γ-Tocopherol partially protects insulin-secreting cells against functional inhibition by nitric oxide

Åke Sjöholm, Per Olof Berggren, Robert V. Cooney

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Preceding the onset of type 1 diabetes mellitus, pancreatic islets are infiltrated by macrophages secreting interleukin-1β (IL-1β) which induces β-cell apoptosis and exerts inhibitory actions on islet β-cell insulin secretion. IL-1β seems to act chiefly through induction of nitric oxide (NO) synthesis. Hence, IL-1β and NO have been implicated as key effector molecules in type 1 diabetes mellitus. In this paper, the influence of endogenously produced and exogenously delivered NO on the regulation of cell proliferation, cell viability and discrete parts of the stimulus-secretion coupling in insulin-secreting RINm5F cells was investigated. Because vitamin E may delay diabetes onset in animal models, we also investigated whether tocopherols may protect β-cells from the suppressive actions of IL-1 and NO in vitro. To this end, the impact of NO on insulin secretory responses to activation of phospholipase C (by carbamylcholine), protein kinase C (by phorbol ester), adenylyl cyclase (by forskolin), and Ca2+ influx through voltage-activated Ca2+ channels (by K+-induced depolarization) was monitored in culture after treatment with IL-1β or by co-incubation with the NO donor spermine-NONOate. It was found that cell proliferation, viability, insulin production and the stimulation of insulin release evoked by carbamylcholine and phorbol ester were impeded by IL-1β or spermine-NONOate, whereas the hormone output by the other secretagogues was not altered by NO. Pretreatment with γ-tocopherol (but not α-tocopherol) afforded a partial protection against the inhibitory effects of NO, whereas specifically inhibiting inducible NO synthase with N-nitro-L-arginine completely reversed the IL-1β effects. In contrast, inhibiting guanylyl cyclase with ODQ (1H-[1,2,4]oxadiazolo[4,3-α]-quinoxaline-1-one) or blocking low voltage-activated Ca2+ channels with NiCl2 failed to influence the actions of NO. In conclusion, our data show that NO inhibits growth and insulin secretion in RINm5F cells, and that γ-tocopherol may partially prevent this. The results suggest that phospholipase C or protein kinase C may be targeted by NO. In contrast, cGMP or low voltage-activated Ca2+ channels appear not to mediate the toxicity of NO in these cells. These adverse effects of NO on the β-cell, and the protection by γ-tocopherol, may be of importance for the development of the impaired insulin secretion characterizing type 1 diabetes mellitus, and offer possibilities for intervention in this process. (C) 2000 Academic Press.

Original languageEnglish
Pages (from-to)334-340
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume277
Issue number2
DOIs
StatePublished - Oct 22 2000
Externally publishedYes

Fingerprint

Tocopherols
Insulin-Secreting Cells
Nitric Oxide
Insulin
Interleukin-1
Medical problems
Type 1 Diabetes Mellitus
Cell proliferation
Carbachol
Type C Phospholipases
Phorbol Esters
Islets of Langerhans
Protein Kinase C
Cell Survival
Electric potential
Cell Proliferation
Calcium-Activated Potassium Channels
Quinoxalines
Cytoprotection
Nitric Oxide Donors

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

γ-Tocopherol partially protects insulin-secreting cells against functional inhibition by nitric oxide. / Sjöholm, Åke; Berggren, Per Olof; Cooney, Robert V.

In: Biochemical and Biophysical Research Communications, Vol. 277, No. 2, 22.10.2000, p. 334-340.

