting that deSUMOylation may improve secretory function. Indeed, knockdown of the SUMOylating enzyme Ubc9 enhances exendin-4-stimulated insulin secretion (42), and upregulation of the deSUMOylating enzyme SENP1 increases exocytosis from rodent ␤-cells at low glucose (10, 48). Whether this elevates insulin secretion above that stimulated by glucose is unclear, as SENP1 does not increase ␤-cell exocytosis above the levels seen with high glucose (10). Thus, while increased SUMOylation results in secretory impairment (10, 42, 48), the effect of the deSUMOylating enzyme SENP1 remains unknown.SUMOyla...

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Section: Discussionmentioning

confidence: 99%

SUMOylation protects against IL-1β-induced apoptosis in INS-1 832/13 cells and human islets

Hajmrle

Ferdaoussi

Plummer

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Lipid stress and hyperglycemia, increased iNOS production in β-cells and resulted in cell dysfunction or cell death [37] . Lipases are involved in insulin secretion; pharmacological inhibition of lipase activity in β-cells impairs insulin secretion and this explained the decrease in the immunostaining of β pancreatic cells [38] .…”

Section: Discussionmentioning

confidence: 99%

Effect of Orlistat on the pancreas of the female albino rat: Histological and Histochemical study

Abdelwahab

Ali

Mahmoud

2017

Journal of Medical Histology

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Introduction: Orlistat is the only FDA approved drug for long term management of obesity. It reduces the absorption of dietary fat by inhibiting lipase enzyme. Many cases of pancreatitis were clinically reported in people who used orlistat. Aim of The work:The aim of the present study is to shed a light on the possible deleterious effect of orlistat on the normal pancreatic tissue, and the molecular mechanisms beyond these changes. Materials & Methods: Thirty six female albino rats were divided into 4 groups: Control Group I (a) without treatment &I (b) received only1 ml fish oil. Group II received 30 mg/kg/day of orlistat dissolved in 1ml of fish oil orally for 8 weeks. Group III, received 40 mg/kg/day of orlistat .Group IV (a) & (b) withdrawal groups. Pancreas was dissected out and processed for histological and immunohistochemical study for CASPASE, TNF, INOS and INSULIN. Results: Orlistat caused variable degrees of pancreatic tissue degeneration, dilatation of pancreatic ducts with retained secretion, fatty degeneration and congestion. Inflammatory cells infiltration observed in both pancreatic acini and islets of Langerhan,s only with high dose (40mg/kg). Positive immunoreactivity for activated caspase 3 and iNOS being more evident in high dose and decrease in immunoreactivity for anti-insulin antibody. immunoreactivity for TNF-α had been shown in high dose. These effects disappear after low dose withdrawal only. Conclusion: Orlistat may induce inflammation, fatty degeneration and impaired insulin production in the pancreas. These effects are dose dependent, and it should be taken in consideration while prescribing orlistat as a treatment for obesity.

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“…Among the possible mediators of insulin-induced increase in cell death are ROS and NO, which have been shown to be deleterious to β cell viability (Konishi et al 1997, Nakamura et al 2006, Hou et al 2008, Sampson et al 2010, Bedoya et al 2012, Broniowska et al 2014). Moreover, insulin was shown to increase ROS release in several cell types (Mahadev et al 2001, Goldstein et al 2005a,b, Biswas et al 2007, Guichard et al 2008, including RINm (rat) pancreatic β-cells (Sampson et al 2010).…”

Section: Insulin Increases Ros Production In Min6 Cellsmentioning

confidence: 99%

Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

Bucris

Beck

Boura‐Halfon

et al. 2016

Journal of Endocrinology

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Insulin resistance results from impaired insulin signaling in target tissues that leads to increased levels of insulin required to control plasma glucose levels. The cycle of hyperglycemia and hyperinsulinemia eventually leads to pancreatic β cell deterioration and death by a mechanism that is yet unclear. Insulin induces ROS formation in several cell types. Furthermore, death of pancreatic β cells induced by oxidative stress could be potentiated by insulin. Here, we investigated the mechanism underlying this phenomenon. Experiments were done on pancreatic β cell lines (Min-6, RINm, INS-1), isolated mouse and human islets, and on cell lines derived from nonpancreatic sources. Insulin (100 nM) for 24 h selectively increased the production of ROS in pancreatic β cells and isolated pancreatic islets, but only slightly affected the expression of antioxidant enzymes. This was accompanied by a time-and dose-dependent decrease in cellular reducing power of pancreatic β cells induced by insulin and altered expression of several ER stress response elements including a significant increase in Trb3 and a slight increase in iNos. The effect on iNos did not increase NO levels. Insulin also potentiated the decrease in cellular reducing power induced by H 2 O 2 but not cytokines. Insulin decreased the expression of MCL-1, an antiapoptotic protein of the BCL family, and induced a modest yet significant increase in caspase 3/7 activity. In accord with these findings, inhibition of caspase activity eliminated the ability of insulin to increase cell death. We conclude that prolonged elevated levels of insulin may prime apoptosis and cell death-inducing mechanisms as a result of oxidative stress in pancreatic β cells.

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Regulation of pancreatic β-cell survival by nitric oxide

Cited by 32 publications

References 152 publications

SUMOylation protects against IL-1β-induced apoptosis in INS-1 832/13 cells and human islets

SUMOylation protects against IL-1β-induced apoptosis in INS-1 832/13 cells and human islets

Effect of Orlistat on the pancreas of the female albino rat: Histological and Histochemical study

Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

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