Research output: Contribution to journalArticle

Sjöholm, Åke ; Berggren, Per Olof ; Cooney, Robert V. / γ-Tocopherol partially protects insulin-secreting cells against functional inhibition by nitric oxide. In: Biochemical and Biophysical Research Communications. 2000 ; Vol. 277, No. 2. pp. 334-340.
@article{786a5c45d6a64b35a839809ec86a4d6c,
title = "γ-Tocopherol partially protects insulin-secreting cells against functional inhibition by nitric oxide",
abstract = "Preceding the onset of type 1 diabetes mellitus, pancreatic islets are infiltrated by macrophages secreting interleukin-1β (IL-1β) which induces β-cell apoptosis and exerts inhibitory actions on islet β-cell insulin secretion. IL-1β seems to act chiefly through induction of nitric oxide (NO) synthesis. Hence, IL-1β and NO have been implicated as key effector molecules in type 1 diabetes mellitus. In this paper, the influence of endogenously produced and exogenously delivered NO on the regulation of cell proliferation, cell viability and discrete parts of the stimulus-secretion coupling in insulin-secreting RINm5F cells was investigated. Because vitamin E may delay diabetes onset in animal models, we also investigated whether tocopherols may protect β-cells from the suppressive actions of IL-1 and NO in vitro. To this end, the impact of NO on insulin secretory responses to activation of phospholipase C (by carbamylcholine), protein kinase C (by phorbol ester), adenylyl cyclase (by forskolin), and Ca2+ influx through voltage-activated Ca2+ channels (by K+-induced depolarization) was monitored in culture after treatment with IL-1β or by co-incubation with the NO donor spermine-NONOate. It was found that cell proliferation, viability, insulin production and the stimulation of insulin release evoked by carbamylcholine and phorbol ester were impeded by IL-1β or spermine-NONOate, whereas the hormone output by the other secretagogues was not altered by NO. Pretreatment with γ-tocopherol (but not α-tocopherol) afforded a partial protection against the inhibitory effects of NO, whereas specifically inhibiting inducible NO synthase with N-nitro-L-arginine completely reversed the IL-1β effects. In contrast, inhibiting guanylyl cyclase with ODQ (1H-[1,2,4]oxadiazolo[4,3-α]-quinoxaline-1-one) or blocking low voltage-activated Ca2+ channels with NiCl2 failed to influence the actions of NO. In conclusion, our data show that NO inhibits growth and insulin secretion in RINm5F cells, and that γ-tocopherol may partially prevent this. The results suggest that phospholipase C or protein kinase C may be targeted by NO. In contrast, cGMP or low voltage-activated Ca2+ channels appear not to mediate the toxicity of NO in these cells. These adverse effects of NO on the β-cell, and the protection by γ-tocopherol, may be of importance for the development of the impaired insulin secretion characterizing type 1 diabetes mellitus, and offer possibilities for intervention in this process. (C) 2000 Academic Press.",
author = "{\AA}ke Sj{\"o}holm and Berggren, {Per Olof} and Cooney, {Robert V.}",
year = "2000",
month = "10",
day = "22",
doi = "10.1006/bbrc.2000.3650",
language = "English",
volume = "277",
pages = "334--340",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - γ-Tocopherol partially protects insulin-secreting cells against functional inhibition by nitric oxide

AU - Sjöholm, Åke

AU - Berggren, Per Olof

AU - Cooney, Robert V.

PY - 2000/10/22

Y1 - 2000/10/22

N2 - Preceding the onset of type 1 diabetes mellitus, pancreatic islets are infiltrated by macrophages secreting interleukin-1β (IL-1β) which induces β-cell apoptosis and exerts inhibitory actions on islet β-cell insulin secretion. IL-1β seems to act chiefly through induction of nitric oxide (NO) synthesis. Hence, IL-1β and NO have been implicated as key effector molecules in type 1 diabetes mellitus. In this paper, the influence of endogenously produced and exogenously delivered NO on the regulation of cell proliferation, cell viability and discrete parts of the stimulus-secretion coupling in insulin-secreting RINm5F cells was investigated. Because vitamin E may delay diabetes onset in animal models, we also investigated whether tocopherols may protect β-cells from the suppressive actions of IL-1 and NO in vitro. To this end, the impact of NO on insulin secretory responses to activation of phospholipase C (by carbamylcholine), protein kinase C (by phorbol ester), adenylyl cyclase (by forskolin), and Ca2+ influx through voltage-activated Ca2+ channels (by K+-induced depolarization) was monitored in culture after treatment with IL-1β or by co-incubation with the NO donor spermine-NONOate. It was found that cell proliferation, viability, insulin production and the stimulation of insulin release evoked by carbamylcholine and phorbol ester were impeded by IL-1β or spermine-NONOate, whereas the hormone output by the other secretagogues was not altered by NO. Pretreatment with γ-tocopherol (but not α-tocopherol) afforded a partial protection against the inhibitory effects of NO, whereas specifically inhibiting inducible NO synthase with N-nitro-L-arginine completely reversed the IL-1β effects. In contrast, inhibiting guanylyl cyclase with ODQ (1H-[1,2,4]oxadiazolo[4,3-α]-quinoxaline-1-one) or blocking low voltage-activated Ca2+ channels with NiCl2 failed to influence the actions of NO. In conclusion, our data show that NO inhibits growth and insulin secretion in RINm5F cells, and that γ-tocopherol may partially prevent this. The results suggest that phospholipase C or protein kinase C may be targeted by NO. In contrast, cGMP or low voltage-activated Ca2+ channels appear not to mediate the toxicity of NO in these cells. These adverse effects of NO on the β-cell, and the protection by γ-tocopherol, may be of importance for the development of the impaired insulin secretion characterizing type 1 diabetes mellitus, and offer possibilities for intervention in this process. (C) 2000 Academic Press.

AB - Preceding the onset of type 1 diabetes mellitus, pancreatic islets are infiltrated by macrophages secreting interleukin-1β (IL-1β) which induces β-cell apoptosis and exerts inhibitory actions on islet β-cell insulin secretion. IL-1β seems to act chiefly through induction of nitric oxide (NO) synthesis. Hence, IL-1β and NO have been implicated as key effector molecules in type 1 diabetes mellitus. In this paper, the influence of endogenously produced and exogenously delivered NO on the regulation of cell proliferation, cell viability and discrete parts of the stimulus-secretion coupling in insulin-secreting RINm5F cells was investigated. Because vitamin E may delay diabetes onset in animal models, we also investigated whether tocopherols may protect β-cells from the suppressive actions of IL-1 and NO in vitro. To this end, the impact of NO on insulin secretory responses to activation of phospholipase C (by carbamylcholine), protein kinase C (by phorbol ester), adenylyl cyclase (by forskolin), and Ca2+ influx through voltage-activated Ca2+ channels (by K+-induced depolarization) was monitored in culture after treatment with IL-1β or by co-incubation with the NO donor spermine-NONOate. It was found that cell proliferation, viability, insulin production and the stimulation of insulin release evoked by carbamylcholine and phorbol ester were impeded by IL-1β or spermine-NONOate, whereas the hormone output by the other secretagogues was not altered by NO. Pretreatment with γ-tocopherol (but not α-tocopherol) afforded a partial protection against the inhibitory effects of NO, whereas specifically inhibiting inducible NO synthase with N-nitro-L-arginine completely reversed the IL-1β effects. In contrast, inhibiting guanylyl cyclase with ODQ (1H-[1,2,4]oxadiazolo[4,3-α]-quinoxaline-1-one) or blocking low voltage-activated Ca2+ channels with NiCl2 failed to influence the actions of NO. In conclusion, our data show that NO inhibits growth and insulin secretion in RINm5F cells, and that γ-tocopherol may partially prevent this. The results suggest that phospholipase C or protein kinase C may be targeted by NO. In contrast, cGMP or low voltage-activated Ca2+ channels appear not to mediate the toxicity of NO in these cells. These adverse effects of NO on the β-cell, and the protection by γ-tocopherol, may be of importance for the development of the impaired insulin secretion characterizing type 1 diabetes mellitus, and offer possibilities for intervention in this process. (C) 2000 Academic Press.

UR - http://www.scopus.com/inward/record.url?scp=0034703623&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034703623&partnerID=8YFLogxK

U2 - 10.1006/bbrc.2000.3650

DO - 10.1006/bbrc.2000.3650

M3 - Article

VL - 277

SP - 334

EP - 340

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 2

ER -